# 21 - 378 Relapsing Polychondritis

### 378 Relapsing Polychondritis

of mycophenolate compared to other immunosuppressive agents is the 
lack of renal or hepatic toxicity.
Rituximab 
Rituximab is a monoclonal antibody directed against 
CD20+ B cells. A large randomized controlled trial found no benefit, 
but there were flaws in the study design. Most authorities feel that 
rituximab can be beneficial in some patients who are refractory to 
prednisone and at least one of the other second-line agents. The typi­
cal dosage is 750 mg/m2 (up to 1 g) IV with a second infusion 2 weeks 
later and with repeat courses (375 mg/m2 as a single infusion or with a 
second infusion 2 weeks apart) every 6–18 months as needed.
Drugs in Clinical Trials 
Trials of a monoclonal antibody to block 
IFN-β and drugs to target downstream pathways (e.g., JAK-1) are 
ongoing in DM and other forms of myositis. Studies targeting the neo­
natal Fc receptor (FcRn) to decrease myositis-specific antibodies are 
underway in DM, ASyS, and IMNM, as are trials with chimeric antigen 
receptor (CAR) T-cell therapy. Ongoing trials in IBM include rapamy­
cin as well as a trial of a monoclonal antibody binding to KLRG1 to 
deplete highly differentiated muscle-invading T cells.
MYOSITIS ASSOCIATED WITH 
CHECKPOINT INHIBITORS
Autoimmune neurologic complications, including inflammatory neu­
ropathy (Chap. 458), myasthenia gravis (Chap. 459), and myositis, can 
occur with use of immune checkpoint inhibitors (anti-CTLA-4, antiPD-1, and anti-PD-L1) to treat various cancers. Patients with myosi­
tis often develop muscle pain and weakness (axial musculature and 
proximal limbs) after one or two cycles. Myocarditis can also develop. 
Additionally, diplopia with extraocular weakness along with dysphagia 
and dysarthria suggesting the co-occurrence of myasthenia gravis 
(MG) may be present. In such cases, an elevated CK level helps sup­
port the diagnosis of myositis, while acetylcholine receptor antibod­
ies or decremental response on slow repetitive nerve stimulation can 
establish the diagnosis of MG. Endomysial inflammatory cell infiltrates 
composed of macrophages expressing PD-L1 and CD8+ lymphocytes 
expressing PD-1, overexpression of MHC-I on sarcolemma of muscle 
fibers, and scattered necrotic and regenerating fibers can be found on 
muscle biopsies.
The immune checkpoint inhibitor should be discontinued, but most 
patients require concurrent treatment with glucocorticoids or IVIG. 
Patients generally improve over several months, during which time 
immunotherapy can be tapered. There are rare reports of patients 
with mild myositis who were able to be successfully re-treated with an 
immune checkpoint inhibitor.
MYOSITIS ASSOCIATED WITH COVID-19 
INFECTION
Early series of patients hospitalized with COVID-19 report that as 
many as 44% of patients experience muscle pain or fatigue and 33% 
have elevated CK levels. Rare cases are complicated by myoglobinuria. 
Histopathology can demonstrate inflammatory cell infiltration and 
necrotic muscle fibers. In autopsy series, SARS-CoV-2 has not been 
demonstrated in muscle fibers, and the myositis is felt in most, if not 
all, to be due to cytokine storm. Whether COVID-19 infection can 
induce a chronic autoimmune myositis is controversial; there have 
been a number of reports of various types of IM, some with MSA, in 
patients following COVID-19 infection, but temporal associations do 
not equal causation.
GLOBAL ISSUES
There is a lack of epidemiologic data with regard to the incidence and 
prevalence of various subtypes of IM throughout the world. Compli­
cating the issue is disease awareness and the inability to obtain and 
process muscle biopsies and MSAs, particularly in less developed 
countries. Nevertheless, each of these disorders occurs throughout the 
world. The specific environmental triggers and genetic risk factors are 
likely variable. Interestingly, a report from Japan found that 28% of 
IBM patients had evidence of exposure to hepatitis C, which was much 
higher than seen in the Western Hemisphere and also more common 

than seen in PM and healthy population controls in Japan. HIV-associated 
PM and IBM are more commonly encountered in areas endemic for 
HIV, and recent studies suggest most of these “PM” patients turn out to 
have IBM and can develop symptoms at an earlier age (e.g., in the 30s). 
Interestingly, while most cases of anti-HMGCR myopathy in North 
America and Europe are associated with prior statin use, the major­
ity of such cases in Asia are not. Pyomyositis and parasitic myositis 
are clearly more common in the tropics. The prevalence of different 
types of cancers varies in different parts of the world, an important 
consideration with respect to paraneoplastic myositis. For example, 
nasopharyngeal cancer is particularly common in Asia; thus, assess­
ment for this type of cancer should be considered in the workup of 
patients from high-risk regions.

