Relapsing polychondritis
Relapsing polychondritis is a rare, systemic autoimmune disease characterized by recurrent episodes of inflammation affecting cartilaginous and proteoglycan-rich structures, primarily the auricle, nasal septum, and tracheobronchial tree, with potential involvement of other connective tissues and organs such as the eyes, joints, heart, and kidneys.[1][2] First described in 1923 and formally named in 1960, the condition leads to progressive cartilage destruction through immune-mediated mechanisms, resulting in symptoms like painful ear swelling, nasal saddle deformity, and respiratory compromise, which can be life-threatening if the airways are involved.[2][1] The etiology of relapsing polychondritis remains unknown, but it is believed to arise from an autoimmune response in genetically susceptible individuals, potentially triggered by infections, trauma, or environmental factors, with associations to human leukocyte antigen (HLA) alleles such as HLA-DR4 and autoantibodies against type II, IX, and XI collagens as well as matrilin-1, and recently associated with VEXAS syndrome in some cases.[1][2] Epidemiologically, it has an annual incidence of 0.7-3.5 cases per million people (as of recent studies), a prevalence estimated at 4.5-25 per million, and typically onset in the fourth or fifth decade of life, affecting people of all races (most commonly reported in individuals of European descent) and showing a female predominance, while 25–35% of patients have concurrent autoimmune or hematologic disorders.[2][1][3][4] Clinically, the disease manifests in episodic flares, with auricular chondritis occurring in up to 90% of cases, nonerosive seronegative arthritis in 50–75%, ocular inflammation in 20–60%, and nasal chondritis in about 25%, alongside potential systemic complications like vasculitis, valvular heart disease, or renal involvement that contribute to morbidity.[1][2] Diagnosis relies on clinical criteria, such as the McAdam's criteria requiring at least three of six characteristic features (e.g., bilateral auricular chondritis, nasal chondritis, nonerosive arthritis, ocular inflammation, respiratory tract chondritis, or audiovestibular dysfunction), often supported by imaging like CT or biopsy showing perichondrial inflammation and cartilage loss.[1] Treatment focuses on suppressing inflammation and preventing relapses, starting with high-dose systemic corticosteroids for acute flares, followed by steroid-sparing immunosuppressants such as methotrexate, cyclophosphamide, or biologics like tumor necrosis factor inhibitors in refractory cases, with surgical interventions like tracheostomy or vascular stenting reserved for complications.[1][2] Prognosis has improved with early intervention, with recent data indicating 5-year survival rates of 66-94% and 8-10 year survival around 90-95%, though mortality is higher in severe cases (e.g., with vasculitis or early respiratory involvement) due to airway obstruction, infection, or cardiovascular events, emphasizing the need for multidisciplinary management.[1][2]Signs and symptoms
Auricular chondritis
Auricular chondritis represents the most common initial manifestation of relapsing polychondritis, occurring in approximately 80-90% of patients over the course of the disease.[5][1] It typically presents with sudden onset of unilateral or bilateral inflammation of the auricular cartilage, characterized by redness, pain, tenderness, and swelling of the pinna.[6][1] The earlobe is characteristically spared, as it lacks cartilaginous tissue and is instead composed of fibrofatty tissue without the elastic cartilage targeted by the autoimmune inflammatory process.[1][7] The inflammation often begins acutely, with episodes lasting from days to weeks, and is typically bilateral in about 95% of cases with auricular involvement.[8] During flares, patients experience significant pain that can disrupt daily activities, posing challenges in management due to the relapsing nature of the disease and the need for rapid response to prevent progression.[9] Initial treatment typically involves nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose corticosteroids to alleviate pain and swelling, though recurrent flares may require escalation to immunosuppressive agents like methotrexate or biologics for sustained control.[1][5] Untreated or recurrent episodes lead to progressive cartilage destruction through mechanisms such as chondrocyte apoptosis, proteolytic enzyme release, and immune-mediated fibrosis, ultimately resulting in permanent deformity known as "cauliflower ear," where the pinna becomes thickened, irregular, and fibrotic.[6][5] This deformity resembles that seen in wrestlers or boxers from repeated trauma but arises from autoimmune damage rather than hematoma formation.[7][10] Auricular chondritis must be distinguished from infectious causes like otitis externa, which often involves the ear canal with purulent discharge, fever, and lymphadenopathy, whereas relapsing polychondritis lacks infectious signs and shows no response to antibiotics.[11][12] Biopsy, if performed, reveals perichondrial inflammation without pathogens, confirming the noninfectious etiology.[1] These flares may coincide with broader systemic inflammation, though auricular symptoms predominate early in the disease.[5]Nasal chondritis
