BOTTOM LINE

Relapsing polychondritis (RPC) is a rare immune-mediated disease causing inflammation of cartilaginous structures. Manifestations include auricular swelling, scleritis, inflammatory arthritis, nasal chondritis, airway inflammation, and rash. RPC may be associated with another disease, including other systemic vasculitis, systemic rheumatic disease, and VEXAS. Order baseline screening renal studies, ANCA, PFT, chest X-ray, ECG in all patients; baseline CT chest if nasal chondritis. Consider arranging UBA1 mutation testing and bone marrow biopsy for VEXAS in older male patients with severe RPC, macrocytosis and thrombocytopenia. Treatment of minor disease includes NSAIDs, steroids, and csDMARDs. Recurrent disease may be require csDMARDs (like methotrexate) or advanced DMARDs: TNF inhibitors, IL-6 inhibitors, JAK inhibitors. Life-threatening severe disease may require cyclophosphamide.
[🕑6 minute read]

EPIDEMIOLOGY

• Population
  • Rare: estimated incidence 0.7-3.5/1,000,000, prevalence unknown
  • No specific ethnic predilection
• Age, Sex
  • Age at onset: 40-60 years; reported age range 4-93 years (case reports)
  • Sex: slight female predominance 1.7:1.0
• Risk Factors
  • Genetic:
    possible HLA-DR4 association (German population); HLA-DRB1*16, HLA-DQB1*05, HLA-B*67 (Japanese)

CLINICAL MANIFESTATIONS

— CLINICAL PHENOTYPES

RPC can present with 3 overlapping disease clusters; RPC may be more than 1 disease.

• Mild RPC
  • Relapsing episodes of minor chondritis of auricular cartilage and nasal bridge
  • Better prognosis
• Respiratory RPC
  • Chondritis of laryngo-tracheo-bronchial tree phenotype
• VEXAS RPC
  • VEXAS: Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic; associated with UBA1 mutation
  • Older age, more males
  • More fever, skin rash, eye involvement, pulmonary infiltration, cardiac involvement, and MDS.
  • Relationship between RPC and VEXAS
    • RPC patients with UBA1 mutation: 7.6%
    • VEXAS patients with diagnostic criteria for RPC: 0-60%
  • Consider screening for UBA1 mutation in male RPC patients, especially if MCV>100 fL or PTL <200×10⁹/L
  • More treatment-refractory disease and death

