14-24 Rheumatology and bone disease

24 Rheumatology and bone disease

Rheumatology and bone disease GPR Clunie SH Ralston Clinical examination of the musculoskeletal system 982 Functional anatomy and physiology 984 Bone 984 Joints 986 Skeletal muscle 987 Investigation of musculoskeletal disease 988 Joint aspiration 988 Imaging 988 Blood tests 990 Tissue biopsy 992 Electromyography 992 Presenting problems in musculoskeletal disease 992 Acute monoarthritis 992 Polyarthritis 993 Fracture 994 Generalised musculoskeletal pain 995 Back pain 995 Regional musculoskeletal pain 997 Neck pain 997 Shoulder pain 997 Elbow pain 998 Hand and wrist pain 998 Hip pain 998 Knee pain 998 Ankle and foot pain 999 Muscle pain and weakness 1000 Principles of management 1000 Education and lifestyle interventions 1000 Non-pharmacological interventions 1001 Pharmacological treatment 1002 Osteoarthritis 1007 Crystal-induced arthritis 1012 Fibromyalgia 1018 Bone and joint infections 1019 Rheumatoid arthritis 1021 Juvenile idiopathic arthritis 1026 Spondyloarthropathies 1027 Axial spondyloarthropathy 1028 Reactive arthritis 1031 Psoriatic arthritis 1032 Enteropathic (spondylo)arthritis 1034 Autoimmune connective tissue diseases 1034 Vasculitis 1040 Diseases of bone 1044 Osteoporosis 1044 Osteomalacia, rickets and vitamin D deﬁciency 1049 Paget’s disease of bone 1053 Other bone diseases 1055 Bone and joint tumours 1056 Rheumatological involvement in other diseases 1057 Miscellaneous conditions 1058

982 • RHEUMATOLOGY AND BONE DISEASE Observation Extensor surfaces Rheumatoid nodules Swollen bursa Psoriasis rash Face Rash Alopecia Mouth ulcers Eyes Trunk Kyphosis Scoliosis Tender spots (fibromyalgia, enthesitis) • General appearance • Gait • Deformity • Swelling • Redness • Rash Hands Swelling Deformity Nail changes Tophi Raynaud’s Feet Deformity Swelling (gout, dactylitis) Redness Rheumatoid nodules Heberden and Bouchard nodes in osteoarthritis Synovitis and deformity in rheumatoid arthritis Butterfly rash in systemic lupus erythematosus Scleritis in rheumatoid arthritis Acute gout Legs Deformity Swelling Restricted movement Bone deformity in Paget’s disease Nail dystrophy in psoriatic arthritis

Clinical examination of the musculoskeletal system

Clinical examination of the musculoskeletal system • 983

Ask patient to put hands behind head (tests shoulder movements) Inspect hands for swelling or deformity 2 Arms Ask patient to make a fist and open and close fingers (tests hand function) Squeeze metacarpals (tests for inflammation) 3 Legs Flex each hip with hand on knee. Rotate hips internally and externally (tests hip movements and detects knee crepitus) Inspect ankles and feet. Squeeze forefoot (tests for metatarsophalangeal synovitis) Palpate each knee for warmth and swelling (tests for synovitis and effusion) 4 Spine 5 Schöber’s test Patient slides hand down leg to knee (tests lateral spine flexion) 10 cm 15 cm Ask patient to try to put ear on shoulder (tests lateral flexion cervical spine) Patient looks at ceiling and then puts chin on chest (tests flexion and extension cervical spine) Mark skin with pen in midline about 4 cm below superior iliac crest. Make another mark in midline 10 cm above first. Ask patient to bend forwards. Normally, distance between marks should increase to 15 cm Stand behind patient and hold their pelvis. Ask them to turn from side to side without moving their feet (tests thoracolumbar rotation) Inspect spine from behind and side, looking for scoliosis, kyphosis or localised deformity. Ask patient to touch toes 1 Gait Ask patient to walk for a few steps, then come back. Look for pain or limp Press over supraspinatus (tests for hyperalgesia) Patient turns palms up and down with elbows at side (tests supination and pronation of wrists and elbow) Patient flexes elbows to touch shoulder (tests elbow flexion) General Assessment of Locomotor System (GALS) and Schöber’s test

984 • RHEUMATOLOGY AND BONE DISEASE ossiﬁcation, in which embryonic ﬁbroblasts differentiate directly into bone within condensations of mesenchymal tissue during early fetal life. Long bones, such as the femur and radius, develop by endochondral ossiﬁcation from a cartilage template. During development, the cartilage is invaded by vascular tissue containing osteoprogenitor cells and is gradually replaced by bone from centres of ossiﬁcation situated in the middle and at the ends of the bone. A thin remnant of cartilage called the growth plate or epiphysis remains at each end of long bones, and chondrocyte proliferation here is responsible for skeletal growth during childhood and adolescence. At the end of puberty, the increased levels of sex hormones halt cell division in the growth plate. The cartilage remnant then disappears as the epiphysis fuses and longitudinal bone growth ceases. Two types of bone tissue are present in the normal skeleton (Fig. 24.1). Cortical bone is formed from Haversian systems, comprising concentric lamellae of bone tissue surrounding a central canal that contains blood vessels. Cortical bone is dense and forms a hard envelope around the long bones. Trabecular or cancellous bone ﬁlls the centre of the bone and consists of an interconnecting meshwork of trabeculae, separated by spaces ﬁlled with bone marrow. The most important cell types in bone are: • Osteoclasts: multinucleated cells of haematopoietic origin, responsible for bone resorption. • Osteoblasts: mononuclear cells of derived from marrow stromal cells responsible for bone formation. Disorders of the musculoskeletal system affect all ages and ethnic groups. In the UK, about 25% of new consultations in general practice are for musculoskeletal symptoms. Musculoskeletal diseases may arise from processes affecting bones, joints, muscles, or connective tissues such as skin and tendon. The principal manifestations are pain and impairment of locomotor function. Diseases of the musculoskeletal system tend to be more common in women and most increase in frequency with increasing age. They are the most common cause of physical disability in older people and account for one-third of physical disability at all ages. Functional anatomy and physiology The musculoskeletal system is responsible for movement of the body, provides a structural framework to protect internal organs, and acts as a reservoir for storage of calcium and phosphate in the regulation of mineral homeostasis. The main components of the musculoskeletal system are depicted in Figure 24.1. Bone Bones fall into two main types, based on their embryonic development. Flat bones, such as the skull, develop by intramembranous Fig. 24.1 Structure of the major musculoskeletal tissues. Osteocytes Osteoblasts Osteoclasts Trabecular bone Haversian system Blood vessels Collagen lamellae Osteocytes Cortical bone Synovium Articular cartilage Growth plate Calcified zone Hypertrophic zone Proliferative zone Bone Synovial lining cells Joint capsule Myofilament Myofibril Fascicle Chondrocytes Calcified cartilage Subchondral bone Muscle Epiphyseal plate

Enthesis Tendon Bone

Functional anatomy and physiology • 985

into mature osteoclasts in response to M-CSF, produced by bone marrow stromal cells, and RANKL, produced by both osteocytes and bone marrow stromal cells. The RANKL binds to and activates a receptor called RANK (receptor activator of nuclear factor kappa B) on osteoclast precursors, promoting osteoclast differentiation and bone resorption. This effect is blocked by osteoprotegerin (OPG), which is a decoy receptor for RANKL that inhibits osteoclast formation. Once formed, mature osteoclasts attach to the bone surface by a tight sealing zone and secrete hydrochloric acid and proteolytic enzymes, including cathepsin K, into the space underneath, which is known as the Howship’s lacuna. The acid dissolves the mineral and cathepsin K degrades collagen. Osteocytes also produce sclerostin (SOST), which is a potent inhibitor of bone formation. Under conditions of mechanical loading, sclerostin production by osteocytes is inhibited, allowing bone formation to proceed, stimulated by members of the Wnt family of signalling proteins. The Wnt molecules stimulate bone formation by activating members of the lipoprotein receptor-related protein (LRP) family, the most important of which are LRP4, LRP5 and LRP6. Sclerostin antagonises the effects of Wnt family members by blocking their interaction with LRP family members. Finally, osteocytes play a critical role in phosphate homeostasis by producing the hormone FGF23, which regulates renal tubular phosphate reabsorption. Key regulators of bone remodelling are summarised in Box 24.1. Mineralisation of bone is critically dependent on the enzyme alkaline phosphatase (ALP), which is produced by osteoblasts and degrades pyrophosphate, an inhibitor of mineralisation. Bone remodelling is predominantly regulated at a local level but can be inﬂuenced by circulating hormones or mechanical loading, which can up-regulate or down-regulate remodelling across the whole skeleton (Box 24.1). • Osteocytes: cells that differentiate from osteoblasts that become embedded in bone matrix during bone formation. They are responsible for sensing and responding to mechanical stimuli and for coordinating osteoclast and osteoblast activity. • Bone marrow stromal cells: cells that produce receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which stimulate osteoclast formation, and other cytokines that support haematopoiesis (p. 914). • Bone lining cells: ﬂattened cells lining the bone surface that differentiate from osteoblasts when bone formation is complete. Bone matrix and mineral The most abundant protein of bone is type I collagen, which is formed from two α1 peptide chains and one α2 chain wound together in a triple helix. Type I collagen is proteolytically processed inside the cell before being laid down in the extracellular space, releasing propeptide fragments that can be used as biochemical markers of bone formation. Subsequently, the collagen ﬁbrils become ‘cross-linked’ to one another by pyridinium molecules, a process that enhances bone strength. When bone is broken down by osteoclasts, the cross-links are released into the circulation. These can be measured biochemically and are sometimes used clinically to assess levels of bone resorption. Bone is normally laid down in an orderly fashion, but when bone turnover is high, as in Paget’s disease or severe hyperparathyroidism, it is laid down in a chaotic pattern, giving rise to ‘woven bone’ that is mechanically weak. Bone matrix also contains growth factors, other structural proteins and proteoglycans, thought to be involved in helping bone cells attach to bone matrix and in regulating bone cell activity. The other major component of bone is mineral, comprised of calcium and phosphate crystals deposited between the collagen ﬁbrils in the form of hydroxyapatite [Ca10 (PO4)6 (OH)2]. Mineralisation is essential for bone’s rigidity and strength but over-mineralisation causes the bone to become brittle. In clinical practice, increased mineralisation can occur in some types of osteogenesis imperfecta and in response to long-term bisphosphonate therapy. Bone remodelling Bone remodelling is required for renewal and repair of the skeleton throughout life. This is a cyclical process that has four phases; quiescence, resorption, reversal and formation, as illustrated in Figure 24.2. Remodelling starts with the attraction of osteoclast precursors in peripheral blood to the target site, probably by local release of chemotactic factors from areas of microdamage. The osteoclasts resorb bone and, after about 10 days, undergo programmed cell death (apoptosis), heralding the start of the reversal phase, when osteoblast precursors are recruited to the resorption site. The osteoblast precursors differentiate into mature osteoblasts and form new bone during the formation phase. Initially, the matrix is unmineralised (osteoid) but eventually becomes mineralised to form mature bone. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes, which play a key regulatory role in coordinating bone formation and resorption, whereas others differentiate into bone-lining cells. The cellular and molecular mediators of this bone remodelling are shown in more detail in Figure 24.3. Osteoclast precursors are derived from haematopoietic stem cells and differentiate Fig. 24.2 The bone remodelling cycle. Bone is renewed and repaired by the process of bone remodelling. This begins by removal of old and damaged bone by osteoclasts during the phase of bone resorption. After about 10 days, the osteoclasts undergo programmed cell death (apoptosis) and during the reversal phase are replaced by osteoclasts, which begin to ﬁll in the resorbed area with new bone matrix, heralding the start of bone formation. The bone matrix is initially uncalciﬁed (osteoid) but then becomes mineralised to form mature bone. Bone-lining cells Osteoclasts Microdamage Formation Quiescence Resorption Reversal Apoptotic osteoclast Osteoblasts Osteoid Osteocytes Mineralisation

986 • RHEUMATOLOGY AND BONE DISEASE Joints There are three main types of joint: ﬁbrous, ﬁbrocartilaginous and synovial (Box 24.2). Fibrous and ﬁbrocartilaginous joints These comprise a simple bridge of ﬁbrous or ﬁbrocartilaginous tissue joining two bones together where there is little requirement for movement. The intervertebral disc is a special type of ﬁbrocartilaginous joint in which an amorphous area, called the nucleus pulposus, lies in the centre of the ﬁbrocartilaginous bridge. The nucleus has a high water content and acts as a cushion to improve the disc’s shock-absorbing properties. 24.2 Types of joint Type Range of movement Examples Fibrous Minimal Skull sutures Fibrocartilaginous Limited Symphysis pubis Costochondral junctions Intervertebral discs Sacroiliac joints Synovial Large Most limb joints Temporomandibular Costovertebral 24.1 Key regulators of bone remodelling Mediator Source Effects Comment RANKL Osteocytes Stromal cells Activated T cells Stimulates bone resorption Activates RANK Osteoprotegerin Stromal cells Lymphocytes Inhibits bone resorption Acts as decoy receptor for RANKL Wnt Stromal cells Stimulates bone formation Activates LRP receptors Sclerostin Osteocytes Inhibits bone formation Blocks effect of Wnt on LRP receptors Parathyroid hormone Parathyroid glands Increases bone resorption and formation Thyroid hormone Thyroid gland Increases bone resorption and formation Oestrogen Ovary Inhibits bone resorption Glucocorticoid Adrenal gland Exogenous Inhibits bone formation (LRP = lipoprotein receptor-related protein; RANKL = receptor activator of nuclear factor kappa B ligand) Fig. 24.3 Cellular and molecular regulators of bone remodelling Osteoclast precursors are derived from haematopoietic stem cells. They differentiate into mature osteoclasts in response to the receptor activator of nuclear factor kappa B ligand (RANKL), which is produced by osteocytes, bone marrow stromal cells and activated T cells (not shown), and macrophage colony-stimulating factor (M-CSF), which is produced by bone marrow stromal cells. Osteoprotegerin (OPG) is also produced in the bone microenvironment, where it inhibits osteoclastic bone resorption by blocking the effect of RANKL. Osteoblasts, which are derived from bone marrow stromal cells, are responsible for bone formation. Osteoblast activity is stimulated by signalling molecules in the Wnt family but inhibited by sclerostin (SOST), which is produced by osteocytes. In addition to their role in regulating osteoclast and osteoblast activity, osteocytes have an endocrine function in regulating phosphate homeostasis by producing ﬁbroblast growth factor 23 (FGF23), which acts on the kidney to promote phosphate excretion. Osteoclast precursor RANKL FGF23 SOST OPG M-CSF RANKL Wnt Haematopoietic stem cell Bone marrow stromal cells Renal phosphate excretion Osteoblast Osteocyte Osteoclast

Functional anatomy and physiology • 987

in reduced water content and shock-absorbing properties. These changes differ from those found in osteoarthritis (p. 1007), where there is abnormal chondrocyte division, loss of proteoglycan from matrix and an increase in water content. Cartilage matrix is constantly turning over and in health there is a perfect balance between synthesis and degradation. Degradation of cartilage matrix is carried out by aggrecanases and matrix metalloproteinases, responsible for the breakdown of proteins and proteoglycans, and by glycosidases, responsible for the breakdown of GAGs. Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor (TNF), which are released during inﬂammation, stimulate production of aggrecanase and metalloproteinases, causing cartilage degradation. Synovial ﬂuid The surfaces of articular cartilage are separated by a space ﬁlled with synovial ﬂuid (SF), a viscous liquid that lubricates the joint. It is an ultraﬁltrate of plasma, into which synovial cells secrete hyaluronan and proteoglycans. Intra-articular discs Some joints contain ﬁbrocartilaginous discs within the joint space that act as shock absorbers. The most clinically important are the menisci of the knee. These are avascular structures that remain viable because of diffusion of oxygen and nutrients from the SF. Synovial membrane, joint capsule and bursae The bones of synovial joints are connected by the joint capsule, a ﬁbrous structure richly supplied with blood vessels, nerves and lymphatics that encases the joint. Ligaments are discrete, regional thickenings of the capsule that act to stabilise joints (see Fig. 24.4). The inner surface of the joint capsule is the synovial membrane, comprising an outer layer of blood vessels and loose connective tissue that is rich in type I collagen, and an inner layer 1–4 cells thick consisting of two main cell types. Type A synoviocytes are phagocytic cells derived from the monocyte/ macrophage lineage and are responsible for removing particulate matter from the joint cavity; type B synoviocytes are ﬁbroblast-like cells that secrete SF. Most inﬂammatory and degenerative joint diseases associate with thickening of the synovial membrane and inﬁltration by lymphocytes, polymorphs and macrophages. Bursae are hollow sacs lined with synovium and contain a small amount of SF. They help tendons and muscles move smoothly in relation to bones and other articular structures. Skeletal muscle Skeletal muscles are responsible for body movements and respiration. Muscle consists of bundles of cells (myocytes) embedded in fine connective tissue containing nerves and blood vessels. Myocytes are large, elongated, multinucleated cells formed by fusion of mononuclear precursors (myoblasts) in early embryonic life. The nuclei lie peripherally and the centre of the cell contains actin and myosin molecules, which interdigitate with one another to form the myoﬁbrils that are responsible for muscle contraction. The molecular mechanisms of skeletal muscle contraction are the same as for cardiac muscle (p. 446). Myocytes contain many mitochondria that provide the large amounts of adenosine triphosphate (ATP) necessary for muscle contraction and are rich in the protein myoglobin, which acts as a reservoir for oxygen during contraction. Individual myoﬁbrils are organised into bundles (fasciculi) that are bound together by a thin layer of connective tissue (the Synovial joints These are complex structures containing several cell types. They are found where a wide range of movement is needed (Fig. 24.4). Articular cartilage This avascular tissue covers the bone ends in synovial joints. Cartilage cells (chondrocytes) are responsible for synthesis and turnover of cartilage, which consists of a mesh of type II collagen fibrils that extend through a hydrated ‘gel’ of proteoglycan molecules. The most important proteoglycan is aggrecan, which consists of a core protein to which several glycosaminoglycan (GAG) side chains are attached (Fig. 24.5). The GAGs are polysaccharides that consist of long chains of disaccharide repeats comprising one normal sugar and an amino sugar. The most abundant GAGs in aggrecan are chondroitin sulphate and keratan sulphate. Hyaluronan is another important GAG that binds to aggrecan molecules to form very large complexes with a total molecular weight of more than 100 million. Aggrecan has a strong negative charge and avidly binds water molecules to assume a shape that occupies the maximum possible volume available. The expansive force of the hydrated aggrecan, combined with the restrictive strength of the collagen mesh, gives articular cartilage excellent shock-absorbing properties. With ageing, the concentration of chondroitin sulphate decreases, whereas that of keratan sulphate increases, resulting Fig. 24.4 Structure of a synovial joint. Bone Skin and subcutaneous tissue Fibrocartilage pad Hyaline articular cartilage Joint space Synovium Capsule Bursa Tendon Tendon sheath Ligamentous thickening of capsule Muscle Bursa Fig. 24.5 Ultrastructure of articular cartilage. Aggrecan Core protein Link protein Chondroitin sulphate Keratan sulphate Type II collagen fibrils Hyaluronan

988 • RHEUMATOLOGY AND BONE DISEASE smaller, rhomboid in shape and usually less numerous than urate crystals; they have weak intensity and positive birefringence (Fig. 24.6B). Imaging Plain X-rays X-rays show structural changes that are of value in the differential diagnosis and monitoring of many bone and joint diseases (Box 24.3). perimysium). The surface of the muscle is surrounded by a thicker layer of connective tissue, the epimysium, which merges with the perimysium to form the muscle tendon. Tendons are tough, ﬁbrous structures that attach muscles to a point of insertion on the bone surface called the enthesis. Investigation of musculoskeletal disease Clinical history and examination usually provide sufﬁcient information for the diagnosis and management of many musculoskeletal diseases. Investigations are helpful in conﬁrming the diagnosis, assessing disease activity and indicating prognosis. Joint aspiration Joint aspiration with examination of SF is pivotal in patients suspected of having septic arthritis, crystal arthritis or intra-articular bleeding. It should be carried out in all individuals with acute monoarthritis, and samples should be sent for microbiology and clinical chemistry. It is possible to obtain SF by aspiration from most peripheral joints and only a small amount is required for diagnostic purposes. Normal SF is present in small volume, is clear and either colourless or pale yellow, and has a high viscosity. It contains few cells. With joint inﬂammation, the volume increases, the cell count and the proportion of neutrophils rise (causing turbidity), and the viscosity reduces (due to enzymatic degradation of hyaluronan and aggrecan). Turbid ﬂuid with a high neutrophil count occurs in sepsis, crystal arthritis and reactive arthritis. High concentrations of urate crystals or cholesterol can make SF appear white. Non-uniform blood-staining usually reﬂects needle trauma to the synovium. Uniform blood-staining is most commonly due to a bleeding diathesis, trauma or pigmented villonodular synovitis (p. 1059) but can occur in severe inﬂammatory synovitis. A lipid layer ﬂoating above blood-stained ﬂuid is diagnostic of intra-articular fracture and is caused by release of bone marrow fat into the joint. Crystals can be identiﬁed by compensated polarised light microscopy of fresh SF (to avoid crystal dissolution and post-aspiration crystallisation). Urate crystals are long and needle-shaped, and show a strong light intensity and negative birefringence (Fig. 24.6A). Calcium pyrophosphate crystals are Fig. 24.6 Compensated polarised light microscopy of synovial ﬂuids (× 400). A Monosodium urate crystals show bright negative birefringence under polarised light and needle-shaped morphology. B Calcium pyrophosphate crystals show weak positive birefringence under polarised light and are few in number. They are more difﬁcult to detect than urate crystals. A B 24.3 Radiographic abnormalities in selected rheumatic diseases Rheumatoid arthritis • Periarticular osteoporosis • Marginal joint erosions • Joint subluxation • Joint space narrowing Osteoporosis • Osteopenia • Vertebral fractures • Non-vertebral fractures • Cortical thinning Paget’s disease • Bone expansion • Abnormal trabecular pattern • Osteosclerosis and lysis • Pseudofractures Psoriatic arthritis • Sacroiliitis • Syndesmophytes • Bone sclerosis • Proliferative enthesis erosions • Enthesophytes • Juxta-articular new bone Osteoarthritis • Joint space narrowing • Osteophytes • Subchondral sclerosis • Joint deformity • Subchondral cysts They are of diagnostic value in osteoarthritis (OA), where they demonstrate joint space narrowing that tends to be focal rather than widespread, as in inﬂammatory arthritis. Other features of OA detected on X-rays include osteophytes, subchondral sclerosis, bone cysts and calciﬁed loose bodies within the synovium (see Fig. 24.21, p. 1010). Erosions and sclerosis of the sacroiliac joints and syndesmophytes in the spine may be observed in patients with spondyloarthritis (SpA; see Fig. 24.40, p. 1030). In peripheral joints, proliferative erosions, associated with new bone formation and periosteal reaction, occur in SpA. In tophaceous gout, well-deﬁned punched-out erosions may occur (see Fig. 24.27, p. 1015). Calciﬁcation of cartilage, tendons and soft tissues or muscle occurs mainly in chondrocalcinosis (see Fig. 24.28, p. 1016), calcium-containing crystal diseases, tumoral calcinosis and autoimmune connective tissue diseases. X-rays are of limited value in the diagnosis of rheumatoid arthritis (RA) because features such as erosions, joint space narrowing and periarticular osteoporosis may be detectable only after several months or even years. The main indication for X-rays in RA is in the assessment of disease over time when structural damage to the joints is suspected. Bone scintigraphy Bone scintigraphy is useful in the diagnosis of metastatic bone disease and Paget’s disease of bone. Abnormalities may also be observed in primary bone tumours, complex regional pain syndrome, osteoarthritis and inﬂammatory arthritis. It involves

Investigation of musculoskeletal disease • 989

Dual X-ray absorptiometry Estimation of bone mineral density (BMD) has a key role in the diagnosis and management of osteoporosis and is best made using dual X-ray absorptiometry (DXA). Measurements at lumbar spine, hip and sometimes forearm are obtained. DXA works on the principle that calcium in bone attenuates passage of X-rays through the tissue in proportion to the amount of mineral present: the more bone mineral present, the higher the BMD value. gamma-camera imaging following an intravenous injection of 99mTc-labelled bisphosphonate. Early post-injection images reﬂect blood ﬂow and can show increased perfusion of inﬂamed synovium, Pagetic bone or primary or secondary bone tumours. Delayed images taken a few hours later reﬂect bone remodelling as the 99mTc-labelled bisphosphonate localises to sites of active bone turnover. Scintigraphy has a high sensitivity for detecting important bone and joint pathology that is not apparent on X-rays (Box 24.4). Single photon emission computed tomography (SPECT) combines radionuclide imaging with computed tomography. It can provide accurate anatomical localisation of abnormal tracer uptake within the bone and is of particular value in the assessment of patients with chronic low back pain of unknown cause. Magnetic resonance imaging Magnetic resonance imaging (MRI) gives detailed information on anatomy, allowing three-dimensional visualisation of bone and soft tissues that cannot be adequately assessed by plain X-rays. The technique is valuable in the assessment and diagnosis of many musculoskeletal diseases (Box 24.5). T1-weighted sequences are useful for deﬁning anatomy, whereas T2-weighted sequences are useful for assessing tissue water content, which is often increased in synovitis and other inﬂammatory disorders (Fig. 24.7). MRI sequences that suppress signal from fat, such as short TI inversion recovery (STIR), are helpful when evaluating inﬂammatory disease. Contrast agents, such as gadolinium, can be administered to increase sensitivity in detecting erosions and synovitis. Ultrasonography Ultrasonography is a useful investigation for conﬁrmation of small joint synovitis and erosions, for anatomical location of periarticular lesions, for characterisation of tendon lesions and for guided injection of joints and bursae. Ultrasound is more sensitive than clinical examination for the detection of early synovitis and is used increasingly in the diagnosis and assessment of patients with suspected inﬂammatory arthritis. In addition to locating synovial thickening and effusions, ultrasound can detect increased blood ﬂow within synovium using power Doppler imaging, an option that is available on most modern ultrasound machines (Fig. 24.8). Computed tomography Computed tomography (CT) is used selectively for assessing patients with bone and joint disease. CT may be used when skeletal conﬁguration needs deﬁning, when calciﬁc lesions are being assessed (crowned dens syndrome, p. 1017), when MRI is contraindicated, or when articular regions are being evaluated in which an adjacent joint replacement creates signal artefacts on MRI, using speciﬁc metal artefact reduction algorithms. Fig. 24.7 Magnetic resonance image showing joint synovitis. Coronal post-contrast T1-weighted image shows extensive enhancement consistent with synovitis (white areas, arrowed) in both wrists, at the second metacarpophalangeal joint and proximal interphalangeal joints of the right hand. Courtesy of Dr I. Beggs. Fig. 24.8 Ultrasound image showing synovitis. Lateral image of a metacarpophalangeal joint in inﬂammatory arthritis. The periosteum (P) of the phalanx shows as a white line. The dark, hypo-echoic area indicates an effusion. The coloured areas demonstrated by power Doppler indicate increased vascularity. The inset shows a transverse image of the same joint. Courtesy of Dr N. McKay. 24.4 Conditions identiﬁed by 99mTc-labelled bisphosphonate bone scintigraphy • Skeletal metastases • Paget’s disease of bone • Stress fractures and osteomalacia (e.g. Looser’s zones) • Complex regional pain syndrome (p. 1055) • Sclerosing bone disorders (e.g. hypertrophic pulmonary osteoarthropathy; p. 1057) • Spondyloarthritides (abnormalities at sacroiliac joints and tendon/ ligament insertions) 24.5 Conditions detected by magnetic resonance imaging • Osteonecrosis • Intervertebral disc disease • Nerve root entrapment • Spinal cord compression • Spinal stenosis • Sepsis • Complex regional pain syndrome • Malignancy • Fractures • Meniscal disease • Synovitis • Sacroiliitis and enthesitides • Inﬂammatory myositis • Rotator cuff tears, bursitis and tenosynovitis

990 • RHEUMATOLOGY AND BONE DISEASE when the T-score lies between −1.0 and −2.5 (shaded pink). BMD values above −1.0 and below +2.5 are considered normal (yellow/green), whereas values above +2.5 indicate high bone mass, the most common cause being OA. The results need to be interpreted carefully and in reference to coexisting conditions, such as aortic calciﬁcation, vertebral fractures, degenerative disc disease and OA, all of which can artefactually raise BMD results. Radiographic correlation is then advisable. Blood tests Haematology Abnormalities in the full blood count (FBC) often occur in inﬂammatory rheumatic diseases but changes are usually nonspeciﬁc. Examples include neutrophilia in crystal arthritides and sepsis; neutropenia in lupus; and lymphopenia in autoimmune rheumatic and connective tissue diseases. Reduced levels of haemoglobin and raised platelets are a common and important ﬁnding in active inﬂammatory rheumatological disorders. Many synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) can cause marrow toxicity and require regular monitoring of the FBC. Additional tests that are useful in assessing rheumatic diseases include the direct antiglobulin test (which can indicate intravascular haemolysis in systemic lupus erythematosus (SLE); p. 948) and the dilute Russell viper venom test (a functional assay for a lupus anticoagulant; p. 978). Biochemistry Routine biochemistry is useful for assessing metabolic bone disease, muscle diseases and gout, and is essential in monitoring DMARDs and biologic drugs (renal and hepatic function). Several bone diseases, including Paget’s disease, renal bone disease and osteomalacia, give a characteristic pattern that can be helpful diagnostically (Box 24.6). Serum levels of uric acid are usually raised in gout but a normal level does not exclude it, especially during an acute attack, when urate levels temporarily fall. Equally, an elevated serum uric acid does not conﬁrm the diagnosis, since most hyperuricaemic people never develop gout. Levels of C-reactive protein (CRP) are a useful marker of infection and inflammation, and are more specific than the erythrocyte sedimentation rate (ESR). An exception is in autoimmune connective tissue diseases, such as SLE and systemic sclerosis, where CRP may be normal but the ESR raised in active disease. Accordingly, an elevated CRP in a patient with lupus or systemic sclerosis suggests an intercurrent illness, such as sepsis, rather than active disease. More detail on the Fig. 24.9 Typical output from a dual X-ray absorptiometry (DXA) scan. A Image from hip DXA scan. B Bone mineral density (BMD) values plotted in g/cm2 (left axis) and as the T-score values (right axis). The solid line represents the population average plotted against age, and the interrupted lines are ± 2 standard deviations. The BMD T-score result from the patient shown aged 70 years (arrow) is −3.0, indicating osteoporosis. Note that, while the patient’s BMD is below average, it lies within the reference range for someone of that age, since BMD normally falls with age. 1.3 +2.0 +1.0 0.0 −1.0 −2.0 −3.0 −4.0 1.0 0.7 0.4

Age (years) T-score BMD (g/cm2)

A B 24.6 Typical biochemical abnormalities in various skeletal diseases (in serum) Calcium Phosphate ALP PTH FGF23 25(OH)D Osteoporosis N N N (↑ after fracture) N or ↑ N N or ↓ Paget’s disease N N ↑↑ N or ↑ N N or ↓ Renal osteodystrophy N or ↓ N or ↑ ↑ ↑↑ ↑↑ N or ↓ Vitamin D-deﬁcient osteomalacia N or ↓ N or ↓ ↑ ↑↑ N or ↓ ↓↓ Hypophosphataemic rickets N ↓↓ ↑ N or ↑ ↑↑ N or ↓ Primary hyperparathyroidism ↑/↑↑ N or ↓ N or ↑ ↑↑ N or ↑ N or ↓ (ALP = alkaline phosphatase; FGF23 = ﬁbroblast growth factor 23; PTH = parathyroid hormone) (N = normal; single arrow = increased or decreased; double arrow = greatly increased or decreased) Bone density measurements are often presented as T-scores, which measure of the number of standard deviations by which the patient’s BMD value differs from that in a young healthy control (Fig. 24.9). Osteoporosis is deﬁned in postmenopausal women and men of more than 50 years old by a T-score of 2.5 or below (shaded red in the ﬁgure); osteopenia is diagnosed

Investigation of musculoskeletal disease • 991

and can be detected in asymptomatic patients several years before the development of RA. Their pathological role is still debated but it is likely that they amplify the synovial response to an inﬂammatory stimulus. Antinuclear antibodies Antinuclear antibodies (ANAs) are directed against one or more components of the cell nucleus, including nucleic acids themselves and the proteins concerned with the processing of DNA or RNA. They occur in many inﬂammatory rheumatic diseases but are also found at low titre in normal individuals and in other diseases (Box 24.9). ANAs are not associated with disease severity or activity. The most common indication for ANA testing is in patients suspected of having SLE or other autoimmune connective tissue diseases. ANA has high sensitivity for SLE (100%) but low speciﬁcity (10–40%). A negative ANA virtually excludes SLE but a positive result does not conﬁrm it. Anti-DNA antibodies bind to double-stranded DNA (dsDNA) and are useful in SLE monitoring as very high titres are associated with more severe disease, including renal or central nervous system (CNS) involvement, and an increase in antibody titre may precede relapse. Anti-DNA antibodies are routinely tested by enzyme-linked immunosorbent assay (ELISA; see also p. 1036). Antibodies to extractable nuclear antigens (ENAs) act as markers for certain autoimmune connective tissue diseases and some complications of SLE but sensitivity and speciﬁcity are poor (Box 24.10). For example, antibodies to Sm are found in a minority of patients with SLE but are associated with renal involvement. Antibodies to Ro occur in SLE and in Sjögren’s syndrome (in association with anti-La antibodies), and are associated with a photosensitive rash and congenital heart block. Antibodies to ribonucleoprotein (RNP) occur in SLE and also in mixed connective tissue disease, where features of lupus, myositis and systemic sclerosis coexist. Anti-topoisomerase 1 (also termed Scl-70) antibodies occur in diffuse systemic sclerosis, whereas anti-centromere antibodies are more speciﬁc for limited systemic sclerosis. Antiphospholipid antibodies Antiphospholipid antibodies bind to a number of phospholipid binding proteins but the most clinically relevant are those that target beta2-glycoprotein 1 (β2GP1). They may be detected in 24.9 Conditions associated with a positive antinuclear antibody* Condition Approximate frequency (%) Systemic lupus erythematosus 100% Systemic sclerosis 60–80% Sjögren’s syndrome 40–70% Dermatomyositis or polymyositis 30–80% Mixed connective tissue disease 100% Autoimmune hepatitis 100% Rheumatoid arthritis 30–50% Autoimmune thyroid disease 30–50% Malignancy Varies widely Infectious diseases Varies widely *Low-titre positive antinuclear antibody can occur in people without autoimmune disease, without obvious clinical consequences, particularly in the elderly. Normal healthy people can be positive for rheumatoid factor. 24.8 Conditions associated with a positive rheumatoid factor Condition Approximate frequency (%) Rheumatoid arthritis with nodules and extra-articular manifestations

Rheumatoid arthritis (overall)

Sjögren’s syndrome

Mixed essential cryoglobulinaemia

Primary biliary cholangitis

Infective endocarditis

Systemic lupus erythematosus

Tuberculosis

Age > 65 years

interpretation of CRP and ESR changes is given on page 72. Serum creatine phosphokinase levels are useful in the diagnosis of myopathy or myositis, but speciﬁcity and sensitivity are poor and raised levels may occur in some conditions (Box 24.7). Immunology Autoantibody tests are widely used in the diagnosis of rheumatic diseases. Whatever test is used, the results must be interpreted in light of the clinical picture and the different detection and assay systems used in different hospitals. Rheumatoid factor Rheumatoid factor (RF) is an antibody directed against the Fc fragment of human immunoglobulin. In routine clinical practice, immunoglobulin M (IgM) RF is usually measured, although different methodologies allow measurement of IgG and IgA RFs too. Positive RF occurs in a wide variety of diseases and some normal adults (Box 24.8), particularly with increasing age. Although the speciﬁcity is poor, about 70% of patients with RA test positive. High RF titres are associated with more severe disease and extra-articular disease. Anti-citrullinated peptide antibodies Anti-citrullinated peptide antibodies (ACPAs) recognise peptides in which the amino acid arginine has been converted to citrulline by peptidylarginine deiminase, an enzyme abundant in inﬂamed synovium and in a variety of mucosal structures. ACPAs have similar sensitivity to RF for RA (70%) but much higher speciﬁcity (> 95%), and should be used in preference to RF in the diagnosis of RA. ACPAs are associated with more severe disease progression The CK-MB cardiac-speciﬁc isoform is disproportionately elevated compared with total CPK. 24.7 Causes of an elevated serum creatinine phosphokinase (CPK) • Inﬂammatory myositis ± vasculitis • Muscular dystrophy • Motor neuron disease • Alcohol, drugs (especially statins) • Myocardial infarction • Trauma, strenuous exercise, prolonged immobilisation after a fall • Hypothyroidism, metabolic myopathy • Viral myositis

992 • RHEUMATOLOGY AND BONE DISEASE Synovial biopsy can be useful in selected patients with chronic inﬂammatory monoarthritis or tenosynovitis to rule out chronic infectious causes, especially mycobacterial infections. Synovial biopsy can be obtained arthroscopically (by conventional means or by use of needle arthroscope) or by using ultrasound guidance under local anaesthetic. Temporal artery biopsy can be of value in patients suspected of having temporal arteritis, especially when the presentation is atypical, but a negative result does not exclude the diagnosis. Biopsies of affected tissues, such as skin, lung, nasopharynx, gut, kidney and muscle, should be sought by default in conﬁrming a diagnosis of systemic vasculitis. Muscle biopsy plays an important role in the investigation of myopathy and inﬂammatory myositis. It is usually taken from the quadriceps or deltoid through a small skin incision under local anaesthetic. Since myositis can be patchy in nature, MRI is sometimes used to localise the best site for biopsy. Immunohistochemical staining, together with plain histology, gives information on primary and secondary muscle and neuromuscular disease. Repeat biopsies are sometimes used to monitor the response to treatment. Bone biopsy is occasionally required where non-invasive tests give inconclusive results, in the diagnosis of inﬁltrative disorders, in patients with renal bone disease, suspected chronic infection or malignancy, and rarely to conﬁrm or exclude the presence of osteomalacia. Bone is taken from the iliac crest using a large-diameter (8 mm) trephine needle under local anaesthetic and processed without demineralisation. For focal lesions, the biopsy should be taken under X-ray guidance or at open surgery, from an affected site. Electromyography Electromyography (p. 1076) is of value in the investigation of suspected myopathy and inﬂammatory myositis, when it shows the diagnostic triad of: • spontaneous ﬁbrillation • short-duration action potentials in a polyphasic disorganised outline • repetitive bouts of high-voltage oscillations on needle contact with diseased muscle. Presenting problems in musculoskeletal disease Acute monoarthritis The most important causes of acute arthritis in a single joint are crystal arthritis, sepsis, SpA and oligoarticular juvenile idiopathic arthritis (JIA; p. 1026). Other potential causes are shown in Box 24.11. Clinical assessment The clinical history, pattern of joint involvement, speed of onset, and age and gender of the patient all give clues to the most likely diagnosis. Gout classically affects the ﬁrst metatarsophalangeal (MTP) joint, whereas pseudogout, which can be a presenting feature of calcium pyrophosphate dihydrate (CPPD) disease, can affect the hand/wrist, ankle, knee or hip. A very rapid onset (6–12 hours) is suggestive of crystal arthritis; joint sepsis develops more slowly and continues to progress until treated. SLE and other autoimmune connective tissue diseases and are key in diagnosing antiphospholipid antibody syndrome (p. 977). Antineutrophil cytoplasmic antibodies Antineutrophil cytoplasmic antibodies (ANCAs) are IgG antibodies directed against the cytoplasmic constituents of granulocytes and are useful in the diagnosis and monitoring of systemic vasculitis. Two common patterns are described by immunoﬂuorescence: cytoplasmic ﬂuorescence (c-ANCA), which is caused by antibodies to proteinase-3 (PR3); and perinuclear ﬂuorescence (p-ANCA), which is caused by antibodies to myeloperoxidase (MPO) and other proteins, such as lactoferrin and elastase. These antibodies are not speciﬁc for vasculitis and positive results may be found in autoimmune liver disease, malignancy, infection (bacterial and human immunodeﬁciency virus, HIV), inﬂammatory bowel disease, RA, SLE and pulmonary ﬁbrosis. Complement Low complement C3 is an indicator of active SLE, owing to ‘consumption’ of complement by immune complexes (see Fig. 4.4, p. 66). Low C4 is less speciﬁc for SLE activity. High C3 and functional measures of complement activation are non-speciﬁc features of inﬂammation. Tissue biopsy Tissue biopsy is useful in conﬁrming the diagnosis in certain musculoskeletal diseases. 24.10 Conditions associated with antibodies to extractable nuclear antigens Antibody (target/other name) Disease association Anti-centromere antibody Localised cutaneous systemic sclerosis (sensitivity 60%, speciﬁcity 98%) Anti-histone antibody Drug-induced lupus (80%) Anti-Jo-1 (anti-histidyl-tRNA synthetase) Polymyositis, dermatomyositis or polymyositis–systemic sclerosis overlap (20–30%) Particularly associated with interstitial lung disease Anti-La antibody (anti-SS-B) Sjögren’s syndrome (60%) SLE (20–60%) Anti-ribonucleoprotein antibody (anti-RNP) Mixed connective tissue disease (100%) SLE (25–50%), usually in conjunction with anti-Sm antibodies Anti-Ro antibody (anti-SS-A) SLE (35–60%): associated with photosensitivity, thrombocytopenia and subacute cutaneous lupus Maternal anti-Ro antibodies associated with neonatal lupus and congenital heart block Sjögren’s syndrome (40–80%) Anti-RNA polymerase Diffuse systemic sclerosis (15%) Anti Sm (anti-Smith antibody) SLE (15–30%); associated with renal disease Anti-Scl-70 (anti-topoisomerase I antibody) Diffuse systemic sclerosis (15%); associated with more severe organ involvement, including pulmonary ﬁbrosis (SLE = systemic lupus erythematosus)