Nasal chondritis manifests during disease flares as inflammation of the nasal cartilage, leading to symptoms such as acute pain, tenderness, redness, and swelling along the nasal bridge, often accompanied by nasal congestion and occasional epistaxis.[1] These symptoms typically affect approximately 25% of patients at the time of diagnosis and up to 76% over the course of the disease, reflecting the episodic nature of relapsing polychondritis.[1][13] Repeated episodes of inflammation result in progressive destruction of the nasal cartilage, particularly the septal cartilage, which can lead to perforation of the nasal septum and subsequent structural instability.[1] This chronic cartilage degradation is a hallmark of the condition, driven by autoimmune-mediated proteoglycan loss and enzymatic breakdown, ultimately contributing to irreversible cosmetic and functional changes.[5] A common long-term outcome is the development of saddle-nose deformity, characterized by a painless collapse and flattening of the nasal bridge due to unsupported cartilage.[1] This deformity occurs in 20-60% of patients, with higher rates observed in females and those under 50 years of age, and may overlap with broader respiratory tract involvement in advanced cases.[1][5] Early differentiation from granulomatous diseases, such as granulomatosis with polyangiitis, is crucial and often achieved clinically without biopsy to avoid exacerbating cartilage damage in the nascent inflammatory phase.[1] Biopsy, if performed later, may reveal characteristic perichondrial inflammation and cartilage necrosis, but initial management prioritizes non-invasive assessment based on recurrent cartilaginous involvement.[5]Respiratory tract involvement
Respiratory tract involvement in relapsing polychondritis manifests as inflammation of the cartilaginous structures in the larynx, trachea, and bronchi, often leading to significant morbidity and representing a critical aspect of the disease.[14] This involvement occurs in up to 50% of patients during the course of the disease, typically developing later rather than at initial presentation.[15] Common symptoms include hoarseness, stridor, dyspnea, and cough, which arise primarily from subglottic stenosis due to inflammatory edema and cartilage destruction in the upper airway.[1] These manifestations can be insidious, mimicking other respiratory conditions such as asthma or chronic obstructive pulmonary disease, and may worsen during disease flares, sometimes accompanied by constitutional fatigue.[14] The condition frequently progresses to airway collapse, affecting approximately 50% of cases with respiratory involvement, through mechanisms involving initial acute inflammation that causes mucosal swelling and wall thickening, followed by chronic cartilage degradation leading to loss of structural integrity and tracheobronchomalacia.[14] This dynamic collapse is exacerbated during expiration or flares, as weakened cartilaginous rings fail to maintain airway patency, resulting in obstructive physiology and potential respiratory failure.[16] Respiratory complications carry the highest mortality risk in relapsing polychondritis, accounting for up to 50% of deaths, primarily from airway obstruction, secondary infections, or ventilatory insufficiency.[17] Monitoring for tracheomalacia and progression is essential and involves serial dynamic computed tomography (CT) scans to visualize airway narrowing and collapse, particularly during inspiration and expiration phases, alongside flexible bronchoscopy to assess mucosal inflammation and stenosis extent.[1] Pulmonary function tests, including flow-volume loops, help quantify obstructive patterns and guide therapeutic interventions to mitigate life-threatening complications.[14]Costochondritis