— SYSTEMIC MANIFESTATIONS

• EAR (90%)
  • Acute/subacute ear inflammation sparing non-cartilaginous ear lobe (lobule) lasting days/week
  • Auditory or vestibular involvement in 30% with ear involvement: tinnitus, vertigo
  • Hearing loss up to 40%: conductive (inflammation of external auditory canal) or sensorineural (inner-ear)
• EYE (20-50%)
  • Episcleritis, scleritis, peripheral ulcerative keratitis, uveitis, conjunctivitis. Proptosis may occur due to inflammation of choroid, posterior globe, or periocular tissues; may look clinically like GPA.
  • Rare reported CRAO, CRVO, optic neuritis, retinopathy and detachment
• NASAL (60%)
  • Nasal congestion, rhinorrhea, epistaxis, hypogeusia; can get saddle nose
• NECK
  • Thyroid cartilage inflammation may present with severe pain and be mistaken for De Quervain Thyroiditis
• RESPIRATORY (30-50%)
  • Hoarseness, aphonia, wheezing/stridor, cough, dyspnea, tracheomalacia, airway collapse/stenosis
  • Tracheobronchial involvement eventually develops in ~50% of RPC patients; major cause of morbidity and mortality
  • Parenchymal inflammation/infiltrates; more common in patients with VEXAS-RPC
• JOINT (50-70%)
  • Parasternal joints (sternoclavicular, costochondral, manubriosternal); can be severe
  • Non-erosive, large and small asymmetrical inflammatory arthritis lasting days/week
• CARDIAC (7-10%)
  • Aortic or mitral valvular disease with mitral regurgitation (2-4%) or aortic regurgitation (4-6%)
  • Aortic aneurysm, dissection, most commonly ascending thoracic aorta but can be anywhere along aorta
  • Pericarditis, heart block, coronary arteritis and myocardial infarction
  • Cardiac involvement in predominantly male patients with more severe disease later in disease course
  • Major cause of mortality
  • May have overlap RPC and Behcets disease with large vessel vasculitis (i.e.: “MAGIC” Syndrome)
• RENAL <2%
  • Rare. Necrotizing glomerulonephritis, tubulointerstitial disease; consider alternate diagnosis of ANCA-negative AAV.
• NEUROLOGICAL (3%)
  • Rare and varied; cranial neuropathies, parenchymal disease (seizures, hemiplegia, dementia, encephalitis), meningitis, peripheral neuropathy
• SKIN (33%)
  • Varied; apthous ulcers, petechiae/purpura, ulcers, livedo, urticaria, neutrophilic dermatoses, phlebitis, angio-edema, erythema elevatum diutinum.
  • Histology often shows lymphocytic vasculitis without leukocytoclasia
• GASTROINTESTINAL
  • · Rare; colitis, dysphagia
• ASSOCIATED DISEASE
  • Systemic vasculitis
    • Concurrent distinct vasculitis or vasculitis as part of RPC; small/medium/large vessel
  • Other rheumatological disease
    • RA, SLE, RS3PE; VEXAS (see above), MAGIC syndrome (overlap Behcet’s disease and RPC)
  • Malignancy
    • MDS (myelodysplastic syndrome, especially if VEXAS-RPC); less often lymphoproliferative or solid malignancy

INVESTIGATIONS

• CBC
  • May have anemia of chronic inflammation
  • Unexplained cytopenias and dysplastic cells on smear may suggest MDS and need for bone marrow biopsy
  • Strongly suggests VEXAS: MCV>100 fL or PTL <200×10⁹/L 
• Creatinine, urinalysis
  • Baseline creatinine and urinalysis; may be abnormal if renal involvement
• ESR, CRP
  • May be elevated during flare; non-specific
• Auto-antibodies
  • No characteristic antibodies; screen ANCA antibodies in all, add ANA, RF depending on clinical suspicion
• Genetics
  • Consider ordering UBA1 mutation in male patients with MCV>100 fL or PTL <200×10⁹/L for VEXAS, or for any patient with refractory RPC
• Biopsy
  • Not routinely done; may not be needed if compatible clinical syndrome of RPC
  • Could consider if atypical features or not responding to prednisone (ex: unilateral ear swelling)
  • Ear histopathology: no characteristic findings. May show basophilic staining of cartilage matrix and perichondral mononuclear inflammatory infiltrate with fibrosis.
• Respiratory
  • PFT
    • May show inspiratory/expiratory obstruction; to rule out other conditions (ex: asthma)
    • Flow volume loops only change in advanced disease; not useful for diagnosis or monitoring disease
  • CT chest
    • Baseline in all if respiratory symptoms, nasal chondritis, abnormal PFT
    • Inspiratory *and expiratory* images to look for irregular caliber airway/collapse
    • May show tracheomalacia, tracheal thickening (>2mm), tracheal calcification
  • Other imaging
    • MRI:
      May evaluate upper airway involvement, distinguish chronic fibrosis from active inflammation
    • PET-CT:
      May stage extent of disease and detect asymptomatic chondritis or treatment response
  • Brochoscopy/laryngoscopy
    • May do with endobronchial ultrasound to assess disease activity if suspected airway involvement
    • High risk due to potentially collapsable airways; done by experienced otolaryngologist
    • May need urgent ENT evaluation if stridor.
• Cardiac
  • ECG:
    Baseline all patients; myocarditis/ischemia may cause arrhythmias
  • Echo:
    If clinical suspicion of valvular, myo/pericardial disease, or aortitis
  • Angiography:
    CT-Angiography for thoracic/abdominal aneurysm if valvular disease present on echo
• Referrals
  • Consider referral to otolaryngology, respirology, optometry/ophthalmology, or hematology for examination (laryngo/bronchoscope, slit lamp, or bone marrow) depending on clinical suspicion and presentation