Presenting problems in musculoskeletal disease • 993

underlying cause (Box 24.13). The most important diagnoses to consider are PsA, RA and inﬂammatory small joint OA. RA is characterised by symmetrical involvement of the small joints of the hands and feet, wrists, ankles and knees. PsA is strongly associated with enthesitis. Viral arthritis (p. 1020), Poncet’s disease (in regions where tuberculosis is highly prevalent; p. 588), polyarticular JIA (in children) and post-streptococcal arthritis should also be considered. The pattern of involvement can be helpful in reaching a diagnosis (Fig. 24.10). Asymmetry, lower limb predominance, enthesitis and greater involvement of large joints are characteristic of the SpAs. In PsA there may be involvement of the proximal and distal interphalangeal (PIP and DIP) joints, as opposed to the metacarpophalangeal (MCP) and PIP joints in RA. Inﬂammatory OA can appear similar to small-joint PsA in the pattern of joint involvement. In PsA there may be nail pitting or early onycholysis. Psoriasis may not be present. SLE can be associated with polyarthritis but more usually causes polyarthralgia and tenosynovitis, mainly of distal limb joints/tendons (p. 1035). Investigations Blood samples should be taken for routine haematology, biochemistry, ESR, CRP, viral serology and an immunological screen, including ANA, RF and ACPA. Ultrasound examination or MRI may be required to conﬁrm the presence of synovitis, if this is not obvious clinically. 24.12 Common causes of polyarthritis Cause Characteristics Rheumatoid arthritis Symmetrical, small and large joints, upper and lower limbs Viral arthritis Symmetrical, small joints; may be associated with rash and prodromal illness; self-limiting Osteoarthritis Symmetrical, targets PIP, DIP and ﬁrst CMC joints in hands, knees, hips, back and neck; associated with Heberden’s and Bouchard’s nodes Psoriatic arthritis Asymmetrical, targets all joints and entheses; associated with nail pitting/ onycholysis, dactylitis Axial spondyloarthritis and enteropathic arthritis Tends to affect midsize and large joints and entheses, lower more than upper limbs; history of inﬂammatory back pain Systemic lupus erythematosus Symmetrical, typically affecting small joints; clinical evidence of synovitis unusual Juvenile idiopathic arthritis Various patterns (p. 1026): polyarticular, oligoarticular and systemic but also enthesitis-predominant Chronic gout Affects distal more than proximal joints; history of acute attacks Chronic sarcoidosis (p. 608) Varies: small and large joints, often involves ankles Calcium pyrophosphate arthritis Chronic polyarthritis with involvement of wrists, ankles, knees and oligoarticular small hand joints (CMC = carpometacarpal; DIP = distal interphalangeal; PIP = proximal interphalangeal) 24.11 Causes of acute monoarthritis Common • Gout • Pseudogout • Trauma • Haemarthrosis • Spondyloarthritis • Psoriatic arthritis • Reactive arthritis • Enteropathic arthritis Less common • Rheumatoid arthritis • Juvenile idiopathic arthritis • Pigmented villonodular synovitis • Foreign body reaction • Tuberculosis • Leukaemia* • Gonococcal infection • Osteomyelitis* *In children, both leukaemia and osteomyelitis may present with monoarthritis. Haemarthrosis typically causes a large effusion, in the absence of periarticular swelling or skin change, in a patient who has suffered an injury. Pigmented villonodular synovitis (p. 1059) also presents with synovial swelling and a large effusion, although the onset is gradual. A previous diarrhoeal illness or genital infection suggests reactive arthritis, whereas intercurrent illness, dehydration or surgery may act as a trigger for crystal-induced arthritis. Rheumatoid arthritis seldom presents with monoarthritis but psoriatic arthritis (PsA) can typically present this way. Osteoarthritis can present with pain and stiffness affecting a single joint, but the onset is gradual and there is usually no evidence of signiﬁcant joint swelling unless it is complicated by crystal-induced inﬂammation. Investigations Aspiration of the affected joint is mandatory. If sepsis is suspected in a large joint, arthroscopic washout is advisable. The ﬂuid should be sent for culture and Gram stain to seek the presence of organisms and should be checked by polarised light microscopy for crystals. Blood cultures should also be taken in patients suspected of having septic arthritis. CRP levels and ESR are raised in sepsis, crystal arthritis and reactive arthritis, and this can be useful in assessing the response to treatment. Serum uric acid measurements may be raised in gout but a normal level does not exclude the diagnosis. Ruling out primary hyperparathyroidism is essential if there is pseudogout. Management If there is any suspicion of sepsis, intravenous antibiotics (see Box 24.50, p. 1020) should be given promptly, pending the results of cultures. Unless atypical infections/tuberculosis (requiring prolonged or special culture) are suspected, intra-articular glucocorticoid injection may be considered after 48 hours of negative synovial ﬂuid culture. Otherwise, management should be directed towards the underlying cause. Polyarthritis This term is used to describe pain and swelling affecting ﬁve or more joints or joint groups. The possible causes are listed in Box 24.12. Clinical assessment The hallmarks of inflammatory arthritis are early-morning stiffness and worsening of symptoms with inactivity, along with synovial swelling and tenderness on examination. Clinical features in other systems can be helpful in determining the

994 • RHEUMATOLOGY AND BONE DISEASE Management Treatment with non-steroidal anti-inﬂammatory drugs (NSAIDs) and analgesics will help. Systemic glucocorticoids can be considered if symptoms are very severe or having a great functional impact, but early immunotherapy (DMARDs) is required in RA and in some cases of PsA. An early accurate and speciﬁc diagnosis is very important. Fracture Fractures are a common presenting symptom of osteoporosis but they also occur in other bone diseases, in osteopenia and in some patients with normal bone. Clinical assessment The presentation is with localised bone pain, which is worsened by movement of the affected limb or region. There is usually a history of trauma but spontaneous fractures can occur in the absence of trauma in severe osteoporosis. Fractures can be divided into several subtypes, based on the precipitating event and presence or absence of an underlying disease (Box 24.14). The main differential diagnosis is soft tissue injury but fracture should be suspected when there is marked pain and swelling, abnormal movement of the affected limb, crepitus or deformity. Femoral neck fractures typically produce a shortened, externally rotated leg that is painful to move. The pain from vertebral fracture is variable and a high index of suspicion is key to making the diagnosis by imaging, as discussed below. Investigations X-rays of the affected site should be taken in at least two planes and examined for discontinuity of the cortical outline (Box 24.15). In addition to demonstrating the fracture, X-rays may also show evidence of an underlying disorder, such as osteoporosis, Paget’s disease or osteomalacia. If the X-ray fails to show evidence of a fracture but clinical suspicion remains high, MRI should be Fig. 24.10 Patterns of joint involvement in different forms of polyarthritis. A Rheumatoid arthritis typically targets the metacarpophalangeal and proximal interphalangeal joints of the hands and metatarsophalangeal joints of the feet, as well as other joints, in a symmetrical pattern. B Psoriatic arthritis targets proximal and distal interphalangeal joints of the hands, entheses and larger joints in an asymmetrical pattern. Sacroiliitis (often asymmetrical) may occur. C Axial spondyloarthritis/ankylosing spondylitis targets the spine, sacroiliac joints, entheses and large peripheral joints in an asymmetrical pattern. D Osteoarthritis targets the proximal and distal interphalangeal joints of the hands, ﬁrst carpometacarpal joint at the base of the thumb, knees, hips, lumbar and cervical spine. A B C D 24.13 Extra-articular features of inﬂammatory arthritis Clinical feature Disease association Skin, nails and mucous membranes Psoriasis, nail pitting and dystrophy Psoriatic arthritis Raynaud’s phenomenon Systemic sclerosis, antiphospholipid syndrome, SLE Photosensitivity SLE Livedo reticularis SLE, antiphospholipid syndrome Splinter haemorrhages, nail-fold infarcts, purpuric lesions Vasculitis Urticaria and erythemas SLE, adult-onset Still’s disease, systemic JIA, rheumatic fever Oral ulcers SLE, reactive arthritis, Behçet’s disease Nodules RA (mainly extensor surfaces), gout (tophi; eccentric, white deposits within), rheumatic fever Xerostomia, dry skin, various rashes Primary Sjögren’s syndrome Eyes Uveitis SpA, sarcoid, JIA, Behçet’s disease Conjunctivitis Reactive arthritis Episcleritis, scleritis RA, vasculitis Heart, lungs Pleuro-pericarditis SLE, RA, rheumatic fever Aortic valve/root disease HLA-B27-related SpA Interstitial lung disease RA, SLE, primary Sjögren’s syndrome Abdominal organs Hepatosplenomegaly RA, SLE Haematuria, proteinuria SLE, vasculitis, systemic sclerosis Urethritis Reactive arthritis and SpA (sterile) Fever, lymphadenopathy Infection, systemic JIA, rheumatic fever (HLA = human leucocyte antigen; JIA = juvenile idiopathic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SpA = spondyloarthritis)

Presenting problems in musculoskeletal disease • 995

in association with hypermobility, most notably Ehlers–Danlos syndrome hypermobility subtype (hEDS; p. 1059). Investigations Bone scintigraphy is of value in patients suspected of having osteomalacia, bone metastases or Paget’s disease, and in characterising lesions at joints and/or entheses in SpAs, including PsA. Myeloma (p. 966) should be screened for with an FBC, measurement of CRP, and plasma and urinary protein electrophoresis. If these results are positive, a radiological skeletal survey should be obtained. Routine biochemistry, vitamin D and parathyroid hormone (PTH) should be measured if osteomalacia is suspected. In Paget’s disease, ALP may be elevated but can be normal in localised disease. Any persistently elevated ESR, CRP, angiotensin-converting enzyme (ACE), immunoglobulins, C3/C4 or platelets invariably indicates inﬂammatory disease. Laboratory investigations are normal in patients with FM alone and in hEDS. Management Management should be directed towards the underlying cause. Chronic pain of unknown cause and that associated with FM respond poorly to analgesics and NSAIDs, but may respond partially to antineuropathic agents, such as amitriptyline, duloxetine, gabapentin and pregabalin. Back pain Back pain is a common symptom that affects 60–80% of people at some time in their lives. Although the prevalence has not increased, reported disability from back pain has risen signiﬁcantly in the last 30 years. In Western countries, back pain is the most common cause of sickness-related work absence. In the UK, 7% of adults consult their GP each year with back pain. Globally, low back pain is thought to affect about 9% of the population. The most important causes are summarised in Box 24.17. Clinical assessment The main purpose of clinical assessment is to differentiate the self-limiting disorder of acute mechanical back pain from serious spinal pathology, as summarised in Figure 24.11. Mechanical back pain is the most common cause of acute back pain in people aged 20–55. This accounts for more than 90% of episodes, and is usually acute and associated with lifting or bending. It is exacerbated by activity and is generally relieved by rest (Box 24.18). It is usually conﬁned to the lumbar–sacral region, buttock or thigh, is asymmetrical and does not radiate beyond the knee (which would imply nerve root irritation). On examination, there may be asymmetric local paraspinal muscle spasm and tenderness, and painful restriction of some, but not all, movements. Low back pain is more common in manual workers, particularly those in occupations that involve heavy lifting and twisting. The prognosis 24.15 How to investigate a suspected fracture • Order X-rays in two projections at right angles to one another • Include the whole bone and the joints at either end (this may reveal an additional unsuspected fracture) • Check for evidence of displacement • Check for a break in the cortex • In suspected vertebral fracture, check for depression of the end plate • If clinical suspicion is high but no fracture is seen, request magnetic resonance imaging 24.14 Characteristics of different fracture types Fracture type Precipitation factor Disease Fragility fracture Fall from standing height or less Osteoporosis Osteopenia Vertebral fracture Bending, lifting, falling Osteoporosis Stress fracture Running, excessive training Normal High-energy fracture Major trauma Normal Pathological fracture Spontaneous, minimal trauma Malignancy Paget’s disease Osteomalacia obtained. Patients who are over the age of 50 and present with fragility fractures should be screened for osteoporosis by DXA. Management Management of fracture in the acute stage requires adequate pain relief, with opiates if necessary, reduction of the fracture to restore normal anatomy, and immobilisation of the affected limb to promote healing. This can be achieved either by the use of an external cast or splint, or by internal ﬁxation. Femoral neck fractures present a special management problem since non-union and avascular necrosis are common. This is especially true with intracapsular hip fractures, which should be treated by joint replacement surgery. Following the fracture, rehabilitation is required with physiotherapy and a supervised exercise programme. If the DXA scan shows evidence of osteoporosis or other metabolic bone disease, this should be treated appropriately (p. 1046). Options for management of painful vertebral fracture are discussed on page 1002. Generalised musculoskeletal pain Clinical assessment Clinical history and examination need to be wide-ranging (Box 24.16). Relentlessly progressive pain occurring in association with weight loss suggests malignant disease with bone metastases. Generalised bone pain may also arise in severe osteomalacia, primary hyperparathyroidism and polyostotic Paget’s disease. Widespread pain can occur in PsA if there is enthesial as well as, or instead of, joint involvement; fatigue is also often present. Polyarticular RA or OA pains tend to be localised to sites of involvement, such as the lumbar spine, hips, knees and hands. Fibromyalgia (FM) syndrome (p. 1018) presents with generalised pain that particularly affects the trunk, back and neck. Accompanying features include fatigue, poor concentration and focal areas of hyperalgesia. Widespread pain may also occur 24.16 Some common causes of generalised pain • Myopathies • Psoriatic arthritis (enthesopathic) • Fibromyalgia • Parvovirus arthromyalgia • Rheumatic fever/post-streptococcal infection • Metastatic cancer • Severe osteomalacia

996 • RHEUMATOLOGY AND BONE DISEASE uphill. Patients may adopt a characteristic simian posture, with a forward stoop and slight ﬂexion at hips and knees. The most common cause is the gradual development of coexisting contributing lesions such as facet joint arthritis, ligament ﬂavum thickening or degenerative spondylolisthesis. Degenerative disc disease is a common cause of chronic low back pain in middle-aged adults. Prolapse of an intervertebral disc presents when discs are still well hydrated (in young and early middle age) with nerve root pain, which can be accompanied by a sensory deﬁcit, motor weakness and asymmetrical reﬂexes. Examination may reveal a positive sciatic or femoral stretch test. About 70% of patients improve by 4 weeks. Inﬂammatory back pain (IBP) due to axial spondyloarthritis (axSpA) or PsA has a gradual onset and almost always occurs before the age of 40. It is associated with morning stiffness and improves with movement. Spondylolisthesis (p. 1059) may cause back pain that is generally good. After 2 days, 30% are better and 90% have recovered by 6 weeks. Recurrences of pain may occur and about 10–15% of patients go on to develop chronic back pain that may be difﬁcult to treat. Psychological elements, such as job dissatisfaction, depression and anxiety, are important risk factors for the transition to chronic pain and disability. Back pain secondary to serious spinal pathology has different characteristics (Box 24.19). If there is clinical evidence of spinal cord or nerve root compression, sepsis including tuberculosis, or a cauda equina lesion (Box 24.20), urgent investigation is needed. Spinal stenosis presents insidiously with leg discomfort on walking that is relieved by rest, bending forwards or walking Fig. 24.11 Initial triage assessment of back pain. Back pain Mechanical Common, Acute onset Self-limiting Other Prolapsed disc Spinal stenosis Paget’s disease Fracture Inflammatory Axial spondyloarthritis Psoriatic spondyloarthritis Clinical assessment (Box 24.20) Destructive Malignancy Infection Persistent pain Fever/weight loss Inflammatory features Cauda equina syndrome Nerve root pain persisting > 4 weeks Further investigation and imaging Urgent investigation ± neurosurgical referral 24.19 Red ﬂags for possible spinal pathology History • Age: presentation < 20 years or > 55 years • Character: constant, progressive pain unrelieved by rest • Location: thoracic pain • Past medical history: carcinoma, tuberculosis, HIV, systemic glucocorticoid use, osteoporosis • Constitutional: systemic upset, sweats, weight loss • Major trauma Examination • Painful spinal deformity • Severe/symmetrical spinal deformity • Saddle anaesthesia • Progressive neurological signs/muscle-wasting • Multiple levels of root signs 24.18 Features of mechanical low back pain • Pain varies with physical activity (improved with rest) • Onset often sudden and precipitated by lifting or bending • Recurrent episodes • Pain limited to back or upper leg • No clear-cut nerve root distribution • No systemic features • Prognosis good (90% recovery at 6 weeks) 24.17 Causes of low back pain • Mechanical (soft-tissue lesion) back pain • Intervertebral disc lesions (e.g. prolapse, disc degeneration) • Facet joint disease (osteoarthritis, psoriatic arthritis) • Vertebral fracture (p. 994) • Paget’s disease • Axial spondyloarthritis • Spondylodiscitis • Bone metastases • Spondylolisthesis (p. 1059) • Scheuermann’s disease (p. 1055)

Presenting problems in musculoskeletal disease • 997

Shoulder pain Shoulder pain is a common complaint over the age of 40 (Box 24.22). Varying pain patterns associated with common lesions are shown in Figure 24.12. For most shoulder lesions, general management is with analgesics, NSAIDs, local glucocorticoid injections and physiotherapy aimed at restoring normal movement and function. Surgery may be required in patients who have debilitating or persistent symptoms in association with rotator cuff lesions or severe acromioclavicular joint arthritis. If there is subacromial impingement, without evidence of a rotator cuff tear on MRI, subacromial glucocorticoid injection and physiotherapy constitute a reasonable ﬁrst step. Calciﬁc supraspinatus tendonitis unresponsive to glucocorticoid injection can be treated with barbotage (needle disruption of deposit under ultrasound guidance). Complete rotator cuff tears in people under 40 years of age may respond well to full surgical repair but results are is typically aggravated by standing and walking. Occasionally, diffuse idiopathic skeletal hyperostosis (DISH; p. 1058) can cause back pain but it is usually asymptomatic. Arachnoiditis is a rare cause of chronic severe low back pain. It is caused by chronic inﬂammation of the nerve root sheaths in the spinal canal and can complicate meningitis, spinal surgery or myelography with oil-based contrast agents. Investigations Investigations are not required in patients with acute mechanical back pain. Those with persistent pain (> 6 weeks) or red ﬂags (see Box 24.19) should undergo further investigation. MRI is the investigation of choice because it can demonstrate spinal stenosis, cord compression or nerve root compression, as well as inﬂammatory changes in axSpA, malignancy and sepsis. Plain X-rays can be of value in patients suspected of having vertebral compression fractures, OA and degenerative disc disease. If metastatic disease is suspected, bone scintigraphy should be considered. Additional investigations that may be required include routine biochemistry and haematology, ESR and CRP (to screen for sepsis and inﬂammatory disease), protein and urinary electrophoresis (for myeloma), human leucocyte antigen (HLA)-B27 status in IBP and prostate-speciﬁc antigen (for prostate carcinoma). Management Education is important in patients with mechanical back pain. It should emphasise the self-limiting nature of the condition and the fact that exercise is helpful rather than damaging. Regular analgesia and/or NSAIDs may be required to improve mobility and facilitate exercise. Return to work and normal activity should take place as soon as possible. Bed rest is not helpful and may increase the risk of chronic disability. Referral for physical therapy should be considered if a return to normal activities has not been achieved by 6 weeks. Low-dose tricyclic antidepressant drugs may help pain, sleep and mood. Other treatment modalities that are occasionally used include epidural and facet joint injection, traction and lumbar supports, though there is limited randomised controlled trial evidence to support their use. Malignant disease, osteoporosis, Paget’s disease and SpAs require speciﬁc treatment of the underlying condition. Surgery is required in less than 1% of patients with low back pain but may be needed in progressive spinal stenosis, 24.20 Clinical features of radicular pain Nerve root pain • Unilateral leg pain worse than low back pain • Pain radiates beyond knee • Paraesthesia in same distribution • Nerve irritation signs (reduced straight leg raising that reproduces leg pain) • Motor, sensory or reﬂex signs (limited to one or adjacent nerve roots) • Prognosis reasonable (50% recovery at 6 weeks) Cauda equina syndrome • Difﬁculty with micturition • Loss of anal sphincter tone or faecal incontinence • Saddle anaesthesia • Gait disturbance • Pain, numbness or weakness affecting one or both legs 24.21 Typical causes of neck pain Mechanical • Postural • Whiplash injury • Facet joint • Cervical spondylosis Inﬂammatory • Infections • Axial spondyloarthritis • Psoriatic arthritis • Rheumatoid arthritis • Polymyalgia rheumatica • Discitis Metabolic • Axial calcium pyrophosphate dihydrate disease • Fibrous dysplasia • Paget’s disease Neoplastic • Metastases • Myeloma • Lymphoma • Intrathecal tumours Other • Fibromyalgia • Torticollis Referred • Pharynx • Cervical lymph nodes • Teeth • Angina pectoris • Aortic aneurysm • Pancoast tumour • Diaphragm in spinal cord compression and in some patients with nerve root compression. Regional musculoskeletal pain Regional musculoskeletal pain is a common presenting complaint, usually occurring as the result of age-related degenerative disease of tendons and ligaments, OA and trauma. Neck pain Neck pain is a common symptom that can occur following an injury or falling asleep in an awkward position, as a result of stress or in association with OA of the spine. The causes are shown in Box 24.21. Most cases resolve spontaneously or with a short course of NSAIDs or analgesics and some exercise therapy. Patients with persistent pain that follows a nerve root distribution and those with upper or lower limb neurological signs should be investigated by MRI and, if necessary, referred for a neurosurgical opinion.

998 • RHEUMATOLOGY AND BONE DISEASE • Tenosynovitis: affects ﬂexor or extensor digital tendons. Pain and tenderness are well localised to the tendon lesions. There is often early-morning ‘claw-like’ digit stiffness. De Quervain’s tenosynovitis involves the tendon sheaths of abductor pollicis longus and extensor pollicis brevis. It produces pain maximal over the radial aspect of the distal forearm and wrist and marked pain on forced ulnar deviation of the wrist with the thumb held across the patient’s palm (Finkelstein’s sign). This test is not speciﬁc for this lesion alone. • Raynaud’s phenomenon: digital vasospasm triggered mostly by cold (p. 1035). • C6, C7 or C8 radiculopathy. • Carpal tunnel syndrome: hand position-dependent and/or nocturnal pain, numbness and paraesthesia of thumb and second to fourth digits. Hip pain Pain from the hip joint is usually felt deep in the groin, with variable radiation to the buttock, anterolateral thigh or knee (Fig. 24.13). Patients who report ‘hip pain’ sometimes point to greater trochanter or buttock areas. Greater trochanter pain syndrome is usually due to either gluteus medius insertional tendonitis/ enthesitis, trochanteric bursitis or referred pain (Box 24.24). Pain at this site may also be referred from the lumbosacral spine. A differential diagnosis of hip joint conditions (groin pain) is symphysitis (SpAs, including psoriasis disease, need ruling out). Other less common causes of pain in the hip/groin area include inguinal hernia, adductor tendonitis and enthesitis of anterior superior/inferior iliac spines. Knee pain In middle and older age, the most common cause of knee pain is OA, the features of which are described on page 1008. Pain that is associated with locking of the knee (sudden painful inability to extend fully) is usually due to a meniscal tear or osteochondritis dissecans. Referred pain from the hip may present at the knee and is reproduced by hip, not knee, movement. Pain from periarticular lesions is well localised to the involved structure (Box 24.25). Anterior knee pain may be due to patellar ligament or retinacular lesions (enthesitis, tendonitis, fat-pad syndrome) occurring typically Fig. 24.12 Pain patterns around the shoulder. The dark shading indicates sites of maximum pain. Rotator cuff and glenohumeral arthritis Acromioclavicular joint disease Bicipital tendinitis 24.23 Typical local causes of elbow pain Lesion Pain Examination ﬁndings Lateral humeral epicondylitis (e.g. traumatic ‘tennis elbow’ or SpA-related enthesitis) Lateral epicondyle Tenderness over epicondyle Radiation to extensor forearm Pain reproduced by resisted active wrist extension Medial humeral epicondylitis (e.g. traumatic ‘golfer’s elbow’ or SpA-related enthesitis) Medial epicondyle Tenderness over epicondyle Radiation to ﬂexor forearm Pain reproduced by resisted active wrist ﬂexion Olecranon bursitis (e.g. gout, rheumatoid arthritis or infective, as in tuberculosis) Olecranon Tender swelling (SpA = spondyloarthritis) 24.22 Clinical ﬁndings in shoulder pain Rotator cuff and subacromial lesions • Pain reproduced by resisted active movement: Abduction: supraspinatus External rotation: infraspinatus, teres minor Internal rotation: subscapularis Acromioclavicular joint • Pain on full abduction and adduction (at 90° of forward elevation) Bicipital (long head) tendinitis • Tenderness over bicipital groove • Pain reproduced by resisted active wrist supination or elbow ﬂexion less good in older people. Adhesive capsulitis (frozen shoulder) presents with pain associated with marked restriction of elevation and external rotation. Adhesive capsulitis is commonly associated with diabetes mellitus and neck/radicular lesions. Treatment in the early stage is with analgesia, intra- and extracapsular glucocorticoid injection, and regular ‘pendulum’ exercises of the arm to mobilise. Complete recovery sometimes takes up to 2 years. For severe or persistent symptoms, joint distension and manipulation under anaesthesia are surgical options. Elbow pain The most common causes are repetitive trauma causing lateral epicondylitis (tennis elbow) and medial epicondylitis (golfer’s elbow) (Box 24.23). SpAs, including psoriatic disease, can present with the same symptoms (tendon insertion enthesitis). Management is by rest, analgesics and topical or systemic NSAIDs. Local glucocorticoid injections may be required in resistant cases. Olecranon bursitis can also follow local repetitive trauma but other causes include infections and gout. Hand and wrist pain Pain from hand or wrist joints is well localised to the affected joint, except for pain from the ﬁrst carpometacarpal (CMC) joint, commonly targeted by OA or PsA; although maximal at the thumb base, the pain often radiates down the thumb and to the radial aspect of the wrist. Non-articular causes of hand pain include:

Presenting problems in musculoskeletal disease • 999

a manifestation of enthesitis. Pain affecting the back of the heel may be due to Achilles tendinitis or enthesitis. The MTP joints of the feet are commonly involved symmetrically in RA. The presentation is with pain on walking felt below the metatarsal heads, often described as ‘walking on marbles’. Patients with active inﬂammation of the MTP joints have pain when the forefoot is squeezed (p. 982). Involvement of the ﬁrst MTP joint is common in OA or PsA and is associated, respectively, with hallux valgus and dactylitis. The hallux also a classical target in acute gout. Morton’s neuroma is a neuropathy of an interdigital nerve and is usually located between the third and fourth metatarsal heads. Women are most commonly affected (tight shoes can be to blame). Local sensory loss and a palpable tender swelling between the metatarsal heads may be detected. Footwear adjustment, with or without a local glucocorticoid injection, often helps but surgical decompression may be required if symptoms persist. from overuse and/or an SpA condition. Anterior knee pain is relatively common in adolescents and may be the result of patellar articular cartilage or ligament insertion osteochondritis. Ankle and foot pain Pain from the ankle (tibiotalar) joint due to OA or osteochondral defect is felt between the malleoli and is worse on weight-bearing. Pain from the subtalar joint (from the same lesions) is also worse on weight-bearing. Inﬂammatory arthritis of either of these joints (RA, PsA, CPPD arthritis or gout) often worsens and swells with rest. These diagnoses can be associated with hindfoot tenosynovitis (peroneal or posterior tibial). Pain under the heel is typically due to plantar fasciitis. This can occur as the result of overuse, which case it may respond to rest, padded footwear and local glucocorticoid injections, but can also arise in SpA as Fig. 24.13 Pain patterns of hip disease and trochanteric pain syndrome. The dark shading indicates sites of maximum pain. Trochanteric bursitis Hip disease 24.24 Local causes of hip pain Lesion Pain Examination ﬁndings Gluteus medius enthesitis Upper lateral thigh, worse on lying on that side at night Tenderness over greater trochanter Trochanteric bursitis As above As above Adductor tendinitis (usually an SpA-enthesitis or sports-related trauma lesion) Upper inner thigh Tenderness over adductor origin/tendon/muscle Pain reproduced by resisted active hip adduction Ischiogluteal enthesitis/bursitis Buttock, worse on sitting Tenderness over ischial prominence Pubic symphysitis (can mimic intra-articular hip lesions) Medial groin pain, can radiate to inner or even outer upper thighs Tenderness over symphysis joint If pain is worse on trunk curl/rectus activation under symphysisresting hand, it may be insertional rectus enthesitis (SpAs) (SpA = spondyloarthritis) 24.25 Local causes of knee pain Lesion Pain Examination ﬁndings Pre-patellar bursitis Over patella Tender ﬂuctuant swelling in front of patella Superﬁcial and deep infrapatellar bursitis and fat-pad syndrome Anterior knee, inferior to patella Tenderness in front of (superﬁcial) or behind (deep) patellar tendon Pain on full ﬂexion Anserine bursitis/ enthesitis Upper medial tibia Tenderness (± swelling) over upper medial tibia Medial collateral ligament lesions (e.g. enthesitis) Upper medial tibia Localised tenderness of upper medial tibia Pain reproduced by valgus stress on partly ﬂexed knee Popliteal cyst (Baker’s cyst) Popliteal fossa Tender swelling of popliteal fossa Patellar ligament enthesopathy Anterior upper tibia Tenderness over tibial tubercle Osteochondritis of patellar ligament (Osgood–Schlatter disease) Anterior upper tibia Adolescents are affected Pain on resisted active knee extension

1000 • RHEUMATOLOGY AND BONE DISEASE serum and urine protein electrophoresis, serum ACE, ANAs/ ENAs, RF, complement and myositis-speciﬁc autoantibodies such as Jo-1. Open muscle biopsy (site guided by MRI detection of abnormal muscle) and electromyography (EMG) are usually required to make the diagnosis. The initial imaging screening for malignancy is usually a CT scan of the chest, abdomen and pelvis; upper gastrointestinal endoscopy and colonoscopy may also be considered. Management Management is determined by the cause but all patients with muscle disease should beneﬁt from physiotherapy and graded exercises to maximise muscle function after the initial inﬂammation is controlled. Principles of management The management of rheumatological disorders should be tailored to the underlying diagnosis. Certain aspects are common to many disorders, however, and the general principles are discussed here. The therapeutic aims are: • to educate patients about their disease • to control pain, if it is present • to optimise function • to modify the disease process where this is possible • to identify and treat comorbidity. These aims are interrelated and success in one area often benefits others. Successful management requires careful assessment of the person as a whole. The management plan should be individualised and patient-centred, should involve relevant members of the multidisciplinary team, and should be agreed and understood by both the patient and all the practitioners that are involved. It must also take into account: • the patient’s activity requirements and occupational and recreational aspirations • risk factors that may inﬂuence the disease • the patient’s perceptions and knowledge of the condition • medications and coping strategies that have already been tried • comorbid disease and its therapy • the availability, costs and logistics of appropriate evidencebased interventions. The simplest and safest interventions should be tried ﬁrst. Symptoms and signs may change with time, so the management plan for most patients will require regular review and re-adjustment. Core interventions that should be considered for everyone with a painful musculoskeletal condition are listed in Box 24.27. There are also other non-pharmacological and drug options, the choice of which depends on the nature and severity of the diagnosis. Education and lifestyle interventions Education Patients must always be informed about the nature of their condition and its investigation, treatment and prognosis, since education can improve outcome. Information and therapist contact can reduce pain and disability, improve self-efﬁcacy and reduce the health-care costs of many musculoskeletal conditions, including OA and RA. The mechanisms are unclear but in part may result from improved adherence. Beneﬁts are modest but potentially long-lasting, safe and cost-effective. Education can be provided through one-to-one discussion, written literature, Muscle pain and weakness Muscle pain and weakness can arise from a variety of causes. It is important to distinguish between a subjective feeling of generalised weakness occurring with fatigue, and an objective weakness with loss of muscle power and function. The former is a non-speciﬁc manifestation of many systemic conditions. Clinical assessment Proximal muscle weakness suggests the presence of a myopathy or myositis, which typically causes difﬁculty with standing from a seated position, walking up steps, squatting and lifting overhead. The causes are shown in Box 24.26. Worsening of symptoms on exercise and post-exertional cramps suggest a metabolic myopathy, such as glycogen storage disease (p. 370). A strong family history and onset in childhood or early adulthood suggest muscular dystrophy (p. 1143). Alcohol excess can cause an inﬂammatory myositis and atrophy of type 2 muscle ﬁbres. Proximal myopathy may be a complication of glucocorticoid therapy, prolonged/severe hypercalcaemia and osteomalacia. Myopathy and myositis can also occur in association with many drugs (see ‘Further information’, p. 1060) and viral infections, including HIV; in the latter case, it may be due to HIV itself or to treatment with zidovudine. Polymyositis and dermatomyositis (p. 1039) are associated with coexisting/ co-presenting malignancy, especially gonadal tumours. Clinical examination should document the presence, pattern and severity of muscle weakness (p. 1081), assessed using the Medical Research Council (MRC) scale (no power (0) to full power (5)). Investigations Investigations should include routine biochemistry and haematology, ESR, CRP, creatine kinase, serum 25(OH)-vitamin D, PTH, parvovirus, hepatitis B/C, HIV and streptococcus serology, 24.26 Causes of proximal muscle pain or weakness Inﬂammatory • Polymyositis • Dermatomyositis • Other autoimmune connective tissue disease • Inclusion body myositis • Sarcoid • Myasthenia gravis Endocrine (Ch. 18) • Hypothyroidism • Hyperthyroidism • Cushing’s syndrome • Addison’s disease Metabolic (Ch. 14) • Myophosphorylase deﬁciency • Phosphofructokinase deﬁciency • Hypokalaemia • Carnitine deﬁciency • Osteomalacia (p. 1049) • Hypercalcaemia Genetic • Muscular dystrophy (various; p. 1143) Drugs/toxins • Alcohol • Cocaine • Glucocorticoids • Statins and ﬁbrates • Tumour necrosis factor inhibitors • Zidovudine Infections (Ch. 11) • Viral (HIV, cytomegalovirus, rubella, Epstein–Barr, echo) • Parasitic (schistosomiasis, cysticercosis, toxoplasmosis) • Bacterial (Clostridium perfringens, staphylococci, tuberculosis, Mycoplasma)

Principles of management • 1001

Hydrotherapy induces muscle relaxation and facilitates enhanced movement in a warm, pain-relieving environment without the restraints of gravity and normal load-bearing. Various manipulative techniques may also help improve restricted movement. The combination of these with education and therapist contact enhances their beneﬁts. Splints can give temporary rest and support for painful joints and periarticular tissues, and can prevent harmful involuntary postures during sleep. Prolonged rest must be avoided, however. Orthoses are more permanent appliances used to reduce instability and excessive abnormal movement. They include working wrist splints, knee orthoses, and iron and T-straps to control ankle instability. Orthoses are particularly suited to severely disabled patients in whom a surgical option is inappropriate and often need to be custom-made for the individual. Aids and appliances can provide dignity and independence for patients with respect to activities of daily living. Common examples are a raised toilet seat, raised chair height, extended handles on taps, a shower instead of a bath, thick-handled cutlery, and extended ‘hands’ to pull on tights and socks. Full assessment and advice from an occupational therapist maximise the beneﬁts of these (Box 24.27). Self-help and coping strategies These help patients to cope better with, and adjust to, chronic pain and disability. They may be useful at any stage but are particularly so for patients with incurable problems, who have tried all available treatment options. The aim is to increase self-management through self-assessment and problem-solving, so that patients can recognise negative but potentially remediable aspects of their mood (stress, frustration, anger or low self-esteem) and their situation (physical, social, ﬁnancial). These may then be addressed by changes in attitude and behaviour, as shown in Box 24.28. Involvement of the spouse or partner in mutual goal-setting can improve partnership adjustment. Such approaches are often an element of group education classes and pain clinics but may require more formal clinical psychological input. Tailored multidisciplinary approaches are required for patients with JIA and other chronic childhood diseases, dependent on age and maturity. Adolescents and young adults have speciﬁc demands, different to those of young children and adults, which are inﬂuenced by many issues in their lives impinging on the disease process, its impact and their ability to cope with it. Weight control Obesity aggravates pain at most sites through increased mechanical strain and is a risk factor for progression of joint damage in patients with OA and other types of arthritis. This should be explained to obese patients and strategies offered patient-led group education classes and interactive computer programs. Inclusion of the patient’s partner or carer is often appropriate; this is essential for childhood conditions but also helps in many chronic adult conditions, such as RA and FM. For children and adolescents with chronic diseases such as JIA, education and support of the whole family, schooling and psychological support is essential and best delivered through a multidisciplinary team. Exercise Several types of exercise can be prescribed: • Aerobic ﬁtness training can produce long-term reduction in pain and disability. It improves well-being, encourages restorative sleep and beneﬁts common comorbidity, such as obesity, diabetes, chronic heart failure and hypertension. • Local strengthening exercise for muscles that act over compromised joints also reduces pain and disability, with improvements in the reduced muscle strength, proprioception, coordination and balance that associate with chronic arthritis. ‘Small amounts often’ of strengthening exercise are better than protracted sessions performed infrequently. • Weight-bearing exercise is of value in osteoporosis, where it can result in modest increases in bone density and slow bone loss. Joint protection Excessive impact-loading and adverse repetitive use of a compromised joint or periarticular tissue can worsen symptoms in patients with arthritis. This can be mitigated by cessation of contact sports and by pacing of activities by dividing physical tasks into shorter segments with brief breaks in between. Other strategies include adaptations to machinery or tools at the workplace; the use of shock-absorbing footwear with thick soft soles, which can reduce impact-loading through feet, knees, hips and back; and the use of a walking stick on the contralateral side to a painful hip, knee or foot. Non-pharmacological interventions Physical and occupational therapy Local heat, ice packs, wax baths and other local external applications can induce muscle relaxation and provide temporary relief of symptoms in a range of rheumatic diseases. 24.27 Interventions for patients with rheumatic diseases Core interventions • Education • Aerobic conditioning • Muscle strengthening • Simple analgesics • Disease-modifying therapy • Reduction of adverse mechanical factors • Pacing of activities • Appropriate footwear • Weight reduction if obese Other options • Other analgesic drugs: Oral non-steroidal anti-inﬂammatory drugs Topical agents Opioid analgesics Amitriptyline Gabapentin/pregabalin • Local glucocorticoid injections • Physical treatments: Heat, cold, aids, appliances • Surgery • Coping strategies (see Box 24.28) 24.28 Self-help and coping strategies • Yoga and relaxation techniques to reduce stress • Avoidance of negative situations or activities that produce stress and increase in pleasant activities that give satisfaction • Information and discussion to alter beliefs about and perspectives on disease • Reduction or avoidance of catastrophising and maladaptive pain behaviour • Imagery and distraction techniques for pain • Expansion of social contact and better use of social services

1002 • RHEUMATOLOGY AND BONE DISEASE therapy and intra-articular injections have provided insufﬁcient relief. The main approaches for damaged joints are osteotomy (cutting bone to alter joint mechanics and load transmission), excision arthroplasty (removing part or all of the joint), joint replacement (insertion of prosthesis in place of the excised joint) and arthrodesis (joint fusion). Surgical ﬁxation of fractures is frequently required in patients with osteoporosis and other bone diseases. The main aims of surgery are to provide pain relief and improve function and quality of life. If surgery is to be successful, the aims and consequences of each operation should be considered as part of an integrated programme of management and rehabilitation by multidisciplinary teams of surgeons, allied health professionals and physicians, and carefully explained to the patient. Assessment of motivation, social support and environment is no less important than careful consideration of patients’ general health, their risks for major surgery, the extent of disease in other joints, and their ability to mobilise following surgery. For some severely compromised people, pain relief and functional independence are better served by provision of a suitable wheelchair, home adjustments and social services than by surgery that is technically successful but following which the patient cannot mobilise. Pharmacological treatment Analgesics Paracetamol (1 g up to 4 times daily) is the oral analgesic of ﬁrst choice for mild to moderate pain. It is thought to work by inhibiting prostaglandin synthesis in the brain while having little effect on peripheral prostaglandin production. It is well tolerated and has few adverse effects and drug interactions. An increased risk of gastrointestinal events and cardiovascular disease has been reported with chronic usage in observational studies, but this may be due to channelling of patients at higher risk of these events for treatment with paracetamol rather than NSAID. Paracetamol can be combined with codeine (co-codamol) or dihydrocodeine (co-dydramol). These compound analgesics are more effective than paracetamol but have more side-effects, including constipation, headache and delirium, especially in the elderly. The centrally acting opioid analgesics tramadol and meptazinol may be useful for temporary control of severe pain unresponsive to other measures but can cause nausea, bowel upset, dizziness and somnolence, and withdrawal symptoms after chronic use. The non-opioid analgesic nefopam (30–90 mg 3 times daily) can help moderate pain, though side-effects (nausea, anxiety, dry mouth) often limit its use. Patients with severe or intractable pain may require strong opioid analgesics, such as oxycodone and morphine. Non-steroidal anti-inﬂammatory drugs NSAIDs are among the most widely prescribed drugs but their use has declined over recent years because long-term prescription is associated with an increased risk of cardiovascular disease. Oral NSAIDs are useful in the treatment of a range of rheumatic diseases with an inﬂammatory component. There is variability in response and patients who do not gain beneﬁt from one NSAID may well do so with another. They inhibit the cyclo-oxygenase (COX) and prostaglandin H synthase enzymes, which convert arachidonic acid, derived from membrane phospholipids, to prostaglandins and leukotrienes by the COX and 5-lipoxygenase pathways, respectively (Fig. 24.14). There are two COX isoforms, on how to lose and maintain an appropriate weight (p. 700). Excessive weight loss can be counterproductive and adults with a BMI of < 20 kg/m2 are at increased risk of fractures. Patients should therefore be advised to maintain BMI within the 20–25 g/m2 range. Surgery A variety of surgical interventions can relieve pain and conserve or restore function in patients with bone, joint and periarticular disease (Box 24.29). Soft tissue release and tenosynovectomy can reduce inflammatory symptoms, improve function and prevent or retard tendon damage for variable periods, sometimes indeﬁnitely. Synovectomy does not prevent disease progression but may be indicated for pain relief when drugs, physical 24.29 Surgical procedures in rheumatology and bone disease Procedure Indication Soft tissue release Carpal tunnel Median nerve compression Tarsal tunnel Posterior tibial nerve entrapment Flexor tenosynovectomy Relief of ‘trigger’ ﬁngers Ulnar nerve transposition Ulnar nerve entrapment at elbow Fasciotomy Severe Dupuytren’s contracture Tendon repairs and transfers Hand extensor tendons Extensor tendon rupture Thumb and ﬁnger ﬂexor tendons Flexor tendon rupture Synovectomy Wrist and extensor tendon sheath (+ excision of radial head) Pain relief and prevention of extensor tendon rupture in RA, resistant inﬂammatory synovitis Knee synovectomy Resistant inﬂammatory synovitis Osteotomy Femoral osteotomy Early OA of hip Tibial osteotomy Unicompartmental knee OA Deformed tibia in OA or Paget’s disease Excision arthroplasty First metatarsophalangeal joint (Keller’s procedure) Painful hallux valgus Radial head Painful distal radio-ulnar joint Lateral end of clavicle Painful acromioclavicular joint Metatarsal head Painful subluxed metatarsophalangeal joints Joint replacement arthroplasty Knee, hip, shoulder, elbow Painful damaged joints in OA and RA Arthrodesis Wrist Damaged joint: pain relief, improvement of grip Ankle/subtalar joints Damaged joint: pain relief, stabilisation of hindfoot Fracture repair Hip arthroplasty Fractured neck of femur External ﬁxation Multiple fractures, open fractures Intramedullary nailing Tibial and femur fractures Screw, plating and wiring Wrist and other fractures Other procedures Nerve root decompression Spinal stenosis, nerve entrapment Kyphoplasty Painful vertebral fracture (evidence base poor) Vertebroplasty Painful vertebral fracture (evidence base poor)