Costochondritis in relapsing polychondritis manifests as inflammation of the costal cartilages connecting the ribs to the sternum, resulting in chest wall pain that often mimics more serious cardiac or pulmonary disorders.[16] This presentation typically involves sharp, localized pain over the sternal or costochondral junctions, exacerbated by upper body movements, deep inspiration, coughing, or sneezing.[18] The pain is frequently retrosternal and unilateral or bilateral, affecting multiple ribs in a significant proportion of cases, particularly those adjacent to the sternum.[16] In clinical cohorts, costochondritis occurs in approximately 20% of patients with relapsing polychondritis, with a higher frequency (around 28%) among those exhibiting respiratory tract involvement compared to those without (about 7%).[19] It is rarely an isolated feature and often accompanies other cartilaginous inflammations, contributing to diagnostic challenges.[16] Differentiation from conditions such as myocardial infarction relies on physical examination findings, including reproducible tenderness upon palpation of the affected area, alongside normal electrocardiographic results and cardiac biomarkers.[20] Unlike Tietze syndrome, which involves focal swelling at a single costochondral junction without systemic features, costochondritis in relapsing polychondritis tends to affect multiple sites and occurs within a broader autoimmune context.[21] The resulting pain can substantially impair daily activities, such as reaching overhead, lifting objects, or even breathing deeply, leading to reduced mobility and quality of life during flares.[22] Management often incorporates local therapies, including intra-articular corticosteroid injections or nonsteroidal anti-inflammatory drugs applied topically or systemically, to alleviate symptoms alongside disease-modifying treatments for the underlying condition.[23] Costochondritis may also coincide with arthropathy in relapsing polychondritis, reflecting shared inflammatory pathways affecting cartilaginous and synovial structures.[16]Arthropathy
Arthropathy in relapsing polychondritis is characterized by non-erosive, seronegative inflammatory arthritis that primarily affects peripheral and axial synovial joints, distinguishing it from erosive arthritides like rheumatoid arthritis.[5] This involvement typically presents as acute, intermittent episodes of joint pain, swelling, and stiffness, without evidence of joint space narrowing or bony erosions on radiographic imaging.[1] Clinically, it mimics seropositive rheumatoid arthritis in its polyarticular distribution but is consistently rheumatoid factor-negative and lacks autoantibodies such as anti-citrullinated protein antibodies.[24] Joint manifestations occur in 50-85% of patients over the course of the disease, making arthropathy the second most common feature after auricular chondritis.[5] The pattern is usually oligoarticular or polyarticular, often asymmetric and involving large joints such as the knees, wrists, and ankles, as well as smaller peripheral joints like the metacarpophalangeal and proximal interphalangeal joints.[24] Axial involvement may include the sternoclavicular and manubriosternal joints, though costochondral junctions are addressed separately. Flares typically last weeks to months, resolving spontaneously or with treatment, and parallel the relapsing inflammation of cartilaginous structures elsewhere in the body, reflecting the systemic autoimmune process targeting proteoglycan-rich tissues.[1] During active flares, arthropathy can cause significant functional impairment, including reduced joint mobility and daily activity limitations due to pain and effusion, though the non-deforming nature generally preserves long-term joint architecture in most cases.[5] Rare instances of progressive joint destruction have been reported, potentially leading to chronic disability. Management focuses on immunosuppression, with corticosteroids providing rapid symptom relief and disease-modifying agents like methotrexate or biologics (e.g., anti-TNF or IL-6 inhibitors) used for refractory cases to prevent recurrent flares and maintain function.[1]Ocular manifestations
Ocular manifestations occur in approximately 14-67% of patients with relapsing polychondritis (RP), affecting various structures of the eye and orbit due to the autoimmune inflammatory process targeting cartilaginous and proteoglycan-rich tissues.[25] These manifestations can present as the initial feature in up to 21% of cases and often require prompt multidisciplinary management to prevent complications.[25] The most common ocular involvements include episcleritis and scleritis, reported in 31% and 32% of affected patients, respectively, typically presenting as unilateral or bilateral redness, pain, and tenderness of the sclera.[25] Uveitis, occurring in about 23% of cases, is usually anterior but can involve posterior segments, leading to symptoms such as photophobia, blurred vision, and hypopyon formation in severe instances.[25] Keratoconjunctivitis sicca, often accompanied by conjunctivitis, affects dry eye symptoms and conjunctival erythema, contributing to ocular surface discomfort in a subset of patients.[26] Orbital involvement, though less frequent, can manifest as proptosis due to inflammatory edema or extraocular muscle involvement, and optic neuritis, seen in 4-6% of cases, which may cause acute vision loss.