Version May 2024
INTRODUCTION — Relapsing polychondritis (RPC) is an immune-mediated condition associated with inflammation in cartilaginous structures and other tissues throughout the body, particularly the ears, nose, eyes, joints, and respiratory tract. Other organs that can be involved include the vasculature, inner ear, central nervous system, and skin. A high percentage of patients with a genetic disease described in 2020 called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome have a clinical diagnosis of RPC [1].
The clinical features and course of RPC vary considerably from patient to patient. Subtle, early manifestations often remain unrecognized for prolonged periods. As a result, the diagnosis is frequently obtained only after the emergence of characteristic manifestations such as auricular inflammation, saddle-nose deformity, or other features of cartilage destruction. No known clinical or laboratory measures predict the expression of specific disease manifestations or the overall disease course.
The clinical features of RPC are reviewed here. The pathogenesis, pathology, diagnosis, and treatment of RPC are discussed separately. (See "Etiology and pathogenesis of relapsing polychondritis" and "Pathology of relapsing polychondritis" and "Diagnostic evaluation of relapsing polychondritis" and "Treatment of relapsing polychondritis".)
EPIDEMIOLOGY — Relapsing polychondritis (RPC) is a rare disease that appears to occur among individuals of all races and age groups. Males and females are affected equally, but much about the epidemiology of RPC remains unknown because of the relatively small number of affected patients. RPC is most prevalent in White individuals. The annual incidence has been estimated at 0.71, 2.0, and 3.5 per million persons from population studies in the United Kingdom, Hungary, and Minnesota, respectively [2-4]. Onset is most likely between the ages of 40 and 60, although RPC can occur in childhood (figure 1) [5].
RPC is not a familial disease, although studies indicate that some genetic contribution to susceptibility is likely. One case report suggested the possibility of placental transmission [6]. However, no other cases of this occurrence are confirmed, and the reported association may be secondary to chance or a confluence of other circumstances. In general, cases suggesting placental transmission are exceptionally rare, even if the mother may be experiencing active multisystem disease [6].
CLINICAL MANIFESTATIONS
Major features and clinical course — The clinical features of relapsing polychondritis (RPC) vary in severity and duration, both at presentation and throughout the course of the illness. Although auricular involvement is the most common feature, it can happen later in the disease course. Recognizing the pattern of organ involvement other than ear chondritis can help with early diagnosis. Other anatomic areas and organs that can be involved include the costal cartilage, eyes, nose, airways, heart, vascular system, skin, musculoskeletal system, kidney, and nervous system (table 1) [2]. Vascular disease is presumed to be the cause of many of the primary manifestations of RPC [7-9]. Nonspecific constitutional symptoms such as fatigue, malaise, and fever may also be seen, and RPC can present as a fever of unknown origin.
Clinical phenotypes have been described in several studies, including a retrospective cluster analysis of 142 patients with RPC from a single center [10]. This study found a group with primary hematologic disorders, especially myelodysplastic syndrome (MDS), which had the worst prognosis. A second group with laryngotracheal or bronchial involvement experienced more infections and intensive care unit (ICU) admissions but surprisingly did not have a worse outcome than the third cluster of patients with mild disease. This improved prognosis compared with earlier series is likely related to better antiinflammatory therapies and respiratory care [10]. Another study that included 73 patients prospectively used latent class analysis and found three subgroups of patients with RPC based on clinical manifestations [11]. Type I RPC was characterized by significant cartilaginous involvement and damage including ear, nose, and upper airway; type II RPC was defined by mainly lower airway involvement; and type III RPC included mainly patients who did not have significant cartilaginous damage. All types of RPC were found to have significant disability and require use of disease-modifying antirheumatic drugs (DMARDs), highlighting the refractory nature of the disease and associated morbidity. Notably, both studies identified a respiratory subgroup.
It is difficult to predict the clinical course of RPC because there is a marked inter-patient variability. The patterns that may be seen include:
●Episodic disease activity.
●Smoldering disease with ever-changing severity.
●Refractory disease with ongoing disease activity.
●A fulminant downhill course resulting in death.