Principles of management • 1003

non-ulcer-associated dyspepsia, abdominal pain and altered bowel habit, and rashes. Interstitial nephritis, asthma and anaphylaxis can also occur but are rare. Recommendations for NSAID prescribing are summarised in Box 24.32. Because of the risk of adverse effects, NSAIDs should be used with great care in the elderly (Box 24.33). Topical agents Topical NSAID creams and gels and capsaicin cream (chilli extract; 0.025%) can help in the treatment of OA and superﬁcial periarticular lesions affecting hands, elbows and knees. They may be used as monotherapy or as an adjunct to oral analgesics. Topical NSAIDs can penetrate superficial tissues and even encoded by different genes. The COX-1 enzyme is constitutively expressed in gastric mucosa, platelets and kidneys, and production of prostaglandins at these sites protects against mucosal damage and regulates platelet aggregation and renal blood ﬂow. The COX-2 enzyme is induced at sites of inﬂammation, producing prostaglandins that cause local pain and swelling. Inﬂammation also up-regulates COX-2 in the spinal cord, where it modulates pain perception. Ibuprofen, diclofenac and naproxen are non-selective drugs that inhibit both COX enzymes, whereas celecoxib and etoricoxib are selective inhibitors of COX-2. While NSAIDs have anti-inﬂammatory activity, they are not thought to have a disease-modifying effect in either OA or inﬂammatory rheumatic diseases. Non-selective NSAIDs can damage the gastric and duodenal mucosal barrier and are associated with an increased risk of upper gastrointestinal ulceration, bleeding and perforation. The adjusted increased risk (odds ratio) of bleeding or perforation from non-selective NSAIDs is 4–5, though differences exist between NSAIDs (Box 24.30). Dyspepsia is a poor guide to the presence of NSAID-associated ulceration and bleeding, and the principal risk factors are shown in Box 24.31. Co-prescription of a proton pump inhibitor (PPI) or misoprostol (200 μg twice or 3 times daily) reduces the risk of NSAID-induced ulceration and bleeding but H2-antagonists in standard doses are ineffective. The COX-2 selective NSAIDs are much less likely to cause gastrointestinal toxicity but beneﬁt is attenuated in patients on low-dose aspirin. The National Institute for Health and Care Excellence (NICE) guidelines advise that a PPI should be co-prescribed with all NSAIDs, including COX-2-selective NSAIDs, even though the risk of gastrointestinal events with these is low. Since chronic PPI therapy is associated with an increased risk of hip fracture, the merits of giving PPI therapy with a COX-2-selective drug need to be weighed up carefully. Other side-effects of NSAIDs include ﬂuid retention and renal impairment due to inhibition of renal prostaglandin production, Fig. 24.14 Mechanism of action of non-steroidal anti-inﬂammatory drugs. Membrane phospholipid Arachidonic acid Phospholipase A2 COX-2 (induced by cytokines) Prostaglandins Non-selective NSAID COX-1 (constitutive expression) Prostaglandins Pain Inflammation Mucosal integrity Platelet aggregation Renal blood flow COX-2 selective NSAID The most important risk factors. 24.31 Risk factors for NSAID-induced ulcers • Age > 60 years • Past history of peptic ulcer* • Past history of adverse event with NSAID • Concomitant glucocorticoid use • High-dose or multiple NSAIDs • High-risk NSAID (see Box 24.30) 24.32 Recommendations for the use of NSAIDs • Use the lowest dose for the shortest time possible to control symptoms • Avoid NSAIDs in patients on warfarin • Allow 2–3 weeks to assess efﬁcacy. If response is inadequate, consider a trial of another NSAID • Never prescribe more than one NSAID at a time • Co-prescribe a proton pump inhibitor for patients with risk factors for gastrointestinal adverse effects (see Box 24.31) • Avoid in patients with vascular disease Drug Daily adult dose Doses/ day Idiosyncratic side-effects, comments Low risk Celecoxib 100–200 mg 1–2 Selective COX-2 inhibitor Etoricoxib 60–120 mg

Selective COX-2 inhibitor Medium risk Ibuprofen 1600–2400 mg Gastrointestinal adverse effects more likely than with COX-2 inhibitors, even with PPI therapy Naproxen 500–1000 mg Diclofenac 75–150 mg 3–4 1–2 2–3 High risk Indometacin 50–200 mg 3–4 High incidence of dyspepsia and CNS side-effects Ketoprofen 100–200 mg 2–4 Piroxicam 20–30 mg 1–2 Restricted use in those

60 years } } 24.30 Commonly used NSAIDs and their risk of gastrointestinal bleeding and perforation (CNS = central nervous system; COX = cyclo-oxygenase; PPI = proton pump inhibitor)

1004 • RHEUMATOLOGY AND BONE DISEASE Methotrexate Methotrexate (MTX) is the core DMARD in RA, JIA and PsA. It inhibits folic acid reductase, preventing formation of tetrahydrofolate, which is necessary for DNA synthesis in leucocytes and other cells. It is given orally in a starting dose of 10–15 mg weekly and escalated in 2.5 mg increments every 2–4 weeks to a maximum of 25 mg weekly until beneﬁt or toxicity occurs. Folic acid (5 mg/week) should be co-prescribed to be taken the day after MTX since it reduces adverse effects without impairing efﬁcacy. Beneﬁt is usually observed after 4–8 weeks but treatment should continue for 3 weeks before the conclusion is reached that MTX has been ineffective. The most common adverse effects are nausea, vomiting and malaise, which usually occur one 1–2 days after the weekly dose. Individuals who experience these effects can sometimes be successfully treated with subcutaneous MTX. Patients should be warned of drug interaction with sulphonamides and the importance of avoiding excess alcohol, which enhances MTX hepatotoxicity. Acute pulmonary toxicity (pneumonitis) is rare but can occur at any time during treatment, and patients should be warned to stop therapy and seek advice if they develop any new respiratory symptoms. If pneumonitis occurs, treatment should be withdrawn and high-dose glucocorticoids given. MTX must be co-prescribed with robust contraception in women of child-bearing potential and treatment must be stopped for 3 months in advance of planning a pregnancy. Sulfasalazine Sulfasalazine (SSZ) can be used alone and or combination with MTX and another DMARD. Its mechanism of action is incompletely understood. Nausea and gastrointestinal intolerance are the main adverse effects but leucopenia, abnormal LFTs and rashes may also occur. The usual starting dose is 500 mg daily, escalating in 500 mg increments every 2 weeks to a maintenance dose of 2–4 g daily until beneﬁt or toxicity occurs. Beneﬁt may be reach the joint capsule, though intrasynovial levels mainly reﬂect blood-borne drug delivery. Capsaicin selectively binds to the protein transient receptor potential vanilloid type 1 (TRPV1), which is a heat-activated calcium channel on the surface of peripheral type C nociceptor ﬁbres. Initial application causes a burning sensation but continued use depletes presynaptic substance P, with subsequent pain reduction that is optimal after a period of 1–2 weeks. Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs (DMARDs) are a group of small-molecule inhibitors of the immune response. They are employed in a range of inﬂammatory rheumatic diseases, as well as in other chronic inﬂammatory conditions. The most common indications are summarised in Box 24.34. Most of these drugs have the potential to cause bone marrow suppression or liver dysfunction and they require regular blood monitoring. Monitoring requirements for commonly used DMARDs are also summarised in Box 24.34. If toxicity occurs, treatment may need to be stopped temporarily and resumed at a lower dose. If toxicity is severe, therapy may have to be withdrawn completely and another drug substituted. 24.33 Use of oral NSAIDs in old age • Gastrointestinal complications: age is a strong risk factor for bleeding and perforation, and for peptic ulceration. Elderly patients are more likely to die if they suffer NSAID-associated bleeding or perforation. • Cardiovascular disease: use NSAIDs with caution in patients with cardiovascular disease. Therapy with NSAIDs may exacerbate hypertension and heart failure. • Renal disease: use of NSAIDs may cause renal impairment. 24.34 Disease-modifying antirheumatic drugs Drug Maintenance dose Monitoring* Indications FBC LFTs Other Methotrexate 10–25 mg weekly orally ᅚ ᅚ RA, PsA, AxSpA, JIA Sulfasalazine 2–4 g daily orally ᅚ ᅚ RA, PsA, AxSpA, JIA Hydroxychloroquine 200–400 mg daily orally – – Visual function RA, SLE Leﬂunomide 10–20 mg daily orally ᅚ ᅚ BP RA, JIA, PsA Azathioprine 1–2.5 mg/kg daily orally ᅚ ᅚ SLE, SV Apremilast 30 mg twice daily orally – – – PsA Tofacitinib 5 mg twice daily orally ᅚ ᅚ Infection RA Baricitinib 2–4 mg daily orally ᅚ ᅚ Infection RA Cyclophosphamide 2 mg/kg daily orally 15 mg/kg IV ᅚ ᅚ eGFR SLE, SV Mycophenolate mofetil (MMF) 2–4 g daily orally ᅚ ᅚ – SLE, SV Gold (myocrisin) 50 mg 4-weekly IM ᅚ – Urinalysis RA Penicillamine 500–1500 mg daily orally ᅚ ᅚ Urinalysis RA Ciclosporin A 3–5 mg/kg daily orally – – BP, eGFR RA, PsA *Monitoring tests are usually done every 2 weeks on initiation of treatment for 6 weeks, then monthly for 3 months, then 3-monthly. (AxSpA = axial spondyloarthritis; BP = blood pressure; eGFR = estimated glomerular ﬁltration rate; FBC = full blood count; IM = intramuscular; IV = intravenous; JIA = juvenile idiopathic arthritis; LFTs = liver function tests; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SV = systemic vasculitis)

Principles of management • 1005

vasculitis and SLE. It can be given orally in a dose of 2 mg/kg/ day for 3–6 months or intravenously in a dose of 15 mg/kg every 3–4 weeks on 6–8 occasions. Adverse effects include nausea, anorexia, vomiting, bone marrow suppression, cardiac toxicity, alopecia and haemorrhagic cystitis. The risk of cystitis can be mitigated by co-administration of mesna (2-mercaptoethane sulfonate, which binds its urotoxic metabolites) and a high ﬂuid intake. Mycophenolate mofetil Mycophenolate mofetil (MMF) works by inhibiting inosine monophosphate dehydrogenase, a rate-limiting enzyme in the synthesis of guanosine nucleotides in lymphocytes. MMF is frequently used in SLE and vasculitis in doses of 2–4 g daily orally. Haematological toxicity is the main adverse effect. Other DMARDs Gold, penicillamine and ciclosporin A have been superseded by more effective alternatives but are still occasionally used. Gold (sodium aurothiomalate, myocrisin) is indicated for RA. Its mechanism of action is unknown. It is given by intramuscular injection of 50 mg weekly after an initial test dose of 10 mg. Treatment is continued for up to 6 months until there is clinical beneﬁt or adverse effects occur. If there is beneﬁt, the frequency of injections is reduced to two-weekly and then monthly, providing that the response is maintained. Penicillamine is indicated for RA but is poorly tolerated. It is given in a starting dose of 125–250 mg daily on an empty stomach, and increased in 125 mg increments every 6 weeks to a maximum dose of 1500 mg daily until there is clinical beneﬁt or adverse effects occur. Ciclosporin A is a calcineurin inhibitor that inhibits lymphocyte activation. It is occasionally used in RA at a dose of 2.5–4 mg/kg/day orally. Glucocorticoids Glucocorticoids have powerful anti-inflammatory and immunosuppressive effects. They promote apoptosis of many immune cells and activation of a wide range of pro-inﬂammatory signalling pathways. They are used orally, intravenously, intramuscularly and by intra-articular injection in the treatment of a wide range of inﬂammatory rheumatic diseases, as well as by local injection in patients with soft tissue rheumatism (p. 1026). Systemic glucocorticoids Systemic glucocorticoids are widely used in moderate to high doses to induce remission in early RA and in systemic and polyarticular JIA. They are also used at lower doses for maintenance therapy and in the treatment of ﬂares in RA, PsA and axSpA with peripheral joint involvement. Glucocorticoids should be used with caution in PsA because of a rebound increase in activity of psoriasis when the effects wear off. Glucocorticoids are also used to induce remission and to maintain disease control in giant cell arteritis, polymyalgia rheumatica, vasculitis and SLE. Intra-articular and intramuscular glucocorticoids Intra-articular glucocorticoids are employed in the treatment of a wide range of inﬂammatory arthritides and are primarily indicated when there are one or two problem joints with persistent synovitis despite good general control of the disease. Methylprednisolone is one of the most widely used, typically in doses of 40–80 mg. Intramuscular methylprednisolone (80–120 mg) is a useful way of controlling inﬂammatory arthritis while waiting for the effects of a newly introduced DMARD to take effect, and is also helpful observed after 4–8 weeks but treatment should be continued for 3 months before the conclusion is reached that it has been ineffective. Orange staining of urine and contact lenses may occur. Hydroxychloroquine Hydroxychloroquine (HCQ) is used in the treatment of RA and SLE in a dose of 200–400 mg daily. Its mechanism of action is incompletely understood. A wide range of side-effects can potentially occur but HCQ is usually well tolerated in practice. With long-term use, there is a risk of ocular toxicity due to accumulation in the retina, although this is uncommon. It is usual to check visual function before starting treatment and to repeat this periodically while treatment is continued. HCQ is generally considered to be safe during pregnancy Leﬂunomide Leﬂunomide can be used alone or in combination with other drugs in a dose of 10–20 mg/day. It works by inhibiting dihydro-orotate dehydrogenase, an enzyme used by activated lymphocytes to synthesise pyrimidines necessary for DNA synthesis. It has low marrow toxicity but may cause liver dysfunction, hypertension and hirsutism. It must be co-prescribed with robust contraception in women of child-bearing potential. Treatment must be stopped for a period of 2 years in advance of planning a pregnancy. Azathioprine Azathioprine is most commonly used in vasculitis and SLE. It is metabolised to 6-mercaptopurine (6-MP), which blocks lymphocyte proliferation by inhibiting DNA synthesis. The typical starting dose is 1 mg/kg body weight per day, increasing to 2.5 mg/kg until a response is observed or toxicity occurs. Bone marrow suppression is the most important side-effect but nausea may also occur. Genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) inﬂuence catabolism of 6-MP and sometimes genetic testing for TPMT variants is done to guide dosages. Allopurinol inhibits catabolism of azathioprine, necessitating a 75% reduction in azathioprine dose. Apremilast Apremilast is used in the treatment of PsA. It works by inhibiting phosphodiesterase D4 in leucocytes, which in turn suppresses production of pro-inﬂammatory cytokines, thereby reducing inﬂammation. Apremilast is given orally in a dose of 30 mg twice daily. The main adverse effects are gastrointestinal upset, weight loss and an increased risk of depression. Janus-activated kinase inhibitors Janus-activated kinase (JAK) inhibitors work by inhibiting JAK enzymes, which are a family of intracellular signalling molecules that play a key role in transducing the effects of several proinﬂammatory cytokines. They are indicated for patients with RA who have responded inadequately to standard DMARDs and provide an alternative to biologic treatments. Two JAK inhibitors are currently available: tofacitinib, which is given orally in a dose of 5 mg twice daily, and baricitinib, which is given orally in a dose of 2–4 mg once daily. The main adverse effects are an increased risk of opportunistic infections, hepatotoxicity and haematological toxicity. Cyclophosphamide Cyclophosphamide is a cytotoxic alkylating agent that cross-links DNA and halts cell division, causing immunosuppression. It is mainly used to induce remission in life-threatening systemic

1006 • RHEUMATOLOGY AND BONE DISEASE in AxSpA unless there is peripheral joint involvement. Anti-TNF therapy is contraindicated in patients with active infections such as untreated tuberculosis and those with indwelling catheters, due to the high risk of infection. Other contraindications are severe heart failure and multiple sclerosis, both of which may be worsened by treatment. Rituximab Rituximab is an antibody directed against the CD20 receptor, which is expressed on B lymphocytes and immature plasma cells. It causes profound B-cell lymphopenia for several months due to complement-mediated lysis of cells that express CD20. Rituximab is indicated in patients with RA who have not responded adequately to ﬁrst-line therapy but is typically employed as a third-line treatment when TNF inhibitors have been ineffective. It is also used in place of cyclophosphamide to induce remission in patients with ANCA-positive vasculitis. In RA, the treatment can be repeated when signs of improvement are wearing off (anything from 6 months to 1 year or longer). In ANCA-positive vasculitis, a single cycle of treatment may last for up to 18 months. Rituximab is sometimes used off-label in SLE, even though clinical trials did not show efﬁcacy. Adverse effects include hypogammaglobulinaemia, infusion reactions, an increased risk of infections and, rarely, progressive multifocal leucoencephalopathy (PML; p. 1123), a serious and potentially fatal infection of the CNS caused by reactivation of JC virus. Belimumab Belimumab is indicated in SLE. It is a monoclonal antibody that blocks the effects of the cytokine B-cell-activating factor of the TNF family (BAFF), which is required for B-cell survival and function. It is usually given when patients have had an inadequate response to glucocorticoids and hydroxychloroquine. The main in patients with stable disease who have a disease ﬂare where a major change in DMARD strategy is not thought to be necessary. Biologics The term ‘biologic’ refers to a group of medications that includes monoclonal antibodies, fusion proteins and decoy receptors, which are used in the treatment of several inﬂammatory rheumatic diseases. They are targeted towards speciﬁc cytokines, receptors and other cell-surface molecules regulating the immune response (Fig. 24.15). The main adverse effect of the biologics used in inflammatory diseases is an increased risk of infections. Biologics are not carcinogenic, but patients who develop cancer while on treatment may exhibit accelerated progression of the tumour due to suppression of the immune response. Treatment costs are much higher than with DMARDs and many countries have set guidelines restricting their use to patients who have active disease despite having had an adequate trial of standard therapies. Their mechanisms of action, dosages and indications are summarised in Box 24.35. Anti-TNF therapy A variety of inhibitors of the pro-inﬂammatory cytokine TNF have been developed. Most are monoclonal antibodies that bind to and neutralise TNF, but etanercept is a decoy receptor that prevents TNF binding to its receptor. Anti-TNF therapy has traditionally been used as the ﬁrst-line biological drug in RA when DMARD therapy has been incompletely effective. It has also traditionally been used as the ﬁrst-line biologic in PsA and AxSpA, but anti IL-17A therapy (see below) has emerged as an equally effective alternative. Anti-TNF therapy is usually co-prescribed with MTX in RA and PsA as this increases efﬁcacy, but TNF inhibitors are also effective as monotherapy. They are usually given as monotherapy Fig. 24.15 Targets for biologic therapies in inﬂammatory rheumatic diseases. Biologic treatments for inﬂammatory rheumatic diseases work by targeting key cytokines and other molecules involved in regulating the immune response. See page 64 for more details. (BAFF = B-cell-activating factor of the TNF family; CD = cluster of differentiation; IL = interleukin; TNF-α = tumour necrosis factor alpha; TNFi = inhibitor of tumour necrosis factor) T cell B cell Autoantibodies Plasma cell TNF-α IL-6 IL-1 Synovial fibroblast Dendritic cell CD80 IL-12 IL-23 IL-17 CD28 CD20 Activation Proliferation Proliferation BAFF Belimumab Rituximab Tocilizumab Anakinra Canakinumab TNFi Secukinumab Abatacept Ustekinumab Th17 cell Macrophage

Osteoarthritis • 1007

} Drug Maintenance dose Mechanism of action Indications Etanercept 50 mg weekly SC Decoy receptor for TNF-α RA, PsA, AxSpA, JIA Inﬂiximab 3–5 mg/kg 8-weekly IV Antibody to TNF-α RA, PsA, AxSpA, JIA Adalimumab 40 mg 2-weekly SC Certolizumab 200 mg 2-weekly SC Golimumab 50 mg 4-weekly SC Rituximab 2 × 1 g 2 weeks apart IV Antibody to CD20; destroys B cells RA, vasculitis Belimumab 10 mg/kg 4-weekly IV Antibody to BAFF; inhibits B-cell activation SLE Abatacept 125 mg weekly SC or 10 mg/kg 4-weekly IV Inhibits T-cell activation RA Tocilizumab 162 mg weekly SC or 8 mg/kg 8-weekly IV Blocks IL-6 receptor RA, JIA Ustekinumab 45 mg 12-weekly SC Antibody to IL-12 and IL-23 PsA Secukinumab 150 mg 4-weekly SC Antibody to IL-17A PsA, AxSpA Anakinra 100 mg daily SC Decoy receptor for IL-1 RA, CAPS, AOSD Canakinumab 150 mg or 2 mg/kg 8-weekly SC Antibody to IL-1β CAPS, sJIA, AOSD, gout 24.35 Biological drugs for inﬂammatory rheumatic disease (AOSD = adult-onset Still’s disease; AxSpA = axial spondyloarthritis; BAFF = B-cell-activating factor of the TNF family; CAPS = cryopyrin-associated periodic syndromes; CD = cluster of differentiation; IL = interleukin; IV = intravenous; JIA = juvenile idiopathic arthritis; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SC = subcutaneous; sJIA = systemic juvenile inﬂammatory arthritis; SLE = systemic lupus erythematosus; TNF-α = tumour necrosis factor alpha) An exception is when patients are MTX-intolerant, in which case it is often used as a ﬁrst-line therapy, based on a randomised trial in which it showed greater efﬁcacy than the TNF inhibitor adalimumab. Adverse effects include leucopenia, abnormal LFTs, hypercholesterolaemia, hypersensitivity reactions and an increase risk of diverticulitis. Ustekinumab Ustekinumab is an antibody to the p40 protein, which is a subunit of IL-23 and IL-12. It is indicated in patients with PsA who have not responded adequately to ﬁrst-line therapy with other biologics. Adverse effects include an increased risk of infections, hypersensitivity reactions and an exfoliative dermatitis. Secukinumab Secukinumab is a monoclonal antibody to IL-17A. It is indicated in patients with PsA and axSpA, including ankylosing spondylitis, and who have not responded adequately to ﬁrst-line therapy. Adverse effects include an increased risk of infections, nasopharyngitis and headache. Anakinra Anakinra is a decoy receptor for IL-1. It is occasionally used in RA but is less effective than other biological drugs. A more frequent indication is for the treatment of adult-onset Still’s disease (p. 1040) and in cryopirin-associated periodic syndromes (p. 81). Adverse effects include an increased risk of infections, hypersensitivity reactions and neutropenia. Canakinumab Canakinumab is indicated for the treatment of systemic JIA (Still’s disease), adult-onset Still’s disease, familial fever syndromes and acute ﬂares of gout resistant to other treatments. It is a monoclonal antibody directed against the pro-inﬂammatory cytokine IL-1β. The usual maintenance dose in adults is 150–300 mg SC every 8 weeks. Adverse effects include an increased risk of infections, hypersensitivity reactions and neutropenia. Osteoarthritis Osteoarthritis (OA) is by far the most common form of arthritis and is a major cause of pain and disability in older people. It is characterised by focal loss of articular cartilage, subchondral osteosclerosis, osteophyte formation at the joint margin, and remodelling of joint contour with enlargement of affected joints. Epidemiology The prevalence rises progressively with age and it has been estimated that 45% of all people develop knee OA and 25% hip OA at some point during life. Although some are asymptomatic, the lifetime risk of having a total hip or knee replacement for OA in someone aged 50 is about 11% for women and 8% for men in the UK. There are major ethnic differences in susceptibility: the prevalence of hip OA is lower in Africa, China, Japan and the Indian subcontinent than in European countries, and that of knee OA is higher. Pathophysiology OA is a complex disorder with both genetic and environmental components (Box 24.36). Genetic factors are recognised as playing a key role in the pathogenesis of OA. Family-based studies have estimated that the heritability of OA ranges from about 43% at the knee to between 60% and 65% at the hip and adverse effects are an increased risk of infection, leucopenia and infusion reactions. Abatacept Abatacept is a fusion protein in which the Fc domain of IgG has been combined with the extracellular domain of CTLA4, which blocks T-cell activation by acting as a decoy for CD28, a co-stimulatory molecule necessary for T-cell activation (p. 69). It is indicated in patients with RA who have not responded adequately to ﬁrst-line therapy but is typically employed as a third-line treatment when TNF inhibitors have been ineffective. The main adverse effect is an increased risk of infections. Tocilizumab Tocilizumab is a monoclonal antibody to the IL-6 receptor. It is indicated in patients with RA who have not responded adequately to ﬁrst-line therapy or to TNF inhibitors. It is sometimes employed as a third-line treatment when TNF inhibitors have been ineffective.

1008 • RHEUMATOLOGY AND BONE DISEASE remodelling and cartilage thinning slowly alter the shape of the OA joint, increasing its surface area. It is almost as though there is a homeostatic mechanism operative in OA that causes enlargement of the failing joint to spread the mechanical load over a greater surface area. Patients with OA also have higher BMD values at sites distant from the joint and this is particularly associated with osteophyte formation. This is in keeping with observations made in epidemiological studies that show that patients with OA are partially protected from developing osteoporosis and vice versa. This is likely to be due to the fact that the genetic factors that predispose to osteoporosis might be protective for OA. The synovium in OA is often hyperplastic and may be the site of inﬂammatory change, but to a much lesser extent than in RA and other inﬂammatory arthropathies. Osteochondral bodies commonly occur within the synovium, reflecting chondroid metaplasia or secondary uptake and growth of damaged cartilage fragments. The outer capsule also thickens and contracts, usually retaining the stability of the remodelling joint. The muscles surrounding affected joints commonly show evidence of wasting and non-speciﬁc type II ﬁbre atrophy. Clinical features OA has a characteristic distribution, mainly targeting the hips, knees, PIP and DIP joints of the hands, neck and lumbar spine (see Fig. 24.10). The main presenting symptoms are pain and functional restriction. The causes of pain in OA are not completely understood but may relate to increased pressure in subchondral bone (mainly causing night pain), trabecular microfractures, capsular distension and low-grade synovitis. Pain may also result from bursitis and enthesopathy secondary to altered joint mechanics. Typical OA pain has the characteristics listed in Box 24.37. For many people, functional restriction of the hands, knees or hips is an equal, if not greater, problem than pain. The clinical ﬁndings vary according to severity but are principally those of joint damage. hand, respectively. In most cases, the inheritance is polygenic and mediated by several genetic variants of small effect. OA can, however, be a component of multiple epiphyseal dysplasias, which are caused by mutations in the genes that encode components of cartilage matrix. Structural abnormalities, such as slipped femoral epiphysis and developmental dysplasia of the hip, are also associated with a high risk of OA, presumably due to abnormal load distribution across the joint. Similar mechanisms probably explain the increased risk of OA in patients with limb deformity secondary to Paget’s disease of bone. Biomechanical factors play an important role in OA related to certain occupations, such as farmers (hip OA), miners (knee OA) and elite or professional athletes (knee and ankle OA). It has been speculated that the higher prevalence of knee OA in the Indian subcontinent and East Asia might be accounted for by squatting. There is also a high risk of OA in people who have had destabilising injuries, such as cruciate ligament rupture, and those who have had meniscetomy. For most individuals, however, participation in recreational sport does not appear to increase the risk signiﬁcantly. There is a strong association between obesity and OA, particularly of the hip. This is thought to be due partly to biomechanical factors but it has also been speculated that cytokines released from adipose tissue may play a role. Oestrogen appears to play a role; lower rates of OA have been observed in women who use hormone replacement therapy (HRT), and women who receive aromatase inhibitor therapy for breast cancer often experience a ﬂare in symptoms of OA. Degeneration of articular cartilage is the deﬁning feature of OA. Under normal circumstances, chondrocytes are terminally differentiated cells but in OA they start dividing to produce nests of metabolically active cells (Fig. 24.16A). Initially, matrix components are produced by these cells at an increased rate, but at the same time there is accelerated degradation of the major structural components of cartilage matrix, including aggrecan and type II collagen (see Fig. 24.5, p. 987). Eventually, the concentration of aggrecan in cartilage matrix falls and makes the cartilage vulnerable to load-bearing injury. Fissuring of the cartilage surface (‘ﬁbrillation’) then occurs, leading to the development of deep vertical clefts (Fig. 24.16B), localised chondrocyte death and decreased cartilage thickness. This is initially focal, mainly targeting the maximum load-bearing part of the joint, but eventually large parts of the cartilage surface are damaged. Calcium pyrophosphate and basic calcium phosphate crystals often become deposited in the abnormal cartilage. OA is also accompanied by abnormalities in subchondral bone, which becomes sclerotic and the site of subchondral cysts (Fig. 24.16C). Fibrocartilage is produced at the joint margin, which undergoes endochondral ossiﬁcation to form osteophytes. Bone 24.36 Risk factors for osteoarthritis Genetics • Skeletal dysplasias • Polygenic inheritance Developmental abnormalities • Developmental dysplasia of the hip • Slipped femoral epiphysis Repetitive loading • Farmers • Miners • Elite athletes Adverse biomechanics • Meniscectomy • Ligament rupture • Paget’s disease Obesity Trauma Hormonal • Oestrogen deﬁciency • Aromatase inhibitors Fig. 24.16 Pathological changes in osteoarthritis. A Abnormal nests of proliferating chondrocytes (arrows) interspersed with matrix devoid of normal chondrocytes. B Fibrillation of cartilage in OA. C X-ray of knee joint affected by OA, showing osteophytes at joint margin (white arrows), subchondral sclerosis (black arrows) and a subchondral cyst (open arrow). A C B

Osteoarthritis • 1009

impairment. Clinically, it may be detected by the presence of crepitus on joint movement, and squaring of the thumb base. Generalised nodal OA has a very strong genetic component: the daughter of an affected mother has a 1 in 3 chance of developing nodal OA herself. People with nodal OA are also at increased risk of OA at other sites, especially the knee. Knee OA At the knee, OA principally targets the patello-femoral and medial tibio-femoral compartments but eventually spreads to affect the whole of the joint (Fig. 24.19). It may be isolated or occur as part of generalised nodal OA. Most patients have bilateral and symmetrical involvement. In men, trauma is often a more important risk factor and may result in unilateral OA. The pain is usually localised to the anterior or medial aspect of the knee and upper tibia. Patello-femoral pain is usually worse going up and down stairs or inclines. Posterior knee pain suggests the presence of a complicating popliteal cyst (Baker’s cyst). Prolonged walking, rising from a chair, getting in or out of 24.38 Characteristics of generalised nodal osteoarthritis • Polyarticular ﬁnger interphalangeal joint osteoarthritis • Heberden’s (± Bouchard’s) nodes • Marked female preponderance • Peak onset in middle age • Good functional outcome for hands • Predisposition to osteoarthritis at other joints, especially knees • Strong genetic predisposition 24.37 Symptoms and signs of osteoarthritis Pain • Insidious onset over months or years • Variable or intermittent nature over time (‘good days, bad days’) • Mainly related to movement and weight-bearing, relieved by rest • Only brief (< 15 mins) morning stiffness and brief (< 5 mins) ‘gelling’ after rest • Usually only one or a few joints painful Clinical signs • Restricted movement due to capsular thickening or blocking by osteophyte • Palpable, sometimes audible, coarse crepitus due to rough articular surfaces • Bony swelling around joint margins • Deformity, usually without instability • Joint-line or periarticular tenderness • Muscle weakness and wasting • Mild or absent synovitis The correlation between the presence of structural change, as assessed by imaging, and symptoms such as pain and disability varies markedly according to site. It is stronger at the hip than at the knee, and poor at most small joints. This suggests that the risk factors for pain and disability may differ from those for structural change. At the knee, for example, reduced quadriceps muscle strength and adverse psychosocial factors (anxiety, depression) correlate more strongly with pain and disability than the degree of radiographic change. Radiological evidence of OA is very common in middle-aged and older people, and the disease may coexist with other conditions, so it is important to remember that pain in a patient with OA may be due to another cause. Generalised nodal OA Characteristics of this common form of OA are shown in Box 24.38. Some patients are asymptomatic whereas others develop pain, stiffness and swelling of one or more PIP and DIP joints of the hands from the age of about 40 years onwards. Gradually, these develop posterolateral swellings on each side of the extensor tendon, which slowly enlarge and harden to become Heberden’s (DIP) and Bouchard’s (PIP) nodes (Fig. 24.17). Typically, each joint goes through a phase of episodic symptoms (1–5 years) while the node evolves and OA develops. Once OA is fully established, symptoms may subside and hand function often remains good. Affected joints are enlarged as a result of osteophyte formation and often show characteristic lateral deviation, reﬂecting the asymmetric focal cartilage loss of OA (Fig. 24.18). Involvement of the ﬁrst CMC joint is also common, leading to pain on trying to open bottles and jars, and functional Fig. 24.17 Nodal osteoarthritis. Heberden’s nodes and lateral (radial/ ulnar) deviation of distal interphalangeal joints, with mild Bouchard’s nodes at the proximal interphalangeal joints. Fig. 24.18 X-ray appearances in hand osteoarthritis. There is joint space narrowing affecting the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints in both hands. There are typical articular subchondral and ‘gullwing’ appearances to some osteoarthritis-affected joints, as well as osteophyte formation that is most marked at the second DIP joints bilaterally and the ﬁrst PIP joint on the right hand (arrows).

1010 • RHEUMATOLOGY AND BONE DISEASE • restricted ﬂexion and extension with coarse crepitus • bony swelling around the joint line. CPPD crystal deposition in association with OA is common at the knee. This may result in a more overt inflammatory component (stiffness, effusions) and super-added acute attacks of synovitis (‘pseudogout’; p. 1016), which may be associated with more rapid radiographic and clinical progression. Hip OA Hip OA most commonly targets the superior aspect of the joint (Fig. 24.21). It is often unilateral at presentation, frequently progresses with superolateral migration of the femoral head, and has a poor prognosis. The less common central (medial) OA shows more central cartilage loss and is largely conﬁned to women. It is often bilateral at presentation and can be associated with generalised nodal OA. It has a better prognosis than superior hip OA and progression to axial migration of the femoral head is uncommon. The hip shows the best correlation between symptoms and radiographic change. Hip pain is usually maximal deep in the anterior groin, with variable radiation to the buttock, anterolateral thigh, knee or shin. Lateral hip pain, worse on lying on that side with tenderness over the greater trochanter, suggests secondary trochanteric bursitis. Common functional difﬁculties are the same as for knee OA; in addition, restricted hip abduction in women may cause pain during sexual intercourse. Examination may reveal: • an antalgic gait • weakness and wasting of quadriceps and gluteal muscles • pain and restriction of internal rotation with the hip ﬂexed – the earliest and most sensitive sign of hip OA; other movements may subsequently be restricted and painful • anterior groin tenderness just lateral to the femoral pulse • ﬁxed ﬂexion, external rotation deformity of the hip • ipsilateral leg shortening with severe joint attrition and superior femoral migration. Obesity is associated with more rapid progression of hip OA. a car, or bending to put on shoes and socks may be difﬁcult. Local examination ﬁndings may include: • a jerky, asymmetric (antalgic) gait with less time weightbearing on the painful side • a varus (Fig. 24.20) or, less commonly, valgus and/or a ﬁxed ﬂexion deformity • joint-line and/or periarticular tenderness (secondary anserine bursitis and medial ligament enthesopathy (see Box 24.25), causing tenderness of the upper medial tibia) • weakness and wasting of the quadriceps muscle Fig. 24.19 X-ray appearances in knee osteoarthritis. A Advanced osteoarthritis showing almost complete loss of joint space affecting both compartments and sclerosis of subchondral bone. B Skyline view of the patella femoral joint in a patient with severe patello-femoral osteoarthritis. There is almost complete loss of joint space and lateral displacement of the patella. A B Fig. 24.20 Typical varus knee deformity resulting from marked medial tibio-femoral osteoarthritis. Fig. 24.21 X-ray of hip showing changes of osteoarthritis. Note the superior joint space narrowing (N), subchondral sclerosis (S), marginal osteophytes (O) and cysts (C). O C N S O

Osteoarthritis • 1011

Erosive OA This term is used to describe an unusual group of patients with hand OA who have a more prolonged symptom phase, more overt inﬂammation, more disability and worse outcome than those with nodal OA. Distinguishing features include preferential targeting of PIP joints, subchondral erosions on X-rays, occasional ankylosis of affected joints and lack of association with OA elsewhere. It is unclear whether erosive OA is part of the spectrum of hand OA or a discrete subset. Investigations A plain X-ray of the affected joint should be performed and often this will show one or more of the typical features of OA (see Figs 24.18–24.22). In addition to providing diagnostic information, X-rays are of value in assessing the severity of structural change, which is helpful if joint replacement surgery is being considered. Non-weight-bearing postero-anterior views of the pelvis are adequate for assessing hip OA. Patients with suspected knee OA should have standing anteroposterior X-rays taken to assess tibio-femoral cartilage loss, and a ﬂexed skyline view to assess patello-femoral involvement. Spine OA can often be diagnosed on a plain X-ray, which typically shows evidence of disc space narrowing and osteophytes. If nerve root compression or spinal stenosis is suspected, MRI should be performed. Routine biochemistry, haematology and autoantibody tests are usually normal, though OA is associated with a moderate acute phase response. Synovial ﬂuid aspirated from an affected joint is viscous with a low cell count. Unexplained early-onset OA requires additional investigation, guided by the suspected underlying condition. X-rays may show typical features of dysplasia or avascular necrosis, widening of joint spaces in acromegaly, multiple cysts, chondrocalcinosis and MCP joint involvement in haemochromatosis (p. 895), or disorganised architecture in neuropathic joints. Management Treatment follows the principles outlined on pages 1000–1007. Measures that are pertinent in older people are summarised in Box 24.40. Education It is important to explain the nature of the condition fully, outlining the role of relevant risk factors such as obesity, heredity and Spine OA The cervical and lumbar spine are the sites most often targeted by OA, where it is referred to as cervical spondylosis and lumbar spondylosis, respectively (Fig. 24.22). Spine OA may occur in isolation or as part of generalised OA. The typical presentation is with pain localised to the low back region or the neck, although radiation of pain to the arms, buttocks and legs may also occur due to nerve root compression. The pain is typically relieved by rest and worse on movement. On physical examination, the range of movement may be limited and loss of lumbar lordosis is typical. The straight leg-raising test or femoral stretch test may be positive and neurological signs may be seen in the legs where there is complicating spinal stenosis or nerve root compression. Early-onset OA Unusually, typical symptoms and signs of OA may present before the age of 45. In most cases, a single joint is affected and there is a clear history of previous trauma. However, speciﬁc causes of OA need to be considered in people with early-onset disease affecting several joints, especially those not normally targeted by OA, in which case rare causes need to be considered (Box 24.39). Kashin–Beck disease is a rare form of OA that occurs in children, typically between the ages of 7 and 13, in some regions of China. The cause is unknown but suggested predisposing factors are selenium deﬁciency and contamination of cereals with mycotoxin-producing fungi. Fig. 24.22 X-ray of spine showing typical changes of osteoarthritis. Cervical spondylosis showing disc space narrowing between C6 and C7, osteophytes at the anterior vertebral body margins (thin arrows) and osteosclerosis at the apophyseal joints (thick arrow). 24.39 Causes of early-onset osteoarthritis Monoarticular • Previous trauma, localised instability Pauciarticular or polyarticular • Juvenile idiopathic arthritis (p. 1026) • Metabolic or endocrine disease: Haemochromatosis (p. 895) Ochronosis Acromegaly (p. 685) • Spondylo-epiphyseal dysplasia • Late avascular necrosis • Neuropathic joint • Kashin–Beck disease 24.40 Osteoarthritis in old age • Pain and disability: osteoarthritis is the principal cause in old age. • Calcium phosphate deposition disease: may cause acute attacks of synovitis (pseudogout) on a background of chronic osteoarthritis. • Falls: reduced muscle strength and pain associated with lower limb osteoarthritis increase the risk. • Muscle-strengthening exercises: safely reduce the pain and disability of knee osteoarthritis with accompanying improvements in balance and reduced tendency to fall. • Oral paracetamol and topical non-steroidal anti-inﬂammatory drugs: safe in older people, with no important drug interactions or contraindications. • Intra-articular injection of glucocorticoid: a very safe and often effective treatment, particularly useful for tiding a patient over a special event. • Total joint replacement: an excellent cost-effective treatment for severe disabling knee or hip osteoarthritis in older people. There is no age limit for joint replacement surgery.