[26] These features arise from periorbital inflammation and vasculitis affecting orbital structures.[27] Such manifestations pose significant threats to visual acuity, including risks of corneal perforation from necrotizing scleritis, glaucoma secondary to uveitis, and permanent optic neuropathy, necessitating immediate ophthalmologic referral for evaluation and treatment with topical or systemic immunosuppressants.[27] RP's ocular features often overlap with autoimmune vasculitis, sharing mechanisms like anti-collagen antibody-mediated inflammation, which underscores the need for comprehensive systemic assessment.[26]Neurological involvement
Neurological involvement in relapsing polychondritis (RP) occurs in approximately 3% of cases and primarily stems from vasculitis or direct inflammatory effects on neural structures, affecting both the central and peripheral nervous systems.[5] This complication is relatively uncommon but can be severe, often presenting with diverse symptoms that mimic other vasculitic or autoimmune disorders. The underlying immune-mediated destruction of cartilaginous tissues may extend to perivascular inflammation, leading to ischemia or direct neural damage.[28] Central nervous system (CNS) manifestations are the most frequently reported neurological features, including cranial nerve palsies, aseptic meningitis, and stroke. Cranial nerve involvement, particularly affecting the trigeminal (V) and facial (VII) nerves, leads to symptoms such as facial weakness, sensory loss, or hearing impairment, occurring in up to half of neurological cases.[29] Aseptic meningitis presents with headache, fever, and neck stiffness, confirmed by cerebrospinal fluid analysis showing pleocytosis without infectious agents, and has been documented in multiple case reports as a relapsing feature responsive to corticosteroids.[30] Stroke, including ischemic or hemorrhagic subtypes, arises from cerebral vasculitis and can result in hemiplegia, ataxia, or seizures, with infarction reported in isolated instances.[31] Other CNS complications, such as limbic encephalitis or meningoencephalitis, may cause confusion, psychosis, or cognitive decline.[32] Peripheral nervous system involvement typically manifests as neuropathy patterns linked to vasculitic processes, including mononeuritis multiplex or sensorimotor polyneuropathy, characterized by asymmetric weakness, paresthesias, or pain in the limbs.[28] Myositis, though less common, can occur as inflammatory muscle involvement, contributing to proximal weakness in some patients with systemic vasculitis.[33] These peripheral features often overlap with broader vasculitic syndromes and may coincide with renal involvement, such as glomerulonephritis, exacerbating systemic inflammation.[34] Diagnosis of neurological involvement relies on clinical correlation with RP features, supported by neuroimaging and laboratory tests. Magnetic resonance imaging (MRI) commonly reveals meningeal enhancement, white matter hyperintensities, or parenchymal lesions indicative of inflammation or ischemia, with leptomeningeal changes observed in cases of meningitis.[35] Cerebrospinal fluid examination aids in confirming aseptic processes, while nerve conduction studies can delineate peripheral neuropathy.[36] Neurological complications in RP carry a high risk of permanent deficits, including chronic neuropathy, cognitive impairment, or motor sequelae, with CNS involvement contributing to mortality in up to 20% of affected cases due to irreversible vascular damage.[37] Early immunosuppressive therapy is crucial to mitigate progression and preserve function.[38]Renal involvement
Renal involvement in relapsing polychondritis (RP) affects approximately 10-30% of patients and is primarily characterized by immune complex-mediated glomerular damage.[5] This manifestation often presents as glomerulonephritis, with clinical features including microscopic hematuria, proteinuria, and, in severe cases, acute or progressive renal failure, which is associated with a poor prognosis and reduced 10-year survival rates.[5][39] Kidney biopsy in affected patients typically reveals mesangial proliferation and expansion, alongside segmental necrotizing glomerulonephritis with crescent formation in some instances.[5][39] Electron microscopy may show mesangial electron-dense deposits, while immunofluorescence demonstrates faint deposition of immunoglobulins (IgG, IgM, or IgA) and complement (C3) predominantly in the mesangium.[39] Additional findings can include tubulointerstitial nephritis or membranous nephropathy, underscoring the immune-mediated nature of the renal pathology.[5] RP with renal involvement may overlap with ANCA-positive vasculitis, such as microscopic polyangiitis, in up to 25% of cases featuring concomitant vasculitis, where MPO-ANCA positivity contributes to necrotizing glomerular lesions.[5][40] This association highlights the potential for systemic vasculitic processes exacerbating kidney damage in RP.[41] Ongoing monitoring of renal function in RP patients with suspected involvement includes serial measurements of serum creatinine and routine urinalysis to detect early signs of hematuria or proteinuria, enabling timely intervention to prevent progression to renal failure.[5]Cutaneous and other manifestations