●A relatively benign course that is free of clinically evident major organ involvement and is easily managed. It is not possible to estimate the prevalence of this self-limited pattern, since it is likely that many of these cases are not diagnosed.
Ear involvement — Unilateral or bilateral external ear inflammation is the most common presenting feature of RPC, seen in approximately 40 percent of patients; it eventually appears in nearly 90 percent of patients. However, this clinical feature can present late in the disease course. Some patients may have subtle ear manifestations that can be missed (picture 1) [2].
●The onset of auricular disease may be acute or subacute and develops without evident cause [12]. In some cases, it can be triggered by minimal trauma. Pain and tenderness can be pronounced. The initial presentation or the first several disease flares are usually misdiagnosed as infection.
●The affected auricles can assume a patchy or diffuse, violaceous, erythematous appearance, in most cases sparing the non-cartilaginous ear lobes (picture 2). However, some patients can have inflammation that includes the earlobes; in addition, inflammation can involve the external auditory canal. Inflammation restricted to the tragus and conchal bowl has been reported, as has extension of the inflammation to the face [13].
●Auricular inflammation may subside within days or persist for several weeks. It can encroach on the external auditory meatus, compromise hearing, and/or extend to the retroauricular soft tissues.
●Sustained or recurrent episodes of inflammation can permanently alter the structural integrity of cartilage, resulting in a "floppy eared" or "cauliflower" appearance (picture 3).
Although relatively uncommon at presentation, auditory and/or vestibular involvement appears acutely or insidiously at some point, each occurring in about one-third of patients with RPC [14,15]. Impaired hearing, tinnitus, or vertigo can result either from inner ear inflammation associated with chondritis-induced destruction of the Eustachian tube, endolymphatic hydrops, or sensorineural hearing loss or from vasculitis of the internal auditory artery or its cochlear branch. (See "Etiology of hearing loss in adults", section on 'Inner ear causes'.)
Eye involvement — Ocular disease is a frequent problem in RPC, affecting about 20 percent of patients at presentation and up to approximately 60 percent at some time during the course of the disease [2,16-18]. Forms of ocular involvement in RPC include [16,17,19,20]:
●Episcleritis – Episcleritis is often noted incidentally when other organ manifestations of RPC are prominent. (See "Episcleritis".)
●Scleritis – Scleritis in RPC is similar to the scleritis associated with rheumatoid arthritis and can range from milder forms such as diffuse anterior scleritis (picture 4) to the more severe forms of necrotizing anterior or posterior scleritis (picture 5). In RPC, it tends to be more necrotizing, bilateral, and recurrent compared with other systemic etiologies of scleritis [21]. (See "Clinical manifestations and diagnosis of scleritis", section on 'Scleritis subtypes'.)
Inflammation within the sclera can lead to a bluish or dark discoloration, caused by scleral thinning that permits visualization of the underlying choroid (picture 6).
●Peripheral ulcerative keratitis – Patients with severe scleritis may also be at risk for necrotizing inflammation of the cornea. Peripheral ulcerative keratitis can lead rapidly to visual loss (picture 7). (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Ocular disease'.)
●Uveitis – Uveal tract disease may occur in either the anterior or posterior portion of the eye in RPC. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Definitions'.)
●Salmon patch conjunctival lesion – The occurrence of a "salmon patch" lesion within the conjunctiva has been reported in RPC [22]. The histopathology of this lesion in RPC is benign reactive lymphoid hyperplasia. Salmon patch conjunctival lesions have also been reported in sarcoidosis, multiple myeloma, lymphoma, leukemia, and amyloidosis [23].
●Proptosis – Unilateral or bilateral proptosis may be caused by inflammation of the choroid, posterior elements of the globe, or other periocular tissues. In this disease manifestation, RPC resembles granulomatosis with polyangiitis. Clinical features accompanying proptosis include chemosis, ophthalmoplegia, and/or lid edema. A pseudotumor of the orbit which fails to respond to antiinflammatory therapy should raise concern for a possible lymphoma [24].