DIAGNOSIS

Suspect RPC in patient, often middle-aged, presenting with spontaneous recurrent cartilaginous inflammation (particularly the ear sparing lobule, inner ear, joints, nose, eye or airway). Screen all patients with CBC, creatinine, urinalysis, ANCA, echocardiogram, and chest imaging. Consider differential of ANCA-associated vasculitis. Investigate for MDS with bone marrow biopsy if unexplained cytopenias and order UBA1 mutation for VEXAS in older male patients with severe or refractory RPC (especially if MCV>100 fL or PTL <200×10⁹/L on CBC).  Biopsy may be helpful in equivocal cases but not needed routinely.

— DIAGNOSTIC CRITERIA

RPC is a clinical diagnosis. The following older criteria may be helpful as a framework for reviewing common manifestations of RPC, but patients may initially manifest an incomplete presentation of RPC requiring clinical evaluation over time.

McAdam Diagnostic Criteria

• ≥3 following clinical criteria plus compatible biopsy if not clinically obvious diagnosis:
  • Bilateral auricular chondritis
  • Nonerosive, seronegative inflammatory polyarthritis
  • Nasal chondritis
  • Ocular inflammation (conjunctivitis, keratitis, scleritis/episcleritis, uveitis)
  • Respiratory tract chondritis (laryngeal and/or tracheal cartilages)
  • Cochlear and/or vestibular dysfunction (neurosensory hearing loss, tinnitus, and/or vertigo)

Modified (Damiani) Criteria

• One of the following:
  • At least three of McAdam’s diagnostic criteria, or
  • ≥1 clinical McAdam criteria, with positive biopsy, or
  • Chondritis at ≥2 separate anatomic locations with a response to glucocorticoids and/or dapsone

— DIFFERENTIAL DIAGNOSIS

• Ear Swelling
  • Infection: usual cellulitis, TB, fungal, syphilis, leprosy, pseudomonas; suspect if regional lymphadenopathy.
  • Pseudomoas infection can be rapidly progressive, necrotizing; associated history of water exposure and diabetes
  • Malignancy: leukemia cutis; requires biopsy
  • Chondrodermatitis nodularis helicis: benign inflammation of  skin and cartilage of the pinna.
  • Red ear syndrome: second-hours of brning auricular pain with history of migraines
• Saddle Nose
  • ANCA associated vasculitis
  • Carcinoma, lymphoma
  • Cocaine abuse
  • Granulomatous lesions (sarcoid, TB)
  • IgG4-related disease
• Airway
  • Epiglotitis (infectious), GPA, traumatic intubation, endobronchial malignancy, infection.
  • Idiopathic subglottic stenosis, amyloid, IgG4 related disease
• Aortitis
  • See aortitis differential in GCA chapter
• Ocular
  • Other systemic vasculitis causing ocular inflammation (GPA, Behcet’s, Cogan’s)
  • Sarcoidosis-related uveitis and systemic granulomatous inflammation
• Inflammatory arthritis
  • RA, spondyloarthropathies, SAPHO
• Hematological
  • VEXAS

TREATMENT

• Rare disease; treatment guided by observational studies, expert opinion, and assessment of disease severity
• Most experience in literature with:
  • csDMARDs: methotrexate; less so leflunomide, azathioprine, mycophenolate.
  • bDMARDs: abatacept, tocilizumab, TNF inhibitors, anakinra; rituximab may be less effective than other bDMARDs for RPC
  • Cyclophosphamide for severe and/or refractory cases

— MILD DISEASE

Ex: Nasal/ear chondritis, cutaneous involvement, mild intermittent peripheral arthritis

No major organ involvement, ex: no airway inflammation/stenosis/collapse, cardiac, renal, ocular, neurological disease, no vasculitis.