Cutaneous manifestations occur in approximately 17% to 37% of patients with relapsing polychondritis, often presenting concurrently with or following episodes of chondritis.[5] These skin lesions are typically nonspecific and include aphthous ulcers (oral or cutaneous), nodules on the limbs, raised purpura, papules, sterile pustules, superficial phlebitis, livedo reticularis, and distal ulcerations or necrosis, with the latter frequently linked to underlying vasculitis.[5][42] Histopathologic examination of affected skin often reveals leukocytoclastic vasculitis, neutrophilic infiltrates, small vessel thrombosis, or septal panniculitis, though findings can be nonspecific in some cases.[42][24] In one large series of 200 patients, dermatologic features were the initial presentation in about 12% of cases and were more prevalent in those with associated myelodysplastic syndrome.[42] Cardiac involvement affects roughly 10% to 25% of patients and represents a significant cause of morbidity and mortality, often manifesting as valvulitis or pericarditis.[5][24] Valvular disease is the most common form, with aortic regurgitation occurring in 4% to 6% and mitral regurgitation in 2% to 4%, potentially leading to heart failure or requiring surgical intervention such as valve replacement.[5] Pericarditis is reported in up to 24% of those with cardiac complications, while other features include aortic root dilatation, aneurysms, myocarditis, and conduction abnormalities like atrioventricular block.[43] Echocardiography is recommended for early detection, as these manifestations can be subclinical and progress rapidly.[24] Audiovestibular symptoms arise in 20% to 46% of patients, primarily due to inflammation affecting the inner ear structures rather than external cartilage alone.[5] Sensorineural hearing loss is the predominant feature, often bilateral and irreversible, resulting from labyrinthine inflammation, vasculitis, or autoantibodies targeting inner ear components, and is accompanied by tinnitus, vertigo, or vestibular dysfunction in many cases.[8] Conductive hearing loss may also occur secondary to serous otitis media or Eustachian tube involvement, though it is less common.[5] Rare manifestations include autoimmune thyroiditis and gastrointestinal involvement, typically as part of associated autoimmune conditions rather than direct primary features.[24] Thyroiditis presents with typical signs of autoimmune thyroid disease, while gastrointestinal symptoms may involve inflammatory bowel disease, though these are infrequent and often overlap with systemic autoimmunity.[24]Constitutional symptoms
Constitutional symptoms in relapsing polychondritis (RP) commonly include fever, fatigue, malaise, and weight loss, which often precede or accompany disease flares and reflect the systemic inflammatory nature of the condition.[44] Fatigue is particularly prevalent, affecting approximately 80% of patients and contributing significantly to overall debility during active disease phases.[13] These symptoms typically resolve with treatment of the underlying inflammation but can persist at lower levels even in remission, exacerbating the chronic burden of the disease.[5] Laboratory findings frequently reveal anemia of chronic disease, characterized as normocytic normochromic, alongside elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, which serve as nonspecific markers of ongoing systemic inflammation.[44] These markers normalize during periods of remission but rise acutely with flares, aiding in monitoring disease progression.[5] The presence of constitutional symptoms markedly impairs quality of life, with fatigue and malaise often leading to disability in a substantial proportion of patients—up to 38% in some cohorts—and contributing to diagnostic delays averaging nearly three years.[45] Such symptoms correlate closely with disease activity as measured by the Relapsing Polychondritis Disease Activity Index (RPDAI), a validated scoring system incorporating fever, fatigue, weight loss, anemia, ESR, and CRP to quantify overall RP severity on a scale up to 265 points.[46] Elevated RPDAI scores during flares underscore the systemic impact, guiding therapeutic decisions to mitigate long-term morbidity.[44]Associated conditions