Nose involvement — Symptoms of nasal cartilage inflammation include stuffiness; crusting; rhinorrhea; epistaxis; pain, redness, and swelling of the bridge of the nose; and/or nose pressure. Nasal chondritis is present in approximately 20 percent of patients at presentation and 60 percent over the course of the illness [2]. The sense of smell may be compromised, with resultant hypogeusia. Cartilage destruction associated with sustained or recurrent episodes of inflammation can result in a characteristic saddle nose deformity, which is seen in about 10 percent of patients at presentation and 25 percent during the disease course (picture 8).
Large airway involvement — Large airway disease that includes the larynx, trachea, and bronchi can begin in a subtle fashion that, if undiagnosed for a prolonged period of time, sometimes evolves into life-threatening disease due to subglottic stenosis and/or tracheobronchomalacia. Laryngotracheal disease occurs in more than half of patients and laryngotracheal stricture in nearly one-quarter [2]. The critical management issue is diagnosing and treating large airway disease promptly, before irreversible damage and loss of tissue integrity occurs. Symptomatic airway disease may be a forme fruste of RPC that occurs in the absence of other discernible features of this disorder, making the recognition of airway involvement imperative for decreasing morbidity in these patients [25-28].
The clinical manifestations of laryngotracheobronchial disease vary with the degree and extent of airway involvement [29]. The early stages of lower airway disease can be asymptomatic or in some cases misdiagnosed as refractory asthma [30]. Symptoms of large airway disease include hoarseness, aphonia, wheezing, inspiratory stridor, a nonproductive cough, and dyspnea. Tenacious upper respiratory tract secretions are a problem in some patients. Tenderness may be noted over the thyroid cartilage and anterior tracheal region.
Other manifestations of large airway disease include:
●Glottic, subglottic, laryngeal, or tracheobronchial inflammation, with luminal encroachment.
●Loss of structural cartilaginous support, resulting in "dynamic" laryngeal collapse during forced inspiration and/or tracheal collapse during expiration. Obstructive sleep apnea caused by partial airway collapse can occur [31].
●Necrotizing sialometaplasia of the larynx, which may be misdiagnosed as a malignancy [32].
●Fibrosis-induced luminal contracture.
●Secondary infection, which can result from obstruction of distal airways.
If the diagnosis is made late in the course, tracheal or subglottic narrowing may warrant immediate tracheostomy. However, intratracheal manipulations cause additional inflammation, and, if present, more distal airway compromise can diminish the efficacy of proximal correction by tracheostomy. Optimal therapy is unclear in these settings.
Joint involvement — Involvement of the parasternal joints (the sternoclavicular, costochondral, and manubriosternal articulations) is typical of RPC. Arthritis is seen at presentation in up to a third of patients, and peripheral joint involvement eventually occurs in approximately 50 to 70 percent. There is no predilection for either large or small joints (table 1) [2,33-36].
In peripheral joints, the processes may differ from the destructive cartilaginous inflammation found in the ears, nose, eyes, and large airways. In particular, peripheral joint disease in RPC is usually nonerosive unless associated with an underlying arthritis such as rheumatoid arthritis. Tenosynovitis is also a common manifestation in patients with RPC.
The peripheral joint disease has the following additional characteristics:
●Both large and small peripheral joints may be affected, with distributions that range from monoarticular disease to oligoarticular involvement to polyarthritis.
●Asymmetric arthritis is not unusual.
●Arthralgia can occur in the absence of objective evidence of inflammation.
●Synovial fluid aspirates are usually noninflammatory.
●The arthritis may resolve spontaneously over days to weeks and can be responsive to antiinflammatory treatment with just nonsteroidal antiinflammatory drugs (NSAIDs); however, in other patients, it can be difficult to treat.
●The asymptomatic interval between flares is variable in length.
●On occasion, vertebral involvement may be observed.
Heart involvement — Clinically significant aortic or mitral valvular disease occurs in approximately 10 percent of patients. Less frequent cardiac manifestations of RPC include pericarditis, heart block, and myocardial infarction due to coronary arteritis.
A review of 440 patients with RPC found the following prevalence of valvular disease [37]:
●Isolated aortic regurgitation: 7.7 percent
●Isolated mitral valve regurgitation: 1.8 percent
●Combined valvular regurgitation: 1.6 percent
Aortic regurgitation can result from the destruction of valvular cusps, aortic ring dilatation, or dilatation or thickening of the aortic root. (See "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults".)