CHAPTER 378
Relapsing Polychondritis
■
■FURTHER READING
Aggarwal  R et al: ProDERM Trial Group. Trial of intravenous 
immune globulin in dermatomyositis. N Engl J Med 387:1264, 2022.
Allenbach  Y et al: Immune-mediated necrotizing myopathy: Clinical 
features and pathogenesis. Nat Rev Rheumatol 16:689, 2020.
Amato AA, Russell JA (eds): Neuromuscular Disorders, 2nd ed. New 
York, McGraw-Hill Education, 2016, pp. 827–871.
Britson  KA et al: Loss of TDP-43 function and rimmed vacuoles persist 
after T cell depletion in a xenograft model of sporadic inclusion body 
myositis. Sci Transl Med 14:eabi9196, 2022.
Greenberg SA: Inclusion body myositis: clinical features and patho­
genesis. Nat Rev Rheumatol 15:257, 2019.
Julien  S et al: Immune-mediated necrotizing myopathy (IMNM): A 
story of antibodies. Antibodies (Basel) 13:12, 2024.
Mariampillai  K et al: Development of a new classification system for 
idiopathic inflammatory myopathies based on clinical manifestations 
and myositis-specific autoantibodies. JAMA Neurol 75:1528, 2018.
Müller  F et al: CD19 CAR T-cell therapy in autoimmune disease: A 
case series with follow-up. N Engl J Med 390:687, 2024.
Pinal-Fernandez  I et al: Pathogenic autoantibody internalization in 
myositis. medRxiv [Preprint]. 17:2024.01.15.24301339, 2024.
Puwanant A et al: Clinical spectrum of neuromuscular complications 
after immune checkpoint inhibition. Neuromuscul Disord 29:127, 
2019.
Suh J et al: Skeletal muscle and peripheral nerve histopathology in 
COVID-19. Neurology 97:e849, 2021.
Marcela A. Ferrada, Peter C. Grayson

Relapsing Polychondritis
Relapsing polychondritis (RP) is a rare systemic disease characterized 
by recurrent inflammation in cartilaginous structures. Involvement of 
the ears, nose, respiratory tract, and joints are hallmark features of the 
disease; however, other organs can be affected including the eyes, inner 
ear, nervous system, skin, and cardiovascular system. Some patients 
with RP may be concomitantly diagnosed with other rheumatologic 
diseases, such as Sjögren’s syndrome or systemic lupus erythematosus. 
Recurrent chondritis of the ears and nose in older male patients with 
severe systemic inflammation and progressive bone marrow failure is 
associated with acquired hematologic mutations in UBA1, a condition 
now known as the VEXAS (vacuoles, E1 enzyme, X-linked, autoin­
flammatory, somatic) syndrome. Prompt recognition and accurate 
diagnosis of RP or VEXAS syndrome are essential to prevent lifethreatening complications of these diseases.
The epidemiology of RP is poorly characterized. The disease is 
commonly reported to primarily affect middle-aged adults without a 
strong sex predilection; some cohort studies report female predilection,

but large, population-based studies typically show equal sex distribu­
tion. Children can be affected; however, these data are limited to case 
reports. Rare instances of familial aggregation have also been reported. 
The estimated incidence rate of disease is 0.7–3.5 cases per million per 
year, and prevalence estimates range from 4.5–25 cases per million. 
Epidemiologic data in RP are limited to older studies, typically evalu­
ating population distributions more than three decades ago in cohorts 
from Europe and North America. Given the diagnostic challenges 
encountered in this condition, these data may underestimate the true 
prevalence of disease. Although RP has been reported in many regions 
of the world, whether racial or ethnic differences are associated with 
variable clinical features or outcomes is not known.

PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders 
■
■PATHOLOGY AND PATHOPHYSIOLOGY
Histologic findings from biopsy of affected cartilage are dependent on 
the timing of tissue sampling. In acute disease, a mixed inflammatory 
infiltrate of myeloid and lymphoid populations is observed at the car­
tilage interface. Over time, cartilage destruction is marked by lacunar 
breakdown and loss of chondrocytes, replaced by fibrosis. Biopsy of 
affected cartilage may cause morbidity, and there are no features on 
histology that are specifically diagnostic for RP. Therefore, biopsy is 
often reserved when there is a high suspicion of conditions that mimic 
RP, particularly infectious diseases and malignancies.
Although genetic, environmental, and immunologic aspects of the 
disease have been studied in humans and in animal models, the exact 
mechanisms that drive the disease are unclear. Limited studies in animal 
models support the concept that autoimmunity to cartilage components 
may play a role in RP. Immunization of specific animals to type II col­
lagen, type IX collagen, or matrillin-1 can recapitulate various aspects 
of the clinical phenotypes observed in patients with RP; however, the 
performance characteristics of these antibodies in clinical practice are 
poor to differentiate RP from other diseases. Autoantibodies to type II 
collagen have been reported in small cohorts of patients with RP but 
are neither sensitive nor specific to be considered as an acceptable diag­
nostic marker of disease. Observational cohort data suggest that B-cell–
depleting therapies are not particularly effective to treat the condition, 
arguing against a strong primary role of antibody-mediated disease.
Acute phase reactants (e.g., erythrocyte sedimentation rate or 
C-reactive protein) are not reliably elevated in patients with RP. 
Proinflammatory cytokines and chemokines related to both innate 
and adaptive immunity have been identified in association with RP; 
A
 