• Initial: NSAIDs
• Recurrent disease
  • csDMARDs: methotrexate, leflunomide, Azathioprine
  • Dapsone, Colchicine (especially for neutrophilic dermatitis and other cutaneous involvement)
  • Low dose prednisone or intra-articular steroids

— MODERATE, RELAPSING DISEASE

Ex: Non-life/organ threatening ocular, inner ear, laryngotracheal/bronchial, cardiovascular, renal, or neurological disease

• Initial:
  • High dose prednisone (0.5-1.0mg/kg/day)
• Maintenance:
  • csDMARDs: methotrexate, leflunomide: azathioprine, mycophenolate
  • Biologics (TNFi, tocilizumab, rituximab, abatacept, anakinra), JAK inhibitors
  • Opthalmology consultation for ocular disease

— SEVERE, LIFE/ORGAN-THREATENING DISEASE

Ex: severe laryngotracheal disease, severe renal or neurological involvement, necrotizing scleritis

• Initial
  • High dose prednisone (0.5-1.0mg/kg/day) ± pulse methylprednisolone (500-1000mg IV x 3 days)
  • Cyclophosphamide (similar regimen for ANCA vasculitis), or biologics, or csDMARDs
• Maintenance
  • Methotrexate, Azathioprine, Mycophenolate, JAK inhibitors
• VEXAS patients may be considered for autologous bone marrow transplant, if a candidate

— SURGERY

• Saddle nose may be surgically repaired when disease is in remission
• Airway collapse (from tracheomalacia, stenosis) may dilated, resected, or stented
• Valvuloplasty or replacement when indicated
• Anesthesia considerations
  • Laryngeal/tracheobronchial disease can make for difficult intubation and ventilation;
  • Local, regional, epidural anesthesia may be favoured

PROGNOSIS

• Standardized mortality ratio 2.16 
• 5-year survival 90%
• Leading causes of death: complications related to airway involvement, cardiovascular complications, and infections

REFERENCES

Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Ospina Cardona, D., Wu, Z., Patel, B., Manthiram, K., Groarke, E. M., Gutierrez-Rodrigues, F., Hoffmann, P., Rosenzweig, S., Nakabo, S., Dillon, L. W., Hourigan, C. S., Tsai, W. L., … Grayson, P. C. (2020). Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. The New England journal of medicine, 383(27), 2628–2638. https://doi.org/10.1056/NEJMoa2026834

Beck, D. B., Bodian, D. L., Shah, V., Mirshahi, U. L., Kim, J., Ding, Y., Magaziner, S. J., Strande, N. T., Cantor, A., Haley, J. S., Cook, A., Hill, W., Schwartz, A. L., Grayson, P. C., Ferrada, M. A., Kastner, D. L., Carey, D. J., & Stewart, D. R. (2023). Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA, 329(4), 318–324. https://doi.org/10.1001/jama.2022.24836

Borgia, F., Giuffrida, R., Guarneri, F., & Cannavò, S. P. (2018). Relapsing Polychondritis: An Updated Review. Biomedicines, 6(3), 84. https://doi.org/10.3390/biomedicines6030084

Damiani, J. M., & Levine, H. L. (1979). Relapsing polychondritis–report of ten cases. The Laryngoscope, 89(6 Pt 1), 929–946.