1012 • RHEUMATOLOGY AND BONE DISEASE indicated when there is signiﬁcant structural damage on X-ray. Although surgery should not be undertaken at an early stage during the development of OA, it is important to consider it before functional limitation has become advanced since this may compromise outcome. Patient-speciﬁc factors, such as age, gender, smoking and presence of obesity, should not be barriers to referral for joint replacement. Only a small proportion of patients with OA progress to the extent that total joint replacement is required but OA is by far the most frequent indication for this. Over 95% of joint replacements continue to function well into the second decade after surgery and most provide life-long, pain-free function. Up to 20% of patients are not satisﬁed with the outcome, however, and a few experience little or no improvement in pain. Other surgical procedures are performed much less frequently. Osteotomy is occasionally carried out to prolong the life of malaligned joints and to relieve pain by reducing intraosseous pressure. Cartilage repair is sometimes performed to treat focal cartilage defects resulting from joint injury. Crystal-induced arthritis A variety of crystals can deposit in and around joints and cause an acute inﬂammatory arthritis, as well as a more chronic arthritis associated with progressive joint damage (Box 24.41). Crystals can be the primary pathogenic agent, as in gout, or an accessory factor, as in calcium pyrophosphate deposition disease, in which crystals are deposited in joints that are already abnormal. Several factors influence crystal formation (Fig. 24.23). There must be sufﬁcient concentration of the chemical components (ionic product), but whether a crystal then forms depends on the balance of tissue factors that promote and inhibit crystal nucleation and growth. The inﬂammatory potential of crystals resides in their physical irregularity and high negative surface charge, which can induce inﬂammation and damage cell membranes. Crystals may also cause mechanical damage to tissues and act as wear particles at the joint surface. They can reside in cartilage or tendon for years without causing inﬂammation or symptoms, and it is only when they are released that they trigger inﬂammation. This may occur spontaneously but can also result from local trauma, rapid changes in the concentration of the components that form crystals, or in association with an acute phase response triggered by intercurrent illness or surgery. In the longer term, a reduction in concentrations of the solutes that form crystals causes dissolution of crystals and remission of the arthritis. Gout Gout is the most common inﬂammatory arthritis in men and in older women. It is caused by deposition of monosodium urate monohydrate crystals in and around synovial joints. Epidemiology The prevalence of gout is approximately 1–2%, with a greater than 5 : 1 male preponderance. Gout has become progressively more common over recent years in afﬂuent societies due to the increased prevalence of obesity and metabolic syndrome (p. 730), of which hyperuricaemia is an integral component. The risk of developing gout increases with age and with serum uric acid (SUA) levels. These are normally distributed in the general population and hyperuricaemia is deﬁned as an SUA of more than 2 standard deviations above the mean for the trauma. The patent should be informed that established structural changes are permanent and that, although a cure is not possible at present, pain and function can often be improved. The prognosis should also be discussed, mentioning that it is generally good for nodal hand OA and better for knee than hip OA. Lifestyle advice Weight loss has a substantial beneﬁcial effect on symptoms if the patient is obese and is probably one of the most effective treatments available for OA of the lower limbs. Strengthening and aerobic exercises also have beneﬁcial effects in OA and should be advised, preferably with reinforcement by a physiotherapist (see Box 24.27). Quadriceps strengthening exercises are particularly beneﬁcial in knee OA. Shock-absorbing footwear, pacing of activities, use of a walking stick for painful knee or hip OA, and provision of built-up shoes to equalise leg lengths can all improve symptoms. Non-pharmacological therapy Acupuncture and transcutaneous electrical nerve stimulation (TENS) have been shown to be effective in knee OA. Local physical therapies, such as heat or cold, can sometimes give temporary relief. Pharmacological therapy If symptoms do not respond to non-pharmacological measures, paracetamol should be tried. Addition of a topical NSAID, and then capsaicin, for knee and hand OA can also be helpful. Oral NSAIDs should be considered in patients who remain symptomatic. These drugs are signiﬁcantly more effective than paracetamol and can be successfully combined with paracetamol or compound analgesics if the pain is severe. Strong opiates may occasionally be required. Antineuropathic drugs, such as amitriptyline, gabapentin and pregabalin, are sometimes used in patients with symptoms that are difﬁcult to control but the evidence base for their use is poor. Neutralising antibodies to nerve growth factor have been developed and are a highly effective treatment for pain in OA but they are not yet licensed for routine clinical use. Intra-articular injections Intra-articular glucocorticoid injections are effective in the treatment of knee OA and are also used for symptomatic relief in the treatment of OA at the ﬁrst CMC joint. The duration of effect is usually short but trials of serial glucocorticoid injections every 3 months in knee OA have shown efﬁcacy for up to 1 year. Intra-articular injections of hyaluronic acid are effective in knee OA but the treatment is expensive and the effect short-lived. In the UK they have not been considered to be cost-effective by NICE. Neutraceuticals Chondroitin sulphate and glucosamine sulphate have been used alone and in combination for the treatment of knee OA. There is evidence from randomised controlled trials that these agents can improve knee pain to a small extent (3–5%) compared with placebo. Surgery Surgery should be considered for patients with OA whose symptoms and functional impairment impact signiﬁcantly on their quality of life despite optimal medical therapy and lifestyle advice. Total joint replacement surgery is by far the most common surgical procedure for patients with OA. It can transform the quality of life for people with severe knee or hip OA and is

Crystal-induced arthritis • 1013

the balance between endogenous synthesis, and elimination by the kidneys (two-thirds) and gut (one-third). Purine nucleotide synthesis and degradation are regulated by a network of enzyme pathways, but xanthine oxidase plays a pivotal role in catalysing the conversion of hypoxanthine to xanthine and xanthine to uric acid. The causes of hyperuricaemia are shown in Box 24.42. In over 90% of patients, the main abnormality is reduced uric acid Fig. 24.23 Mechanisms of crystal formation. Solute excess pH Temperature Pressure [Na+] + [Urate] [Ca2+] + [PO4] Nucleating factors Growth-promoting factors Crystals Inflammation Trauma Rapidly reduced solute levels Reduced solute levels Inhibitors of crystal growth Shedding Dissolution Bone Cartilage 24.41 Crystal-associated arthritis and deposition in connective tissue Crystal Associations Common Monosodium urate monohydrate Acute gout Chronic tophaceous gout Calcium pyrophosphate dihydrate Acute ‘pseudogout’ Chronic (pyrophosphate) arthropathy Chondrocalcinosis Basic calcium phosphates Calciﬁc periarthritis Calcinosis Uncommon Cholesterol Chronic effusions in rheumatoid arthritis Calcium oxalate Acute arthritis in dialysis patients Extrinsic crystals/ semi-crystalline particles: Synthetic crystals Acute synovitis Plant thorns/sea urchin spines Chronic monoarthritis, tenosynovitis population. SUA levels are higher in men, increase with age and are positively associated with body weight. Levels are higher in some ethnic groups (such as Maoris and Paciﬁc islanders). Although hyperuricaemia is strong risk factor for gout, only a minority of hyperuricaemic individuals actually develop gout. Pathophysiology About one-third of the body uric acid pool is derived from dietary sources and two-thirds from endogenous purine metabolism (Fig. 24.24). The concentration of uric acid in body ﬂuids depends on Fig. 24.24 Uric acid metabolism. The main pathways for uric acid production and elimination are shown, along with the site of action for urate-lowering therapies. Endogenous purines (~800mg/24 hrs) Renal excretion acid (~800mg/24 hrs) Intestinal excretion acid (~400mg/24 hrs) Purine salvage pathway Game, seafood, oily fish, offal De novo synthesis Inosine Inhibition of pathway Stimulation of pathway Hypoxanthine Xanthine oxidase Xanthine Allantoin Uricosuric drugs Pegloticase Allopurinol Febuxostat Xanthine oxidase Uric acid (~1200mg) Dietary purines (~400mg/24 hrs) 24.42 Causes of hyperuricaemia and gout Diminished renal excretion • Increased renal tubular reabsorption* • Renal failure • Lead toxicity • Lactic acidosis • Alcohol • Drugs: Thiazide and loop diuretics Low-dose aspirin Ciclosporin Pyrazinamide Increased intake • Game • Seafood • Offal • Red meat Increased production • Myeloproliferative and lymphoproliferative disease • Psoriasis • High fructose intake • Glycogen storage disease (p. 370) • Inherited disorders: Lesch–Nyhan syndrome (HPRT mutations) Phosphoribosyl pyrophosphate synthetase 1 mutations *Usually genetically determined (see text). (HPRT = hypoxanthine guanine phosphoribosyl transferase)

1014 • RHEUMATOLOGY AND BONE DISEASE • marked swelling with overlying red, shiny skin • self-limiting over 5–14 days, with complete resolution. During the attack, the joint shows signs of marked synovitis, swelling and erythema. There may be accompanying fever, malaise and even delirium, especially if a large joint such as the knee is involved. As the attack subsides, pruritus and desquamation of overlying skin are common. The main differential diagnosis is septic arthritis, infective cellulitis or reactive arthritis. Acute attacks may also manifest as bursitis, tenosynovitis or cellulitis, which have the same clinical characteristics. Many patients describe milder episodes lasting just a few days. Some have attacks in more than one joint. Others have further attacks in other joints a few days later (cluster attacks), the ﬁrst possibly acting as a trigger. Simultaneous polyarticular attacks are unusual. Some people never have a second episode and in others several years may elapse before the next one. In many, however, a second attack occurs within 1 year and may progress to chronic gout, with chronic pain and joint damage, and occasionally severe deformity and functional impairment. Patients with uncontrolled hyperuricaemia who suffer multiple attacks of acute gout may also progress to chronic gout. The presentation of gout in the elderly may be atypical with chronic symptoms rather than acute attacks (Box 24.43). Crystals may be deposited in the joints and soft tissues to produce irregular ﬁrm nodules called tophi. These have a predilection for the extensor surfaces of ﬁngers, hands, forearm, elbows, Achilles tendons and sometimes the helix of the ear. Tophi have a white colour (Fig. 24.26), differentiating them from rheumatoid nodules. Tophi can ulcerate, discharging white gritty material, become infected or induce a local inﬂammatory response, with erythema and pus in the absence of secondary infection. They are usually a feature of long-standing gout but can sometimes develop within 12 months in patients with chronic renal failure. Occasionally, tophi may develop in the absence of previous acute attacks, especially in patients on thiazide therapy who have coexisting OA. In addition to causing musculoskeletal disease, chronic hyperuricaemia may be complicated by renal stone formation (p. 431) and, if severe, renal impairment due to the development of interstitial nephritis as a result of urate deposition in the kidney. This is particularly common in patients with chronic tophaceous gout who are on diuretic therapy. Investigations The diagnosis of gout can be conﬁrmed by the identiﬁcation of urate crystals in the aspirate from a joint, bursa or tophus (see Fig. 24.6A, p. 988). In acute gout, the synovial ﬂuid may be excretion by the kidney, which is genetically determined. Impaired renal excretion of urate also accounts for the occurrence of hyperuricaemia in chronic renal failure, and for hyperuricaemia associated with thiazide diuretic therapy. Other risk factors for gout include metabolic syndrome, high alcohol intake (predominantly beer, which contains guanosine), generalised OA, and a diet relatively high in game, offal, seafood, red meat and fructose, or low in vitamin C. Lead poisoning may cause gout (saturnine gout). The association between OA and gout is thought to be due to a reduction in levels of proteoglycan and other inhibitors of crystal formation in osteoarthritic cartilage, predisposing to crystal formation. Some patients develop gout because they over-produce uric acid. The mechanisms are poorly understood, except in the case of a few single gene disorders where there are mutations in genes that regulate purine metabolism (Box 24.42). Lesch–Nyhan syndrome is an X-linked recessive form of gout that is also associated with mental retardation, selfmutilation and choreoathetosis. An inherited cause should be suspected if other clinical features are present or there is an early age at onset with a positive family history. Severe hyperuricaemia can also occur in patients with haematological and other cancers who are undergoing chemotherapy due to increased purine turnover (tumour lysis syndrome). This is seldom connected with gout but can be associated with acute kidney injury (p. 411). Clinical features The classical presentation is with an acute monoarthritis, which affects the ﬁrst MTP joint in over 50% of cases (Fig. 24.25). Other common sites are the ankle, midfoot, knee, small joints of hands, wrist and elbow. The axial skeleton and large proximal joints are rarely involved. Typical features include: • rapid onset, reaching maximum severity in 2–6 hours, and often waking the patient in the early morning • severe pain, often described as the ‘worst pain ever’ • extreme tenderness, such that the patient is unable to wear a sock or to let bedding rest on the joint Fig. 24.25 Podagra. Acute gout causing swelling, erythema and extreme pain and tenderness of the ﬁrst metatarsophalangeal joint. 24.43 Gout in old age • Aetiology: a higher proportion of older patients have gout secondary to diuretic use and chronic kidney disease. Gout is often associated with osteoarthritis. • Presentation: may be atypical, with painful tophi and chronic symptoms, rather than acute attacks. Joints of the upper limbs are more frequently affected. • Management: acute attacks are best treated by aspiration and intra-articular injection of glucocorticoids, followed by early mobilisation. Non-steroidal anti-inﬂammatory drugs and colchicine should be used with caution because of increased risk of toxicity. Low doses of allopurinol (50 mg/day) should be given and increased gradually to avoid toxicity.

Crystal-induced arthritis • 1015

that are similar to those in other forms of advanced inﬂammatory arthritis. Management Management should focus on ﬁrst dealing with the acute attack and then giving prophylaxis to lower SUA and prevent further attacks. Acute gout Oral colchicine given in doses of 0.5 mg twice or 3 times daily is the treatment of ﬁrst choice in acute gout. It works by inhibiting microtubule assembly in neutrophils. The most common adverse effects are nausea, vomiting and diarrhoea. Oral NSAIDs are also effective but are used less commonly since many patients affected by acute gout have coexisting cardiovascular, cerebrovascular or chronic kidney disease. Oral prednisolone (15–20 mg daily) or intramuscular methylprednisolone (80–120 mg daily) for 2–3 days are highly effective and are a good choice in elderly patients where there is an increased risk of toxicity with colchicine and NSAID (Box 24.43). The IL-1β inhibitor canakinumab (see Box 24.35) is effective but extremely expensive and so seldom given. Local ice packs can also be used for symptomatic relief. Patients with recurrent episodes can keep a supply of an NSAID, colchicine or prednisolone and take it as soon as the ﬁrst symptoms occur, continuing until the attack resolves. Joint aspiration can give pain relief, particularly if a large joint is affected, and may be combined with an intra-articular glucocorticoid injection if the diagnosis is clear and infection can be excluded. Prophylaxis Patients who have had a single attack of gout do not necessarily need to be given urate-lowering therapy, but individuals who have more than one acute attack within 12 months and those with complications such as tophi or erosions should be offered it (Box 24.44). The long-term therapeutic aim is to prevent attacks occurring by bringing uric acid levels below the level at which monosodium urate monohydrate crystals form. A therapeutic target of 360 μmol/L (6 mg/dL) is recommended in the British Society of Rheumatology guidelines, whereas the European League Against Rheumatism guidelines recommend a threshold of 300 μmol/L (5 mg/dL). Allopurinol is the drug of ﬁrst choice. It inhibits xanthine oxidase, which reduces the conversion of hypoxanthine and xanthine to uric acid. The recommended starting dose is 100 mg daily, or 50 mg in older patients and in renal impairment. The dose of allopurinol should be increased by 100 mg every 4 weeks (50 mg in the elderly and those with renal impairment) until the target uric acid level is achieved, side-effects occur or the maximum recommended dose is reached (900 mg/day). Acute ﬂares of gout often follow initiation of urate-lowering therapy. The patient should be warned about this and told to continue therapy, even if an attack occurs. The risk of ﬂares can be reduced by prophylaxis with oral colchicine (0.5 mg twice daily) or an NSAID for the ﬁrst few months. Alternatively, patients can be given a supply of colchicine, an NSAID or prednisolone to be taken at the ﬁrst turbid due to an elevated neutrophil count. In chronic gout, the appearance is more variable but occasionally the ﬂuid appears white due to the presence of urate crystals. Between attacks, aspiration of an asymptomatic ﬁrst MTP joint or knee may still reveal crystals. A biochemical screen, including renal function, uric acid, glucose and lipid proﬁle, should be performed because of the association with metabolic syndrome. Hyperuricaemia is usually present in gout but levels may be normal during an attack because serum urate falls during inﬂammation. Acute gout is characterised by an elevated ESR and CRP and with a neutrophilia, all of which return to normal as the attack subsides. Tophaceous gout may be accompanied by a modest but chronic elevation in ESR and CRP. X-rays are usually normal in acute gout but well-demarcated erosions may be seen in patients with chronic or tophaceous gout (Fig. 24.27). Tophi may also be visible on X-rays as soft tissue swellings. In late disease, destructive changes may occur Fig. 24.26 Tophus with white monosodium urate monohydrate crystals visible beneath the skin. Diuretic-induced gout in a patient with pre-existing nodal osteoarthritis. Fig. 24.27 Erosive arthritis in chronic gout. Punched-out (‘Lulworth Cove’) erosions (arrows) in association with a destructive arthritis affecting the ﬁrst metatarsophalangeal joint. 24.44 Indications for urate-lowering drugs • Recurrent attacks of acute gout • Evidence of bone or joint damage • Tophi • Renal impairment • Nephrolithiasis

1016 • RHEUMATOLOGY AND BONE DISEASE levels are raised in patients with CPPD crystal deposition disease, possibly due to over-production, but why this happens is unclear. In hypophosphatasia (see Box 24.75, p. 1050), the predisposing factor is thought to be impaired degradation of pyrophosphate due to deﬁciency of ALP. In OA, it is thought that a reduction in the amounts of proteoglycan and other natural inhibitors of crystal formation in the abnormal cartilage also predispose to crystal deposition (see Fig. 24.23). Clinical features The typical presentation is with a swollen tender joint that is warm and erythematous with a large effusion. Fever is common and the patient may appear confused and ill. The knee is most commonly affected, followed by the wrist, shoulder, ankle and elbow. Trigger factors include trauma, intercurrent illness, dehydration and surgery. Septic arthritis and gout are the main differential diagnoses. Chronic arthropathy may also occur in association with CPPD crystal deposition disease, affecting the same joints that are involved in acute pseudogout. The presentation is with chronic pain, early morning stiffness, inactivity gelling and functional impairment. Acute attacks of pseudogout may be superimposed. Affected joints usually show features of OA, with varying degrees of synovitis. Effusion and synovial thickening are usually most apparent at knees and wrists. Wrist involvement may result in carpal tunnel syndrome and second and third MCP joints can be sign of an acute attack. In the longer term, annual monitoring of uric acid levels is recommended. In most patients, urate-lowering therapy needs to be continued indeﬁnitely. Febuxostat also inhibits xanthine oxidase. It is typically used in patients with an inadequate response to allopurinol, and when allopurinol is contraindicated or causes adverse effects. Febuxostat undergoes hepatic metabolism and no dose adjustment is required for renal impairment. It is more effective than allopurinol but commonly provokes acute attacks when therapy is initiated. The usual starting dose is 80 mg daily, increasing to 120 mg daily in patients with an inadequate response. Prophylaxis against acute attacks should be given on initiating therapy, as described for allopurinol. Uricosuric drugs, such as probenecid, sulﬁnpyrazone and benzbromarone, lower urate levels but are seldom used in routine clinical practice. They are contraindicated in over-producers and those with renal impairment or urolithiasis and require patients to maintain a high ﬂuid intake to avoid uric acid crystallisation in the renal tubules. Pegloticase is a biological treatment in which the enzyme uricase (oxidises uric acid to 5-hydroxyisourate, which is then converted to allantoin) has been conjugated to monomethoxypolyethylene glycol. It is indicated for the treatment of tophaceous gout resistant to standard therapy and is administered as an intravenous infusion every 2 weeks for up to 6 months. It is highly effective at controlling hyperuricaemia and can cause regression of tophi. The main adverse effects are infusion reactions (which can be treated with antihistamines or glucocorticoids) and ﬂares of gout during the ﬁrst 3 months of therapy. A limiting factor for longer-term treatment is the development of antibodies to pegloticase, which occur in a high proportion of cases and are associated with an impaired therapeutic response. Lifestyle measures are equally important as drug therapy in the treatment of gout. Patients should be advised to lose weight where appropriate and to reduce excessive alcohol intake, especially beer. Several antihypertensive drugs, including thiazides, β-blockers and ACE inhibitors, increase uric acid levels, whereas losartan has a uricosuric effect and should be substituted for other drugs if possible. Patients should be advised to avoid large amounts of seafood and offal, which have a high purine content, but a highly restrictive diet is not necessary. Calcium pyrophosphate dihydrate crystal deposition disease This condition is associated with deposition of calcium pyrophosphate dihydrate (CPPD) crystals within articular and hyaline cartilage and is often referred to as ‘pseudogout’. It is rare under the age of 55 years but occurs in 10–15% of people between 65 and 75 and 30–60% of those over 85. The knee (hyaline cartilage and menisci) is by far the most common site, followed by the wrist (triangular ﬁbrocartilage) and pelvis (symphysis pubis). Risk factors are shown in Box 24.45. In many patients, chondrocalcinosis is asymptomatic and an incidental ﬁnding on X-ray. A proportion of patients present with an acute inﬂammatory arthritis (pseudogout) or a chronic inﬂammatory arthropathy superimposed on a background of OA, especially at the knee (Fig. 24.28), associated with joint damage and functional limitation. Pathophysiology The underlying mechanisms of crystal deposition are poorly understood. Clinical studies have shown that pyrophosphate Fig. 24.28 Chondrocalcinosis of the knee. The X-ray shows calciﬁcation of the ﬁbrocartilaginous menisci (M) and articular hyaline cartilage (H). There is also narrowing (N) of the medial tibio-femoral compartment and osteophyte (O) formation. H M N O Common • Age • Osteoarthritis* Rare • Familial factors* • Haemochromatosis* • Hypophosphatasia *May be associated with structural damage to affected joints. • Hypomagnesaemia • Wilson’s disease • Primary hyperparathyroidism 24.45 Risk factors for chondrocalcinosis

Crystal-induced arthritis • 1017

and fever are common. Tendon calciﬁcation may be seen on X-ray. If the affected joint or bursa is aspirated, inﬂammatory ﬂuid containing many calcium-staining (alizarin red S) aggregates may be obtained. During an acute attack, there may be a neutrophilia with an elevation in ESR and CRP. Routine biochemistry is normal. Treatment is with analgesics and NSAIDs. Attacks may also respond to a local injection of glucocorticoid. The condition usually resolves spontaneously over 1–3 weeks and this is often accompanied by dispersal and disappearance of calciﬁc deposits on X-ray. Large deposits sometimes accumulate, causing limitation of joint movement, and may require surgical removal. Acute inﬂammatory arthritis Deposition of BCP occurs commonly in OA, both alone and in combination with CPPD crystals, in which case it is referred to as mixed crystal deposition disease. It may present with pseudogout or be an incidental ﬁnding. Milwaukee shoulder syndrome This is a rare syndrome, in which extensive deposition of BCP crystals in large joints is associated with progressive joint destruction. It is more common in women than in men. The onset is gradual with joint pain, sometimes precipitated by injury affected. Inﬂammatory features may be sufﬁciently pronounced to suggest RA. Inﬂammatory changes can occur at entheses and may involve tendons and the ligamentum ﬂavum. Inﬂammation around the odontoid may occur secondary to CPPD deposition, leading to crowned dens syndrome; this presents clinically with neck pain. Severe damage and instability of knees or shoulders can mimic a neuropathic joint but no neurological abnormalities will be found. Investigations The pivotal investigation is joint aspiration, followed by examination of synovial ﬂuid using compensated polarised microscopy to demonstrate CPPD crystals (see Fig. 24.6B, p. 988) and to permit distinction from gout. The aspirated ﬂuid is often turbid and may be uniformly blood-stained, reﬂecting the severity of inﬂammation. Since sepsis and pseudogout can coexist, Gram stain and culture of the ﬂuid should be performed to exclude sepsis, even if CPPD crystals are identiﬁed in synovial ﬂuid. X-rays of the affected joint may show evidence of calciﬁcation in hyaline cartilage and/or ﬁbrocartilage, although absence of calciﬁcation does not exclude the diagnosis. Signs of OA are frequently present. Screening for secondary causes (Box 24.45) should be undertaken, especially in patients who present under the age of 25 and those with polyarticular disease. Management Joint aspiration can sometimes provide symptomatic relief in pseudogout and in a few patients no further treatment is required. People with persistent symptoms can be treated with intra-articular glucocorticoids, colchicine or an NSAID. Since most patients with pseudogout are elderly, NSAIDs and colchicine must be used with caution. Early active mobilisation is also important. Chronic pyrophosphate-induced arthropathy should be managed as for OA (p. 1011). Basic calcium phosphate deposition disease Basic calcium phosphate (BCP) deposition disease is caused by the deposition of hydroxyapatite or apatite crystals and other basic calcium phosphate salts (octacalcium phosphate, tricalcium phosphate) in soft tissues. The main affected sites are tendons, ligaments and hyaline cartilage in patients with degenerative disease, and skeletal muscle and subcutaneous tissues in connective tissue diseases. Pathophysiology Under normal circumstances, inhibitors of mineralisation, such as pyrophosphate and proteoglycans, prevent calciﬁcation of soft tissues. When these protective mechanisms break down, abnormal calciﬁcation occurs. There are many causes (Box 24.46). In most situations calciﬁcation is of no consequence, but when the crystals are released an inﬂammatory reaction may be initiated, causing local pain and inﬂammation. Calciﬁc periarthritis This occurs as the result of deposition of BCP in tendons, which provokes an acute inﬂammatory response. The most commonly affected site is the supraspinatus tendon (Fig. 24.29) but other sites may also be involved, including the tendons around the hip, feet and hands. The presentation is with acute pain, swelling and local tenderness that develops rapidly over 4–6 hours. The overlying skin may be hot and red, raising the possibility of infection. Attacks sometimes occur spontaneously but can also be triggered by trauma. Modest systemic upset Fig. 24.29 Shoulder X-ray showing supraspinatus tendon calciﬁcation (arrow). 24.46 Rheumatic diseases associated with basic calcium phosphate deposition Disease Site of calciﬁcation Calciﬁc periarthritis Tendons and ligaments Dermatomyositis and polymyositis Subcutaneous tissue Systemic sclerosis (lcSScl) Subcutaneous tissue Mixed connective tissue disease Subcutaneous tissue Paget’s disease of bone Blood vessels Ankylosing spondylitis Ligaments Fibrodysplasia ossiﬁcans progressiva Subcutaneous tissues and muscle Milwaukee shoulder syndrome Tendons and ligaments Albright’s hereditary osteodystrophy (p. 664) Muscle (lcSScl = localised cutaneous systemic sclerosis)

1018 • RHEUMATOLOGY AND BONE DISEASE for all or some of the patient’s symptoms (Box 24.48). Extensive imaging is not recommended but bone scintigraphy can identify many conditions that can contribute to widespread pain and is a useful ‘negative’ test. The aims of management are to educate the patient about the condition, address unresolved psychological issues, achieve pain control and improve sleep. Wherever possible, education should include the spouse, family or carer. It should be acknowledged that the cause of FM is not fully understood but the widespread pain does not reﬂect inﬂammation, tissue damage or disease. The model of a self-perpetuating cycle of poor sleep and pain (see Fig. 24.30) is a useful framework for problem-based management. Understanding the diagnosis can often help the patient come to terms with the symptoms. Repeat or drawn-out investigation may reinforce beliefs in occult serious pathology and should be avoided. Low-dose amitriptyline (10–75 mg at night), with or without ﬂuoxetine, may help by encouraging delta sleep and reducing or overuse. The disease progresses over a few months to cause severe pain and disability, associated with joint destruction. X-rays show joint space narrowing, osteophytes and calciﬁcation. Aspiration yields large volumes of relatively non-inﬂammatory ﬂuid containing abundant BCP aggregates and often cartilage fragments. The differential diagnosis is end-stage avascular necrosis, chronic sepsis or neuropathic joint. There is no acute phase response and synovial ﬂuid cultures are negative. Treatment is with analgesics, intra-articular injection of glucocorticoids, local physical treatments and physiotherapy. The clinical outcome is poor, however, and most patients require joint replacement. The cause is incompletely understood but it has been speculated that deposition of BCP crystals activates collagenase and other proteases in articular cells, which are responsible for the tissue damage. Autoimmune connective tissue disease Deposition of BCP may occur in the subcutaneous tissues and muscle of patients with systemic sclerosis and other autoimmune connective tissue diseases. Usually, the deposits are asymptomatic but they may be associated with pain and local ulceration. The mechanism by which this occurs is unclear and there is no speciﬁc treatment. Fibromyalgia Fibromyalgia (FM) is a condition of generalised pain and consequent disability. It is frequently associated with medically unexplained symptoms in other systems (p. 1187). The prevalence in the UK and US is about 2–3%. Although FM can occur at any age, including adolescence, it increases in prevalence with age, to reach a peak of 7% in women aged over 70. There is a strong female predominance of around 10 : 1. Risk factors include life events that cause (unresolved) psychosocial distress relating to previous abuse, marital disharmony, alcoholism or illness in the family, poor sleep health, previous injury or assault, and low income. FM arises in a variety of races and cultures. Pathophysiology The cause of FM is poorly understood but two abnormalities that may be interrelated (Fig. 24.30) and have been consistently reported in affected patients are disturbed, non-restorative sleep and pain sensitisation, probably caused by abnormal central pain processing. Clinical features The main presenting feature is widespread pain, which is often worst in the neck and back (Box 24.47). It is characteristically diffuse and unresponsive to analgesics and NSAIDs. Physiotherapy often makes FM pain worse. Fatiguability, most prominent in the morning, is another major problem and disability is often marked. Although people can usually dress, feed and groom themselves, they may be unable to perform tasks such as shopping or housework. They may have experienced major difﬁculties at work or may even retire because of pain and fatigue. Examination is unremarkable, apart from the presence of hyperalgesia on moderate digital pressure (enough just to whiten the nail) over multiple sites (Fig. 24.31). Investigations and management There are no abnormalities on routine blood tests or imaging but it is important to screen for other conditions that could account Fig. 24.30 Possible causative mechanisms in ﬁbromyalgia. Disease Illness Regional pain syndrome Anxiety Life crisis Sleep disturbance Non-restorative sleep Reduced activity Poor aerobic fitness Pain Fatigue Functional disturbance 24.47 The spectrum of symptoms in ﬁbromyalgia Usual symptoms • Widespread pain • Fatiguability • Disability • Broken, non-restorative sleep • Low affect, irritability, poor concentration Variable locomotor symptoms • Early-morning stiffness • Feeling of swelling in hands • Distal ﬁnger tingling Additional, variable, non-locomotor symptoms • Non-throbbing bifrontal headache (tension headache) • Colicky abdominal pain, bloating, variable bowel habit (irritable bowel syndrome) • Bladder fullness, nocturnal frequency (irritable bladder) • Hyperacusis, dyspareunia, discomfort when touched (allodynia) • Frequent side-effects with drugs (chemical sensitivity)

Bone and joint infections • 1019

support. Although treatment may improve quality of life and ability to cope, most people remain symptomatic for many years. Bone and joint infections Septic arthritis Septic arthritis is the most rapid and destructive joint disease. The incidence is 2–10 per 100 000 in the general population and 30–70 per 100 000 in those with pre-existing joint disease or joint replacement. Septic arthritis is associated with signiﬁcant morbidity and still has a mortality of about 10% despite advances in antimicrobial therapy. The most important risk factor for mortality is increasing age. Pathogenesis Septic arthritis usually occurs as a result of haematogenous spread from infections of the skin or upper respiratory tract; infection from direct puncture wounds or secondary to joint aspiration is uncommon. Risk factors include increasing age, pre-existing joint disease (principally RA), diabetes mellitus, immunosuppression (by drugs or disease) and intravenous drug misuse. In RA, the skin is a frequent portal of entry because of maceration of skin between the toes due to joint deformity and difﬁculties with foot hygiene caused by hand deformity. Box 24.49 describes the particular considerations in old age. Clinical features The usual presentation is with acute or subacute monoarthritis and fever. The joint is usually swollen, hot and red, with pain at rest and on movement. Although any joint can be affected, lower limb joints, such as the knee and hip, are most commonly spinal cord wind-up. Many people with FM, however, are intolerant of even small doses of amitriptyline. There is limited evidence for the use of tramadol, serotonin–noradrenaline (norepinephrine) re-uptake inhibitors (SNRIs) such as duloxetine, and the anticonvulsants pregabalin and gabapentin. A graded increase in aerobic exercise can improve well-being and sleep quality. The use of self-help strategies and a cognitive behavioural approach with relaxation techniques should be encouraged. Sublimated anxiety relating to distressing life events should be speciﬁcally explored with appropriate counselling. There are patient organisations that provide additional information and Fig. 24.31 Typical tender points in ﬁbromyalgia. Interspinous ligaments C5–7 Mid-supraspinatus Interspinous ligaments L4/5 Mid-gluteal Second/third costochondral junctions 1 cm distal to lateral epicondyle Medial fat pad (upper medial tibia) Skin-fold rolling of mid-trapezius 24.48 Laboratory investigations recommended before ﬁnalising a diagnosis of ﬁbromyalgia Test Condition screened for Full blood count, liver and renal function tests General disease indicators Erythrocyte sedimentation rate, C-reactive protein, serum amyloid A, immunoglobulins Inﬂammatory disease Thyroid function Hypo-/hyperthyroidism Calcium, albumin, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin-D, serum angiotensin-converting enzyme Hyperparathyroidism, osteomalacia, sarcoid Antinuclear antibodies, extractable nuclear antigens, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, complement C3 and C4, lupus anticoagulant, anti-cardiolipin antibodies, streptococcal antibodies Autoinﬂammatory and autoimmune diseases

1020 • RHEUMATOLOGY AND BONE DISEASE depending on the organism that is isolated. Microbiology advice should always be sought in complicated situations, such as when treating intravenous drug users, patients in intensive care and those who might be colonised by resistant organisms. It is traditional to continue intravenous antibiotics for 2 weeks and to follow this with oral treatment for another 4 weeks, but there is no evidence to support the optimal duration of treatment. Joint aspiration should be performed using a large-bore needle once or twice daily. If this is not possible, arthroscopic or open surgical drainage may be needed performed. Regular passive movement should be undertaken from the outset, and active movements encouraged once the condition has stabilised. Infected prosthetic joints require management by the orthopaedic team, but prolonged antibiotic treatment on its own is often ineffective and removal of the prosthesis is required for eradication of the infection. Arthritis may be a feature of Lyme disease caused by members of the Borrelia species of microorganisms (p. 255). It is generally a late manifestation, which usually affects large joints. Brucellosis presents with an acute febrile illness, followed in some cases by the development of localised infection, which can result in arthritis, bursitis, osteomyelitis, sacroiliitis and paravertebral or psoas abscesses. These conditions are discussed on pages 254 and 255. Viral arthritis The usual presentation is with acute polyarthritis following a febrile illness, which may be accompanied by a rash. Most cases of targeted. Patients with pre-existing arthritis may present with multiple joint involvement. In adults, the most likely organism is Staphylococcus aureus, particularly in patients with RA and diabetes. In young, sexually active adults, gonococcus may be responsible. Disseminated gonococcal infection occurs in up to 3% of patients with untreated gonorrhoea. This usually presents with migratory arthralgia, low-grade fever and tenosynovitis, which may precede the development of an oligo- or monoarthritis. Painful pustular skin lesions may also be present. Gram-negative bacilli or group B, C and G streptococci are important causes among the elderly and intravenous drug users. Less commonly, septic arthritis may be caused by group A streptococci, pneumococci, meningococci and Haemophilus inﬂuenzae. Investigations The pivotal investigation is joint aspiration but blood cultures should also be taken. The synovial ﬂuid is usually turbid or bloodstained but may appear normal. If the joint is not readily accessible, aspiration should be performed under imaging guidance or in theatre. Prosthetic joints should only be aspirated in theatre. Synovial ﬂuid should be sent for Gram stain and culture; cultures are positive in around 90% of cases but the Gram stain is positive in only 50%. In contrast, synovial ﬂuid culture is positive in only 30% of gonococcal infections, making it important to obtain concurrent cultures from the genital tract (positive in 70–90% of cases). There is a leucocytosis with raised ESR and CRP in most patients, but these features may be absent in elderly or immunocompromised patients, or early in the disease course. Serial measurements of CRP and ESR are useful in following the response to treatment. Management The principles of management are summarised in Box 24.50. The patient should be admitted to hospital for pain relief and administration of parenteral antibiotics. Flucloxacillin (2 g IV 4 times daily) is the antibiotic of ﬁrst choice pending the results of cultures, since it will cover most staphylococcal and streptococcal infections. If there is reason to suspect meticillin-resistant Staphylococcus aureus (such as a known carrier), vancomycin should be used instead while awaiting cultures. If a Gram-negative infection is suspected, gentamicin or vancomycin should be considered as ﬁrst-line treatments. Cephalosporins are a potential alternative for Gram-negative infections but carry a high risk of Clostridium difﬁcile infection in those aged over 65. Whatever antibiotic is chosen, the regimen may need to be changed, 24.49 Joint and bone infection in old age • Vertebral infection: more common. Recognition may be delayed, as symptoms may be attributed to compression fractures caused by osteoporosis. • Peripheral vascular disease: leads to more frequent involvement of the bones of the feet, and diabetic foot ulcers are also commonly complicated by osteomyelitis. • Prosthetic joint infections: now more common because of the increased frequency of prosthetic joint insertion in older people. • Gram-negative bacilli: more frequent pathogens than in younger people. • Cephalosporins: contraindicated due to the high risk of Clostridium difﬁcile. • Septic arthritis: mortality is high in elderly patients. The evidence base for choice of antibiotic selection is poor. Local guidelines should be followed where available. 24.50 Emergency management of suspected septic arthritis Admit patient to hospital Perform urgent investigations • Aspirate joint: Send synovial ﬂuid for Gram stain and culture Use imaging guidance if required • Send blood for culture, routine biochemistry and haematology, including erythrocyte sedimentation rate and C-reactive protein • Consider sending other samples (sputum, urine, wound swab) for culture, depending on patient history, to determine primary source of infection Commence intravenous antibiotic • Flucloxacillin (2 g 4 times daily) • If penicillin-allergic: Clindamycin (450–600 mg 4 times daily in younger patients) Intravenous vancomycin (1 g twice daily if age > 65 years) • If high risk of Gram-negative sepsis (recurrent urinary tract infection): Intravenous gentamicin (5 mg/kg once daily) or vancomycin (750–1000 mg twice daily) Relieve pain • Oral and/or intravenous analgesics • Consider local ice-packs Aspirate joint • Perform serial needle aspiration to dryness (1–3 times daily or as required) • Consider arthroscopic drainage if needle aspiration difﬁcult Arrange physiotherapy • Early regular passive movement, progressing to active movements once pain controlled and effusion not re-accumulating

Rheumatoid arthritis • 1021

Investigations Patients suspected of having osteomyelitis should have an MRI, which is more sensitive than X-ray for detecting early changes. Where possible, cultures should be obtained by open or imagingguided biopsy of the lesion. Evidence of osteopenia, localised osteolysis and osteonecrosis may be seen on X-ray. Blood cultures should be taken, which may also reveal the causative organism. Routine bloods typically show evidence of an acute phase response with a neutrophilia and raised ESR and CRP. Management Early recognition is critical as once osteomyelitis becomes established and chronic, it may prove very hard to eradicate with antibiotics alone. The principles are those followed for septic arthritis, with parenteral antibiotics for 2 weeks, followed by oral antibiotics for at least 4 weeks. An exception is in localised osteomyelitis of the toes and ﬁngers, which can often be treated successfully with a prolonged course of oral antibiotics. Resection of the infected bone and subsequent reconstruction may be required. Complications of chronic osteomyelitis include secondary amyloidosis (p. 81) and skin malignancy at the margin of a discharging sinus (Marjolin’s ulcer). Discitis Discitis is an unusual condition in which there is infection of the intervertebral disc, often extending into the epidural space or paravertebral soft tissues. Staph. aureus is the most common pathogen. Risk factors include diabetes mellitus, immunodeﬁciency or immunosuppressive therapy, and intravenous drug use. The presentation is with back pain accompanied by fever, and an acute phase response with high ESR and CRP and a neutrophilia. If the diagnosis is suspected, an MRI should be performed and blood cultures taken. If blood cultures are negative, open or imaging-guided biopsy of the lesion should be performed to try to identify the organism responsible. Management is with supportive care and parenteral antibiotics followed by oral antibiotics, as described for osteomyelitis. Tuberculosis Tuberculosis can affect the musculoskeletal system, usually targeting the spine (Pott’s disease) or large joints such as the hip, knee or ankle. The presentation is with pain, swelling and fever. The X-ray changes are non-speciﬁc and mycobacteria are seldom identiﬁed in the synovial ﬂuid, so tissue biopsy is required for a deﬁnitive diagnosis. Medical management is described on page 592. In some cases, surgical débridement may be required for extensive joint disease, and spinal involvement may require surgical stabilisation and decompression. Rheumatoid arthritis Rheumatoid arthritis (RA) is a common form of inﬂammatory arthritis, occurring throughout the world and in all ethnic groups. The prevalence of RA is approximately 0.8–1.0% in Europe and the Indian subcontinent, with a female-to-male ratio of 3 : 1. The prevalence is lower in South-east Asia (0.4%). The highest prevalence in the world is in Pima Indians (5%). It is a chronic disease characterised by a clinical course of exacerbations and remissions. viral arthritis are self-limiting and settle down within 4–6 weeks. Human parvovirus arthropathy (mainly B19; p. 237) is the most common in Europe; adults may not have the characteristic ‘slapped cheek’ facial rash seen in children. The diagnosis can be conﬁrmed by a rise in speciﬁc IgM. Polyarthritis may also occur rarely with hepatitis B and C, rubella (including rubella vaccination) and HIV infection. A variety of mosquito-borne viruses may cause epidemics of acute polyarthritis, including Ross River (Australia, Paciﬁc), Chikungunya and O’nyong-nyong (Asia, Africa), and Mayaro viruses (South America). A wide variety of articular symptoms have been associated with HIV, mainly in the later stages of infection (Box 24.51). Management is symptomatic, with NSAIDs and analgesics. Osteomyelitis In osteomyelitis, the primary sites of infection are bone and bone marrow. Any part of a bone may be involved but there is preferential targeting of the juxta-epiphyseal regions of long bones adjacent to joints. The risk of osteomyelitis increases with age; the incidence is about 8.8 cases per 100 000 person-years in those under 18, rising to 40.8 cases in those aged 60–69 and 88.3 cases in those above the age of 80. Pathogenesis Haematogenous spread is the most common cause in children but contiguous spread of infection from adjacent soft tissues or as the result of surgery is more important in adults. Diabetes is a particularly important risk factor, accounting for about 30% of cases in recent series. Other risk factors include immunosuppressive therapy, HIV infection and sickle-cell disease, which particularly increases the risk of Salmonella infection. The organisms most frequently implicated are Staph. aureus, Staph. epidermidis and streptococci. The infection often results in a ﬂorid inﬂammatory response, with a greatly increased intraosseous pressure. If untreated, the condition may cause localised areas of osteonecrosis, leading to the development of a fragment of necrotic bone that is called a sequestrum. Eventual perforation of the cortex by pus stimulates local new bone formation (involucrum) in the periosteum, often leading to the development of sinuses that discharge through the skin. Clinical features The presentation is with localised bone pain and tenderness, often accompanied by malaise, night sweats and pyrexia. The adjacent joint may be painful to move and may develop a sterile effusion or secondary septic arthritis. 24.51 Musculoskeletal manifestations of HIV Condition Comment Non-speciﬁc arthralgia Most common; intermittent and polyarticular Reactive arthritis Psoriatic arthritis Idiopathic lower limb inﬂammatory arthritis Especially in men who have sex with men Osteonecrosis Myositis Vasculitis Sjögren’s-like disease Unclear if related to HIV, its treatment or intercurrent disease