Valvular disease may appear within months of the onset of other RPC symptoms or may be delayed for more than a decade [38]. Progression of the disease is often insidious; as a result, echocardiography should be performed periodically to assess for valvular thickening or regurgitation [39]. The clinician must be alert to changes in the intensity or character of an existing murmur or to the development of a new murmur. (See "Auscultation of cardiac murmurs in adults".)
The interval from RPC onset to the need for operative intervention ranged from five months to 21 years (mean 6.5 years) in one review [37]. Surgery was performed on average one year after the diagnosis of valvular regurgitation. During the first four postoperative years, reoperation was required in approximately 25 percent of patients because of either early valvular leaks or aneurysm formation secondary to tissue friability. Fifty-three percent of patients who required surgery ultimately died of a cardiovascular event during this same period [37]. (See "Natural history and management of chronic aortic regurgitation in adults" and "Chronic primary mitral regurgitation: Indications for intervention".)
In addition, one case of chondritis complicated by rapidly fatal giant cell myocarditis and myositis has been reported [40]. This rare form of cardiomyopathy has also been associated with other autoimmune diseases. With more systematic screening and improved echocardiographic technology, up to 22 percent of patients in a large 2016 single-center series were estimated to possibly have a cardiac valvulopathy [10].
Kidney involvement — The frequency of kidney disease in RPC remains unclear and likely very rare. Kidney disease, as determined by biopsy or the presence of hematuria and/or proteinuria, was present in 29 of 129 patients (23 percent) seen at the Mayo Clinic between 1943 and 1984 [41]. At that time, there was no specific test to diagnose patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); due to the similarities between patients with RPC and AAV, it remains unclear how many patients in this study would likely have been reclassified as having AAV rather than RPC by use of subsequently developed criteria.
The most frequent kidney lesions observed by biopsy are mesangial expansion with cellular proliferation and segmental necrotizing glomerulonephritis [41]. Tubulointerstitial disease and immunoglobulin A (IgA) nephropathy have also been reported [42].
Nervous system involvement — In unusual cases, RPC presents with primarily neurologic manifestations. Neurologic involvement is presumed to be due to vasculitis, although this has seldom been documented [43].
The most common neurologic features are cranial neuropathies of the second, sixth, seventh, and eighth nerves [44]. A variety of other neurologic complications of RPC have been reported, often in association with underlying diseases: hemiplegia, seizures, organic brain syndrome, dementia [45], myelitis, peripheral neuropathy, aseptic meningitis, lymphocytic meningoencephalitis [46], rhomboencephalitis [47], limbic encephalitis [48], and pachymeningitis related to polyangiitis with granulomatosis [49].
Skin disease — A variety of skin findings can occur in RPC. However, none are pathognomonic for RPC, and some are nonspecific (table 2). A retrospective analysis of 200 patients with RPC followed at a single center reported the following observations [50]:
●Skin lesions were noted in 36 percent of patients, including an array of clinical findings usually associated with vasculitis: aphthous ulcers, purpura, papules, nodules, pustules, ulcerations, superficial thrombophlebitis, livedo reticularis, and distal necrosis. Neutrophilic dermatosis (Sweet syndrome) is observed in RPC related to MDS.
●Histologic examination of biopsied lesions demonstrated vasculitis, cutaneous vessel thrombosis, septal panniculitis, and neutrophilic dermatosis.
Dermatologic manifestations were the presenting symptom in 12 percent of patients. There was no correlation between skin features and sex, age at RPC onset, or sites of cartilaginous or major organ involvement. The frequency of skin lesions was significantly higher among patients with concurrent MDS.
Gastrointestinal tract involvement — Gastrointestinal involvement in RPC is infrequent unless there are concurrent manifestations of systemic vasculitis. There have been sporadic reports of coexisting ulcerative colitis, Crohn disease, systemic sclerosis, and diabetic autonomic dysfunction. At times, dysphagia can result from esophageal manometric abnormalities similar to those of systemic sclerosis [51]. Rare associations with sclerosing cholangitis and primary biliary cholangitis (previously referred to as primary biliary cirrhosis) and pneumatosis cystoides have also been reported.