FIGURE 378-1  Representation of ear involvement in relapsing polychondritis. A and B. Examples of typical ear chondritis, with significant inflammation of the pinnae. 
C. Mild ear cartilage inflammation. D. Cartilage damage.

however, these findings are not consistent and, therefore, are not rou­
tinely measured to guide management in clinical practice.
■
■CLINICAL MANIFESTATIONS AND 

ORGAN INVOLVEMENT
RP is associated with a wide range of clinical manifestations. In the 
absence of a diagnostic blood test, a detailed medical history and 
physical examination are the most essential tools for diagnosis and, 
most importantly, further management. Because disease activity is 
intermittent and patients may not exhibit clear signs of inflammation 
during direct evaluation, it is crucial to consider the patient’s symptoms 
over time and to review any provided photographic documentation of 
disease features.
Ears, Nose, and Throat 
Ear involvement is one of the most 
common clinical manifestations of relapsing polychondritis, affecting 
80–90% of the patients. However, there are no clear definitions of ear 
chondritis, and patient descriptions of pain and associated symptoms 
are variable. The typical description includes involvement of only the 
cartilaginous aspect of the ear (pinnae) (Fig. 378-1A and B). However, 
a subset of patients may report pain in the ears with minimal associ­
ated findings visualized on physical examination, such as mild swell­
ing or erythema (Fig. 378-1C). Although damage to the cartilaginous 
portion of the external ear (i.e., “cauliflower ear”) is observed in RP 

(Fig. 378-1D), it is present only in a small number of patients, usually 
in the setting of recurrent episodes of ear inflammation. Questions 
that can be helpful to elicit the nature of ear pain include asking about 
onset, duration, and triggers. Common triggers include minimal 
trauma to the ear (such as from lying on the effected side or wearing 
glasses) or temperature changes.
Patients usually describe a sensation of pressure at the bridge of the 
nose that may not be accompanied by other associated symptoms. Some 
patients may have overt redness and swelling of the bridge or tip of 
nose, but this is less common (Fig. 378-2A). While a “saddle nose” has 
been described as a typical clinical finding in RP, many patients will not 
develop an obvious nasal deformity (Fig. 378-2B). The nasal septum and 
nasal passages should always be evaluated in patients with suspected RP, 
as many patients can have septal ulcers and mucosal inflammation. In 
contrast to granulomatosis with polyangiitis (GPA) where a saddle nose 
deformity is usually associated with a septal perforation (Chap. 375), 
patients with RP who have a saddle nose deformity usually do not have 
B

C
 
FIGURE 378-1  (Continued)
a septal perforation, as most of the nasal perforations in patients with RP 
are located anteriorly.
Patients can have complaints of throat pain or a sensation of globus, 
usually described as a “choking sensation.” Patients can also report 
pain on the anterior aspect of the neck, in some cases associated with 
erythema, usually located at the level of the thyroid cartilage.
Upper and Lower Airway 
Conditions like subglottic stenosis 
may manifest acutely or subacutely, leading to cough, voice changes, or 
breathlessness. Severe narrowing can result in stridor, requiring urgent 
medical attention to avoid mortality (Fig. 378-3A). Often misdiag­
nosed as adult-onset asthma, timely recognition of airway involvement 
is important to prevent chronic damage to the large airways, which 
can result in tracheomalacia, bronchomalacia, or tracheal calcification 
(Fig. 378-3B and C). Patients with intermittent episodes of wheezing 
A
 
FIGURE 378-2  Nose involvement in relapsing polychondritis. A. Redness and swelling of the base and tip of the nose. B. Saddle nose deformity.