1022 • RHEUMATOLOGY AND BONE DISEASE The disease is characterised by inﬁltration of the synovial membrane with lymphocytes, plasma cells, dendritic cells and macrophages. There is evidence that CD4+ T lymphocytes and B cells play important roles in the pathogenesis of RA by interacting with other cells in the synovium, as illustrated in Figure 24.32. Lymphoid follicles form within the synovial membrane in which T- and B-cell interactions occur, causing activation of T cells to produce cytokines and activation of B cells to produce autoantibodies, including RF and ACPA. Synovial macrophages are activated by TNF and interferon gamma (IFN-γ), produced by T cells. The macrophages produce several pro-inﬂammatory cytokines, including TNF, IL-1 and IL-6, which act on synovial ﬁbroblasts to produce further cytokines, setting up a positive feedback loop. The synovial fibroblasts proliferate, causing synovial hypertrophy and producing matrix metalloproteinases and the proteinase ADAMTS-5, which degrade soft tissues and cartilage. Prostaglandins and nitric oxide produced within the inﬂamed synovium cause vasodilatation, resulting in swelling and pain. Systemic release of IL-6 triggers production of acute phase proteins by the liver. At the joint margin, the inﬂamed synovium (pannus) directly invades bone and cartilage to cause joint erosions. A key pathogenic factor in bone erosions and periarticular osteoporosis is osteoclast activation, stimulated by the production of M-CSF by synovial cells and RANKL by activated T cells (Fig. 24.32). New blood-vessel formation (angiogenesis) occurs, causing the inﬂamed synovium to become highly vascular. Pathophysiology RA is a complex disease with both genetic and environmental components. The importance of genetic factors is demonstrated by higher concordance of RA in monozygotic (12–15%) compared with dizygotic twins (3%), and an increased frequency of disease in ﬁrst-degree relatives of patients. Genome-wide association studies have detected nearly 100 loci that are associated with the risk of developing RA. The strongest association is with variants in the HLA region. Recent studies have shown that the association with HLA is determined by variations in three amino acids in the HLA-DRβ1 molecule (positions 11, 71 and 74) and single variants HLA-B (at position 9) and HLA-DPβ1 (at position 9). The non-HLA loci generally lie within or close to genes involved in regulating the immune response. It is currently believed that RA occurs when an environmental stimulus, such as infection, triggers autoimmunity in a genetically susceptible host by modifying host proteins through processes like citrullination so that they become immunogenic. However, no single speciﬁc pathogen has been identiﬁed as a cause. An important environmental risk factor is cigarette smoking, which is also associated with more severe disease and reduced responsiveness to treatment. Remission may occur during pregnancy and sometimes RA ﬁrst presents post-partum. This is likely to be due to suppression of the immune response during pregnancy but hormonal changes may also play a role. Fig. 24.32 Pathophysiology of rheumatoid arthritis. Some of the cytokines and cellular interactions believed to be important in rheumatoid arthritis are shown. (ADAMTS5 = aggrecanase; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MMP = matrix metalloproteinase; RANKL = receptor activator of nuclear factor kappa B ligand; TNF = tumour necrosis factor) Autoantibodies B cell T cell TNF-α RANKL M-CSF MMP ADAMTS-5 TNF-α IL-1 IL-6 TNF-α IFN-γ TNF-α IL-1 IL-6 Activated B cells Immune complexes Osteoclast precursors Activated T cells Synovial fibroblasts Prostaglandins Nitric oxide Pain Vasodilatation Cartilage breakdown Acute phase proteins Bone erosions Vasculitis Plasma cells Host protein Protein becomes immunogenic Protein modified Immunogenic protein processed and presented to T cells by dendritic cells and B cells Peptide presented to T cell with HLA T cell activates B cell Dendritic cell Environmental trigger • Smoking • Infection Genetic predisposition • HLA-DR • Other immune response genes Macrophage

Rheumatoid arthritis • 1023

sheaths. Subluxation of the MTP joints of the feet may result in ‘cock-up’ toe deformities, causing pain on weight-bearing on the exposed MTP heads and the development of secondary adventitious bursae and callosities. In the hindfoot, a valgus deformity of the calcaneus may be observed as the result of damage to the ankle and subtalar joints. This is often associated with loss of the longitudinal arch (ﬂat foot) due to rupture of the tibialis posterior tendon. Popliteal (Baker’s) cysts may occur in patients with knee synovitis, in which synovial ﬂuid communicates with the cyst but is prevented from returning to the joint by a valve-like mechanism; this is not speciﬁc to RA. Rupture may be induced by knee ﬂexion, leading to calf pain and swelling that may mimic a deep venous thrombosis (DVT). These joint deformities tend to be observed in older patients with long-standing disease but are becoming much less common with more aggressive treatment of RA in its early stages. Systemic features Anorexia, weight loss and fatigue may occur throughout the disease course. Osteoporosis is a common complication (p. 1044) and muscle-wasting may occur as the result of systemic inﬂammation and reduced activity. Extra-articular features are most common in patients with long-standing seropositive erosive disease but may occasionally occur at presentation, especially in men. Most are due to serositis, granuloma and nodule formation or vasculitis (Box 24.53). Nodules Rheumatoid nodules occur almost exclusively in RF- or ACPApositive patients, usually in extensor tendons (Fig. 24.34). They 24.52 Criteria for diagnosis of rheumatoid arthritis* Criterion Score Joints affected 1 large joint

2–10 large joints

1–3 small joints

4–10 small joints

10 joints (at least 1 small joint)

Serology Negative RF and ACPA

Low positive RF or ACPA

High positive RF or ACPA

Duration of symptoms < 6 weeks

6 weeks

Acute phase reactants Normal CRP and ESR

Abnormal CRP or ESR

Patients with a score ≥ 6 are considered to have deﬁnite RA. (ACPA = anti-citrullinated peptide antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor) *European League Against Rheumatism/American College of Rheumatology 2010 criteria. Within these blood vessels, pro-inﬂammatory cytokines activate endothelial cells, which support recruitment of yet more leucocytes to perpetuate the inﬂammatory process. Later, ﬁbrous or bony ankylosis may occur. Muscles adjacent to inﬂamed joints atrophy and may be inﬁltrated with lymphocytes. This leads to progressive biomechanical dysfunction and may further amplify destruction. Rheumatoid nodules occur in patients who are RF- or ACPApositive and primarily affect extensor tendons. They consist of a central area of ﬁbrinoid material surrounded by a palisade of proliferating mononuclear cells. Granulomatous lesions may occur in the pleura, lung, pericardium and sclera. Clinical features The typical presentation is with pain, joint swelling and stiffness affecting the small joints of the hands, feet and wrists in a symmetrical fashion. Large joint involvement, systemic symptoms and extra-articular features may also occur. Clinical criteria for the diagnosis of RA are shown in Box 24.52. Sometimes RA has an acute onset, with severe early morning stiffness, polyarthritis and pitting oedema. This occurs more commonly in old age. Another presentation is with proximal muscle stiffness mimicking polymyalgia rheumatica (p. 1042). Occasionally, the onset is palindromic, with relapsing and remitting episodes of pain, stiffness and swelling that last for only a few hours or days. Examination typically reveals swelling and tenderness of the affected joints. Erythema is unusual and its presence suggests coexistent sepsis. Characteristic deformities may develop with long-standing uncontrolled disease, although these have become less common over recent years with more aggressive management. They include ulnar deviation of the ﬁngers, ‘swan neck’ deformity, the boutonnière or ‘button hole’ deformity, and a Z deformity of the thumb (Fig. 24.33). Dorsal subluxation of the ulna at the distal radio-ulnar joint may occur and contribute to rupture of the fourth and ﬁfth extensor tendons. Triggering of ﬁngers may occur because of nodules in the ﬂexor tendon Fig. 24.33 The hand in rheumatoid arthritis. A Ulnar deviation of the ﬁngers with wasting of the small muscles of the hands and synovial swelling at the wrists, the extensor tendon sheaths, the metacarpophalangeal and proximal interphalangeal joints. B ‘Swan neck’ deformity of the ﬁngers. B A

1024 • RHEUMATOLOGY AND BONE DISEASE Ocular involvement The most common symptom is dry eyes (keratoconjunctivitis sicca) due to secondary Sjögren’s syndrome (p. 1038). Scleritis and peripheral ulcerative keratitis are uncommon but more serious and potentially sight-threatening complications that usually present with pain and redness. Clinical features and management are discussed in more detail on page 1172. Serositis Serositis is usually asymptomatic but may present with pleural or pericardial pain and breathlessness. Pericardial effusion and constrictive pericarditis may rarely occur. Cardiac involvement Heart block, cardiomyopathy, coronary artery occlusion and aortic regurgitation have all been reported but are rare. The risk of cardiovascular disease is increased due to a combination of conventional risk factors, such as high cholesterol, smoking, hypertension, reduced physical activity, NSAIDs, glucocorticoids and the effects of inﬂammatory cytokines on vascular endothelium. Pulmonary involvement Pulmonary ﬁbrosis may occur but is often asymptomatic. There is some evidence that the risk of pulmonary ﬁbrosis is increased by anti-TNF therapy, although its uncertain whether this is causal or a marker of more severe disease in patients who require anti-TNF treatment. Peripheral neuropathy Entrapment neuropathies may result from compression by hypertrophied synovium or by joint subluxation. Median nerve compression is the most common and bilateral carpal tunnel syndrome can occur as a presenting feature of RA. Other syndromes include ulnar nerve compression at the elbow or wrist, compression of the lateral popliteal nerve at the head of the ﬁbula, and tarsal tunnel syndrome (entrapment of the posterior tibial nerve in the ﬂexor retinaculum), which causes burning, tingling and numbness in the distal sole and toes. Diffuse symmetrical peripheral neuropathy and mononeuritis multiplex may occur in patients with rheumatoid vasculitis. Spinal cord compression This rare complication is caused by compression of the spinal cord from subluxation of the cervical spine at the atlanto-axial joint or at a subaxial level (Fig. 24.35). Atlanto-axial subluxation is due to erosion of the transverse ligament posterior to the odontoid peg. It can lead to cord compression or sudden death following minor trauma or manipulation. It should be suspected in any RA patient who describes new onset of occipital headache, particularly if symptoms of paraesthesia or electric shock are present in the arms. The onset is often insidious, with subtle loss of function that may initially be attributed to active disease. Reﬂexes and power can be difﬁcult to assess in patients with extensive joint disease and therefore sensory or upper motor signs are most important. Patients with evidence of spinal cord compression require urgent neurosurgical referral for stabilisation and ﬁxation. Other complications Amyloidosis is a rare complication of long-standing disease that usually presents with nephrotic syndrome. Microcytic anaemia can occur due to iron deﬁciency resulting from NSAIDinduced gastrointestinal blood loss, whereas normochromic, normocytic anaemia with thrombocytosis occurs in patients Fig. 24.34 Rheumatoid nodules and olecranon bursitis. Nodules were palpable within, as well as outside, the bursa. 24.53 Extra-articular manifestations of rheumatoid disease Systemic • Fever • Weight loss • Fatigue • Susceptibility to infection Musculoskeletal • Muscle-wasting • Tenosynovitis • Bursitis • Osteoporosis Haematological • Anaemia • Thrombocytosis • Eosinophilia Lymphatic • Felty’s syndrome (see Box 24.54) • Splenomegaly Nodules • Sinuses • Fistulae Ocular • Episcleritis • Scleritis • Scleromalacia • Keratoconjunctivitis sicca Vasculitis • Digital arteritis • Ulcers • Pyoderma gangrenosum • Mononeuritis multiplex • Visceral arteritis Cardiac • Pericarditis • Myocarditis • Endocarditis • Conduction defects • Coronary vasculitis • Granulomatous aortitis Pulmonary • Nodules • Pleural effusions • Fibrosing alveolitis • Bronchiolitis • Caplan’s syndrome (p. 611) Neurological • Cervical cord compression • Compression neuropathies • Peripheral neuropathy • Mononeuritis multiplex Amyloidosis (p. 81) are frequently asymptomatic but some may be complicated by ulceration and secondary infection. Vasculitis This is uncommon but may occur in seropositive patients. The presentation is with systemic symptoms, such as fatigue and fever and nail-fold infarcts. Rarely, cutaneous ulceration, skin necrosis and mesenteric, renal or coronary artery occlusion may occur.

Rheumatoid arthritis • 1025

there is clinical uncertainty about the presence of synovitis. Plain X-rays of the hands, wrist and feet are usually normal in early RA but periarticular osteoporosis and marginal joint erosions may be observed with more advanced disease. The main indication for an X-ray is in the assessment of patients with painful joints to determine whether signiﬁcant structural damage has occurred. Patients who are suspected of having atlanto-axial disease should have lateral X-rays taken in ﬂexion and extension, and an MRI. In those with suspected Baker’s cyst, ultrasound may be required to establish the diagnosis. DAS28 is widely used to assess disease activity, response to treatment and need for biological therapy. It involves counting the number of swollen and tender joints in the upper limbs and knees, and combining this with the ESR and the patient’s assessment of the activity of their arthritis on a visual analogue scale, where 0 indicates no symptoms and 100 the worst symptoms possible. This data are entered into a calculator to generate a numerical score. The higher the value, the more active the disease (Fig. 24.36). Management The treatment goal is to suppress inﬂammation, control symptoms and prevent joint damage. This involves a combination of pharmacological and non-pharmacological therapies. When RA occurs in women of child-bearing age, additional considerations need to be taken into account and these are summarised in Box 24.56. Pharmacological therapy DMARD therapy should be introduced in all patients as this improves outcome. A typical algorithm is shown in Figure 24.37. On ﬁrst diagnosis, prednisolone should be started in a dose of 30 mg daily gradually reducing in 5 mg increments every 2 weeks until therapy is withdrawn after about 12 weeks. At the same time, methotrexate should be started in an initial dose of 15 mg weekly, along with folic acid 5 mg weekly, and escalated up to a maximum of 25 mg weekly, depending on the response. If the patient fails to respond adequately or dose-limiting toxicity occurs, then an additional DMARD should be commenced in combination with MTX. The most common combination is triple therapy, in which with active disease. Felty’s syndrome is a rare complication of seropositive RA in which splenomegaly occurs in combination with neutropenia and thrombocytopenia (Box 24.54). Localised or generalised lymphadenopathy can occur in patients with active disease but persistent lymphadenopathy may indicate the development of lymphoma, which is more common in patients with long-standing RA. Investigations The diagnosis of RA is essentially clinical but investigations are useful in conﬁrming the diagnosis and assessing disease activity (Box 24.55). The ESR and CRP are usually raised but normal results do not exclude the diagnosis, especially if only a few joints are involved. Tests for ACPA are positive in about 70% of cases and are highly speciﬁc for RA, occurring in many patients before clinical onset of the disease. Similarly, RF is also positive in about 70% of cases, most of whom also test positive for ACPA. RF is less speciﬁc than ACPA, however, and positive tests can occur in other diseases (p. 991). Ultrasound examination and MRI are not routinely required but can be value in patients with symptoms suggestive of RA where Fig. 24.35 Subluxation of cervical spine. A Flexion, showing widening of the space (arrow) between the odontoid peg of the axis (behind) and the anterior arch of the atlas (in front). B Extension, showing reduction in this space. A B 24.54 Felty’s syndrome Risk factors • Age of onset 50–70 years • Female > male • Caucasians > blacks • Long-standing rheumatoid arthritis • Deforming but inactive disease • Seropositive for rheumatoid factor Common clinical features • Splenomegaly • Lymphadenopathy • Weight loss • Skin pigmentation • Keratoconjunctivitis sicca • Vasculitis, leg ulcers • Recurrent infections • Nodules Laboratory ﬁndings • Normochromic, normocytic anaemia • Neutropenia • Abnormal liver function • Thrombocytopenia • Impaired T- and B-cell immunity 24.55 Investigations and monitoring of rheumatoid arthritis To establish diagnosis • Clinical criteria • Erythrocyte sedimentation rate and C-reactive protein • Ultrasound or magnetic resonance imaging • Rheumatoid factor and anti-citrullinated peptide antibodies To monitor disease activity and drug efﬁcacy • Pain (visual analogue scale) • Early morning stiffness (minutes) • Joint tenderness • Joint swelling • DAS28 score (see Fig. 24.36) • Erythrocyte sedimentation rate and C-reactive protein To monitor disease damage • X-rays • Functional assessment To monitor drug safety • Urinalysis • Full blood count • Chest X-ray • Urea and creatinine • Liver function tests

1026 • RHEUMATOLOGY AND BONE DISEASE ﬂares can be dealt with by intra-articular glucocorticoid injections or a short course of oral glucocorticoids, but if a sustained ﬂare occurs, a change in systemic DMARD and/or biologic therapy may need to be considered. Non-pharmacological therapy Physical and occupational therapy play important roles and it is vital for all patients to be assessed by an occupational therapist and physiotherapist and the appropriate advice and treatment provided. Surgery Synovectomy can be helpful in joints that have failed to respond adequately to systemic therapy and intra-articular injections. Joint replacement surgery may be required but the need for this has diminished over recent years, presumably as the result of more aggressive medical management. Other surgical procedures that can be helpful are excision of the metatarsal heads in patients with subluxation of the MTP joints; neurosurgery in patients with atlanto-axial subluxation; and fusion or the wrist or ankle in patients with joint damage (see Box 24.29, p. 1002). Juvenile idiopathic arthritis Juvenile idiopathic arthritis (JIA) is the term, accepted by the international community, for several forms of arthritis deﬁned by the International League of Associations for Rheumatology 2001 criteria (Box 24.57). This includes juvenile forms of psoriatic arthritis (JPsA), rheumatoid arthritis (JRA) and more undifferentiated forms of inﬂammatory arthritis. The majority of patients with JIA have a phenotype that is distinct from adult inﬂammatory arthritis Fig. 24.36 Calculation of the Disease Activity Score 28 (DAS28). Erythrocyte sedimentation rate or C-reactive protein can be used for the calculation. Calculation • Count swollen joints • Count tender joints • Measure erythrocyte sedimentation rate • Note patient global health assessment (1–100) • Enter data into calculator: www.4s-dawn.com/das28 Interpretation • >5.1 High activity • 2.6–5.1 Moderate activity • <2.6 Remission

24.56 Rheumatoid arthritis in pregnancy • Immunological changes in pregnancy: many patients with rheumatoid arthritis go into remission during pregnancy. • Conception: methotrexate should be discontinued for at least 3 months and leﬂunomide discontinued for at least 24 months before trying to conceive. • Paracetamol: the oral analgesic of choice during pregnancy. • Oral non-steroidal anti-inﬂammatory drugs and selective cyclo-oxygenase 2 (COX-2) inhibitors: can be used from implantation to 20 weeks’ gestation. • Glucocorticoids: may be used to control disease ﬂares; the main maternal risks are hypertension, glucose intolerance and osteoporosis. • Disease-modifying antirheumatic drugs (DMARDs) that may be used: sulfasalazine, hydroxychloroquine and azathioprine if required to control inﬂammation. • DMARDs that must be avoided: methotrexate, leﬂunomide, cyclophosphamide, mycophenolate and gold. • Biologic therapies: experience is limited but they may be relatively safe during pregnancy. The main theoretical risk is immunosuppression in the neonate, except for certolizumab, which does cross the placenta in negligible amounts. • Breastfeeding: methotrexate, leﬂunomide and cyclophosphamide are contraindicated. methotrexate, sulfasalazine and hydroxychloroquine are combined (Fig. 24.37). Other DMARDs can be substituted or added, along with a low-dose glucocorticoid such as prednisolone (5–10 mg daily) if the patient fails to respond fully. If disease activity remains high (DAS28 > 5.1) despite triple therapy, however, it is usual to progress to biologic therapy. The most commonly used ﬁrst-line biologics in RA are TNF inhibitors, although several other options are available (p. 1006). When the patient has been stabilised on biologic treatment for 12 months or more, a reduction in dose should be considered, since it is possible to reduce the dose in up to 50% of patients without loss of therapeutic effect. The JAK inhibitors tofacitinib and baricitinib have efﬁcacy in patients who fail to respond adequately to other DMARDs and provide an alternative to biologic therapies. RA is a chronic disease and ﬂares can occur even in patients who are established on DMARD and biologic therapy. Transient Fig. 24.37 Algorithm for the management of rheumatoid arthritis. (DAS28 = Disease Activity Score 28; DMARD = disease-modifying antirheumatic drug; HCQ = hydroxychloroquine; MTX = methotrexate; SSZ = sulfasalazine) Decrease dose over 12 weeks Increase dose over 12 weeks Prednisolone MTX + New diagnosis of rheumatoid arthritis Continue triple therapy DAS28

2.6 Add SSZ

HCQ DAS28 <2.6 Continue MTX DAS28

5.1 DAS28 2.6–5.1 Add biologic Change DMARD or add low-dose prednisolone DAS28 <2.6

Spondyloarthropathies • 1027

uveitis alone. Drug combinations are not well studied in JIA. Biologic therapies, including anti-TNF, are effective in JIA and are now a standard treatment in the presence of refractory disease or intolerance of methotrexate or other non-biologic immunotherapies. Tocilizumab is also effective in sJIA, and has been approved by NICE for use in the UK. Prognosis Suboptimal outcomes are associated with delayed diagnosis and referral to the specialist multidisciplinary team, inadequate disease control, presentation with uveitis, sJIA in males and poor engagement with services. Psychological support of affected children and their families is associated with improved outcome. Oligo-JIA often resolves at puberty. Polyarticular disease and sJIA remain active into adulthood in about 50% of cases. Common issues around the transition of adolescent patients into adulthood are shown in Box 24.58. Spondyloarthropathies Spondyloarthropathies (SpAs) comprise a group of related inﬂammatory musculoskeletal diseases that show overlap in their clinical features and have a shared immunogenetic association with HLA-B27 (Box 24.59). They include: • axial spondyloarthritis • ankylosing spondylitis • reactive arthritis • psoriatic arthritis and includes a strong association with uveitis. JIA affects about 1 : 1000 children and young people up to 16 years of age – similar to the prevalence of diabetes (1 : 700). The annual incidence is approximately 1 per 10 000 children and young people. Whereas joint restriction is attributed to damage in adults, in children it indicates inﬂammatory activity. Arthritis in children affects limb growth and has a negative effect on height and weight attainment. In young children, effective disease control can repair joint damage before puberty. Oligoarthritis is the most common form of JIA, accounting for about 60% of cases. It is more common in females and tends to affect large joints in an asymmetrical pattern. There is an association with uveitis and many patients are ANA-positive. Polyarticular JIA is heterogeneous: some patients are RF- and/ or ACPA-positive, while others are negative for autoantibodies. Systemic juvenile idiopathic arthritis (sJIA, formerly known as Still’s disease) is characterised by fever, rash, arthritis, hepatosplenomegaly and serositis in association with anaemia and a raised ESR and CRP. Autoantibody tests are negative. This form of JIA is associated with haemophagocytic syndrome. Many cases of enthesitis-related arthritis (ERA) are likely to be self-limiting forms of spondyloarthritis. ERA can progress over time into a more obviously deﬁned spondyloarthropathy. Investigations ESR and CRP do not correlate well with the extent or severity of inﬂammation and may be normal. A very high ESR may indicate the presence of inﬂammatory bowel disease or (very rarely) leukaemia. Low haemoglobin is likely to be due to anaemia of chronic disease rather than iron deﬁciency. A positive ANA occurs in 40–75% of cases of JIA and indicates an increased risk of eye disease. Ultrasound is the radiological investigation of choice to conﬁrm synovitis or tenosynovitis. The false-negative rate is higher in foot and ankle disease than in other joints. Arthroscopy should be avoided unless a biopsy is required. Synovial ﬂuid aspiration, but not arthroscopy, is essential when considering sepsis and tuberculosis. Management The key approach is to gain early rapid control of inﬂammation, minimise the adverse effects of treatment and support the general physical and mental health of the patient, which requires full multidisciplinary team input. The standard immunotherapy is methotrexate (subcutaneous methotrexate is typically used in the young child). Alternative treatment includes leﬂunomide, sulfasalazine and hydroxychloroquine. Azathioprine and ciclosporin can be used to treat JIA with uveitis. Mycophenolate and tacrolimus are considered to have a speciﬁc role in treating 24.57 Clinical features of juvenile idiopathic arthritis Subtype Frequency Clinical features Immunology Systemic juvenile idiopathic arthritis 5% Fever, rash, arthralgia, hepatosplenomegaly Autoantibody-negative Oligoarthritis (≤ 4 joints) 60% Large-joint arthritis, uveitis ANA-positive Polyarthritis (≥ 5 joints) 20% Polyarthritis; may be extended form of oligoarthritis ANA-positive Enthesis-related 5% Sacroiliitis, enthesopathy HLA-B27-positive RF-positive 5% Polyarthritis, similar to RA RF-positive, ACPA-positive Psoriatic arthritis 5% Same as adult disease (p. 1032) Autoantibody-negative (ACPA = anti-citrullinated peptide antibody; ANA = antinuclear antibody; HLA = human leucocyte antigen; RA = rheumatoid arthritis; RF = rheumatoid factor) 24.58 Juvenile idiopathic arthritis in adolescence • Uveitis: may be clinically silent and persist into adulthood. All (not just those who are ANA-positive) need ophthalmic screening for eye involvement. • Persistence into adulthood: occurs in 50% of cases, especially in systemic disease. Speciﬁc supportive management through transition from adolescence to adulthood should be planned. • Reduced peak bone mass: common in polyarthritis and systemic juvenile idiopathic arthritis but there are few data on fracture risk and the evidence base for treatment is poor. • Therapy: methotrexate is standard treatment, used after NSAIDs alone are insufﬁcient. Anti-TNF therapy is effective in all forms of juvenile idiopathic arthritis but long-term safety remains unclear. (ANA = antinuclear antibody; NSAIDs = non-steroidal anti-inﬂammatory drugs; TNF = tumour necrosis factor)

1028 • RHEUMATOLOGY AND BONE DISEASE Th17 axis (p. 65). In some situations, a triggering organism can be identiﬁed, as in reactive arthritis following bacterial dysentery or chlamydial urethritis, but in others the environmental trigger remains obscure. Familial clustering not only is common to the speciﬁc condition occurring in the proband, but also may extend to other diseases in the spondyloarthropathy group. Axial spondyloarthropathy Axial spondyloarthropathy includes classical ankylosing spondylitis (AS) as well as axial spondyloarthritis (axSpA). Inﬂammatory changes in the entire axial skeleton are characteristic of axSpA and can be visualised by MRI; structural alterations, such as new bone formation with syndesmophytes and ankylosis, develop later in the course of the disease. Accordingly, the criteria for diagnosing AS (Box 24.60), which require evidence of sacroiliitis on X-ray, are often only able to be applied many years after a patient’s symptoms started. Not all patients with axSpA will go on to develop AS. Pathophysiology Axial SpA and AS arise from an interaction between environmental pathogens and the host immune system in genetically susceptible individuals. Increased faecal carriage of Klebsiella aerogenes has been reported in patients with established AS and may relate to exacerbation of both joint and eye disease. There is increasing evidence that axSpA and AS are due to an abnormal host response to the intestinal microbiota with involvement of Th17 cells, which have a key role in mucosal immunity. This leads to production of various inﬂammatory cytokines, including IL-12, IL-23, IL-17 and TNF-α, which play vital roles in the pathogenesis of enthesitis and other inﬂammatory lesions (Fig. 24.38). There a strong association between axial spondyloarthropathy and carriage of the major histocompatibility complex (MHC) • arthritis with inﬂammatory bowel disease (enteropathic spondyloarthritis). In axial spondylitis and ankylosing spondylitis, the axial skeleton (i.e. the central core skeleton) is predominantly affected. In contrast to RA, in the SpAs there are frequent and notable non-synovial musculoskeletal lesions – mainly inﬂammatory in nature – of ligaments, tendons, periosteum and other bone lesions. A hallmark lesion of all SpAs is enthesitis, which is inﬂammation at the site of a ligament or tendon insertion into bone. Dactylitis, inﬂammation of a whole ﬁnger or toe, may also occur (see Fig. 24.43). It has been estimated that about 1% of the adult population in the USA may have an SpA (about 2.7 million). There is a striking association with HLA-B27, particularly for ankylosing spondylitis (> 95%). Additionally, SpAs are thought to arise as the result of an aberrant host response to infection and abnormal mucosal immunity mediated through changes in the IL-12, IL-23 and 24.59 Features common to spondyloarthropathies • Asymmetrical inﬂammatory oligoarthritis (lower > upper limb) • History of inﬂammatory back pain • Sacroiliitis and spinal osteitis • Enthesitis (e.g. gluteus medius insertion, plantar fascia origin) • Tendency for familial aggregation • HLA-B27 association • Psoriasis (of skin and/or nails) • Uveitis • Sterile urethritis and/or prostatitis • Inﬂammatory bowel disease • Aortic root lesions (aortic incompetence, conduction defects) (HLA = human leucocyte antigen) 24.60 Comparison of diagnostic criteria for axial spondyloarthritis (ASAS) and ankylosing spondylitis (modiﬁed New York) Axial spondyloarthritis Ankylosing spondylitis Imaging Sacroiliitis on MRI only Bilateral sacroiliitis on X-ray, even if changes are mild Unilateral sacroiliitis on X-ray if changes are deﬁnite History Back pain > 3 months that has four of the following characteristics:

improved by exercise
not relieved by rest
insidious onset
night pain
age at onset < 45 Good response of back pain to NSAID Family history of spondyloarthritis History of inﬂammatory bowel disease Low back pain > 3 months improved by exercise and not relieved by rest Clinical examination Arthritis Enthesitis Uveitis Dactylitis Psoriasis Limitation of lumbar spine movement in sagittal and frontal planes Chest expansion reduced Investigations HLA-B27-positive Elevated CRP Axial spondyloarthritis is diagnosed from: sacroiliitis on MRI + one other feature on history, clinical examination or investigation. The diagnosis can also be made in HLA-B27-positive patients with >1 clinical feature in the absence of sacroiliitis Ankylosing spondylitis can be diagnosed on X-ray evidence of sacroiliitis with one other feature on history or examination (ASAS = Assessment of Spondylitis International Society; CRP = C-reactive protein; HLA = human leucocyte antigen; MRI = magnetic resonance imaging; NSAID = non-steroidal anti-inﬂammatory drug)

Spondyloarthropathies • 1029

attachments at humeral epicondyles. A number of validated clinical questionnaires, such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP), can be used to assess disease activity and functional status in AS, though newer assessment tools are being developed that are more speciﬁc to a diagnosis of axSpA, such as the Assessment of Spondyloarthritis International Society Health Index (ASAS-H). Investigations The diagnosis is aided by ultrasound or MRI of entheses, or by MRI of the sacroiliac joints and spine (Fig. 24.39). Other ﬁndings class I molecule HLA-B27. This is particularly striking in patients deﬁned as having AS, more than 95% of whom are positive for HLA-B27. Other susceptibility genes also implicated in susceptibility to AS include ERAP-1 (an endoplasmic reticulum protein with a role facilitating intracellular antigen processing and binding with its presenting MHC molecule HLA-B27), the IL-23 receptor and downstream signalling molecules involved in directing Th17 cell responses, such as STAT3 (see Fig. 4.3, p. 65). The HLA-B27 molecule itself is implicated through its antigen-presenting function or because of its propensity to form homodimers that activate leucocytes. HLA-B27 molecules may also misfold, causing increased endoplasmic reticulum stress. This could lead to inﬂammatory cytokine release by macrophages and dendritic cells, thus triggering inﬂammatory disease. Axial spondyloarthritis Clinical features The cardinal feature of axSpA is inﬂammatory back pain and early morning stiffness, with low back pain radiating to the buttocks or posterior thighs if the sacroiliac joints are involved. Symptoms are exacerbated by inactivity and relieved by movement. Musculoskeletal symptoms may be prominent at entheses, may be episodic and, if persistent, can present as widespread pain and be mistaken for ﬁbromyalgia. Fatigue is common. A history of psoriasis (current, previous or in a ﬁrst-degree relative) and inﬂammatory bowel symptoms (current or previous) are important clues. Physical signs include a reduced range of lumbar spine movements in all directions, pain on sacroiliac stressing and a high enthesitis index. Entheses that are typically affected include Achilles’ insertion, plantar fascia origin, patellar ligament entheses, gluteus medius insertion at the greater trochanter and tendon Fig. 24.38 Pathophysiology of axial spondyloarthropathy. In genetically susceptible individuals, it is thought that bacterial components penetrate the mucosal barrier to activate macrophages and dendritic cells in the intestinal submucosa. These cells produce increased amounts of interleukin 23 (IL-23), which acts on T cells, neutrophils and mast cells to make IL-17; IL-17 in turn has a pivotal role in driving inﬂammation, causing sacroiliitis and enthesitis. Presentation of antigen by dendritic cells also plays a pathogenic part in activating T cells, and tumour necrosis factor (TNF), produced by macrophages and activated T cells, contributes to the pathogenesis of inﬂammation. Production of IL-22 by T cells is thought to be involved in causing the new bone formation that is typical of axial spondyloarthropathy. T cell IL-17 TNF-α IL-17 IL-22 New bone formation IL-17 IL-23 Antigen IL-23 IL-23 Dendritic cell Macrophage Activation of immune cells in submucosa Gut epithelium Gut flora Microbial products Tissue immune cells Neutrophil Mast cell TNF-α Environmental trigger Genetic predisposition • HLA-B27 • ERAP-1 • STAT3, IL23R Inflammation Fig. 24.39 Magnetic resonance imaging appearances in sacroiliitis. Coronal MRI short T1 inversion recovery (STIR) sequence showing bilateral sacroiliitis in axial spondyloarthritis. Bone marrow oedema (circles) is present around both sacroiliac joints, which show irregularities due to erosions (arrows).

1030 • RHEUMATOLOGY AND BONE DISEASE develops in many patients over a period of many years. Secondary osteoporosis of the vertebral bodies frequently occurs, leading to an increased risk of vertebral fracture. In AS, spinal fusion varies in its extent and in most cases does not cause a gross ﬂexion deformity, but a few patients develop marked kyphosis of the dorsal and cervical spine that may interfere with forward vision. This may prove incapacitating, especially when associated with ﬁxed ﬂexion contractures of hips or knees. Up to 40% of patients also have peripheral musculoskeletal lesions (asymmetrical, affecting entheses of large joints, such as the hips, knees, ankles and shoulders). Fatigue is a major complaint and is common to all SpAs, but its cause is unknown. Acute anterior uveitis is the most common extra-articular feature, which occasionally precedes joint disease. Other extra-articular features are occasionally observed but are rare (Box 24.61). Investigations In AS, X-rays of the sacroiliac joint show irregularity and loss of cortical margins, widening of the joint space and subsequently sclerosis, joint space narrowing and fusion. Lateral thoracolumbar spine X-rays may show anterior ‘squaring’ of vertebrae due to erosion and sclerosis of the anterior corners and periostitis of the waist. Bridging syndesmophytes may also be seen. These are areas of calciﬁcation that follow the outermost ﬁbres of the annulus (Fig. 24.40). In advanced disease, ossiﬁcation of the anterior longitudinal ligament and facet joint fusion may also be visible. The combination of these features may result in the may include raised ESR and CRP (although these can be normal), anaemia and positive HLA-B27. Faecal calprotectin is a useful screening test for associated inﬂammatory bowel disease. Management Patient education, NSAID use (optimally, once daily or slow release taken at bedtime) and physical therapy are key interventions at the outset. For severe and/or persistent peripheral musculoskeletal features of SpA, both sulfasalazine and methotrexate are reasonable therapy choices. These medications have no impact on spinal symptoms or disease progression. In patients who fail to respond adequately or who cannot tolerate NSAIDs, progression to biologic therapy with either TNF inhibitors or the IL-7A inhibitor secukinumab should be considered (see Box 24.35, p. 1007). Anti-TNF therapy is effective for both the axial and peripheral lesions of axSpA, but it is as yet unclear whether anti-TNF therapy modiﬁes the natural history of the disease. Prognosis With such a recent deﬁnition of disease, the markers of prognosis in patients diagnosed with axSpA are not fully understood. It is clear that axSpA can remain mild and/or episodic in many patients for many years. HLA-B27 positivity, high persistent CRP and high functional incapacity are likely to be markers of poor prognosis, if not markers of extension ultimately to AS. Ankylosing spondylitis Ankylosing spondylitis (AS) is deﬁned by the presence of sacroiliitis on X-ray and other structural changes on spine X-rays, which may eventually progress to bony fusion of the spine. There is a male-to-female ratio of about 3 : 1. In Europe, more than 90% of those affected are HLA-B27-positive (Caucasian HLA-B27 population prevalence is 9%). The overall prevalence of AS is below 0.5% in most populations. Over 75% of patients are able to remain in employment and enjoy a good quality of life. Even if severe ankylosis develops, functional limitation may not be marked, as long as the spine is fused in an erect posture. Clinical features Clinical features are the same as in axSpA. AS typically evolves slowly, with ﬂuctuating symptoms of spinal inﬂammation; ankylosis 24.61 Extra-articular features of axial spondyloarthritis and ankylosing spondylitis • Fatigue, anaemia • Anterior uveitis (25%) • Prostatitis (80% of men) and sterile urethritis • Inﬂammatory bowel disease (up to 50% have IBD lesions) • Osteoporosis • Cardiovascular disease (aortic valve disease 20%) • Amyloidosis (rare) • Atypical upper lobe pulmonary ﬁbrosis (very rare) Fig. 24.40 Radiographic changes in spondyloarthritis. A Fine symmetrical marginal syndesmophytes typical of ankylosing spondylitis (arrow). B Coarse, asymmetrical non-marginal syndesmophytes typical of psoriatic spondylitis (arrow). A B

Spondyloarthropathies • 1031

Reactive arthritis Reactive (spondylo)arthritis (ReA) is a ‘reaction’ to a number of bacterial triggers with clinical features in keeping with all SpA conditions. The known triggers are Chlamydia, Campylobacter, Salmonella, Shigella and Yersinia. Notably, non-SpA-related reactive arthritis can occur following infection with many viruses, Mycoplasma, Borrelia, streptococci and mycobacteria, including M. leprae, which causes leprosy (Hansen’s disease); however, the ‘reaction’ in these instances consists typically of myoarthralgias, is not associated with HLA-B27 and is generally not chronic. The arthritis associated with rheumatic fever (p. 515) is also an example of a reactive arthritis that is not associated with HLA-B27. Sexually acquired reactive arthritis (SARA) is predominantly a disease of young men, with a male preponderance of 15 : 1. This may reﬂect a difﬁculty in diagnosing the condition in young women, in whom Chlamydia infection is often asymptomatic and is hard to detect in practical terms. Between 1% and 2% of patients with non-speciﬁc urethritis seen at genitourinary medicine clinics have SARA (p. 1031). The syndrome of chlamydial urethritis, conjunctivitis and reactive arthritis was formerly known as Reiter’s disease. With enteric triggering infections (enteropathic ReA), HLA-B27 may predict the reactive arthritis and its severity, though the condition occurs in HLA-B27-negative people. The incidence of speciﬁc triggering infections causing reactive arthritis around the world varies, depending on the epidemiology of the infection and prevalence of HLA-B27 in the local population. Clinical features The onset is typically acute, with an inﬂammatory enthesitis, oligoarthritis and/or spinal inﬂammation. Lower limb joints and entheses are predominantly affected. In all types of ReA, there may be considerable systemic disturbance, with fever and weight loss. Achilles insertional enthesitis/tendonitis or plantar fasciitis may also be present. The ﬁrst attack of arthritis is usually self-limiting, but recurrent or chronic arthritis can develop and about 10% still have active disease 20 years after the initial presentation. Low back pain and stiffness due to enthesitis and osteitis are common and 15–20% of patients develop sacroiliitis. Many extra-articular features in ReA involve the skin, especially in SARA: • circinate balanitis, which starts as vesicles on the coronal margin of the prepuce and glans penis, later rupturing to form superﬁcial erosions with minimal surrounding erythema, some coalescing to give a circular pattern • keratoderma blennorrhagica, which begins as discrete waxy, yellow–brown vesico-papules with desquamating margins, occasionally coalescing to form large crusty plaques on the palms and soles of the feet • pustular psoriasis • nail dystrophy with subungual hyperkeratosis • mouth ulcers • conjunctivitis • uveitis, which is rare with the ﬁrst attack but arises in 30% of patients with recurring or chronic arthritis. Other complications in ReA are very rare but include aortic incompetence, conduction defects, pleuro-pericarditis, peripheral neuropathy, seizures and meningoencephalitis. Investigations The diagnosis is usually made clinically but joint aspiration may be required to exclude crystal arthritis and articular infection. typical ‘bamboo’ spine (Fig. 24.41). Erosive changes may be seen in the symphysis pubis, ischial tuberosities and peripheral joints. Osteoporosis is common and vertebral fractures may occur. Atlanto-axial dislocation can arise as a late feature. MRI is more sensitive for detection of early sacroiliitis than X-rays (see Fig. 24.39) and can also detect inﬂammatory changes in the lumbar spine. DXA scanning is important as part of a fragility fracture assessment. As in axSpA, ESR and CRP are usually raised in active disease but may be normal; anaemia is often present. Autoantibodies, such as RF, ACPA and ANA, are negative. Management The aims of management are the same as in axSpA: to relieve pain and stiffness, maintain a maximal range of skeletal mobility and avoid the development of deformities. Mobilising exercises are important and are shown on many online resource sites (e.g. National Ankylosing Spondylitis Society, UK). A long-acting NSAID at night is helpful for alleviation of morning stiffness. Anti-TNF or anti-IL-17A therapy should be considered in patients who are inadequately controlled on standard therapy, as described for axSpA. Biologic therapies are often highly effective at improving symptoms but it is not clear whether they prevent ankylosis or alter the natural history of the disease. Local glucocorticoid injections can be useful for persistent plantar fasciitis, other enthesopathies and peripheral arthritis. Oral glucocorticoids may be required for acute uveitis but do not help spinal disease. Severe hip, knee or shoulder arthritis with secondary OA may require arthroplasty. Spinal osteotomy, to correct stoop and make eyeline/posture ‘more normal’, can make a signiﬁcant difference to patients with severe ankylosed kyphotic spines. Fig. 24.41 ‘Bamboo’ spine of advanced ankylosing spondylitis. Note the symmetrical marginal syndesmophytes (arrows), sacroiliac joint fusion and generalised osteopenia.