Not all gastrointestinal symptoms are due to gastrointestinal disease. As an example, odynophagia and dysphagia can result from epiglottitis, thyroid, laryngeal, or tracheal cartilage inflammation.
Miscellaneous — Unifocal or multifocal abscesses characterized by deep, sterile, antibiotic resistant lesions have been described in RPC [52]. These lesions typically respond to glucocorticoids. Involvement may potentially include abdominal lymph nodes, liver, spleen, pancreas, lung, and brain.
LABORATORY STUDIES — Laboratory abnormalities can be seen in patients with relapsing polychondritis (RPC) but are nonspecific. Some of these changes reflect the presence of active inflammatory disease and may be helpful adjuncts in evaluation and management. In some instances, patients with RPC can have normal inflammatory markers despite objective findings of inflammation on physical exam (table 3) (see "Diagnostic evaluation of relapsing polychondritis" and "Treatment of relapsing polychondritis"):
●Elevations in the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level and a modest leukocytosis or thrombocytosis are associated with clinical and subclinical disease activity. However, these parameters are not informative as indices of disease progression, which often results from insidiously advancing fibrosis.
●Anemia is usually present at some point during the course of illness. It is typically normocytic and normochromic, consistent with anemia of chronic disease (see "Anemia of chronic disease/anemia of inflammation"). Coombs reactive hemolysis is unusual.
●Eosinophilia occurs in about 10 percent of patients. Its significance is unclear since it does not appear to correlate with disease activity.
Nonspecific autoantibodies — Serologic studies have revealed antinuclear antibodies (ANA) in percentages varying from 22 to 66 percent of RPC patients [53]. A homogeneous or speckled pattern is usually evident by immunofluorescence, but the specificity of the responsible antigens is unknown. Antibodies to native deoxyribonucleic acid (DNA), Sm, U1 RNP, and Ro/La are not characteristic of RPC itself.
Other serologic abnormalities including rheumatoid factor (in 16 percent of cases), a false positive serologic test for syphilis, and antiphospholipid antibodies (positive in one of eight reported cases, manifested clinically by acute thrombosis) can also occur [54]. (See "Clinical manifestations of antiphospholipid syndrome".)
Antineutrophil cytoplasmic antibodies — There are several features of RPC which suggest the potential for an increased frequency of antineutrophil cytoplasmic antibodies (ANCA). (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
●ANCA is prevalent in granulomatosis with polyangiitis (GPA), which shares a number of features with RPC such as laryngotracheal bronchial disease, necrotizing glomerulonephritis, episcleritis, saddle nose deformity, and auricular chondritis. The presence of an ANCA in this setting suggests the diagnosis of GPA, not RPC.
Fourteen percent of patients with RPC have clinically evident vasculitis that is not GPA or MPA [8].
●Vasculitis is likely operative in the pathogenesis of specific organ system involvement in many RPC patients.
There is discordance in the literature regarding the role of ANCA in the vasculitis of RPC. One report, for example, found low titer ANCA (as assessed by immunofluorescence) in 8 of 23 patients with RPC [55]. Three had a C-ANCA pattern (diffuse granular cytoplasmic staining), and five had P-ANCA reactivity (perinuclear staining) (picture 9A-B). The specificity of these antibodies was examined by ELISA. None of the C-ANCA responders were positive for serine proteinase 3, the dominant antigen responsible for this pattern in GPA. Four of the five positive P-ANCA patients were reactive with myeloperoxidase, the antigen associated with P-ANCA in GPA and microscopic polyarteritis. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
A subsequent study demonstrated ANCA reactivity in three of six patients in whom RPC appeared in conjunction with a systemic necrotizing form of vasculitis (GPA or microscopic polyarteritis) [56]. Thus, although ANCA may be detected in patients thought to have RPC, when present, its relevance and relationship to associated vasculitis require further analysis. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
Other studies — Total hemolytic complement and C3 and C4 levels are usually normal in RPC [33]. Occasional elevations in complement levels probably reflect an acute phase response. The prevalence and significance of circulating immune complexes have not been systematically evaluated. Using varying methodologies, immune complexes have been identified in 15 of 35 reported cases (43 percent) [57]. Cryoglobulins appear to occur less frequently, being detected in 7 of 32 cases (22 percent) compiled from the literature.