Relapsing polychondritis (RP) is frequently associated with other autoimmune and inflammatory conditions, as well as hematologic disorders, occurring in approximately 25-30% of cases.[47] These overlaps can complicate diagnosis and management, often requiring multidisciplinary approaches.[48] One prominent association is MAGIC syndrome (mouth and genital ulcers with inflamed cartilage), a rare autoinflammatory disorder combining features of RP and Behçet's disease, such as recurrent oral and genital ulcers alongside cartilaginous inflammation.[49] First described in 1985, it affects fewer than 100 reported cases worldwide and typically presents in adulthood with episodic flares involving mucosal and chondral tissues.[50] The syndrome highlights the shared vasculitic and inflammatory pathways between RP and Behçet's disease, though its exact prevalence among RP patients remains unclear due to underdiagnosis.[51] RP also overlaps with vasculitides, particularly ANCA-associated vasculitis (AAV), in up to one-third of cases where autoimmune comorbidities are present.[52] This association may manifest as concurrent small-vessel inflammation, often positive for p-ANCA or MPO-ANCA, leading to shared organ involvement like respiratory or renal damage.[53] Behçet's disease, beyond MAGIC syndrome, has been linked to RP in isolated reports, potentially through common innate immune dysregulation.[54] Hematologic associations are common, with myelodysplastic syndromes (MDS) occurring in 10-25% of RP patients, particularly in older males with late-onset disease.[55] These cases often involve refractory anemia or cytopenias preceding or coinciding with RP flares, suggesting a possible shared clonal hematopoiesis mechanism.[56] Recent discoveries have linked a subset of RP cases to VEXAS syndrome via somatic UBA1 gene mutations, reported in 2024-2025 studies as defining a distinct adult-onset inflammatory phenotype.[57] These mutations, typically in the UBA1 methionine-46 locus, affect ubiquitination and inflammasome activation, leading to RP-like chondritis alongside systemic inflammation and cytopenias in about 10-20% of late-diagnosed RP cohorts.00197-3/fulltext) Genetic testing for UBA1 variants is now recommended in RP patients over age 50 with hematologic features to identify this overlap.[58]Pathophysiology
Etiology
Relapsing polychondritis (RP) is considered an idiopathic autoimmune disorder characterized by a relapsing-remitting pattern of inflammation targeting cartilaginous structures throughout the body.[1] The exact cause remains unknown, but it is thought to arise in genetically predisposed individuals, with no evidence of familial clustering or a single identifiable etiologic agent.[2] Instead, a multifactorial model is proposed, involving interplay between genetic susceptibility and environmental triggers that initiate aberrant immune responses against self-cartilage antigens.[48] Hypotheses regarding potential initiators focus on external factors that may precipitate the disease in susceptible hosts. Infectious agents have been implicated as possible triggers, with reports suggesting that viral or bacterial infections could release cryptic antigens from cartilage, thereby activating autoimmunity.[1] Trauma to cartilaginous tissues, such as the auricle or nasal septum, has also been associated with disease onset, potentially through mechanical disruption leading to exposure of immunogenic components.[1] These environmental insults are hypothesized to mimic or cross-react with cartilage components, but direct causality has not been established.[48] More recently, iatrogenic factors have emerged as contributors, particularly in the context of cancer immunotherapy. Post-2023 case reports document RP onset following PD-1 inhibitor administration, such as pembrolizumab or nivolumab, suggesting that immune checkpoint blockade can unmask or exacerbate underlying autoimmune tendencies against cartilage.[59] For instance, a 2023 report described RP developing shortly after PD-1 blockade in a patient with lung cancer, highlighting immunotherapy as a potential trigger in oncologic settings.[59] Similarly, a 2025 case confirmed RP diagnosis via PET/CT imaging after PD-1 therapy, with resolution upon steroid treatment.[60] These observations underscore the role of dysregulated immunity in RP pathogenesis, though such cases remain rare and require further investigation to clarify mechanisms.[59]Immune mechanisms