1032 • RHEUMATOLOGY AND BONE DISEASE Pathophysiology Genetic factors have an important role in PsA and family studies have suggested that heritability may exceed 80%. Variants in the HLA-B and HLA-C genes are the strongest genetic risk factors but more than 30 other variants also play a part. Many of these variants overlap with those implicated in psoriasis (p. 1247), where there are more than 40 susceptibility loci. These lie within or close to genes in the IL-12, IL-23 and nuclear factor kappa B (NFκB) signalling pathways. It is thought that an environmental trigger, probably infectious in nature, triggers the disease in genetically susceptible individuals, leading to immune activation involving dendritic cells and T cells. CD8+ T cells (which recognise antigen presented in the context of HLA class I) are more abundant than CD4+ T cells within the joint, which is in keeping with the genetic association between PsA and HLA-C and B variants. There is increasing evidence that the IL-23/ IL-17 pathway plays a pivotal role in PsA. It is thought that the triggering stimulus causes over-production of IL-23 by dendritic cells, which in turn promotes differentiation and activation of Th17 cells, which produce the pro-inﬂammatory cytokine IL-17A. This, along with Th1 cytokines like IFN-γ and TNF-α, acts on macrophages and tissue-resident stromal cells at entheses, in bone and within the joint to produce additional pro-inﬂammatory cytokines and other mediators, which contribute to inﬂammation and tissue damage, as shown in Figure 24.42. Clinical features The presentation is with pain and stiffness affecting joints, tendons, spine and entheses. Joints are typically not swollen; however, several patterns of joint involvement are recognised (see below), including an oligoarticular form. These patterns are not mutually exclusive. Marked variation in disease patterns exists, including a disease course of intermittent exacerbation and remission. Destructive arthritis and disability are uncommon, except in the case of arthritis mutilans. Asymmetrical inﬂammatory mono-/oligoarthritis This often presents abruptly with a combination of synovitis and adjacent periarticular inﬂammation. It occurs most characteristically in the hands and feet, when synovitis of a ﬁnger or toe is coupled with tenosynovitis, enthesitis and inﬂammation of intervening tissue to give a ‘sausage digit’ or dactylitis (Fig. 24.43A). Large joints, such as the knee and ankle, may also be involved, sometimes with very large effusions. Symmetrical polyarthritis This accounts for about 25% of cases. It predominates in women and may resemble RA, with symmetrical involvement of small and large joints in both upper and lower limbs. Nodules and other extra-articular features of RA are absent and arthritis is generally less extensive and more benign. Distal interphalangeal joint arthritis This is quite a common pattern and can be difﬁcult to distinguish from inﬂammatory generalised OA. PsA DIP joint disease is associated with psoriatic nail disease (Fig. 24.43B). Psoriatic spondylitis This type presents with inﬂammatory back or neck pain and prominent stiffness symptoms. Any structure in the spine can be involved, including intervertebral disc entheses and facet joints. It may occur alone or with any of the other clinical patterns described above and is typically unilateral or asymmetric in severity. ESR and CRP are raised, urethritis may be conﬁrmed in the ‘two-glass test’ by demonstration of mucoid threads in the ﬁrst-void specimen that clear in the second. High vaginal swabs may reveal Chlamydia on culture. Except for post-Salmonella arthritis, stool cultures are usually negative by the time the arthritis presents but serology may help conﬁrm previous dysentery. RF, ACPA and ANA are negative. In chronic or recurrent disease, X-rays show periarticular osteoporosis; proliferative erosions, notably at entheses; periostitis, especially of metatarsals, phalanges and pelvis; and large, ‘ﬂuffy’ calcaneal spurs. In contrast to AS, radiographic sacroiliitis is often asymmetrical and sometimes unilateral, and syndesmophytes are predominantly coarse and asymmetrical, often extending beyond the contours of the annulus (‘non-marginal’) (see Fig. 24.40B). Radiographic changes in the peripheral joints and spine are identical to those seen in psoriasis. Management Acute ReA should be treated with rest, NSAIDs and analgesics. Intra-articular or systemic glucocorticoids may be required in patients with severe monarticular synovitis or polyarticular disease, respectively. There is no convincing evidence for the use of antibiotics unless a triggering infection is identiﬁed. If chlamydial urethritis is diagnosed, it should be treated empirically with a short course of doxycycline or a single dose of azithromycin. Treatment with DMARDs (usually sulfasalazine or methotrexate) should be considered for patients with persistent marked symptoms, recurrent arthritis or severe keratoderma blennorrhagica. Anterior uveitis is a medical emergency requiring topical, subconjunctival or systemic glucocorticoids. For DMARD-recalcitrant cases, anti-TNF therapy should be considered. Psoriatic arthritis In the UK and Denmark the estimated population prevalence of psoriatic arthritis (PsA) from registry and coding data is approximately 0.2%. It is likely the true prevalence is considerably higher but this has not been extensively studied. The prevalence of PsA in psoriasis patients, based on clinical assessment, is variable but may be up to 40%. Early PsA may present as axSpA. The onset is usually between 25 and 40 years of age but juvenile forms exist. Occasionally, the arthritis and psoriasis develop synchronously but the onset of musculoskeletal and skin disease is frequently separated by many years. Classiﬁcation of PsA requires key assessments of family history and screening for enthesitis (Box 24.62). 24.62 The CASPAR criteria for psoriatic arthritis Inﬂammatory articular disease (joint, spine or enthesis) with ≥ 3 points from the following (1 point each unless stated): • Current psoriasis (scores 2 points) • History of psoriasis in ﬁrst- or second-degree relative • Psoriatic nail dystrophy • Negative IgM rheumatoid factor1 • Current dactylitis • History of dactylitis • Juxta-articular new bone2 (CASPAR = ClASsiﬁcation for Psoriatic ARthritis) 2Ill-deﬁned ossiﬁcation near joint 1Established by any method except latex. margins (excluding osteophytes) on X-rays of hands or feet.

Spondyloarthropathies • 1033

Investigations The diagnosis is made on clinical grounds. Autoantibodies are generally negative and acute phase reactants, such as ESR and CRP, are raised in only a proportion of patients with active disease. X-rays may be normal or show erosive change with joint space narrowing. Features that favour PsA over RA include the characteristic distribution (see Fig. 24.10, p. 994) of proliferative erosions with marked new bone formation, absence of periarticular osteoporosis and osteosclerosis. Imaging of the axial skeleton often reveals features similar to those in chronic ReA, with coarse, asymmetrical, non-marginal syndesmophytes and asymmetrical sacroiliitis. MRI and ultrasound with power Doppler are increasingly employed to detect synovial inﬂammation and inﬂammation at the entheses. Management Therapy with NSAIDs and analgesics may be sufficient to manage symptoms in mild disease. Intra-articular glucocorticoid injections can control isolated synovitis or enthesitis. Splints and prolonged rest should be avoided because of the tendency to ﬁbrous and bony ankylosis. Patients with spondylitis should be prescribed the same exercise and posture regime as in axSpA/AS. Therapy with DMARDs should be considered for persistent synovitis unresponsive to conservative treatment. Methotrexate is the drug of ﬁrst choice and is also effective Arthritis mutilans This is a deforming erosive arthritis targeting the ﬁngers and toes; it occurs in 5% of cases of PsA. Prominent cartilage and bone destruction results in marked instability. The encasing skin appears invaginated and ‘telescoped’ (‘main en lorgnette’) and the ﬁnger can be pulled back to its original length. Enthesitis-predominant This form of disease presents with pain and stiffness at the insertion sites of tendons and ligaments into bone (enthesitis). Symptoms can be extensive or localised. Typically affected entheses include Achilles tendon insertions, plantar fascia origins, patellar ligament attachments, hip abductor complex insertion at lateral femoral condyle, gluteus medius insertion at greater trochanter, humeral epicondyle tendon attachments, deltoid origin at acromial edge, intercostal muscle attachments at ribs, and pelvic ligament attachments. Nail changes include pitting, onycholysis, subungual hyperkeratosis and horizontal ridging, which are found in 85% of patients with PsA and can occur in the absence of skin disease. The characteristic rash of psoriasis (p. 1247) may be widespread, or conﬁned to the scalp, natal cleft, umbilicus and genitals, where it is easily overlooked. Obtaining a history of psoriasis in a ﬁrst-degree relative can be tricky but is important, given that a positive response contributes to making a diagnosis. Fig. 24.42 Pathogenesis of psoriatic arthritis. Some of the cytokines and cellular interactions believed to be important in psoriatic arthritis are shown. (ADAMTS-5 = aggrecanase; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MMP = matrix metalloproteinase; TNF = tumour necrosis factor; RANKL = RANK ligand) IL-12 Th1 Th17 Th1 Th17 IL-23 IL-17 IL-17 IL-17 RANKL M-CSF Osteoclast precursors MMP ADAMTS-5 TNF-α IL-1 IL-6 TNF-α IFN-γ TNF-α IL-1 IL-6 Dysregulation of immune response in mucosa or skin Synovial fibroblasts Prostaglandins Nitric oxide Pain Vasodilatation Cartilage breakdown Enthesitis at tendon insertions Acute phase proteins Bone erosions Dendritic cell Environmental trigger • Infection • Trauma Genetic predisposition • HLA-C, HLA-B • Other immune response genes Macrophage IL-6

1034 • RHEUMATOLOGY AND BONE DISEASE In Crohn’s disease, more than in colitis, the arthritis usually coincides with exacerbations of the underlying bowel disease and the arthritis improves with effective treatment of the bowel disease. There is some suggestion that the severity and onset of inﬂammatory musculoskeletal symptoms can vary in association with changes in the integrity of the ileocaecal valve, raising the possibility that changes in gut ﬂora may act as triggers for the associated SpA. NSAIDs are best avoided, since they can exacerbate IBD. Instead, judicious use of glucocorticoids, sulfasalazine and methotrexate may be considered. Liaison is necessary between gastroenterologist and rheumatologist with regard to choice of therapy. Anti-TNF therapy is effective in enteropathic arthritis but etanercept should be avoided, as it has no efﬁcacy in IBD. When musculoskeletal symptoms worsen despite anti-TNF therapy, it is wise to exclude bacterial overgrowth as a triggering cause (blind-loop syndrome). Autoimmune connective tissue diseases Autoimmune connective tissue diseases (AICTDs) share many clinical features and are characterised by dysregulation of immune responses, autoantibody production that is often directed at components of the cell nucleus, and tissue damage. Systemic lupus erythematosus Systemic lupus erythematosus (SLE, ‘lupus’) is a rare disease with a prevalence that ranges from about 0.03% in Caucasians to 0.2% in Afro-Caribbeans. Some 90% of affected patients are female and the peak age at onset is between 20 and 30 years. SLE is associated with considerable morbidity and a ﬁvefold increase in mortality compared to age- and gender-matched controls, mainly because of an increased risk of premature cardiovascular disease. Pathophysiology The cause of SLE is incompletely understood but genetic factors play an important role. There is a higher concordance in monozygotic twins and the disease is strongly associated with polymorphic variants at the HLA locus. In a few instances, SLE is associated with inherited mutations in complement components C1q, C2 and C4, in the immunoglobulin receptor FcγRIIIb or in the DNA exonuclease TREX1. Genome-wide association studies have identiﬁed common polymorphisms near several other genes that predispose to SLE, most of which are involved in regulating immune cell function. From an immunological standpoint, the characteristic feature of SLE is autoantibody production. These autoantibodies have speciﬁcity for a wide range of targets but many are directed against antigens present within the cell or within the nucleus. This has led to the hypothesis that SLE may occur because of defects in apoptosis or in the clearance of apoptotic cells, which causes inappropriate exposure of intracellular antigens on the cell surface, leading to polyclonal B- and T-cell activation and autoantibody production. This is supported by the fact that environmental factors that cause ﬂares of lupus, such as ultraviolet light and infections, increase oxidative stress and cause cell damage. Whatever the underlying cause, autoantibody production and immune complex formation are thought to be important mechanisms of tissue damage in active SLE, leading to vasculitis and organ damage. for skin disease (see EULAR guidelines, ‘Further information’, p. 1060). Other DMARDs may also be helpful, including sulfasalazine, ciclosporin and leﬂunomide. Particular attention should be paid to monitoring liver function in patients treated with DMARDs, since abnormalities are common in PsA. Hydroxychloroquine is generally avoided, as it can cause exfoliative skin reactions; it may, however, be tried in the small subset of patients who have mild PsA but no psoriasis and are ANA-positive. Anti-TNF treatment should be considered for individuals with active synovitis who respond inadequately to standard DMARDs, and treatment is effective for both PsA and psoriasis. Ustekinumab, a monoclonal antibody that binds to and neutralises the p40 subunit of IL-12 and IL-23, improves joint, dactylitis and enthesitis lesions in PsA. Secukinumab, a monoclonal antibody that targets IL-17A, has similar efﬁcacy to TNF inhibitors in PsA. Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), which is effective in PsA when DMARD therapy fails, although it appears to be less efﬁcacious than biologic treatment. Adverse effects include weight loss, depression and suicidal ideation. Enteropathic (spondylo)arthritis The overall prevalence of inﬂammatory musculoskeletal disease in inﬂammatory bowel diseases (IBDs: Crohn’s disease and ulcerative colitis) is not well known, as studies have not adequately assessed enthesitis and osteitis lesions, but the musculoskeletal manifestations are in keeping with an SpA phenotype. Involvement of the peripheral joints is seen in about 20% of IBD patients. Oligoarticular disease predominantly affects the large lower limb joints (knees, ankles and hips). Radiographic evidence of sacroiliitis is present in about 20–25% of IBD patients. Fig. 24.43 Psoriatic arthropathy. A Dactylitis. B Distal interphalangeal joint pattern with accompanying nail dystrophy (pitting and onycholysis). A B

Autoimmune connective tissue diseases • 1035

due to the adverse effects of inﬂammation on the endothelium, chronic glucocorticoid therapy and the procoagulant effects of antiphospholipid antibodies. Lung Lung involvement is common and most frequently manifests as pleuritic pain (serositis) or pleural effusion. Other features include pneumonitis, atelectasis, reduced lung volume and pulmonary ﬁbrosis that leads to breathlessness. The risk of thromboembolism is increased, especially in patients with antiphospholipid antibodies. Neurological Fatigue, headache and poor concentration are common and often occur in the absence of laboratory evidence of active disease. More speciﬁc features of cerebral lupus include visual hallucinations, chorea, organic psychosis, transverse myelitis and lymphocytic meningitis. Haematological Neutropenia, lymphopenia, thrombocytopenia and haemolytic anaemia may occur, due to antibody-mediated destruction of Clinical features Symptoms such as fever, weight loss and mild lymphadenopathy may occur during ﬂares of disease activity, whereas others such as fatigue and low-grade joint pains can be constant and not particularly associated with active inﬂammatory disease. Arthritis Arthralgia is a common symptom, occurring in 90% of patients, and is often associated with early morning stiffness. Tenosynovitis may also occur but clinically apparent synovitis with joint swelling is rare. Joint deformities may arise (Jaccoud’s arthropathy) as the result of tendon damage but joint erosions are not a feature. Raynaud’s phenomenon Raynaud’s phenomenon (p. 504) is common and may antedate other symptoms by months or years. SLE can present with Raynaud’s phenomenon, along with arthralgia or arthritis. Secondary Raynaud’s phenomenon associated with SLE and other AICTDs needs to be differentiated from primary Raynaud’s phenomenon, which is common in the general population (up to 5%). Features in favour of secondary Raynaud’s phenomenon include age at onset of over 25 years, absence of a family history of Raynaud’s phenomenon, and occurrence in a male. Examination of capillary nail-fold loops using an ophthalmoscope (and oil placed on the skin) can show loss of the normal loop pattern, with capillary ‘fallout’ and dilatation and branching of loops; these features support either a diagnosis of systemic sclerosis or severe primary Raynaud’s phenomenon. If Raynaud’s phenomenon is severe, digital ulceration can occur (Fig. 24.44). Skin The skin is commonly involved in SLE, and many SLE skin eruptions are precipitated by exposure to ultraviolet light. The main types of skin involvement are: • The classic facial rash (up to 20% of patients). This is erythematous, raised and painful or itchy, and occurs over the cheeks with sparing of the nasolabial folds (Fig. 24.45). Rosacea is a mimic of this rash. • A discoid rash characterised by hyperkeratosis and follicular plugging, with scarring alopecia if it occurs on the scalp. • Diffuse, usually non-scarring alopecia, which may also occur with active disease. • Urticarial eruptions. • Livedo reticularis (Fig. 24.46), which is also a feature of antiphospholipid syndrome (p. 977) and can become frankly vasculitic, if severe. Kidney Renal involvement is one of the main determinants of prognosis and regular monitoring of urinalysis and blood pressure is essential. The typical renal lesion is a proliferative glomerulonephritis (p. 397), characterised by heavy haematuria, proteinuria and casts on urine microscopy. Cardiovascular The most common manifestation is pericarditis. Myocarditis and Libman–Sacks endocarditis can also occur. The endocarditis is due to accumulation on the heart valves of sterile fibrincontaining vegetations, which is thought to be a manifestation of hypercoagulability associated with antiphospholipid antibodies. The risk of atherosclerosis is greatly increased, as is the risk of stroke and myocardial infarction. This is thought to be multifactorial Fig. 24.44 Severe secondary Raynaud’s phenomenon leading to digital ulceration. Fig. 24.45 Malar rash of systemic lupus erythematosus, sparing the nasolabial folds. The rash is notably similar to rosacea, which may itself be associated with inﬂammatory joint diseases such as psoriatic arthritis.

1036 • RHEUMATOLOGY AND BONE DISEASE damage and maintain normal function. Patients should be advised to avoid sun and ultraviolet light exposure and to employ sun blocks (sun protection factor 25–50). Mild to moderate disease Patients with mild disease restricted to skin and joints can sometimes be managed with analgesics, NSAIDs and hydroxychloroquine. Frequently, however, glucocorticoids are also necessary (prednisolone 5–20 mg/day), often in combination with immunosuppressants such as methotrexate, azathioprine or mycophenolate mofetil (MMF). Increased doses of glucocorticoids may be required for ﬂares in activity or complications such as pleurisy or pericarditis. The monoclonal antibody belimumab, which targets the β-cell growth factor BLyS, has recently been shown to be effective in patients with active SLE who have responded inadequately to standard therapy. Severe and life-threatening disease High-dose glucocorticoids and immunosuppressants are required for the treatment of renal, CNS and cardiac involvement. A commonly used regimen is pulsed methylprednisolone (10 mg/kg IV) plus cyclophosphamide (15 mg/kg IV), repeated at 2–3-weekly intervals for six cycles. Cyclophosphamide may cause haemorrhagic cystitis but the risk can be minimised by good hydration and co-prescription of mesna (2-mercaptoethane sulfonate), which binds its urotoxic metabolites. Because of the risk of azoospermia and premature menopause, sperm or oöcyte collection and storage need to be considered prior to treatment with cyclophosphamide. peripheral blood cells. The degree of lymphopenia is a good guide to disease activity. Gastrointestinal Mouth ulcers may occur and may or may not be painful. Peritoneal serositis can cause acute pain. Mesenteric vasculitis is a serious complication, which can present with abdominal pain, bowel infarction or perforation. Hepatitis is a recognised, though rare, feature. Paediatric disease Renal disease and cutaneous manifestations are more frequent in juvenile-onset SLE compared to disease in adults. Similarly, there is subsequently a higher incidence of renal disease, malar rash, Raynaud’s phenomenon, cutaneous vasculitis and neuropsychiatric manifestations than in adults. Investigations The diagnosis is based on a combination of clinical features and laboratory abnormalities. To fulﬁl the classiﬁcation criteria for SLE, at least 4 of the 11 factors shown in Box 24.63 must be present or have occurred in the past. Checking of ANAs, antibodies to ENAs and complement, routine haematology, biochemistry and urinalysis are mandatory. Patients with active SLE test positive for ANA. Some authorities believe that ANA-negative SLE occurs (e.g. in the presence of antibodies to Ro) but others regard SLE as necessarily ANA-positive; the issue may be more to do with sensitivity of the ANA assay at any given time in a disease course. Anti-dsDNA antibodies are positive in many, but not all, patients and are tested at the time of diagnosis by most laboratories using ELISA. ELISAs have low speciﬁcity, whereas testing for anti-dsDNA antibodies using Crithidia luciliae is highly speciﬁc. Patients with active disease tend to have low levels of C3 due to complement consumption, but in some people low C3 and C4 may be the result of inherited complement deﬁciency in C1, C2 or C4 that predisposes to SLE (p. 66). Studies of other family members can help to differentiate inherited deﬁciency from complement consumption. A raised ESR, leucopenia and lymphopenia are typical of active SLE, along with anaemia, haemolytic anaemia and thrombocytopenia. CRP is often normal in active SLE, except in the presence of serositis; thus an elevated CRP suggests infection. Management The therapeutic goals are to educate the patient about the nature of the illness, to control symptoms and to prevent organ Fig. 24.46 Livedo reticularis (systemic lupus erythematosus and anti-phospholipid syndrome). 24.63 Criteria for the classiﬁcation of systemic lupus erythematosus Features Characteristics Malar rash Fixed erythema, ﬂat or raised, sparing the nasolabial folds Discoid rash Erythematous raised patches with adherent keratotic scarring and follicular plugging Photosensitivity Rash due to unusual reaction to sunlight Oral ulcers Oral or nasopharyngeal ulceration, which may be painless Arthritis Non-erosive, involving two or more peripheral joints Serositis Pleuritis (history of pleuritic pain or rub, or pleural effusion) or pericarditis (rub, electrocardiogram evidence or effusion) Renal disorder Persistent proteinuria > 0.5 g/24 hrs or cellular casts (red cell, granular or tubular) Neurological disorder Seizures or psychosis, in the absence of provoking drugs or metabolic derangement Haematological disorder Haemolytic anaemia or leucopenia* (< 4 × 109/L) or lymphopenia* (< 1 × 109/L) or thrombocytopenia* (< 100 × 109/L) in the absence of offending drugs Immunological Anti-DNA antibodies in abnormal titre or presence of antibody to Sm antigen or positive antiphospholipid antibodies Antinuclear antibody (ANA) Abnormal titre of ANA by immunoﬂuorescence An adult has SLE if any 4 of 11 features are present serially or simultaneously *On two separate occasions.

Autoimmune connective tissue diseases • 1037

Pathophysiology The cause of SScl is not completely understood. There is evidence for a genetic component and associations with alleles at the HLA locus have been found. The disease occurs in all ethnic groups and race may inﬂuence severity. Isolated cases have been reported in which an SScl-like disease has been triggered by exposure to silica dust, vinyl chloride, epoxy resins and trichloroethylene. There is clear evidence of immunological dysfunction: T lymphocytes, especially those of the Th17 subtype, inﬁltrate the skin and there is abnormal ﬁbroblast activation, leading to increased production of extracellular matrix in the dermis, primarily type I collagen. This results in symmetrical thickening, tightening and induration of the skin (scleroderma). Arterial and arteriolar narrowing occurs due to intimal proliferation and vessel wall inﬂammation. Endothelial injury causes release of vasoconstrictors and platelet activation, resulting in further ischaemia, which is thought to exacerbate the ﬁbrotic process. Clinical features Skin Initially, there is non-pitting oedema of ﬁngers and ﬂexor tendon sheaths. Subsequently, the skin becomes shiny and taut, and distal skin creases disappear. There can be capillary loss. The face and neck are often involved, with thinning of the lips and radial furrowing. In some patients, skin thickening stops at this stage. Skin involvement restricted to sites distal to the elbow or knee (apart from the face) is thus classiﬁed as lcSScl (Fig. 24.48). Involvement proximal to the knee and elbow and on the trunk is classiﬁed as ‘diffuse disease’ (dcSScl). Raynaud’s phenomenon This is a universal feature and can precede other features by many years. Involvement of small blood vessels in the extremities may cause critical tissue ischaemia, leading to localised distal skin infarction and necrosis. Musculoskeletal features Arthralgia and ﬂexor tenosynovitis are common. Restricted hand function is due to skin rather than joint disease and erosive arthropathy is uncommon. Muscle weakness and wasting can result from myositis. Gastrointestinal involvement Smooth muscle atrophy and ﬁbrosis in the lower two-thirds of the oesophagus lead to reﬂux with erosive oesophagitis. MMF has been used successfully with high-dose glucocorticoids for renal involvement with results similar to those of pulsed cyclophosphamide but fewer adverse effects. Belimumab in combination with standard therapy signiﬁcantly decreases disease activity in SLE patients and is safe and well tolerated. Its role in patients with renal and neurological disease is still under investigation. Rituximab has been reported as being effective in selected cases, though randomised controlled trials have not shown signiﬁcant overall efﬁcacy. Maintenance therapy Following control of acute disease, a typical maintenance regimen is oral prednisolone in a dose of 40–60 mg daily, gradually reducing to 10–15 mg/day or less by 3 months. Azathioprine (2–2.5 mg/kg/day), methotrexate (10–25 mg/week) or MMF (2–3 g/day) should also be prescribed. The long-term aim is to continue the lowest dose of glucocorticoid and immunosuppressant to maintain remission. Cardiovascular risk factors, such as hypertension and hyperlipidaemia, should be controlled and patients should be advised to stop smoking. Patients with SLE and the antiphospholipid antibody syndrome, who have had previous thrombosis, require life-long warfarin therapy. SLE patients are at risk of osteoporosis and hypovitaminosis D, and should be screened with biochemistry and DXA scanning accordingly. Systemic sclerosis Systemic sclerosis (SScl) is an autoimmune disorder of connective tissue, which results in ﬁbrosis affecting the skin, internal organs and vasculature. It is characterised typically by Raynaud’s phenomenon, digital ischaemia (Fig. 24.47), sclerodactyly, and cardiac, lung, gut and renal disease. The peak age of onset is in the fourth and ﬁfth decades and overall prevalence is 10–20 per 100 000, with a 4 : 1 female-to-male. It is subdivided into diffuse cutaneous systemic sclerosis (dcSScl: 30% of cases) and limited cutaneous systemic sclerosis (lcSScl: 70% of cases). Some patients with lcSScl have calcinosis and telangiectasia. The prognosis in dcSScl is poor (5-year survival about 70%). Features that associate with a poor prognosis include older age, diffuse skin disease, proteinuria, high ESR, a low gas transfer factor for carbon monoxide (TLCO) and pulmonary hypertension. Fig. 24.47 Systemic sclerosis. Hands showing tight, shiny skin, sclerodactyly, ﬂexion contractures of the ﬁngers and thickening of the left middle ﬁnger extensor tendon sheath. Fig. 24.48 Typical facial appearance showing telangiectasias in localised cutaneous systemic sclerosis.

1038 • RHEUMATOLOGY AND BONE DISEASE may help patients with symptoms of dysmotility/ pseudo-obstruction. • Hypertension. Aggressive treatment with ACE inhibitors is needed, even if renal impairment is present. • Joint involvement. This may be treated with analgesics and/or NSAIDs. If synovitis is present and both RA (i.e. an ‘overlap’ condition, which needs treatment on its own merit) and OA have been ruled out, low-dose methotrexate can be of value. • Progressive pulmonary hypertension. Early treatment with bosentan is required. In severe or progressive disease, heart–lung transplant may be considered. • Interstitial lung disease. Glucocorticoids and (pulse intravenous) cyclophosphamide are the mainstays of treatment in patients who have progressive interstitial lung disease. Mixed connective tissue disease Mixed connective tissue disease (MCTD) is a condition in which some clinical features of SScl, myositis and SLE all occur in the same patient. It commonly presents with indolent pufﬁness of the ﬁngers (the appearance is between that of SpA-type dactylitis and sclerodactyly) with Raynaud’s phenomenon and myalgias. Most patients have anti-RNP antibodies. Management focuses on treating the components of the disease (see other sections). Primary Sjögren’s syndrome Primary Sjögren’s syndrome (PSS) is characterised by lymphocytic inﬁltration of salivary and lacrimal glands, leading to glandular ﬁbrosis and exocrine failure. The typical age of onset is between 40 and 50, with a 9 : 1 female-to-male ratio. The disease may occur with other autoimmune diseases (secondary Sjögren’s syndrome). Clinical features The eye symptoms, termed keratoconjunctivitis sicca, are due to a lack of lubricating tears, which reﬂects inﬂammatory inﬁltration of the lacrimal glands. Conjunctivitis and blepharitis are frequent, and may lead to ﬁlamentary keratitis due to binding of tenacious mucous ﬁlaments to the cornea and conjunctiva. Oral involvement manifests as a dry mouth (xerostomia). There is a high incidence of dental caries and high risk of dental failure. Other sites of extraglandular involvement are listed in Box 24.64. Often the most disabling symptom is fatigue. There may be an association with inﬂammatory small-joint OA (clinical suspicion, though formal studies have not been done). Sialadenitis, osteoarthritis and xerostomia (SOX) syndrome has been described; this may occur independently of PSS or, more likely, constitute a mild form. Both interstitial lung disease and interstitial nephritis (sometimes complicated by renal tubular acidosis) require proactive screening. PSS is associated with a 40-fold increased lifetime risk of lymphoma, though the complication is still very rare. Investigations The diagnosis can be established by the Schirmer tear test, which measures tear flow over 5 minutes using absorbent paper strips placed on the lower eyelid; a normal result is more than 6 mm of wetting. Staining with rose bengal may show punctate epithelial abnormalities over the area not covered by the open eyelid. If the diagnosis remains in doubt, it can be conﬁrmed by demonstrating focal lymphocytic inﬁltrate in a minor salivary gland biopsy. Most patients have an elevated ESR and Dysphagia and odynophagia may also occur. Involvement of the stomach causes early satiety and occasionally outlet obstruction. Recurrent occult upper gastrointestinal bleeding may indicate a ‘watermelon’ stomach (antral vascular ectasia; up to 20% of patients). Small intestine involvement may lead to malabsorption due to bacterial overgrowth and intermittent bloating, pain or constipation. Dilatation of bowel due to autonomic neuropathy may cause pseudo-obstruction with nausea, vomiting, abdominal discomfort and distension, often worse after food (symptoms can mimic those of an acute abdomen and can lead to erroneous laparotomy). Pulmonary involvement Pulmonary hypertension complicates long-standing disease and is six times more prevalent in lcSScl than in dcSScl. It usually presents with insidiously evolving exertional dyspnoea and signs of right heart failure. Interstitial lung disease is common in patients with dcSScl who have topoisomerase 1 antibodies (Scl70). Dyspnoea can evolve slowly over time or rapidly in occasional cases. Renal involvement One of the main causes of death is hypertensive renal crisis, characterised by rapidly developing accelerated phase hypertension (p. 514) and renal failure. Hypertensive renal crisis is much more likely to occur in dcSScl than in lcSScl, and in patients with topoisomerase 1 and RNP antibodies. Investigations As SScl can affect multiple organs, routine haematology, renal, liver and bone function tests and urinalysis are essential. ANA is positive in about 70%. About 30% of patients with dcSScl have antibodies to topoisomerase 1 (Scl70). About 60% of patients with lcSScl syndrome have anticentromere antibodies (p. 991). Chest X-ray, transthoracic echocardiography and lung function tests are recommended to assess for interstitial lung disease and pulmonary hypertension (low corrected transfer factor may indicate early pulmonary hypertension). High-resolution lung CT is recommended if interstitial lung disease suspected. If pulmonary hypertension is suspected, right heart catheter measurements should be arranged at a specialist cardiac centre. A barium swallow can assess oesophageal involvement. A hydrogen breath test can indicate bacterial overgrowth (p. 808). Management No treatments are available that halt or reverse the ﬁbrotic changes that underlie the disease. The focus of management, therefore, is to slow the effects of the disease on target organs. • Raynaud’s phenomenon and digital ulcers. Avoidance of cold exposure, use of thermal insulating gloves/socks and maintenance of a high core temperature all help. If symptoms are persistent, calcium channel blockers, losartan, ﬂuoxetine and sildenaﬁl have efﬁcacy. Courses of intravenous prostacyclin are used for severe disease and critical ischemia (e.g. 6–8 hours daily for 5 days). The endothelin-1 antagonist bosentan is licensed for treating ischaemic digital ulcers, and digital tip tissue health can be maintained with regular use of fucidin–hydrocortisone cream. • Gastrointestinal complications. Oesophageal reﬂux should be treated with proton pump inhibitors and anti-reﬂux agents. Rotating courses of antibiotics may be required for bacterial overgrowth (e.g. rifaximin, a tetracycline and metronidazole), while metoclopramide or domperidone

Autoimmune connective tissue diseases • 1039

Polymyositis and dermatomyositis Polymyositis (PM) and dermatomyositis (DM) are characterised by proximal skeletal and (cardiac and gut) smooth muscle inﬂammation. In DM, characteristic skin changes also occur. Both diseases are rare, with an incidence of 2–10 cases per million/year. They can occur in isolation or in association with other autoimmune diseases, and both are notably connected with (either previously diagnosed or undisclosed) malignancy. Clinical features The typical presentation of PM and DM is with symmetrical proximal muscle weakness over a few weeks, usually affecting the lower limbs more than the upper, in adults between 40 and 60 years of age. Patients report difﬁculty rising from a chair, climbing stairs and lifting, often (though not always) with muscle pain. Systemic features of fever, weight loss and fatigue are common. Respiratory or pharyngeal muscle involvement can lead to ventilatory failure or aspiration that requires urgent treatment. Interstitial lung disease occurs in up to 30% of patients and is strongly associated with the presence of antisynthetase (Jo-1) antibodies. In DM, the skin lesions include Gottron’s papules, which are scaly, erythematous or violaceous, psoriasiform plaques occurring over the extensor surfaces of PIP and DIP joints, and a heliotrope rash that is a violaceous discoloration of the eyelid in combination with periorbital oedema (Fig. 24.49). Similar rashes occur on the upper back, chest and shoulders (‘shawl’ distribution). Periungual nail-fold capillaries are often enlarged and tortuous. Investigations Muscle biopsy is the pivotal investigation and shows the typical features of ﬁbre necrosis, regeneration and inﬂammatory cell inﬁltrate (Fig. 24.50). Occasionally, however, a biopsy may be normal, particularly if myositis is patchy so, invariably, MRI should be used to identify areas of abnormal muscle for biopsy. Serum levels of creatine kinase are typically raised and are a useful measure of disease activity, although a normal creatine kinase does not exclude the diagnosis, particularly in juvenile myositis. Electromyography is very useful for highlighting non-autoimmune/ non-inﬂammatory myopathies. Screening for underlying malignancy should be undertaken routinely (full examination, chest X-ray, serum urine and protein electrophoresis, CT of chest/abdomen/ pelvis; prostate-speciﬁc antigen should be included in men, and mammography in women). hypergammaglobulinaemia, and one or more autoantibodies, including ANA and RF. ANA-negative disease exists. Anti-Ro and anti-La antibodies are commonly present (see Box 24.10, p. 992). Patients with joint pain, fatigue and RF (with or without ANA) need careful assessment because a number of possibilities exist: PSS and inﬂammatory OA; RA with incidental ANA; RA/ SLE overlap; or RA/PSS overlap. Knowing ACPA status can help (it is positive in RA). Interstitial lung disease complicates PSS in a sizable minority of patients (persistent dry cough, dyspnoea, coarse ‘Velcro’ crackles on lung auscultation). A chest X-ray and lung function tests should be performed. Management No treatments that have disease-modifying effects have yet been identified and management is symptomatic. Lacrimal substitutes, such as hypromellose, should be used during the day in combination with more viscous lubricating application at night. Soft contact lenses can be useful for corneal protection in patients with ﬁlamentary keratitis, and occlusion of the lacrimal ducts is occasionally needed. Artiﬁcial saliva sprays, saliva-stimulating tablets, and pastilles and oral gels can be tried for xerostomia but often chewing gum is most effective. Adequate postprandial oral hygiene and prompt treatment of oral candidiasis are essential. Vaginal dryness is treated with lubricants. A trial of systemic pilocarpine (5–30 mg daily in divided doses) is worthwhile in early disease to amplify glandular function. Hydroxychloroquine (200 mg twice daily) is often used to address skin and musculoskeletal features and may help fatigue. Immunosuppression does not improve sicca symptoms but is essential for progressive interstitial lung disease (e.g. glucocorticoids and cyclophosphamide) and for interstitial nephritis (if hydroxychloroquine is ineffective alone). If non-resolving lymphadenopathy or salivary gland enlargement develops, biopsy should be undertaken to exclude malignancy. 24.64 Features of primary Sjögren’s syndrome Risk factors • Age of onset 40–60 • Female > male • HLA-B8/DR3 Common clinical features • Keratoconjunctivitis sicca • Xerostomia • Salivary gland enlargement • Rashes/skin irritation • Non-erosive arthralgia • Generalised osteoarthritis • Raynaud’s phenomenon • Fatigue Less common features • Low-grade fever • Interstitial lung disease • Anaemia, leucopenia • Thrombocytopenia • Cryoglobulinaemia • Vasculitis • Peripheral neuropathy • Lymphadenopathy • Lymphoreticular lymphoma • Glomerulonephritis • Interstitial nephritis • Renal tubular acidosis Autoantibodies frequently detected • Rheumatoid factor • Antinuclear antibody • SS-A (anti-Ro) • SS-B (anti-La) • Gastric parietal cell • Thyroid Associated autoimmune disorders • Systemic lupus erythematosus • Systemic sclerosis • Coeliac disease • Primary biliary cholangitis • Chronic active hepatitis • Myasthenia gravis (HLA = human leucocyte antigen) Fig. 24.49 Typical eyelid appearance in dermatomyositis. Note the oedema and telangiectasia.

1040 • RHEUMATOLOGY AND BONE DISEASE and results of investigations do not allow a clear diagnosis to be made on the basis of conventional criteria. However, recognising that autoimmunity is present (‘autoimmune diathesis’) without making a speciﬁc diagnosis can help patients move forwards with chronic symptomology. Some of these individuals will progress to having a recognisable AICTD with time; others will continue to have an undifferentiated disease that remains the same for many years, and in others the symptoms will recede. Clinical monitoring and periodic autoimmune serological testing of all patients is sensible. Adult-onset Still’s disease Adult-onset Still’s disease is a rare systemic inﬂammatory disorder of unknown cause, possibly triggered by infection; it is similar to sJIA. It presents with intermittent fever, rash and arthralgia, and has been associated with pregnancy and the postpartum period and with high levels of IL-18. Splenomegaly, hepatomegaly and lymphadenopathy may be present. Investigations typically provide evidence of an acute phase response, with a markedly elevated serum ferritin. Tests for RF and ANA are negative and so adult-onset Still’s disease may be better classiﬁed as an autoinﬂammatory rather than an autoimmune disease. Most patients respond to glucocorticoids but immunosuppressants, such as azathioprine or MMF, can be added when response is inadequate. Canakinumab or anakinra can be used for patients with resistant disease. Vasculitis Vasculitis is characterised by inflammation and necrosis of blood-vessel walls, with associated damage to skin, kidney, lung, heart, brain and gastrointestinal tract. There is a wide spectrum of involvement and severity, ranging from mild and transient disease affecting only the skin, to life-threatening fulminant disease with multiple organ failure. Principal sites of involvement for the main types of vasculitis are summarised in Figure 24.51. The clinical features result from a combination of local tissue ischaemia (due to vessel inﬂammation and narrowing) and the systemic effects of widespread inﬂammation. Systemic vasculitis should be considered in any patient with fever, weight loss, fatigue, Management Oral glucocorticoids (prednisolone 1 mg/kg daily) are the mainstay of initial treatment of PM and DM but high-dose intravenous methylprednisolone (1 g/day for 3 days) may be required in patients with respiratory or pharyngeal weakness. If there is a good response, glucocorticoids should be reduced by approximately 25% per month to a maintenance dose of 5–7.5 mg. Although most patients respond well to glucocorticoids, many need additional immunosuppressive therapy. Methotrexate and MMF are the ﬁrst choices of many but azathioprine and ciclosporin are also used as alternatives. Rituximab appears to show efﬁcacy in a majority of patients, although the only controlled study (which was criticised for its suboptimal design) was negative. In clinical practice, rituximab is an option for use with glucocorticoids, to maintain an early glucocorticoid-induced remission. Intravenous immunoglobulin (IVIg) may be effective in refractory cases. Mepacrine or hydroxychloroquine has been used for skinpredominant disease to some good effect in certain cases. One risk of treatment is glucocorticoid-induced myopathy. If the initial response to treatment is poor, further biopsy then shows type II ﬁbre atrophy in glucocorticoid myopathy (compared with ﬁbre necrosis and regeneration in active myositis). Juvenile dermatomyositis Juvenile dermatomyositis (JDM) is by far the most common inﬂammatory myopathy in children and adolescents, and typically does not require a search for malignancy. The incidence is 2–4 per million (USA and UK) with a median age of onset of 7 years (25% are below 4 years at diagnosis). Many clinical features are similar to those in the adult disease. JDM can be monocyclic, lasting up to 3 years (25–40%), or polycyclic, with periods of remission and relapse (60–75%). In some cases, polycyclic JDM can be chronic and life-long. It is ulcerative in 10–20%. As in adults, calcinosis occurs in about 30%. Intravenous methylprednisolone, then oral glucocorticoids and methotrexate produce a rapid response in many cases. Cyclophosphamide is used for lesional ulceration. IVIg is given in resistant cases. Undifferentiated autoimmune connective tissue disease In some patients, clinical features of AICTD occur, either simultaneously or sequentially, but at any one time the features Fig. 24.50 Muscle biopsy from a patient with polymyositis. The sample shows an intense inﬂammatory cell inﬁltrate in an area of degenerating and regenerating muscle ﬁbres. Fig. 24.51 Types of vasculitis. The anatomical targets of different forms of vasculitis are shown. Giant cell arteritis Kawasaki disease Takayasu arteritis Polyarteritis nodosa Behçet’s disease Behçet’s disease Henoch-Schönlein purpura Polyangiitis with granulomatosis

Eosinophilic granulomatosis with polyangiitis Cryoglobulinaemic vasculitis Microscopic polyangiitis

Vasculitis • 1041

with MRI can be useful in localising abnormalities but, where possible, the diagnosis should be conﬁrmed by biopsy of the kidney or lesions in the sinuses and upper airways. Management for organ-threatening or acute–severe disease is with high-dose glucocorticoids (e.g. daily pulse intravenous methylprednisolone 0.5–1 g for 3 days, then oral prednisolone 0.5 mg/kg) and intravenous cyclophosphamide (e.g. 0.5–1 g every 2 weeks for 3 months), followed by maintenance therapy with lower-dose glucocorticoids and azathioprine, methotrexate or MMF. Plasmapheresis should be considered for fulminant lung disease. Rituximab in combination with high-dose glucocorticoids is equally effective as oral cyclophosphamide at inducing remission in AAV. Glucocorticoids and methotrexate are an effective combination for treating limited AAV where there is indolent sinus, lung or skin disease. AAV has a tendency to relapse and patients must be followed on a regular and long-term basis, monitoring urinalysis for blood and protein, plasma creatinine, ESR, CRP, lung function and PR3 or MPO antibody titres. Takayasu arteritis Takayasu arteritis affects the aorta, its major branches and occasionally the pulmonary arteries. The typical age at onset is 25–30 years, with an 8 : 1 female-to-male ratio. It has a worldwide distribution but is most common in Asia. Takayasu arteritis is characterised by granulomatous inﬂammation of the vessel wall, leading to occlusion or weakening of the vessel wall. It presents with claudication, fever, arthralgia and weight loss. Clinical examination may reveal loss of pulses, bruits, hypertension and aortic incompetence. Investigation will identify an acute phase response and normocytic, normochromic anaemia but the diagnosis is based on angiography, which reveals coarctation, occlusion and aneurysmal dilatation. Treatment is with high-dose glucocorticoids and immunosuppressants, as described for ANCA-associated vasculitis. With successful treatment, the 5-year survival is 83%. Kawasaki disease Kawasaki disease is a vasculitis that mostly involves the coronary vessels. It presents as an acute systemic disorder, usually affecting children under 5 years. It occurs mainly in Japan and other Asian countries, such as China and Korea, but other ethnic groups may also be affected. Presentation is with fever, generalised rash, including palms and soles, inﬂamed oral mucosa and conjunctival injection resembling a viral exanthem. The cause is unknown but evidence of multisystem involvement, rashes, raised inﬂammatory markers and abnormal urinalysis (Box 24.65). Antineutrophil cytoplasmic antibody-associated vasculitis Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a life-threatening disorder characterised by inﬂammatory inﬁltration of small blood vessels, ﬁbrinoid necrosis and the presence of circulating antibodies to antineutrophil cytoplasmic antibody (ANCA). The combined incidence is about 10–15/1 000 000. Two main subtypes are recognised. Microscopic polyangiitis is a necrotising small-vessel vasculitis found with rapidly progressive glomerulonephritis, often in association with alveolar haemorrhage. Cutaneous and gastrointestinal involvement is common and other features include neuropathy (15%) and pleural effusions (15%). Patients are usually myeloperoxidase (MPO) antibody-positive. Secondly, granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) is characterised by granuloma formation, mainly affecting the nasal passages, airways and kidney. A minority of patients present with glomerulonephritis. The most common presentation of granulomatosis with polyangiitis is with epistaxis, nasal crusting and sinusitis, but haemoptysis and mucosal ulceration may also occur. Deafness may be a feature due to inner ear involvement, and proptosis may occur because of inﬂammation of the retro-orbital tissue (Fig. 24.52). This causes diplopia due to entrapment of the extra-ocular muscles, or loss of vision due to optic nerve compression. Disturbance of colour vision is an early feature of optic nerve compression. Untreated nasal disease ultimately leads to destruction of bone and cartilage. Migratory pulmonary inﬁltrates and nodules occur in 50% of patients (as seen on high-resolution CT of lungs). Patients with granulomatosis with polyangiitis are usually proteinase-3 (PR3) antibody-positive (ELISA). Patients with active disease usually have a leucocytosis with elevated CRP, ESR and PR3. Complement levels are usually normal or slightly elevated. Imaging of the upper airways or chest 24.65 Clinical features of systemic vasculitis Systemic • Malaise • Fever • Night sweats • Weight loss with arthralgia and myalgia Rashes • Palpable purpura • Pulp infarcts • Ulceration • Livedo reticularis Ear, nose and throat • Epistaxis • Recurrent sinusitis • Deafness Respiratory • Haemoptysis • Cough • Poorly controlled asthma Gastrointestinal • Abdominal pain (due to mucosal inﬂammation or enteric ischaemia) • Mouth ulcers • Diarrhoea Neurological • Sensory or motor neuropathy Fig. 24.52 Eye involvement in antineutrophil cytoplasmic antibodyassociated vasculitis.