Transient increases may occur in immunoglobulin G (IgG), IgA, or IgE levels. Serum protein electrophoresis may show nonspecific abnormalities, such as a decrease in albumin and elevations in the alpha-1 and gamma globulin regions.
An adequate laboratory gauge defining active cartilage catabolism and, thus, a means of monitoring disease activity are lacking in RPC. Studies have investigated the feasibility of measurement of serum content of noncollagenous cartilage-specific adhesive glycoproteins and serum matrillin-1 fragments to reflect active inflammation [58-60]. Urine levels of a type II collagen specific neoepitope generated by specific interstitial collagenase CII cleavage are being investigated, but the clinical usefulness is uncertain [61]. Serum cartilage oligomeric matrix protein (COMP) is also being investigated as a potential biomarker of disease activity [62].
Collagen II antibodies can be positive in patients with RPC, but are not specific to this disorder [63,64].
Although analysis of cerebrospinal fluid may be normal in the presence of clinical evidence of central nervous system involvement, there is usually a pleocytosis with a predominance of lymphocytes, a protein content that is either normal or slightly elevated, and a normal glucose concentration [46].
COEXISTENT DISEASE — Up to one-third of patients with relapsing polychondritis (RPC) present with a recognizable form of systemic vasculitis, a connective tissue disease or other autoimmune disorder, or a malignant or premalignant condition (table 4) [2,50,65]. The intercurrent disease may precede RPC by months to years, occur after the diagnosis of RPC, or present simultaneously with RPC. In the last setting, RPC symptoms and signs may bring the patient to medical attention. (See 'Systemic vasculitis' below and 'Other autoimmune diseases' below and 'Malignancy' below and 'Immunodeficiency' below.)
Whether the association of RPC with other diseases is coincidental or representative of a shared genetic predisposition to different disorders is not known. One study that examined the immunogenetics of RPC found that human leukocyte antigen (HLA)-DR4 was significantly more common in patients with RPC than in healthy controls (60 versus 26 percent) [66]. This parallels the established observation of DR4 positivity in RA. However, no predominance of any of the DRB1*04 subtype alleles was seen in the polychondritis group in contrast to the clear association of DRB1*0401 and DRB1*0404 in patients with RA. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
Systemic vasculitis — Vasculitis is proven histologically in approximately 14 to 25 percent of patients with RPC [67]. Features of vasculitis may appear at any stage of the disease, either simultaneous with or independent of other manifestations, and may be indolent or fulminant.
Vasculitis may involve large vessels, including the aorta and its branches to the head, neck, and extremities; medium-sized vessels such as the coronary, hepatic, mesenteric and renal arteries; and small vessels, including the post-capillary venules [50]. Death can result from rupture of aneurysms of the ascending, thoracic, and abdominal aorta and the subclavian arteries [68].
The presence of systemic vasculitis is generally associated with a poor prognosis. In a series of 112 patients from the Mayo Clinic, the five-year survival rate was 45 percent, similar to that of polyarteritis alone [69].
Among patients with RPC, vasculitis may be an integral part of the primary disease process or may exist in a concurrent pathologically distinct form. Virtually all of the major types of vasculitis have been reported in association with RPC. Some of these simultaneous occurrences are probably related to chance alone. However, for others, the co-occurrence of these two diseases probably represents common predisposition to autoimmune disease:
●Aortitis [70]
●Polyarteritis nodosa [71]
●Behçet syndrome
●Immunoglobulin A vasculitis (Henoch-Schönlein purpura)
●Cogan syndrome
●Thromboangiitis obliterans
●Cutaneous leukocytoclastic angiitis
An overlap syndrome of RPC and Behçet syndrome has been described in which patients present with features resembling both conditions. This syndrome is termed the "MAGIC" syndrome, an acronym for mouth and genital ulcers with inflamed cartilage [72,73]. These patients can have distinct manifestations including aortitis, more eye inflammatory disease, Raynaud phenomenon, and thromboembolic events [63].