CHAPTER 378
Relapsing Polychondritis
D
and with a review of symptoms positive for possible RP should be fol­
lowed closely and further evaluated for lower airway involvement.
Musculoskeletal 
• 
JOINTS  RP is associated with a nonerosive 
inflammatory arthritis that can affect small and large peripheral joints 
and as well as the axial skeleton. Erosions have been described in the 
sacroiliac joints but not in other joints. The most common large joint 
affected is the knees, often presenting with effusions. The pattern of 
small joint involvement emulates rheumatoid arthritis, without ero­
sions or deformities.
TENOSYNOVITIS  Different tendons can be affected including Achilles 
and peroneal tendons.
COSTOCHONDRAL JOINTS  Located at the rib-sternum junction, these 
joints are frequently inflamed in RP, producing constant pain that 
B

PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders 
A
 
B
C
FIGURE 378-3  Airway involvement in relapsing polychondritis. A. Subglottic 
stenosis. B and C. Computed tomography demonstrating tracheal calcification and 
tracheomalacia.

stands out due to its unique severe quality. Pain due to costochondritis 
can be so severe that patients will seek evaluation in the emergency 
room due to concerns for an acute coronary event. The pain is bilateral, 
reproducible with palpation, and not associated with movement of the 
affected rib.
Inner Ear 
All patients with RP should undergo hearing tests to 
evaluate for conductive and sensorineural hearing loss. During the 
physical exam, the ear canal should be evaluated as some patients can 
have severe inflammation or eustachian tube dysfunction leading to 
conductive hearing loss. The presence of dizziness necessitates further 
evaluation through maneuvers like finger-to-nose, Romberg, and nys­
tagmus to rule out vestibular involvement.
Ocular Involvement 
Episcleritis is the most frequent type of ocu­
lar inflammation in RP. It might coincide with other flare symptoms or 
occur independently. Although rare, features suggesting scleritis man­
date urgent ophthalmologic evaluation due to its potential catastrophic 
outcomes, including vision loss, scleromalacia, or global rupture neces­
sitating enucleation (Fig. 378-5A).
Cardiovascular 
Patients with mouth and genital ulcers with 
inflamed cartilage (MAGIC) syndrome may exhibit symptoms seen in 
Behçet’s syndrome (Chap. 376), including pathergy and gastrointes­
tinal involvement. These patients can also have large-vessel vasculitis 
involving the aorta.
Neurologic 
The diagnosis of neurologic involvement due to RP is 
one of exclusion. All possible etiologies including infection and malig­
nancy should be ruled out before attributing the clinical findings to RP; 
however, encephalitis and meningitis can be seen in RP.
■
■DIAGNOSIS
There are no circulating or tissue-based biomarkers with adequate 
performance characteristics to function as a diagnostic test for RP. 
As such, diagnosis is based primarily on clinical pattern recognition 
informed by a comprehensive review of systems and physical examina­
tion. Several diagnostic criteria have been proposed; however, these 
criteria were developed in small cohorts, are largely based on expert 
opinion, and have not been formally validated. McAdam’s criteria 
require presence of three of six symptoms, including bilateral auricular 
chondritis, nonerosive seronegative inflammatory polyarthritis, nasal 
chondritis, ocular inflammation, respiratory tract chondritis, or ves­
tibular/cochlear dysfunction. Damiani and Levine modified McAdam’s 
criteria to include either three clinical features or one clinical feature 
with histologic evidence of chondritis or two clinical features with 
clinical response to glucocorticoids, dapsone, or both. Michet’s criteria 
propose three major criteria (inflammation of ear, nose, or respira­
tory tract) and four minor criteria (ocular inflammation, hearing loss, 
vestibular dysfunction, and seronegative inflammatory arthritis) and 
require fulfillment of two major criteria or one major plus two minor 
criteria to establish the diagnosis. Another important limitation of 
these criteria is the lack of precise definitions of organ involvement.
The differential diagnosis for RP includes conditions that mimic 
chondritis in specific cartilaginous organs and systemic diseases for 
which chondritis may be a manifestation. Ear chondritis can be mim­
icked by infectious and cutaneous diseases of the external ear, trau­
matic otohematoma, or red ear syndrome. Various infectious diseases 
and angiocentric centrofacial lymphoma can mimic nasal chondritis. 
Asthma, traumatic airway stenosis, infectious diseases, and congenital 
disorders involving the airway can mimic airway chondritis. Systemic 
diseases that mimic RP include GPA (Chap. 375) and autoinflamma­
tory diseases (Chap. 381). GPA can be differentiated from RP in part 
by the presence of antineutrophil cytoplasmic autoantibodies (ANCA) 
and glomerulonephritis, which are not features of RP. Presence of 
cytopenia, most notably macrocytosis and lymphopenia, in older male 
patients should trigger consideration of genetic testing and bone mar­
row assessment for VEXAS.
Audiometry to assess hearing loss and dynamic expiratory phase 
computed tomography of the chest to assess tracheobronchomalacia are 
critical studies that should be performed in all patients with suspected