1042 • RHEUMATOLOGY AND BONE DISEASE have symptoms of PMR, and many patients with PMR go on to develop GCA if untreated, many rheumatologists consider them to be different manifestations of the same underlying disorder. Both diseases are rare under the age of 60 years. The average age at onset is 70, with a female-to-male ratio of about 3 : 1. The overall prevalence is about 20 per 100 000 in those over the age of 50 years. Clinical features The cardinal symptom of GCA is headache, which is often localised to the temporal or occipital region and may be accompanied by scalp tenderness. Jaw pain develops in some patients, brought on by chewing or talking. Visual disturbance can occur (most speciﬁcally amaurosis) and a catastrophic presentation is with blindness in one eye due to occlusion of the posterior ciliary artery. On fundoscopy, the optic disc may appear pale and swollen with haemorrhages, but these changes may take 24–36 hours to develop and the fundi may initially appear normal. Rarely, neurological involvement may occur, with transient ischaemic attacks, brainstem infarcts and hemiparesis. In GCA, constitutional symptoms, such as weight loss, fatigue, malaise and night sweats, are common. With PMR, there may be stiffness and painful restriction of active shoulder movements on waking. Muscles are not otherwise tender, and weakness and muscle-wasting are absent. Other conditions that cause PMR-like symptoms are shown in Box 24.66. Investigations The typical laboratory abnormality is an elevated ESR, often with a normochromic, normocytic anaemia. CRP may also be elevated and abnormal liver function can occur. Rarely, PMR and GCA can present with a normal ESR. More objective evidence for GCA should be obtained whenever possible. There are three investigations to consider: temporal artery biopsy, ultrasound of the temporal arteries and 19ﬂuorodeoxyglucose positron emission tomography (19FDG PET scan). Characteristic biopsy ﬁndings are fragmentation of the internal elastic lamina with necrosis of the media in combination with a mixed inﬂammatory cell inﬁltrate. Diagnostic yield is highest with multiple biopsies and multiple section analysis (to detect ‘skip’ lesions). A negative biopsy does not exclude the diagnosis. On ultrasound examination, affected temporal arteries show a ‘halo’ sign. A strongly positive 19FDG PET scan is highly speciﬁc but sensitivity is low. Caution is needed in interpreting weakly positive images. Low-grade vascular uptake may occur in atheromatous arterial disease. Management Prednisolone should be commenced urgently in suspected GCA because of the risk of visual loss (Box 24.67). Response is thought to be an abnormal immune response to an infectious trigger. Cardiovascular complications include coronary arteritis, leading to myocardial infarction, transient coronary dilatation, myocarditis, pericarditis, peripheral vascular insufﬁciency and gangrene. Treatment is with aspirin (5 mg/kg daily for 14 days) and IVIg (400 mg/kg daily for 4 days). Polyarteritis nodosa Polyarteritis nodosa has a peak incidence between the ages of 40 and 50, with a male-to-female ratio of 2 : 1. The annual incidence is about 2/1 000 000. Hepatitis B is an important risk factor and the incidence is 10 times higher in the Inuit of Alaska, in whom hepatitis B infection is endemic. Presentation is with fever, myalgia, arthralgia and weight loss, in combination with manifestations of multisystem disease. The most common skin lesions are palpable purpura (Fig. 24.53), ulceration, infarction and livedo reticularis (see Fig. 24.46). Pathological changes comprise necrotising inﬂammation and vessel occlusion, and in 70% of patients arteritis of the vasa nervorum leads to neuropathy, which is typically symmetrical and affects both sensory and motor function. Severe hypertension and/or renal impairment may occur due to multiple renal infarctions but glomerulonephritis is rare (in contrast to microscopic polyangiitis). The diagnosis is conﬁrmed by conventional or magnetic resonance angiography, which shows multiple aneurysms and smooth narrowing of mesenteric, hepatic or renal systems, or by muscle or sural nerve biopsy, which reveals the histological changes described above. Treatment is with high-dose glucocorticoids and immunosuppressants, as described for ANCA-associated vasculitis. Giant cell arteritis and polymyalgia rheumatica Giant cell arteritis (GCA) is a granulomatous arteritis that affects any large (including aorta) and medium-sized arteries. It is commonly associated with polymyalgia rheumatica (PMR), which presents with symmetrical, immobility-associated neck and shoulder girdle pain and stiffness. Since many patients with GCA Fig. 24.53 Rash of systemic vasculitis (palpable purpura). 24.66 Conditions that can mimic polymyalgia rheumatica • Calcium pyrophosphate disease • Spondyloarthritis • Hyper-/hypothyroidism • Psoriatic arthritis (enthesopathic) • Systemic vasculitis • Myeloma • Inﬂammatory myopathy (particularly inclusion body myositis, p. 1059) • Lambert–Eaton syndrome (p. 1143) • Multiple separate lesions (cervical spondylosis, cervical radiculopathy, bilateral subacromial impingement, facet joint arthritis, osteoarthritis of the acromioclavicular joint)

Vasculitis • 1043

It is predominantly a disease of children and young adults. The usual presentation is with purpura over the buttocks and lower legs, accompanied by abdominal pain, gastrointestinal bleeding and arthralgia. Nephritis can also occur and may present up to 4 weeks after the onset of other symptoms. Biopsy of affected tissue shows a vasculitis with IgA deposits in the vessel wall. Henoch–Schönlein purpura is usually a self-limiting disorder that settles spontaneously without speciﬁc treatment. Glucocorticoids and immunosuppressive therapy may be required in patients with more severe disease, particularly in the presence of nephritis. Cryoglobulinaemic vasculitis This is a small-vessel vasculitis that occurs when immunoglobulins precipitate out in the cold. Cryoglobulins are classiﬁed into three types (see Box 4.21, p. 84). Types II and III are associated with vasculitis. The typical presentation is with a vasculitic rash over the lower limbs, arthralgia, Raynaud’s phenomenon and neuropathy. Some cases are secondary to hepatitis C infection and others are associated with other autoimmune diseases. Affected patients should be screened for evidence of hepatitis B and C infection, and if the results are positive, these should be treated appropriately (pp. 875 and 878). There is no consensus as to how best to treat cryoglobulinaemic vasculitis in the absence of an obvious trigger. Glucocorticoids and immunosuppressive therapy are often used empirically but their efﬁcacy is uncertain. In severe cases, plasmapheresis can be considered. Behçet’s disease This is a vasculitis of unknown aetiology that characteristically targets small arteries and venules. It is rare in Western Europe but more common in ‘Silk Route’ countries, around the Mediterranean and in Japan, where there is a strong association with HLA-B51. Oral ulcers are universal (Fig. 24.54). Unlike aphthous ulcers, they are usually deep and multiple, and last for 10–30 days. Genital ulcers are also a common problem, occurring in 60–80% of cases. The usual skin lesions are erythema nodosum or acneiform lesions but migratory thrombophlebitis and vasculitis also occur. Ocular involvement is common and may include anterior or posterior uveitis or retinal vasculitis. Neurological involvement occurs in 5% and mainly involves the brainstem, is dramatic, such that symptoms will completely resolve within 48–72 hours of starting therapy in virtually all patients. It is customary to use higher doses in GCA (60–80 mg prednisolone) than in PMR (15–20 mg), although the evidence base for this is weak. In both conditions, the glucocorticoid dose should be progressively reduced, guided by symptoms and ESR, with the aim of reaching a dose of 10–15 mg by about 8 weeks. The rate of reduction should then be slowed by 1 mg per month. If symptoms recur, the dose should be increased to that which previously controlled the symptoms, and reduction attempted again in another few weeks. Most patients need glucocorticoids for an average of 12–24 months. For advice on prophylaxis against giant cell-induced osteoporosis, see page 1047. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) Eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss syndrome) is a small-vessel vasculitis with an incidence of about 1–3 per 1 000 000. It is associated with eosinophilia. Some patients have a prodromal period for many years, characterised by allergic rhinitis, nasal polyposis and late-onset asthma that is often difﬁcult to control. The typical acute presentation is with a triad of skin lesions (purpura or nodules), asymmetric mononeuritis multiplex and eosinophilia. Pulmonary inﬁltrates and pleural or pericardial effusions due to serositis may be present. Up to 50% of patients have abdominal symptoms provoked by mesenteric vasculitis. Patients with active disease have raised levels of ESR and CRP and an eosinophilia. Although antibodies to MPO or PR3 can be detected in up to 60% of cases, eosinophilic granulomatosis with polyangiitis is considered to be a distinct disorder from the other ANCA-associated vasculitides. Biopsy of an affected site reveals a small-vessel vasculitis with eosinophilic inﬁltration of the vessel wall. Management is with high-dose glucocorticoids and cyclophosphamide, followed by maintenance therapy with low-dose glucocorticoids and azathioprine, methotrexate or MMF. Henoch–Schönlein purpura Henoch–Schönlein purpura is a small-vessel vasculitis caused by immune complex deposition following an infectious trigger. 24.67 Emergency management of giant cell arteritis • Take blood for CRP, ESR, FBC, bone/liver/renal function, serum protein electrophoresis, CPK, RF, ACPA, ANA, ANCA, complement C3 and C4, immunoglobulins, PTH, TSH, vitamin D and urine electrophoresis • Commence prednisolone (40–60 mg daily), and simultaneously, a weekly oral bisphosphonate and calcium with vitamin D supplements • Consider urgent ophthalmology examination and temporal artery biopsy in patients with visual symptoms • Consider obtaining temporal artery ultrasound or 19FDG-PET scan • Review within 1 week and adjust glucocorticoid doses according to clinical response and results of investigations (ACPA = anti-citrullinated peptide antibody; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; CPK = creatine phosphokinase; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FBC = full blood count; 19FDG-PET = 19ﬂuorodeoxyglucose positron emission tomography; PTH = parathyroid hormone; RF = rheumatoid factor; TSH = thyroid-stimulating hormone) Fig. 24.54 Oral ulceration in Behçet’s disease.

1044 • RHEUMATOLOGY AND BONE DISEASE in rural areas, due to low provision of technologies like DXA, which are required to make the diagnosis. Fractures in patients with osteoporosis can affect any bone but common sites are the forearm (Colles’ fracture), spine (vertebral fractures), humerus and hip. All of these fractures become more common with increasing age (Fig. 24.55). Since only about one-third of vertebral fractures come to medical attention (clinical vertebral fractures), the true number of patients with vertebral fracture is much greater than that shown in Figure 24.55. Of these, hip fractures are the most serious and have an immediate mortality of about 12% and a continued increase in mortality of about 20% when compared with age-matched controls. Treatment of hip fracture accounts for the majority of the health-care costs associated with osteoporosis. Pathophysiology The deﬁning feature of osteoporosis is reduced bone density, which causes micro-architectural deterioration of bone tissue and leads to an increased risk of fracture, in response to minor trauma. The risk of fracture increases markedly with age in both genders (Fig. 24.55). This is mostly attributable to an increased risk of falling with age (p. 1308) but is also due in part to an age-related decline in bone mass, especially in women (Fig. 24.56). Bone mass increases during growth to reach a peak between the ages of 20 and about 45 years, but falls thereafter in both genders with an accelerated phase of bone loss after the menopause in women due to oestrogen deﬁciency. The loss of bone with ageing is caused by an imbalance in the bone remodelling cycle, whereby the amount of new bone formed by osteoblasts cannot keep pace with the amount that is removed by osteoclasts (see Fig. 24.2, p. 985). The reduction in bone formation is thought to be partly due to differentiation of bone marrow stem cells to adipocytes, as opposed to osteoblasts. Osteoporosis sometimes occurs because of failure to attain adequate levels of peak bone mass but is more commonly due to age-related bone loss. Osteoporosis is a complex disease that can occur in association with a wide variety of risk factors, as summarised in Box 24.69. Genetic factors account for up to 80% of variation in bone density, and genome-wide association studies have shown that susceptibility is determined in part by a large number of common variants, some of which are involved in the RANK and Wnt signalling pathways (see Fig. 24.3, p. 986). Rarely, osteoporosis may be caused by mutations in single genes. Environmental factors, such as exercise and calcium intake during growth and adolescence, are important in maximising peak bone mass and in regulating rates of post-menopausal bone loss. Smoking has a detrimental effect on BMD and is associated with an increased fracture risk, partly because female smokers have an earlier menopause than non-smokers. Heavy alcohol intake is a recognised cause of osteoporosis and fractures but moderate intake does not substantially alter risk. Idiopathic osteoporosis The term idiopathic osteoporosis is frequently used to describe the occurrence of osteoporosis in patients with no speciﬁc underlying cause. It is slightly misleading, since most, if not all, patients in this category have age-related osteoporosis or osteoporosis associated with inheritance of genetic variants that regulate bone density. Secondary osteoporosis Osteoporosis can occur in association with a variety of diseases and drug treatments, and in many cases more than one disease although the meninges, hemispheres and cord can also be affected, causing pyramidal signs, cranial nerve lesions, brainstem symptoms or hemiparesis. Recurrent thromboses also occur. Renal involvement is extremely rare. The diagnosis is primarily made on clinical grounds (Box 24.68) but one characteristic feature that can be of diagnostic value is the pathergy test, which involves pricking the skin with a needle and looking for evidence of pustule development within 48 hours. Oral ulceration can be managed with topical glucocorticoid preparations (soluble prednisolone mouthwashes, glucocorticoid pastes). Colchicine can be effective for erythema nodosum and arthralgia. Thalidomide (100–300 mg per day for 28 days initially) is very effective for resistant oral and genital ulceration but is teratogenic and neurotoxic. Glucocorticoids and immunosuppressants are indicated for uveitis and neurological disease. Relapsing polychondritis Relapsing polychondritis is a rare inﬂammatory disease of cartilage that classically presents with acute pain and swelling of one or both ear pinnae, sparing the lower non-cartilaginous portion. Around 30% of patients have coexisting autoimmune or connective tissue disease. Involvement of tracheobronchial cartilage leads to a hoarse voice, cough, stridor or expiratory wheeze. Other manifestations include collapse of the bridge of the nose, scleritis, hearing loss and cardiac valve dysfunction. Cartilage biopsy shows an inﬂammatory inﬁltrate in the perichondrium. Both ESR and CRP are raised in active disease. Pulmonary function tests, including ﬂow–volume loops, should be performed to assess the degree of laryngotracheal disease, since this is an important cause of mortality. Mild disease usually responds to low-dose glucocorticoids or NSAIDs, whereas major tracheobronchial involvement requires high-dose glucocorticoids and immunosuppressants, as described for SLE. Diseases of bone Osteoporosis Osteoporosis is the most common bone disease. It has been estimated that more than 8.9 million fractures occur annually worldwide and most of these occur in patients with osteopenia or osteoporosis. About one-third of all women and one-ﬁfth of men aged 50 and above suffer fractures at some point in life. The burden of osteoporosis-related fractures is predicted to increase by two- to threefold by 2050 on a worldwide basis, due to ageing of the population. Osteoporosis is under-diagnosed and under-treated in Asia and the Indian subcontinent, particularly 24.68 Criteria for the diagnosis of Behçet’s disease Recurrent oral ulceration: minor aphthous, major aphthous or herpetiform ulceration at least three times in 12 months plus two of the following: • Recurrent genital ulceration • Eye lesions: anterior uveitis, posterior uveitis, cells in vitreous on slit-lamp examination, retinal vasculitis • Skin lesions: erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules • Positive pathergy test

Diseases of bone • 1045

Other contributory mechanisms include inhibition of intestinal calcium absorption, increased renal excretion of calcium and secondary hyperparathyroidism, which stimulates osteoclastic bone resorption. Pregnancy-associated osteoporosis This is a rare form of osteoporosis that typically presents with back pain and multiple vertebral fractures during the second or third trimester. The cause is unknown but may relate to an exaggeration of the bone loss that normally occurs during pregnancy in patients with pre-existing low bone mass. Clinical features Osteoporosis does not cause symptoms until a fracture occurs. Non-vertebral fractures are almost always caused by a traumatic event, most usually a simple fall. The term ‘fragility fracture’ is used to describe a fracture that occurs as the result of a fall from standing height or less. These are typical of osteoporosis. It is important to remember that the majority of people who suffer a fragility fracture do not have osteoporosis; some have normal bone density but most have osteopenia (Fig. 24.57 and p. 988). The clinical signs of fracture are pain, local tenderness and deformity. In hip fracture, the patient is (with rare exceptions) unable to weight-bear and has a shortened and externally rotated limb on the affected side. The presentation of vertebral fractures is variable. Some patients present with acute severe back pain. This may radiate to the anterior chest or abdominal wall and be mistaken for a myocardial infarction, aortic dissection or intra-abdominal pathology (p. 176). In others the presentation is with height loss and kyphosis in the absence of pain or with chronic back pain. Sometimes the presentation of osteoporosis is with radiological osteopenia or as a vertebral deformity on an X-ray that has been performed for other reasons. or risk factor is operative. The most important causes are summarised in Box 24.69. Secondary causes of osteoporosis are particularly common in men, occurring in up to 50% of patients. Hypogonadism, glucocorticoid use (see below) and alcohol excess are the most important predisposing factors. Glucocorticoid-induced osteoporosis Glucocorticoid-induced osteoporosis is a common problem in patients with systemic inﬂammatory and chronic pulmonary diseases. The risk of osteoporosis is related to dose and duration of glucocorticoid therapy and increases substantially in patients who have taken more than 7.5 mg of prednisolone daily for more than 3 months (or an equivalent dose of another glucocorticoid). Inhaled glucocorticoids can reduce bone density but the risk of osteoporosis is much lower than with systemic therapy. Glucocorticoids mainly cause osteoporosis by inhibiting bone formation and causing apoptosis of osteoblasts and osteocytes. Fig. 24.55 Fractures associated with osteoporosis. A X-ray of wrist. B Vertebrae. C Humerus. D Hip. E and F The changing incidence of each of these fractures with age in women and men, respectively. From Curtis EM, van der Velde R, Moon RJ, et al. Epidemiology of fractures in the United Kingdom 1988–2012: variation with age, sex, geography, ethnicity and socioeconomic status. Bone 2016; 87:19–26. A B C D E

Fractures 10 000 person-years 45 50 55 60 Age Women 65 70 75 80 85

Fractures 10 000 person-years 45 50 55 60 Age Men 65 70 75 80 85 F Hip Wrist Humerus Clinical vertebral Hip Wrist Humerus Clinical vertebral Fig. 24.56 Changes in bone mass and microstructure with age. Changes in men (blue line) and women (red line). Normal +1.0

–1.0 –2.0 –3.0

Age (years)

Osteopenia Osteoporosis Bone density T-score

1046 • RHEUMATOLOGY AND BONE DISEASE Investigations The most important investigation is DXA at the lumbar spine and hip (see Fig. 24.9, p. 990). This should be considered in patients age over 50 who have already suffered a fragility fracture, and in those with clinical risk factors (Box 24.70) when a fracture risk assessment tool (p. 1060) has returned an elevated value. The risk at which DXA should be performed remains a subject of debate but a 10-year risk of over 10% has been suggested, since there is evidence of beneﬁt from treatment at this level. Other indications for DXA are in patients under 50 years who have very strong risk factors, such as premature menopause or high-dose glucocorticoids. Figure 24.58 provides a suggested algorithm for the investigation of patients with suspected osteoporosis. A history should be taken to identify any predisposing causes, such as early menopause, excessive alcohol intake, smoking and glucocorticoid therapy. Signs of endocrine disease, neoplasia and inﬂammatory disease should be sought on clinical examination. A falls history should be taken and a ‘get up and go’ test performed, especially in older patients (p. 1303). Screening for secondary causes of osteoporosis should be performed, as summarised in Box 24.71. Management The aim of treatment is to reduce the risk of fracture and this can be achieved by a combination of approaches. 24.69 Risk factors for osteoporosis Genetics • Single-gene disorders: LRP5 mutations Oestrogen receptor mutations • Polygenic inheritance: Common variants in many pathways Endocrine disease • Hypogonadism • Hyperthyroidism • Hyperparathyroidism • Cushing’s syndrome Inﬂammatory disease • Inﬂammatory bowel disease • Ankylosing spondylitis • Rheumatoid arthritis Drugs • Glucocorticoids • Gonadotrophin-releasing hormone (GnRH) agonists • Levothyroxine over-replacement • Aromatase inhibitors • Thiazolidinediones • Anticonvulsants • Alcohol intake > 3 U/day • Heparin Gastrointestinal disease • Malabsorption • Chronic liver disease Lung disease • Chronic obstructive pulmonary disease • Cystic ﬁbrosis Miscellaneous • Myeloma • Homocystinuria • Anorexia nervosa* • Highly trained athletes* • HIV infection • Gaucher’s disease • Systemic mastocytosis • Immobilisation • Body mass index < 18 • Heavy smoking • Autoantibodies to osteoprotegerin (OPG) *Hypogonadism also plays a role in osteoporosis associated with these conditions. Fig. 24.57 Relation between bone mineral density (BMD) and fractures. A The relative risk of fracture increases exponentially as BMD falls (blue line), and is 14-fold higher in people with a T-score of <−3.5 compared with those with normal BMD. In absolute terms, however, more fractures occur in people with normal BMD or osteopenia (red line). B The proportions of fractures that occur in people with normal BMD, osteopenia and osteoporosis. +1 to +0.5

+1 +0.5 to 0 0 to -0.5 -0.5 to -1.0 -1.0 to -1.5 -1.5 to -2.0 -2.0 to -2.5 -2.5 to -3.0 -3.0 to -3.5 < -3.5

Number of fractures

Bone density T-score 18% Normal BMD Osteopenia Osteoporosis 50% 32% Normal BMD Osteopenia Osteoporosis Relative risk of fracture A B 24.70 Indications for dual X-ray absorptiometry (DXA) • Low-trauma fracture, age > 50 years • Clinical risk factors and 10-year fracture risk > 10% • Glucocorticoid therapy (> 7.5 mg prednisolone daily for > 3 months) • Assessment of response of osteoporosis to treatment • Assessment of progression of osteopenia to osteoporosis • Age < 50 years and very strong risk factors for osteoporosis

Diseases of bone • 1047

(p. 1308). Hip protectors can reduce the risk of hip fracture in selected patients but adherence is often poor. Pharmacological interventions Several drug treatments are now available to reduce the risk of fracture in osteoporosis. The dosages, mode of administration and indications are summarised in Box 24.72. More detail on the individual drugs is provided below. Bisphosphonates Bisphosphonates are the ﬁrst-line treatment for osteoporosis. These are a class of drugs with a central core of P-C-P atoms, to which various side-chains are attached. Following administration, they target bone surfaces and are ingested by osteoclasts during the process of bone resorption. The bisphosphonate is released within the osteoclasts and impairs bone resorption. This in turn causes an increase in bone density but this is principally due to increased mineralisation of bone, rather than an increase in bone mass (Fig. 24.59). Bisphosphonates reduce the risk of fracture in patients with osteoporosis but do not completely prevent fractures occurring. Oral bisphosphonates are typically given for a period of 5 years, at which point the need for continued therapy should be evaluated, with a repeat DXA if possible. If patients have remained free of fractures after 5 years and if BMD levels have increased and no longer remain in the osteoporotic range, it is usual to instigate a 5-year spell off therapy. Treatment may be continued for up to 10 years in patients whose BMD levels remain in the osteoporotic range after 5 years. A change in treatment should be considered in patients who have lost BMD despite oral bisphosphonates (more than 4%). Most commonly, this will be a switch to parenteral zoledronic acid but teriparatide (TPTD) can also be considered in those with severe spinal osteoporosis. With intravenous zoledronic acid, 3 years of therapy is equivalent to 6 years in terms of fracture risk reduction and many experts recommend periods of 3 years on and 3 years off treatment to reduce the risk of over-suppression of bone turnover. Oral bisphosphonates are poorly absorbed from the gastrointestinal tract and should be taken on an empty stomach Non-pharmacological interventions Advice on smoking cessation, moderation of alcohol intake, adequate dietary calcium intake and exercise should be given. Those with recurrent falls or unsteadiness on a ‘get up and go’ test should be referred to a multidisciplinary falls prevention team Fig. 24.58 Algorithm for the investigation of patients with suspected osteoporosis. Fracture risk is assessed using FRAX or QFracture (see ‘Further information’, p. 1060). Age >50 Fracture risk >10% Age > 50 Low-trauma fracture Age <50 Very strong risk factors DXA spine and hip Screen for secondary causes Correct modifiable risk factors

give drug treatment Correct modifiable risk factors Reassess at a later date Osteopenia Osteoporosis Normal 24.71 Investigations in osteoporosis Investigation Secondary cause of osteoporosis Urea, creatinine and electrolytes Chronic kidney disease Liver function tests and albumin Chronic liver disease Full blood count, erythrocyte sedimentation rate Inﬂammatory disease Myeloma Tissue transglutaminase antibodies Coeliac disease Serum calcium and phosphate Primary hyperparathyroidism Serum 25(OH)D and alkaline phosphatase Vitamin D deﬁciency Osteomalacia Serum parathyroid hormone Primary hyperparathyroidism Thyroid function tests Hyperthyroidism Serum protein electrophoresis Myeloma Monoclonal gammopathy of uncertain signiﬁcance Urinary Bence Jones protein Myeloma Testosterone and gonadotrophins Male hypogonadism Oestrogen and gonadotrophins Female hypogonadism1 Bone biopsy Unexplained early-onset osteoporosis2 Renal disease Multiple possible causes of low bone mass 1Only required for unexplained osteoporosis in young women who are amenorrhoeic. 2Seldom required. Fig. 24.59 Mechanism of action of bisphosphonates. Bisphosphonate given orally or intravenously Bisphosphonate binds avidly to bone surface Bisphosphonate released within osteoclast, causing cell death Osteoclast inhibition increases bone density and mineralisation Osteoclasts resorb bone containing bisphosphonate

1048 • RHEUMATOLOGY AND BONE DISEASE have received long-term bisphosphonates and appear to be the result of over-suppression of normal bone remodelling. In the vast majority, the beneﬁts of bisphosphonate therapy far outweigh the risks but it is important for treatment to be targeted to patients with low BMD who are most likely to beneﬁt. Denosumab Denosumab is a monoclonal antibody that inhibits bone resorption by neutralising the effects of RANKL (see Fig. 24.2, p. 985). It is administered by subcutaneous injection of 60 mg every 6 months in the treatment of osteoporosis and has similar efﬁcacy to zoledronic acid. One potential adverse effect is hypocalcaemia but this can be mitigated by calcium and vitamin D supplements. Denosumab may rarely cause osteonecrosis of the jaw and atypical subtrochanteric fractures. If it is stopped, there is a rebound increase in bone turnover that can be associated with a greater risk of fracture and even hypercalcaemia. Because of this, many experts advise giving a bisphosphonate following cessation of denosumab. Calcium and vitamin D Combined calcium and vitamin D supplements have limited efﬁcacy in the prevention of osteoporotic fractures when given alone but are widely used as an adjunct to other treatments. A typical daily dosage is 1000 mg calcium and 800 IU vitamin D. Calcium and vitamin D supplements have efﬁcacy in preventing fragility fractures in elderly or institutionalised patients who are at high risk of deﬁciency (Box 24.74). Vitamin D supplements alone do not prevent fractures in osteoporosis but there is evidence that the response to bisphosphonates is blunted in patients with vitamin D deﬁciency. If the patient’s dietary calcium is sufﬁcient, stand-alone vitamin D supplements (800 IU daily) can be prescribed as an adjunct to anti-osteoporosis therapies. Teriparatide Teriparatide (TPTD) is the 1-34 fragment of human PTH. It is an effective treatment for osteoporosis, which works by stimulating new bone formation. Although TPTD also stimulates bone resorption, the increase in bone formation is greater, resulting in increased bone density, particularly at sites rich in trabecular bone such as the spine. It is given by a self-administered subcutaneous injection in a dose of 20 μg daily for 2 years. At the end of this period, bisphosphonate therapy or another 24.72 Drug treatments for osteoporosis Drug Regimen Postmenopausal osteoporosis Glucocorticoid osteoporosis Male osteoporosis Alendronic acid 70 mg/week orally ᅚ ᅚ ᅚ Risedronate 35 mg/week orally ᅚ ᅚ ᅚ Ibandronate 150 mg/monthly orally 3 mg/3-monthly IV ᅚ ᅚ ᅚ Zoledronic acid 5 mg annually IV ᅚ ᅚ ᅚ Denosumab 60 mg 6-monthly SC ᅚ – ᅚ Calcium/vitamin D Calcium 500–1000 mg daily Vitamin D 400–800 IU orally ᅚ ᅚ ᅚ Teriparatide 20 μg/day SC ᅚ ᅚ ᅚ Abaloparatide 80 μg/day SC ᅚ – – Hormone replacement therapy Various preparations ᅚ – – Raloxifene 60 mg/day orally ᅚ – – Tibolone 1.25 mg/day orally ᅚ – – (IV = intravenous; SC = subcutaneous) with plain water; no food should be eaten for 30–45 minutes after administration. They are contraindicated in patients with oesophageal stricture or achalasia, since tablets may stick in the oesophagus, causing ulceration and perforation. Upper gastrointestinal upset occurs in about 5% of cases. Oral bisphosphonates can be used in patients with gastro-oesophageal reﬂux disease but may cause worsening of symptoms. The most common adverse effect with intravenous bisphosphonates is a transient inﬂuenza-like illness typiﬁed by fever, malaise, anorexia and generalised aches, which occurs 24–48 hours after administration. This is self-limiting but can be treated with paracetamol or NSAIDs if necessary. It predominantly occurs after the ﬁrst exposure and tolerance develops thereafter. Other adverse effects are shown in Box 24.73. Osteonecrosis of the jaw is characterised by the presence of necrotic bone in the mandible or maxilla, typically occurring after tooth extraction when the socket fails to heal. This complication is very rare in osteoporosis but patients receiving bisphosphonates should be advised to pay attention to good oral hygiene. There is no evidence that temporarily stopping bisphosphonates for tooth extraction alters the risk of osteonecrosis of the jaw. Atypical subtrochanteric fractures have been described in patients who 24.73 Adverse effects of bisphosphonates Common • Upper gastrointestinal intolerance (oral) • Acute phase response (intravenous) Less common • Atrial ﬁbrillation (intravenous zoledronic acid) • Hypocalcaemia (intravenous bisphosphonates) • Atypical subtrochanteric fractures Rare • Uveitis • Osteonecrosis of the jaw • Oesophageal ulceration

Diseases of bone • 1049

prevent vertebral and non-vertebral fractures in post-menopausal osteoporosis. Treatment is associated with a slightly increased risk of stroke but a reduced risk of breast cancer. Other drugs Romosozumab is antibody directed against sclerostin, which is under development for the treatment of osteoporosis. It increases bone formation, inhibits bone resorption and increases BMD. When given subcutaneously in a dose of 210 mg monthly, it reduces the risk of vertebral fractures in patients with postmenopausal osteoporosis. Calcitriol (1,25(OH)2D3), the active metabolite of vitamin D, is licensed for treatment of osteoporosis but it is seldom used because the data on fracture prevention are less robust than for other agents. Surgery Orthopaedic surgery with internal ﬁxation is frequently required to reduce and stabilise osteoporotic fractures. Patients with intracapsular fracture of the femoral neck generally need hemiarthroplasty or total hip replacement in view of the high risk of avascular necrosis. Vertebroplasty is sometimes used in the treatment of painful vertebral compression fractures. It involves injecting methyl methacrylate (MMA) into the affected vertebral body under sedation and local anaesthesia. While randomised trials have shown that vertebroplasty provides no better pain relief than a sham procedure, it is still widely used, particularly in North America. Kyphoplasty is used under similar circumstances, but in this case a needle is introduced into the affected vertebral body and a balloon is inﬂated, which is then ﬁlled with MMA. It has similar efﬁcacy to vertebroplasty but adverse effects are more common. Adverse effects with both procedures include spinal cord compression due to leakage of MMA and fat embolism. Osteomalacia, rickets and vitamin D deﬁciency Osteomalacia and rickets are characterised by defective mineralisation of bone. The most common cause is vitamin D deﬁciency, but both conditions can also occur as the result of inherited defects in renal phosphate excretion, and inherited defects in the vitamin D receptor and in the pathways responsible for vitamin D activation. Other causes are summarised in Box 24.75 and are discussed in more detail below. The term osteomalacia refers to the syndrome when it occurs in adults and rickets is the equivalent syndrome in children. The disease remains prevalent in frail older people who have a poor diet and limited sunlight exposure, and in some Muslim women. Vitamin D deﬁciency Vitamin D deﬁciency is deﬁned to exist when serum 25(OH)D concentrations are below 25 nmol/L (10 ng/mL). People with vitamin D levels in the range 25–50 nmol/L (10–20 ng/mL) are classiﬁed as having vitamin D insufﬁciency, whereas those with 25(OH)D levels above 50 nmol/L (20 ng/mL) are classiﬁed as having normal vitamin D status. In the elderly, a more appropriate normal threshold may be 75 nmol/L (30 ng/mL) or more, though there is some debate on the issue and evidence is not conclusive. The likelihood of developing vitamin D deﬁciency is strongly related to sunlight exposure. It is common in northern latitudes (or southern latitudes in the southern hemisphere) and shows seasonal variation. Vitamin D deﬁciency is also common in women who, for cultural reasons, cover their skin and face. Vitamin D 24.74 Osteoporosis in old age • Bone loss: due to increased bone turnover, with an age-related defect switch in differentiation of bone marrow stromal cells to form adipocytes as opposed to osteoblasts. • Fractures due to osteoporosis: common cause of morbidity and mortality, although fracture healing is not delayed by age. • Recurrent fractures: those who suffer a fragility fracture are at increased risk of further fracture, so should be investigated for osteoporosis and treated if this is conﬁrmed. • Falls: risk factors for falls (such as visual and neuromuscular impairments) are independent risk factors for hip fracture in elderly individuals, so intervention to prevent falls is as important as treatment of osteoporosis (p. 1308). • Intravenous zoledronic acid: reduces mortality and subsequent fracture in selected elderly patients with hip fractures. • Calcium and vitamin D: reduce the risk of fractures in those who are housebound or living in care homes. inhibitor of bone resorption should be administered to maintain the increase in BMD. TPTD and oral bisphosphonates should not be given in combination, however, since the bisphosphonate blunts the anabolic effect. The efﬁcacy of TPTD for prevention of non-vertebral fractures is similar to that of bisphosphonates but it is superior to oral bisphosphonates in preventing vertebral fractures. The most common adverse effects are headache, muscle cramps and dizziness. Mild hypercalcaemia may occur but it is usually asymptomatic and does not require discontinuation of treatment. Monitoring of serum calcium is not required during TPTD treatment. Abaloparatide Abaloparatide is the 1-34 fragment of PTH-related protein. It works in a similar way to TPTD to stimulate bone formation. It is given as a self-administered injection of 80 μg daily for 18 months. At the end of this period an inhibitor of bone resorption should be given to maintain the increase in bone mass. Efﬁcacy has been demonstrated for the prevention of vertebral fractures with effects similar to those of TPTD. Adverse effects are similar to those of TPTD. Hormone replacement therapy Cyclical HRT with oestrogen and progestogen prevents post-menopausal bone loss and reduces the risk of vertebral and non-vertebral fractures in postmenopausal women. It is primarily indicated for the prevention of osteoporosis in women with an early menopause (p. 655) and for treatment of women with osteoporosis in their early ﬁfties who have troublesome menopausal symptoms. It is not recommended above the age of 60 because the risk of an increased risk of breast cancer, cardiovascular disease and venous thromboembolic disease. Raloxifene Raloxifene is a selective oestrogen receptor modulator (SERM) that acts as a partial agonist at oestrogen receptors in bone and liver, but as an antagonist in breast and endometrium. It is effective in reducing the risk of vertebral fractures but does not inﬂuence the risk of non-vertebral fracture and is seldom used. Adverse effects include muscle cramps, worsening of hot ﬂushes and an increased risk of venous thromboembolic disease. Bazedoxifene is a related SERM that has similar effects to raloxifene. Tibolone Tibolone has partial agonist activity at oestrogen, progestogen and androgen receptors. It has been shown to

1050 • RHEUMATOLOGY AND BONE DISEASE about 70% is made in the skin, where 7-dehydrocholesterol is converted to cholecalciferol under the inﬂuence of ultraviolet light, whereas the remaining 30% is derived from the diet. The main dietary sources are oily ﬁsh and meat, although bread and dairy products are fortiﬁed with vitamin D in some countries. On entering the circulation, vitamin D is hydroxylated in the liver to form 25(OH) vitamin D and this is further hydroxylated in the kidney to form 1,25(OH)2D, the biologically active metabolite. The 1,25(OH)2D primarily acts on the gut to increase intestinal calcium absorption but also acts on the skeleton to stimulate bone remodelling. Synthesis of 1,25(OH)2D is regulated by a negative feedback loop orchestrated by the parathyroid glands. When vitamin D levels fall – as the result of lower sunlight exposure or dietary lack – production of 1,25(OH)2D is reduced, causing a reduction in calcium absorption from the gut. This causes a transient fall in serum calcium, which is detected by calciumsensing receptors on the parathyroid chief cells; this increases PTH secretion, which restores calcium levels to normal. Vitamin D deﬁciency is, therefore, usually characterised by a low level of 25(OH)D and a raised level of PTH. Sometimes, low 25(OH) D levels may be observed in the presence of a normal PTH concentration. This is of uncertain clinical signiﬁcance but might be due to variations in levels of vitamin D-binding protein. Serum concentrations of vitamin D are under genetic control and are associated with variants close to the GC gene, which encodes vitamin D-binding protein; the DHCR7 gene, which encodes 7-dehydrocholesterol reductase, responsible for catalysing conversion of 7-DHC to 25(OH)D; the CYP2R1 gene, which encodes vitamin D-25-hydroxylase, responsible for hydroxylation of vitamin D in the liver; and the CYP24A1 gene, which encodes vitamin D-24-hydroxylase, responsible for converting 25(OH)D to the inactive metabolite 24,25(OH)2D. deﬁciency is more common in the winter and spring, and less common in summer and autumn (Fig. 24.60). Pathogenesis The source of vitamin D and pathways involved in regulating its metabolism are shown in Figure 24.61. In normal individuals, vitamin D (also known as cholecalciferol) comes from two sources: 24.75 Causes of osteomalacia and rickets Cause Predisposing factor Mechanism Vitamin D deﬁciency Classical Lack of sunlight exposure and poor diet Reduced cholecalciferol synthesis in the skin/low levels of vitamin D in the diet Gastrointestinal disease Malabsorption Malabsorption of dietary vitamin D and calcium Failure of 1,25 vitamin D synthesis Chronic renal failure Hyperphosphataemia and kidney damage Impaired conversion of 25(OH)D3 to 1,25(OH)2D3 Vitamin D-resistant rickets type I (autosomal recessive) Loss-of-function mutations in renal 25(OH)D 1α-hydroxylase enzyme Impaired conversion of 25(OH)D3 to 1,25(OH)2D3 Vitamin D receptor defects Vitamin D-resistant rickets type II (autosomal recessive) Loss-of-function mutations in vitamin D receptor Impaired response to 1,25(OH)2D3 Defects in phosphate and pyrophosphate metabolism Hypophosphataemic rickets (X-linked dominant) Mutations in PHEX Increased FGF23 production (mechanism unclear) Autosomal dominant hypophosphataemic rickets Mutation in FGF23 Mutant FGF23 is resistant to degradation Autosomal recessive hypophosphataemic rickets Mutations in DMP1 Increased production of FGF23 Local deﬁciency of DMP1 inhibits mineralisation Tumour-induced hypophosphataemic osteomalacia Ectopic production of FGF23 by tumour Over-production of FGF23 Hypophosphatasia Mutations in ALPL, which encodes alkaline phosphatase Inhibition of bone mineralisation due to accumulation of pyrophosphate in bone Iatrogenic and other causes Bisphosphonate therapy High-dose etidronate/pamidronate Drug-induced impairment of mineralisation Aluminium Use of aluminium-containing phosphate binders or aluminium in dialysis ﬂuid Aluminium-induced impairment of mineralisation Fluoride High ﬂuoride in water Inhibition of mineralisation by ﬂuoride (FGF23 = ﬁbroblast growth factor 23) Fig. 24.60 Seasonal changes in vitamin D concentrations. To convert nmol/L to ng/mL, multiply by 2.5. Adapted from McDonald HM, Mavroeidi A, Fraser WD, et al. Sunlight and dietary contributions to the seasonal vitamin D status of cohorts of healthy postmenopausal women living at northerly latitudes: a major cause for concern? Osteoporosis Int 2011; 22:2461–2472.