Other autoimmune diseases — RPC can occur in patients with other connective tissue diseases such as rheumatoid arthritis, systemic lupus erythematosus, and the syndrome of remitting, seronegative, symmetrical synovitis with pitting edema (RS3PE) [74]. Organ-specific autoimmune diseases such as Graves' disease, Hashimoto's thyroiditis, ulcerative colitis, idiopathic hypoparathyroidism, and Crohn disease have also been reported in association with RPC.
A case of RPC associated with hepatitis C virus (HCV) infection with mixed cryoglobulinemia has been reported [75]. This case was remarkable for the fact that treatment of the underlying HCV with interferon gamma and ribavirin resulted in an undetectable HCV load and resolution of the RPC symptoms.
Malignancy — Historically, myelodysplastic syndrome (MDS) has been described in association with RPC [10,50,76]. In a series of 200 patients with RPC, MDS was diagnosed in 22 (11 percent) [50]. MDS can occur before, simultaneously with, or after RPC. The etiology of this conglomeration of symptoms and bone marrow involvement is likely the genetically described disease called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'VEXAS syndrome'.)
Isolated instances of Hodgkin lymphoma, non-Hodgkin lymphoma, and carcinoma of a variety of types have been described [77].
Immunodeficiency — RPC has been reported rarely in association with common variable immunodeficiency (CVID), with descriptions in both a child and an adult with CVID [78,79]. In patients with human immunodeficiency virus (HIV) infection, RPC may occur during immune restoration with antiretroviral therapy [80].
PREGNANCY — Few reports have evaluated the effect of pregnancy on relapsing polychondritis (RPC) and vice versa. This issue was addressed in a study of 11 females of childbearing age with RPC [81]:
●Of 24 pregnancies, RPC remained stable during pregnancy in 16, entered remission in one, and flared during seven.
●When combined with previously published case reports, the onset of RPC appeared to occur during pregnancy in 4 of 15 patients. The mean time of disease onset in these four patients was at 20 weeks of gestation.
●Fetal loss was disproportionately high compared with pregnancies in healthy females (3 of 24 pregnancies).
●Features of cartilaginous inflammation and other manifestations of RPC were not found in the mothers' offspring.
SUMMARY
●Relapsing polychondritis (RPC) is a rare immune-mediated condition associated with systemic inflammation with a predilection for the involvement of cartilaginous structures within such organs as the ears, nose, eyes, joints, and respiratory tract (table 1). (See 'Introduction' above and 'Epidemiology' above and 'Clinical manifestations' above.)
●Unilateral or bilateral external ear inflammation that characteristically spares the earlobe is typical of the ear involvement of RPC, but ear chondritis can be subtle. (See 'Ear involvement' above.)
●RPC can cause a number of ocular lesions, including episcleritis, scleritis, and orbital pseudotumor. (See 'Eye involvement' above.)
●Cartilaginous inflammation in RPC may cause pain over the bridge of the nose and may eventually lead to nasal bridge collapse (saddle nose deformity). (See 'Nose involvement' above.)
●Large airway disease in RPC can affect the larynx, trachea, and bronchi and sometimes causes significant obstructive respiratory disease, the sleep apnea syndrome, and post-obstructive pneumonias. (See 'Large airway involvement' above.)
●Musculoskeletal involvement in RPC can assume many patterns, including tenosynovitis and arthritis that can be mono-, oligo-, or polyarticular, and are usually nonerosive. (See 'Joint involvement' above.)
●Aortic and/or mitral regurgitation caused by inflammation of the cartilaginous components of the valve can lead to the need for valve replacement. (See 'Heart involvement' above.)
●A variety of skin findings can occur in RPC and affect more than one-third of patients, but none are pathognomonic (table 2). Skin lesions may include aphthous ulcers, purpura, papules, nodules, pustules, ulcerations, superficial thrombophlebitis, livedo reticularis, distal necrosis, and neutrophilic dermatosis. (See 'Skin disease' above.)
●Approximately one-third of cases occur in association with another recognizable condition, particularly systemic vasculitis, connective tissue diseases, or malignancy (table 4). (See 'Coexistent disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Clement J Michet, MD, who contributed to an earlier version of this topic review.
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