Relapsing polychondritis (RP) is characterized by an autoimmune response targeting cartilaginous extracellular matrix components, leading to recurrent inflammation and tissue destruction. Humoral immunity plays a central role, with autoantibodies directed against type II collagen, a major structural protein in cartilage, detected in the serum of patients during acute flares.[61] Similarly, antibodies to matrilin-1, a non-collagenous cartilage matrix protein, are present in RP patients and correlate with tracheolaryngeal involvement, binding directly to affected cartilage in vivo.[62] Autoantibodies targeting chondrocyte antigens, including surface components, further contribute to the humoral attack, facilitating immune complex deposition and perpetuating inflammation.[63] Cellular immune mechanisms involve T-cell mediated responses, predominantly Th1-driven, with elevated levels of interferon-γ, interleukin-12, and interleukin-2 paralleling disease activity.[64] This T-cell activation triggers a cytokine storm featuring interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which amplify inflammation and are therapeutic targets via IL-6 inhibitors and TNF-α blockers in refractory cases.[64] Monocyte/macrophage activation is also evident, marked by increased chemokines such as monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β.[65] The immune assault results in proteoglycan degradation, primarily through elevated matrix metalloproteinase-3 activity, which erodes the cartilage's glycosaminoglycan-rich matrix and diminishes its resilience and hydration capacity.[64] Complement activation exacerbates tissue damage, with antibody-mediated deposition leading to chondrocyte lysis and further matrix breakdown in affected sites.[66]Genetic factors
Relapsing polychondritis (RP) exhibits a genetic predisposition primarily linked to human leukocyte antigen (HLA) class II alleles, with HLA-DR4 identified as a significant susceptibility factor. Studies have shown that the frequency of HLA-DR4 is substantially higher in RP patients compared to healthy controls, occurring in approximately 56% of patients versus 26% in controls, conferring an odds ratio of about 3 for disease risk.[67] This association suggests that HLA-DR4 may influence immune recognition of cartilage-specific antigens, though no specific DR4 subtype predominates in affected individuals. Familial cases of RP are exceedingly rare, comprising less than 5% of reported instances, with no clear pattern of mendelian inheritance observed.[2] Instead, evidence points to a polygenic model of susceptibility, where multiple genetic variants, including rare coding changes in genes like DCBLD2 and components of the tumor necrosis factor (TNF) pathway, may contribute to disease predisposition in genetically vulnerable individuals.[68] A notable genetic overlap exists with VEXAS syndrome, an autoinflammatory disorder driven by somatic mutations in the UBA1 gene, affecting up to 7.6% of RP patients, particularly older males with hematologic abnormalities.[69] These mutations, typically at methionine-41, arise somatically in hematopoietic stem cells and are restricted to myeloid and erythroid lineages, leading to ubiquitination defects and systemic inflammation that manifests as RP-like chondritis.[69] Recent studies from 2024 confirm this subset's distinct clinical profile, including higher mortality and frequent macrocytic anemia, distinguishing it from idiopathic RP.[57] In cases of RP associated with myelodysplastic syndrome (MDS-RP), somatic mutations accumulate in myeloid lineages, exacerbating autoinflammatory features through clonal hematopoiesis.[70] These mutations, often involving genes beyond UBA1 such as those in epigenetic regulators, highlight a shared pathogenic mechanism where dysregulated myeloid cells drive cartilage-targeted autoimmunity.[71]Diagnosis
Diagnostic criteria
The diagnosis of relapsing polychondritis (RP) relies on clinical features, as no single laboratory or imaging test is pathognomonic. The foundational diagnostic criteria were established by McAdam et al. in 1976, requiring at least three of six characteristic manifestations for a definitive diagnosis. These criteria emphasize recurrent inflammation of cartilaginous structures and associated systemic involvement, as observed in a prospective study of 23 patients. The six features are summarized in the following table:| Feature | Description |
|---|---|
| Bilateral auricular chondritis | Recurrent inflammation of the cartilage of both ears, sparing the earlobes. |
| Nonerosive seronegative inflammatory polyarthritis | Symmetric arthritis affecting multiple joints without erosions on radiography and negative serology for rheumatoid factor. |
| Nasal chondritis | Painful inflammation of the nasal septum leading to saddle-nose deformity over time. |
| Ocular inflammation | Conditions such as conjunctivitis, keratitis, scleritis, episcleritis, or uveitis. |
| Respiratory tract chondritis | Inflammation of laryngeal or tracheal cartilage, potentially causing hoarseness, dyspnea, or stridor. |
| Audiovestibular damage | Sensorineural hearing loss or vestibular dysfunction, such as vertigo. |