25(OH)D (nmol/L) SW England NE Scotland Summer Autumn Winter Spring

Diseases of bone • 1051

vitamin D deﬁciency or vitamin D insufﬁciency is uncertain. There is some evidence that response to bisphosphonate treatment of osteoporosis is impaired in patients with vitamin D deﬁciency and this is another indication for supplements. In patients who are receiving intravenous bisphosphonates and denosumab for osteoporosis, vitamin D deﬁciency should be corrected by supplementation to reduce the risk of hypocalcaemia. In this case, it is customary to give higher doses of vitamin D, such as 20 000–25 000 IU once a week for 4 weeks or to give lower doses over a more prolonged period. Osteomalacia and rickets Severe and prolonged vitamin D deﬁciency can result in the occurrence of osteomalacia in adults and rickets in children. Improvements in nutrition mean that these are now relatively uncommon conditions in developed countries but they remain prevalent in elderly housebound individuals, some Muslim women who wear a veil (hijab) that covers a large amount of exposed skin, and people with malabsorption. Pathogenesis Osteomalacia and rickets occur as the result of chronic secondary hyperparathyroidism, which invariably accompanies severe and long-standing vitamin D deﬁciency. The sustained elevation in PTH levels maintains normal levels of serum calcium by increasing bone resorption, which eventually causes progressive demineralisation of the skeleton. Phosphate that is released during the process of bone resorption is lost through increased renal excretion, resulting in hypophosphataemia. The raised levels of PTH stimulate osteoblast activity and cause new bone formation Fig. 24.61 Vitamin D metabolism. Vitamin D is produced in the skin from 7-dehydrocholesterol (7-DHC) by ultraviolet B (UVB) light. The 7-dehydrocholesterol reductase enzyme, which is encoded by the DHCR7 gene, opposes the effect of UVB by converting 7-DHC to cholesterol. The vitamin D then undergoes hydroxylation steps in the liver and kidney to form the active metabolite 1,25(OH)2D, which regulates calcium homeostasis by stimulating calcium absorption from the diet and bone resorption. See text for details. Liver Kidney Parathyroids Gut Sunlight 7-DHC 1,25(OH2)D (active) Calcium absorption↑ Bone resorption↑ -ve feedback Renal tubules 24,25(OH2)D (inactive) Serum calcium↑ Serum phosphate↓ CYP2R1 Vitamin D Cholesterol UVB DCHR7 PTH Calcium-sensing receptor PTH secretory granules Parathyroid chief cell –ve Ca2+ Ca2+ Ca2+ Bone CYP27B1 CYP24A1 25(OH)D (inactive) PTH Clinical features Vitamin D deﬁciency does not cause symptoms and the diagnosis is made as the result of biochemical testing. Low circulating concentrations of vitamin D have been associated with a wide range of diseases, including most types of cancer, diabetes, multiple sclerosis and chronic inﬂammatory diseases. These associations are unlikely to be causal but most probably arise as the result of reduced sunlight exposure and poor diet in people who are ill. If vitamin D deﬁciency is prolonged and severe, then osteomalacia and rickets may occur, as discussed below. The consequences of biochemical vitamin D deﬁciency and insufﬁciency on bone health and general health are unclear. Investigations The diagnosis can be made by measurement of serum 25(OH)D. In patients with low 25(OH)D, measurements of PTH, serum calcium, phosphate and ALP should also be considered. Low levels of 25(OH)D in the absence of other abnormalities is unlikely to be of any clinical signiﬁcance and may be due to low levels of vitamin D-binding protein. If low 25(OH)D levels are combined with raised levels of PTH, this is of more signiﬁcance since it indicates secondary hyperparathyroidism. Serum ALP, calcium and phosphate levels are normal in uncomplicated vitamin D deﬁciency. Management The clinical beneﬁt of treating biochemical vitamin D deﬁciency is uncertain. Vitamin D supplements should be considered in patients who have low 25(OH)D levels and raised levels of PTH. In most patients, cholecalciferol in a dose of 800 IU daily should be sufﬁcient to correct the deﬁciency. The beneﬁt of treating seasonal

1052 • RHEUMATOLOGY AND BONE DISEASE thickening and widening of the epiphyseal plate. A radionuclide bone scan may show multiple hot spots in the ribs and pelvis at the site of fractures and the appearance may be mistaken for metastases. Where there is doubt, the diagnosis can be conﬁrmed by bone biopsy, which shows the pathognomonic features of increased thickness and extent of osteoid seams (Fig. 24.62B). Management Osteomalacia and rickets respond promptly to treatment with vitamin D. A wide variety of doses can be used. Treatment with between 10 000 and 25 000 IU daily for 2–4 weeks is associated with rapid clinical improvement, an elevation in serum 25(OH)D and a reduction in PTH. Serum ALP levels sometimes rise initially as mineralisation of bone increases but eventually fall to within the reference range as the bone disease heals. Subsequently, the dose of vitamin D can usually be reduced to a maintenance level of 800–1600 IU daily (10–20 μg), except in patients with malabsorption, who may require higher doses. Vitamin D-resistant rickets This is a genetically determined condition that presents in childhood with rickets that is resistant to therapy with vitamin D in standard dosages. Pathogenesis Type I vitamin D-resistant rickets (VDRR) is caused by inactivating mutations in the 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) enzyme, which converts 25(OH)D to the active metabolite 1,25(OH)2D3. Type II VDRR is caused by inactivating mutations in the vitamin D receptor, which impair its ability to activate gene transcription. Both are recessive disorders and consanguinity is common. Clinical features These are as described above for infantile rickets. The diagnosis is usually ﬁrst suspected when the patient fails to respond to vitamin D supplementation. Investigations The biochemical features of type I VDRR are similar to those of ordinary vitamin D deﬁciency, except that levels of 25(OH)D are normal but 1,25(OH)2D is low. In type II VDRR, 25(OH)D is normal but PTH and 1,25(OH)2D3 values are raised. Management Type I VDRR responds fully to treatment with the active vitamin D metabolites 1α-hydroxyvitamin D (1–2 μg daily, orally) or 1,25-dihydroxyvitamin D (0.25–1.5 μg daily, orally). Calcium supplements are not necessary unless there is dietary deﬁciency. Type II VDRR sometimes responds partially to very high doses of active vitamin D metabolites, which can activate the mutant receptor, although additional calcium and phosphate supplements are also necessary. Hereditary hypophosphataemic rickets This group of disorders are caused by inherited defects in renal tubular phosphate reabsorption. The most common is X-linked hypophosphataemic rickets (XLH), but autosomal dominant and autosomal recessive forms also occur (Box 24.75). but the matrix is not mineralised properly because of deﬁciency of calcium and phosphate. The under-mineralised bone is soft, mechanically weak and subject to fractures, particularly stress fractures. Normal levels of serum calcium tend to be maintained until a very advanced stage, when hypocalcaemia may occur. Clinical features Vitamin D deﬁciency in children causes delayed development, muscle hypotonia, craniotabes (small unossiﬁed areas in membranous bones of the skull that yield to ﬁnger pressure with a cracking feeling), bossing of the frontal and parietal bones and delayed anterior fontanelle closure, enlargement of epiphyses at the lower end of the radius, and swelling of the rib costochondral junctions (‘rickety rosary’). Osteomalacia in adults can present with fractures and low BMD, mimicking osteoporosis. Other symptoms include bone pain and general malaise. Proximal muscle weakness is prominent and the patient may walk with a waddling gait and struggle to climb stairs or stand up from a chair. There may be bone and muscle tenderness on pressure, and focal bone pain can be due to ﬁssure fractures of the ribs and pelvis. Investigations The diagnosis can usually be made by measurement of serum 25(OH)D, PTH, calcium, phosphate and ALP. Typically, serum ALP levels are raised, 25(OH)D levels are undetectable and PTH is markedly elevated. Serum phosphate levels tend to be low but serum calcium is usually normal, unless the disease is advanced. X-rays often show osteopenia or vertebral crush fractures and, with more advanced disease, focal radiolucent areas (pseudofractures or Looser’s zones) may be seen in ribs, pelvis and long bones (Fig. 24.62A). In children, there is Fig. 24.62 Osteomalacia. A X-ray of the pelvis showing pseudofractures affecting the inferior and superior pubic rami on the left side (arrows). Healing pseudofractures with callus formation are also visible at the inferior and superior pubic rami on the right side (arrows). B Photomicrograph of bone biopsy from an osteomalacic patient showing thick osteoid seams (stained light blue, arrows) that cover almost all of the bone surface. Calciﬁed bone is stained dark blue. A B

Diseases of bone • 1053

be identiﬁed by whole-body MRI or CT. Medical management is with phosphate supplements and active vitamin D metabolites but the treatment of choice is surgical resection of the primary tumour, which is curative. Hypophosphatasia Hypophosphatasia is an autosomal recessive disorder caused by loss-of-function mutations in the TNALP gene, which result in accumulation of pyrophosphate and inhibition of bone mineralisation. Chondrocalcinosis may also occur. The typical presentation is with severe intractable rickets during infancy, sometimes in association with seizures. Investigations show low or undetectable levels of serum ALP but normal levels of calcium, phosphate, PTH and vitamin D metabolites. Urinary excretion of pyridoxal 5′ phosphate and phosphoethanolamine (substrates for ALP) is increased. Until recently, this condition was fatal during childhood but remarkable therapeutic responses have been obtained with recombinant ALP therapy (asfotase alfa), which is curative. Heterozygous carriers of mutation in TNALP may present in adulthood with osteoporosis, fractures and low ALP values. The best mode of treatment for these patients remains to be determined, except that bisphosphonates should be avoided since they may exacerbate the mineralisation defect. Other causes of osteomalacia These are summarised in Box 24.75. Osteomalacia may occur as a component of renal osteodystrophy in patients with chronic kidney disease. The mechanism is reduced conversion of 25(OH)D into the active metabolite 1,25(OH)2D by the failing kidney (p. 418). Aluminium intoxication is now rare due to reduced use of aluminium-containing phosphate binders and removal of aluminium from the water supplies used in dialysis. If aluminium intoxication is suspected, the diagnosis can be conﬁrmed by demonstration of aluminium at the calciﬁcation front in a bone biopsy. Osteomalacia due to bisphosphonates has mostly been described in patients with Paget’s disease who are receiving etidronate and high-dose pamidronate. It is usually asymptomatic and healing occurs when treatment is stopped. Excessive ﬂuoride intake causes osteomalacia due to direct inhibition of mineralisation and is common in parts of the world where there is a high ﬂuoride content in drinking water. The condition reverses when ﬂuoride intake is reduced. Paget’s disease of bone Paget’s disease of bone (PDB) is characterised by focal areas of increased and disorganised bone remodelling involving one or more skeletal sites. The disease is common in the UK, affecting about 1% of those aged above 55, and in other countries in Europe. It is rare in Scandinavia, the Indian subcontinent and the rest of Asia. The prevalence doubles each decade from the age of 50 onwards and affects up to 8% of the UK population by the age of 85. Pathophysiology The primary abnormality is increased osteoclastic bone resorption, accompanied by marrow ﬁbrosis, increased vascularity of bone and increased, but disorganised, bone formation. Osteoclasts in PDB are greater in number and unusually large, containing characteristic nuclear inclusion bodies. Genetic factors are important and mutations in the SQSTM1 gene are a common Pathophysiology All forms of hereditary hypophosphataemic rickets are associated with raised circulating concentrations of the phosphate-regulating hormone ﬁbroblast growth factor 23 (FGF23). This hormone is produced by osteocytes (see Fig 24.3, p. 986) and enters the circulation, where it is normally inactivated by proteolytic cleavage. Production of FGF23 by osteocytes is under tonic inhibition by DMP1 and PHEX. In XLH, the inhibitory effect on FGF23 production is lost due to mutations in PHEX and a similar situation occurs in autosomal recessive hypophosphataemic rickets (ARHR1) due to loss-of-function mutations in DMP1. Mutations in the ENPP1 gene, which encodes a phosphatase responsible for degradation of pyrophosphate, can also cause a recessive form of hypophosphataemic rickets (ARHR2). In autosomal dominant hypophosphataemic rickets (ADHR), the FGF23 protein carries mutations that prevent FGF23 being degraded, thereby causing accumulation of intact FGF23 hormone in the circulation. In all three diseases, the elevation in FGF23 results in osteomalacia and rickets by causing phosphaturia by up-regulation of sodium-dependent phosphate transporters in the renal tubules, and also by inhibiting conversion of 25(OH)D to 1,25(OH)2D by the kidney, which in turn causes reduced calcium and phosphate absorption from the gut. Clinical features The presentation is with symptoms and signs of rickets during childhood that do not respond to vitamin D supplementation. In adults, hypophosphataemic rickets may be accompanied by dental abscesses, and by bone and joint pain due to the development of an enthesopathy. Investigations The diagnosis can be conﬁrmed by the ﬁnding of low serum phosphate levels and a reduction in tubular reabsorption of phosphate. Serum levels of vitamin D are normal and PTH is normal or slightly elevated. Serum concentrations of FGF23 are markedly elevated. The causal mutation can be deﬁned by genetic testing. Management The aim of treatment is to ameliorate symptoms, restore normal growth and maintain serum phosphate levels within the reference range. Traditionally, treatment has been with phosphate supplements (1–4 g daily) and 1-α-hydroxyvitamin D (1–2 μg daily) or 1,25-dihydroxyvitamin D (0.5–1.5 μg daily) with the aim of promoting intestinal calcium and phosphate absorption. Levels of calcium and phosphate, as well as renal function, should be monitored regularly and the doses of phosphate and vitamin D metabolites carefully titrated to maintain serum phosphate within the normal range but avoid hypercalcaemia. Recently, a neutralising antibody to FGF23 has been developed that can reverse the biochemical abnormalities in hereditary hypophosphataemic rickets and it is likely that this will be a future treatment option. Tumour-induced osteomalacia This is a rare syndrome caused by over-production of FGF23 by mesenchymal tumours. The presentation is with severe osteomalacia and hypophosphataemia in an adult patient with no obvious predisposing risk factor for vitamin D deﬁciency. Biochemical ﬁndings are as described for hereditary hypophosphataemic rickets. The underlying tumour can sometimes

1054 • RHEUMATOLOGY AND BONE DISEASE in affected bones (Fig. 24.63A). If the bone scan is positive, X-rays should be taken to conﬁrm the diagnosis. Bone biopsy is not usually required but may help to exclude osteosclerotic metastases in cases of diagnostic uncertainty. Management The main indication for treatment with inhibitors of bone resorption is bone pain, which is thought to be due to increased metabolic activity (Box 24.76). Patients should be carefully assessed to determine the cause of the pain since it can be difficult to differentiate the pain caused by increased metabolic activity of PDB from that caused by complications such as bone deformity, nerve compression symptoms and OA. The bisphosphonates pamidronate, risedronate and zoledronic acid are highly effective at suppressing the elevations in bone turnover that are characteristic of PDB and also improve bone pain that is caused by increased metabolic activity. If there is doubt about whether the pain is due to PDB, it can be worthwhile giving a therapeutic trial of bisphosphonate to determine whether the symptoms improve. A positive response indicates that the pain was due to increased metabolic activity. There is no evidence as yet to suggest that bisphosphonates prevent the development of complications in PDB. Repeated courses of bisphosphonates can be given if symptoms recur. cause of classical PDB. The presence of nuclear inclusion bodies in osteoclasts has fuelled speculation that PDB might be caused by a slow virus infection but this is unproven. Biomechanical factors may inﬂuence which bones are affected, as PDB often starts at sites of muscle insertions into bone and, in some cases, localises to bones or limbs that have been subjected to repetitive trauma or overuse. Involvement of subchondral bone can compromise the joint and predispose to OA. The prevalence of PDB has fallen in many countries over recent decades, suggesting that environmental factors play a role, but the identity of these triggers remains unclear. Clinical features The axial skeleton is predominantly affected and common sites of involvement are the pelvis, femur, tibia, lumbar spine, skull and scapula. The most common presentation is with bone pain localised to an affected site but bone deformity, deafness and pathological fractures may also be presenting features. Many patients are asymptomatic and the diagnosis is frequently made on the basis of an X-ray or blood test performed for another reason. Clinical signs include bone deformity and expansion, and increased warmth over an affected bone. Neurological problems, such as deafness, cranial nerve defects, nerve root pain, spinal cord compression and spinal stenosis, may occur due to enlargement of affected bones and encroachment on the spinal cord and nerve foramina. Surprisingly, deafness seldom results from compression of the auditory nerve but is conductive, due to osteosclerosis of the temporal bone. The increased vascularity of Pagetic bone can rarely precipitate high-output cardiac failure in elderly patients with limited cardiac reserve. Osteosarcoma is an unusual but serious complication that presents with increasing pain and swelling of an affected site. Investigations The characteristic features are an isolated elevation in ALP and bone expansion on X-rays, with alternating areas of radiolucency and osteosclerosis (Fig. 24.63B). Levels of ALP can be normal if only a single bone is affected. The best way of identifying affected sites is a radionuclide bone scan, which shows increased uptake 24.76 Medical management of Paget’s disease Drug Route of administration Dose Etidronate Oral 400 mg daily for 3–6 months Tiludronate Oral 400 mg daily for 3–6 months Risedronate Oral 30 mg daily for 2 months Pamidronate IV 1–3 × 60 mg infusions Zoledronic acid IV 1 × 5 mg infusion Calcitonin SC 100–200 IU 3 times weekly for 2–3 months Fig. 24.63 Paget’s disease. A 99mTc-labelled bisphosphonate scintigraphy from a patient with Paget’s disease, illustrating the intense tracer uptake and deformity of the affected femur. B The typical radiographic features with expansion of the femur, alternating areas of osteosclerosis and radiolucency of the trochanter, and pseudofractures breaching the bone cortex (arrows). A B

Diseases of bone • 1055

important predisposing factors include high-dose glucocorticoid treatment, alcohol excess, SLE, HIV and radiotherapy, but in many of these conditions the pathophysiology is poorly understood. The presentation is with pain localised to the affected site, which is exacerbated by weight-bearing. The diagnosis can be conﬁrmed by MRI, which shows evidence of subchondral necrotic bone and bone marrow oedema. X-rays are normal in the early stages but later may show evidence of osteosclerosis and deformity of the affected bone. There is no speciﬁc treatment. Management should focus on controlling pain and encouraging mobilisation (p. 1000). Symptoms often improve spontaneously with time but joint replacement may be required in patients who have persisting pain in association with signiﬁcant structural damage to the affected joint. Scheuermann’s osteochondritis This disorder predominantly affects adolescent boys, who develop a dorsal kyphosis in association with irregular radiographic ossiﬁcation of the vertebral end plates. It has a strong genetic component and may be inherited in an autosomal dominant manner. Most patients are asymptomatic but back pain, aggravated by exercise and relieved by rest, may occur. Excessive exercise and heavy manual labour before epiphyseal fusion has occurred may aggravate symptoms. Management consists of advice to avoid excessive activity and provision of protective postural exercises. Rarely, corrective surgery may be required if there is severe deformity. Scheuermann’s disease can sometimes present for the ﬁrst time in adulthood, when it can be confused with osteoporotic vertebral fractures. It can be differentiated from osteoporosis by the characteristic X-ray changes, which show mild wedge deformity of 3–4 adjacent vertebrae, irregularity of the vertebral end plates, and normal BMD on DXA examination. Polyostotic ﬁbrous dysplasia This is an acquired systemic disorder that mainly affects the skeleton and is caused by somatic mutations in the GNAS1 gene. The characteristic presentation is with bone pain and pathological fractures. Associated features include endocrine dysfunction, especially precocious puberty, and café-au-lait skin pigmentation (McCune–Albright syndrome). The diagnosis can usually be made by imaging, which shows focal, predominantly osteolytic lesions with bone expansion on X-rays (Fig. 24.65), and focal increased uptake on bone scan. The condition can resemble Paget’s disease of bone but the earlier age of onset and pattern of involvement are usually distinctive. Very rarely, malignant change can occur and should be suspected if there is a sudden increase in pain and swelling. Management is symptomatic. Intravenous bisphosphonates are often used in an attempt to control pain but the evidence base for their use is weak. Orthopaedic surgery may be required for treatment of fracture and deformity. Endocrine manifestations, such as precocious puberty (p. 654), may require speciﬁc treatment. Osteogenesis imperfecta Osteogenesis imperfecta (OI) is the name given to a group of disorders characterised by severe osteoporosis and multiple fractures in infancy and childhood. Most cases are caused by mutations in the COL1A1 and COL1A2 genes, which encode the proteins that make type I collagen. These result in reduced collagen production (in mild OI) or in formation of abnormal collagen chains that are rapidly degraded (in severe OI). Mutations Other bone diseases Complex regional pain syndrome type 1 Complex regional pain syndrome (CRPS) type 1 is characterised by gradual onset of pain, swelling and local tenderness, usually affecting a limb extremity. It may be triggered by fracture but can also occur in association with soft tissue injury, pregnancy and intercurrent illness or can develop spontaneously. The cause is unknown but abnormalities of the sympathetic nervous system are thought to play a pathogenic role. The affected limb is swollen and tender, and there may be evidence of regional autonomic dysfunction, with abnormal sweating and changes in skin colour and temperature. The diagnosis is primarily clinical, based on the features shown in Box 34.12 (p. 1349). Support for the diagnosis can be obtained with MRI, which shows bone marrow oedema, or radionuclide bone scan, which shows a local increase in tracer uptake (Fig. 24.64). X-rays show localised osteoporosis. Haematology, biochemistry and immunology are normal. The aims of treatment are to control pain and encourage mobilisation. Analgesics, NSAIDs, antineuropathic agents, calcitonin, glucocorticoids, β-adrenoceptor antagonists (β-blockers), sympathectomy and bisphosphonates have all been tried but none is particularly effective. Although some cases resolve with time, many individuals have persistent symptoms and fail to regain normal function. Osteonecrosis Osteonecrosis describes death of bone due to impairment of its blood supply. The most commonly affected sites are the femoral head, humeral head and femoral condyles. In some cases, the condition occurs as the result of direct trauma that interrupts the blood supply to the affected bone. This is the reason for osteonecrosis of the femoral head in patients with subtrochanteric fractures of the femoral neck, and in patients with thrombophilia and haemoglobinopathies, such as sickle cell disease. Other Fig. 24.64 Complex regional pain syndrome (osteodystrophy). 99mTc-labelled bisphosphonate scintigraphy showing increased uptake in femoral condyle.

1056 • RHEUMATOLOGY AND BONE DISEASE disease) shows autosomal dominant inheritance and presents with bone pain, cranial nerve palsies, osteomyelitis, OA or fracture, or is sometimes detected as an incidental radiographic ﬁnding. The responsible mutations affect either the genes that regulate osteoclast differentiation (RANK, RANKL), causing ‘osteoclast-poor’ osteopetrosis, or the genes involved in bone resorption, causing ‘osteoclast-rich’ osteopetrosis. These include mutations in the TCIRG1 gene, which encodes a component of the osteoclast proton pump, and mutations in the CLCN7 gene, which encodes the osteoclast chloride pump. Management is difﬁcult. IFN-γ treatment can improve blood counts and reduce frequency of infections, but in severe cases haematopoietic stem cell transplantation is required to provide a source of osteoclasts that resorb bone normally. Sclerosing bone dysplasias These are rare diseases characterised by osteosclerosis and increased bone formation. Van Buchem’s disease and sclerosteosis are recessive disorders caused by loss-of-function mutations in the SOST gene, which normally suppresses bone formation (see Fig. 24.3, p. 986). The resulting lack of sclerostin causes increased bone formation and bone overgrowth, leading to enlargement of the cranium and jaw, tall stature and cranial nerve palsies. There is no effective treatment. High bone mass syndrome is a benign disorder caused by mutations in the LRP4 or LRP5 gene, which is characterised by unusually high bone density. The mutations render the LRP receptors resistant to the inhibitory effects of SOST. Most patients are asymptomatic but bone overgrowth in the palate (torus palatinus) and enlargement of the mandible can occur in later life. Treatment is not usually required. Camurati–Engelmann disease is an autosomal dominant condition caused by gain of function in the TGFB1 gene. It presents with bone pain, muscle weakness and osteosclerosis mainly affecting the diaphysis of long bones. Glucocorticoids can help the bone pain, although usually analgesics are also required. Bone and joint tumours Primary tumours of bones and joints are rare, have a peak incidence in childhood and adolescence, and can be benign or malignant (Box 24.77). Paget’s disease of bone (p. 1053) accounts for most cases of osteosarcoma occurring above the age of 40. Osteosarcoma This is a rare tumour with an incidence of 0.6–0.85 per 100 000 population. It is the most common primary bone tumour. Most in several other genes have been described that can cause OI, some of which affect post-translational modiﬁcation of collagen and others that affect bone formation. Many patients have no family history. Some of these have new mutations whereas others may have recessive forms of the disease. The Sillence classiﬁcation is commonly used to grade severity. This varies from neonatal lethal OI (type II), through very severe OI with multiple fractures in infancy and childhood (types III and IV), to mild (type I), in which affected patients typically have blue sclerae. The diagnosis of OI is usually obvious clinically, based on the presentation with multiple low-trauma fractures during infancy. The disease can be mistaken for non-accidental injury in childhood and for osteoporosis in adulthood; in such cases, genetic testing can be of diagnostic value. Treatment is multidisciplinary, involving surgical reduction and ﬁxation of fractures and correction of limb deformities, and physiotherapy and occupational therapy for rehabilitation of patients with bone deformity. Bisphosphonates are widely used in the treatment of OI, especially intravenous pamidronate in children, but there is limited evidence for efﬁcacy in fracture prevention. Osteopetrosis Osteopetrosis is a rare group of inherited diseases caused by failure of osteoclast function. Presentation is highly variable, ranging from a lethal disorder that presents with bone marrow failure in infancy to a milder and sometimes asymptomatic form that presents in adulthood. Severe osteopetrosis is inherited in an autosomal recessive manner and presents with failure to thrive, delayed dentition, cranial nerve palsies (due to absent cranial foramina), blindness, anaemia and recurrent infections due to bone marrow failure. The adult-onset type (Albers–Schönberg Fig. 24.65 McCune–Albright syndrome. X-ray of tibia in a patient with McCune–Albright syndrome showing expansile osteolytic lesion. 24.77 Primary tumours of the musculoskeletal system Cell type Benign Malignant Osteoblast Osteoid osteoma Osteosarcoma Chondrocyte Chondroma Osteochondroma Chondrosarcoma Fibroblast Fibroma Fibrosarcoma Bone marrow cell Eosinophilic granuloma Ewing’s sarcoma Endothelial cell Haemangioma Angiosarcoma Osteoclast precursor Giant cell tumour Malignant giant cell tumour

Rheumatological involvement in other diseases • 1057

Endocrine disease Hypothyroidism (p. 639) may present with carpal tunnel syndrome or, rarely, with painful, symmetrical proximal myopathy and muscle hypertrophy. Both resolve with levothyroxine replacement. Primary hyperparathyroidism (p. 663) is associated with osteoporosis and also predisposes to calcium pyrophosphate dihydrate deposition disease and to calciﬁc periarthritis, especially in patients with renal disease. Diabetes mellitus (Ch. 20) commonly causes diabetic cheiroarthropathy, characterised by tightening of skin and periarticular structures, causing ﬂexion deformities of the ﬁngers that may be painful. Diabetic osteopathy presents as forefoot pain with radiographic progression from osteopenia to complete osteolysis of the phalanges and metatarsals. Diabetes also predisposes to osteoporosis, fragility fractures, adhesive capsulitis, Dupuytren’s contracture, septic arthritis and Charcot’s joints. Acromegaly (p. 685) can be associated with mechanical back pain, with normal or excessive movement; carpal tunnel syndrome; and Raynaud’s syndrome and an arthropathy (50%). The arthropathy mainly affects the large joints and has clinical similarities to OA but with a normal or increased range of movement. X-rays may show widening of joint spaces, squaring of bone ends, generalised osteopenia and tufting of terminal phalanges. It does not improve with treatment of the acromegaly. patients present under the age of 30 but osteosarcoma also occurs in the elderly in association with Paget’s disease. The presentation is with local pain and swelling. X-rays show expansion of the bone with a surrounding soft tissue mass, often containing islands of calciﬁcation. If the diagnosis is being considered, MRI or CT should be performed to determine the extent of tumour. Patients suspected of having osteosarcoma should be referred to a specialist team for biopsy. Treatment depends on histological type but generally involves surgical removal of the tumour, followed by chemotherapy and radiotherapy. The prognosis is normally good in cases that present in childhood and adolescence, but poor in elderly patients with osteosarcoma related to Paget’s disease of bone. Chondrosarcoma This is the second most common primary bone tumour. Presentation is as described for osteosarcoma. The treatment of choice is surgical resection since chondrosarcomas are relatively resistant to chemotherapy and radiotherapy. The prognosis is good for low-grade tumours but poor for anaplastic tumours. Ewing’s sarcoma This is the third most common sarcoma, which presents almost exclusively under the age of 40. Presentation is as described for osteosarcoma. Treatment is by local excision and surgical resection. The prognosis is excellent for patients who present before metastasis has occurred. Metastatic bone disease Metastatic bone disease may present in a variety of ways: with localised or generalised progressive bone pain, generalised regional pain, symptoms of spinal cord compression, or acute pain due to pathological fracture. Systemic features, such as weight loss and anorexia, and symptoms referable to the primary tumour are often present. The tumours that most commonly metastasise to bone are myeloma and those of bronchus, breast, prostate, kidney and thyroid. Management is discussed in Chapter 33. Rheumatological involvement in other diseases Many systemic diseases can affect the locomotor system, and many drugs may cause adverse locomotor effects (Box 24.78). The most common examples are described here. Bone disease in sarcoidosis is described on page 608, haemophilia on page 972 and sickle-cell anaemia on page 952. Malignant disease Malignant disease can cause a variety of non-metastatic musculoskeletal problems (Box 24.79). One of the most striking is hypertrophic pulmonary osteoarthropathy (HPOA), characterised by clubbing and painful swelling of the limbs, periosteal new bone formation and arthralgia/arthritis. The most common causes are bronchial carcinoma and mesothelioma (pp. 598 and 618). Bone scans show increased periosteal uptake before new bone is apparent on X-ray. The course follows that of the underlying malignancy and HPOA resolves if this is cured. 24.78 Drug-induced effects on the musculoskeletal system Musculoskeletal problem Principal drug Secondary gout Thiazides, furosemide, alcohol Osteoporosis Glucocorticoids, heparin, glitazones, aromatase inhibitors, GnRH agonists Osteomalacia Anticonvulsants, etidronate and pamidronate (high-dose) Osteonecrosis Glucocorticoids, alcohol Drug-induced lupus syndrome Procainamide, hydralazine, isoniazid, chlorpromazine Arthralgias, arthritis Glucocorticoid withdrawal, glibenclamide, methyldopa, ciclosporin, isoniazid, barbiturates Myalgia Glucocorticoid withdrawal, L-tryptophan, ﬁbrates, statins Myopathy Glucocorticoids, chloroquine Myositis, myasthenia Penicillamine, statins Cramps Glucocorticoids, ACTH, diuretics, carbenoxolone Vasculitis Amphetamines, thiazides (ACTH = adrenocorticotrophic hormone; GnRH = gonadotrophin-releasing hormone) 24.79 Rheumatological manifestations of malignancy • Polyarthritis • Dermatomyositis and polymyositis • Hypophosphataemic osteomalacia • Hypertrophic osteoarthropathy • Vasculitis, connective tissue disease • Raynaud’s syndrome • Polymyalgia rheumatica-like syndrome

1058 • RHEUMATOLOGY AND BONE DISEASE (hypertrophic) new bone formation. Management principally involves orthoses and occasionally arthrodesis. Miscellaneous conditions Anterior tibial compartment syndrome This is characterised by severe pain in the front of the lower leg, aggravated by exercise and relieved by rest. Symptoms result from fascial compression of the muscles in the anterior tibial compartment and may be associated with foot drop. Treatment is by surgical decompression. Carpal tunnel syndrome This is a common nerve entrapment syndrome caused by compression of the median nerve at the wrist. It presents with numbness, tingling and pain in a median nerve distribution (p. 1139). The most common causes are hypothyroidism, diabetes mellitus, RA, obesity and pregnancy, especially in the third trimester. In some patients, no underlying cause may be identiﬁed. Carpal tunnel syndrome often responds to treatment of the underlying condition but other options include local glucocorticoid injections and surgical decompression. Diffuse idiopathic skeletal hyperostosis Diffuse idiopathic skeletal hyperostosis (DISH) is a common disorder, affecting 10% of men and 8% of women over the age of 65, and is associated with obesity, hypertension and type 2 diabetes mellitus. It is characterised by ﬂorid new bone formation along the anterolateral aspect of at least four contiguous vertebral bodies (Fig. 24.67). DISH is distinguished from lumbar spondylosis by the absence of disc space narrowing and marginal vertebral body sclerosis, and from ankylosing spondylitis by the absence of sacroiliitis or apophyseal joint fusion. It is usually an Haematological disease Haemochromatosis (p. 895) is complicated by an arthropathy in about 50% of cases. It typically presents between the ages of 40 and 50, and may predate other features of the disease. The small joints of the hands and wrists are typically affected but the hips, shoulders and knees may also be involved. The X-ray changes resemble OA but cysts are often multiple and prominent, with little osteophyte formation. Involvement of the radiocarpal and MCP joints may occur, which is unusual in primary OA, and about 30% have calcium pyrophosphate dihydrate deposition disease and/ or pseudogout. Treatment of the haemochromatosis does not inﬂuence the arthropathy, and management is as described for OA. Haemophilia (p. 972) can be complicated by haemarthrosis, which, if recurrent, can result in the development of secondary OA. Sickle-cell disease (p. 952) may be associated with bone pain, osteonecrosis and osteomyelitis. Thalassaemia (p. 953) may be complicated by bone deformity, especially affecting the craniofacial bones, and by osteoporosis. Neurological disease Neurological disease may result in rapidly destructive arthritis of joints, ﬁrst described by Charcot in association with syphilis. The cause is incompletely understood but may involve repetitive trauma as the result of sensory loss and altered blood ﬂow secondary to impaired sympathetic nervous system control. The main predisposing diseases and sites of involvement are: • diabetic neuropathy (hindfoot) • syringomyelia (shoulder, elbow, wrist) • leprosy (hands, feet) • tabes dorsalis (knees, spine). The presentation is with subacute or chronic monoarthritis. Pain can occur, especially at the onset, but once the joint is severely deranged, pain is often minimal and signs become disproportionately greater than symptoms. The joint is often grossly swollen, with effusion, crepitus, marked instability and deformity, but usually no increased warmth. X-rays show disorganisation of normal joint architecture and often multiple loose bodies (Fig. 24.66), and either no (atrophic) or gross Fig. 24.66 Wrist X-ray showing a neuropathic (Charcot) joint in a patient with syringomyelia. Note the disorganised architecture with complete loss of the proximal carpal row, bony fragments and soft tissue swelling. Fig. 24.67 Diffuse idiopathic skeletal hyperostosis (DISH). Anteroposterior X-ray of the thoracic spine showing right-sided, ﬂowing new bone joining more than four contiguous vertebrae. The disc spaces are preserved.

Miscellaneous conditions • 1059

muscle weakness and atrophy, with pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. Inclusion body myositis typically presents with distal muscle weakness. In time, muscles atrophy. Investigation is the same as for polymyositis (p. 1039). There is typically a slightly elevated creatine kinase and myopathic changes on EMG. Muscle biopsy shows abnormal fibres containing rimmed vacuoles and ﬁlamentous inclusions in the nucleus and cytoplasm. Therapeutic response to glucocorticoids and immunosuppressants is notably poor. There is anecdotal report of efﬁcacy with IVIg but trial evidence is lacking. Periodic fever syndromes These are a group of rare inherited disorders that present with intermittent attacks of fever, rash, arthralgia and myalgia. They are discussed in more detail on page 81. Pigmented villonodular synovitis Pigmented villonodular synovitis is an uncommon proliferative disorder of synovium, which typically affects young adults. It is caused by a somatic chromosomal translocation in synovial cells that places the CSF1 gene downstream of the COL6A3 gene promoter. The result is local over-production of M-CSF, which causes accumulation of macrophages in the joint. The presentation is with joint swelling, limitation of movement and local discomfort. The diagnosis can be confirmed by MRI or synovial biopsy. Treatment is by surgical or radiation synovectomy. Scoliosis Scoliosis is characterised by an abnormal lateral curvature of the spine of greater than 10°. It typically presents during childhood or adolescence but usually persists into adulthood, when it can be associated with back pain, deformity and secondary OA. In about 20% of cases, scoliosis is secondary to a neuromuscular disorder, such as muscular dystrophy, cerebral palsy or neuroﬁbromatosis. It may also occur in association with connective tissue disorders, such as Marfan’s syndrome. The term idiopathic scoliosis is used to described the remaining cases where there is no obvious cause. In fact, there is strong evidence from twin studies that idiopathic scoliosis is genetically mediated. The diagnosis can usually be made clinically by physical examination, which shows the characteristic spinal deformity. Spinal X-rays can be used to conﬁrm the diagnosis and assess severity. External bracing and/ or surgical intervention are often performed in adolescents with severe deformities to correct deformity or prevent progression but the evidence base is poor. In adulthood, treatment is symptomatic in nature with analgesics, NSAID or antineuropathic medications. Spondylolysis Spondylolysis describes a break in the integrity of the neural arch. The principal cause is an acquired defect in the pars interarticularis due to a fracture, mainly seen in gymnasts, dancers and runners, in whom it is an important cause of back pain. Spondylolisthesis describes the condition in which a defect causes slippage of a vertebra on the one below. This may be congenital, post-traumatic or degenerative. Rarely, it can result from metastatic destruction of the posterior elements. Uncomplicated spondylolysis does not cause symptoms but spondylolisthesis can lead to low back pain asymptomatic radiographic ﬁnding but can cause back pain or pain at peripheral sites, such as the heel, in association with calcaneal spur formation. Dupuytren’s contracture Dupuytren’s contracture results from ﬁbrosis and contracture of the superﬁcial palmar fascia of the hands. The patient is unable to extend the ﬁngers fully and there is puckering of the skin with palpable nodules. The ring and little ﬁngers are usually the ﬁrst and worst affected. Dupuytren’s contracture is usually painless but causes problems due to limitation of hand function and snagging of the curled ﬁngers in pockets. It is age-related, usually bilateral and more common in men. There is a strong genetic component and sometimes may be familial, with dominant inheritance. The condition can be associated with plantar ﬁbromatosis, Peyronie’s disease, alcohol misuse and chronic vibration injury. It is very slowly progressive. Often no treatment is required but it can be treated medically by local injections of collagenase or surgically by fasciotomy if symptoms are troublesome. Hypermobility syndromes Hypermobility is characterised by increased joint laxity and joint pain. Causes include Marfan’s syndrome, resulting from mutations in the FBN1 gene (p. 508); osteogenesis imperfecta (p. 1055); and Ehlers–Danlos syndrome types I, II and IV, caused by mutations in the COL3A1, COL5A1 and COL5A2 genes (p. 970). The term hypermobile Ehlers–Danlos syndrome (hEDS), which is also known as EDS type III, is used to describe a polygenic form of hypermobility. Many patients with this condition have hypermobile joints but do not have symptoms, whereas in others a range of symptoms can occur, including chronic joint and ligamentous pain, ﬁbromyalgia-like symptoms, recurrent dislocations, easy bruising, abdominal symptoms, mitral valve prolapse (p. 520) and postural tachycardia syndrome, in which there is dizziness, hypotension and an increased heart rate on standing. The diagnosis of EDS type III is clinical and can be made when the modiﬁed Beighton score is 4 or above in the presence of arthralgia in four or more joints (Box 24.80). There is no speciﬁc treatment, apart from the general principles listed on page 1000, but some patients become very disabled as the result of their symptoms and are difﬁcult to manage. Inclusion body myositis Inclusion body myositis is the most frequent primary myopathy in middle age and after. It is characterised by slowly progressive 24.80 Modiﬁed Beighton score for joint hypermobility Clinical test Score Extend little ﬁnger > 90° 1 point each side Bring thumb back parallel to/touching forearm 1 point each side Extend elbow > 10° 1 point each side Extend knee > 10° 1 point each side Touch ﬂoor with ﬂat of hands, legs straight 1 point Hypermobile = a score of 6 or more points out of a possible 9 for epidemiological studies, or 4 or more points (with arthralgia in four or more joints) for a clinical diagnosis of the benign joint hypermobility syndrome

1060 • RHEUMATOLOGY AND BONE DISEASE Further information Journal articles Campion EW. Calcium pyrophosphate deposition disease. N Engl J Med 2016; 374:2575–2578. Compston J. Osteoporosis: advances in risk assessment and management. Clin Med (Lond) 2016; 16(Suppl 6): s121–s124. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016; 75:499–510. Mukhtyar C, Flossman O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis 2008; 67:1004–1010. Ralston SH. Paget’s disease of bone. N Engl J Med 2013; 368:644–650. Scott DL, Woolf F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376:1094–1108. Taurog JD, Avneesh C, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med 2016; 374:2563–2567. Teng MWL, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immunemediated inﬂammatory diseases. Nat Med 2015; 21:719–729. Zhang W, Doherty M, Bardin T, et al. EULAR recommendations for gout. Part II: Management. Ann Rheum Dis 2006; 65:1312–1324. Websites 4s-dawn.com/DAS28 Calculator for this measure of activity in rheumatoid arthritis. asas-group.org Repository of resources to aid assessment of spondyloarthritis. basdai.com/BASDAI.php BASDAI calculator for assessing ankylosing spondylitis. omim.org Online Mendelian Inheritance in Man (OMIM): genetic diseases. shef.ac.uk/FRAX/ and qfracture.org/ Fracture risk assessment tools. sign.ac.uk Scottish Intercollegiate Guidelines Network 142 – Management of osteoporosis and the prevention of fragility fractures. thefreelibrary.com Information on drug-induced myopathies. vasculitis.org/ Vasculitis resources from the European Vasculitis Society. aggravated by standing and walking. Occasionally, symptoms of nerve root or spinal compression may occur. The diagnosis can be made on lateral X-rays of the lumbar spine but MRI may be required if there is neurological involvement. Advice on posture and muscle-strengthening exercises is required in mild cases. Surgical fusion is indicated for severe and recurrent low back pain. Surgical decompression is mandatory prior to fusion in patients with signiﬁcant lumbar stenosis or symptoms of cauda equina compression. Synovitis–acne–pustulosis–hyperostosis– osteitis syndrome The synovitis–acne–pustulosis–hyperostosis–osteitis (SAPHO) syndrome is a disorder characterised by bone pain and swelling due to a sterile osteomyelitis and hyperostosis predominantly targeting the clavicles and bones of the anterior chest wall. SAPHO syndrome is thought to be part of a spectrum of autoinﬂammatory bone diseases that includes chronic recurrent (sterile) multifocal osteomyelitis in children and adolescents. Other features include a pustulotic rash affecting the palms and soles of the feet, sacroiliitis and synovitis of peripheral joints. It most commonly presents in children and young or middle-aged adults. Various treatments have been used, including glucocorticoids, DMARDs, bisphosphonates, anakinra and TNF blockers, with most success arising from biologic use. The cause is unknown but has been suggested to be an autoimmune process triggered by a bacterial or viral pathogen. Trigger ﬁnger This occurs as the result of stenosing tenosynovitis in the flexor tendon sheath, with intermittent locking of the finger in flexion. It can arise spontaneously or in association with inﬂammatory diseases such as RA. Symptoms usually respond to local glucocorticoid injections but surgical decompression is occasionally required.

01-1 Clinical decision-making

02-2 Clinical therapeutics and good prescribing

03-3 Clinical genetics

04-4 Clinical immunology

05-5 Population health and epidemiology

06-6 Principles of infectious disease

01-7 Poisoning

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22-32 Ageing and disease

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25-35 Laboratory reference ranges

14-24 Rheumatology and bone disease

24 Rheumatology and bone disease