Ferrada, M. A., Sikora, K. A., Luo, Y., Wells, K. V., Patel, B., Groarke, E. M., Ospina Cardona, D., Rominger, E., Hoffmann, P., Le, M. T., Deng, Z., Quinn, K. A., Rose, E., Tsai, W. L., Wigerblad, G., Goodspeed, W., Jones, A., Wilson, L., Schnappauf, O., Laird, R. S., … Grayson, P. C. (2021). Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS. Arthritis & rheumatology (Hoboken, N.J.), 73(10), 1886–1895. https://doi.org/10.1002/art.41743

Hazra, N., Dregan, A., Charlton, J., Gulliford, M. C., & D’Cruz, D. P. (2015). Incidence and mortality of relapsing polychondritis in the UK: a population-based cohort study. Rheumatology (Oxford, England), 54(12), 2181–2187. https://doi.org/10.1093/rheumatology/kev240

Heiblig, M., Patel, B. A., Groarke, E. M., Bourbon, E., & Sujobert, P. (2021). Toward a pathophysiology inspired treatment of VEXAS syndrome. Seminars in hematology, 58(4), 239–246. https://doi.org/10.1053/j.seminhematol.2021.09.001

Khitri, M. Y., Guedon, A. F., Georgin-Lavialle, S., Terrier, B., Saadoun, D., Seguier, J., le Besnerais, M., De Moreuil, C., Denis, G., Gerfaud-Valentin, M., Allain, J. S., Maria, A., Bouillet, L., Grobost, V., Galland, J., Kosmider, O., Dumont, A., Devaux, M., Subran, B., Schmidt, J., … French VEXAS group and MINHEMON (2022). Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients. RMD open, 8(2), e002255. https://doi.org/10.1136/rmdopen-2022-002255

Kent, P. D., Michet, C. J., Jr, & Luthra, H. S. (2004). Relapsing polychondritis. Current opinion in rheumatology, 16(1), 56–61. https://doi.org/10.1097/00002281-200401000-00011

Kingdon, J., Roscamp, J., Sangle, S., & D’Cruz, D. (2018). Relapsing polychondritis: a clinical review for rheumatologists. Rheumatology (Oxford, England), 57(9), 1525–1532. https://doi.org/10.1093/rheumatology/kex406

McAdam, L. P., O’Hanlan, M. A., Bluestone, R., & Pearson, C. M. (1976). Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine, 55(3), 193–215.

Mertz, P., Sparks, J., Kobrin, D., Ogbonnaya, S. A., Sevim, E., Michet, C., Arnaud, L., & Ferrada, M. (2023). Relapsing polychondritis: Best Practice & Clinical Rheumatology. Best practice & research. Clinical rheumatology, 37(1), 101867. https://doi.org/10.1016/j.berh.2023.101867

Moncrieff, M., & Sassoon, E. M. (2004). Effective treatment of chondrodermatitis nodularis chronica helicis using a conservative approach. The British journal of dermatology, 150(5), 892–894. https://doi.org/10.1111/j.1365-2133.2004.05961.x

Moulis, G., Pugnet, G., Costedoat-Chalumeau, N., Mathian, A., Leroux, G., Boutémy, J., Espitia, O., Bouillet, L., Berthier, S., Gaultier, J. B., Jeandel, P. Y., Konaté, A., Mékinian, A., Solau-Gervais, E., Terrier, B., Wendling, D., Andry, F., Garnier, C., Cathébras, P., Arnaud, L., … Sailler, L. (2018). Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study. Annals of the rheumatic diseases, 77(8), 1172–1178. https://doi.org/10.1136/annrheumdis-2017-212705

Padoan, R., Campaniello, D., Iorio, L., Doria, A., & Schiavon, F. (2022). Biologic therapy in relapsing polychondritis: navigating between options. Expert opinion on biological therapy, 22(5), 661–671. https://doi.org/10.1080/14712598.2022.2048647

Raieli, V., Compagno, A., & D’Amelio, M. (2016). Red Ear Syndrome. Current pain and headache reports, 20(3), 19. https://doi.org/10.1007/s11916-016-0547-y

Rednic, S., Damian, L., Talarico, R., Scirè, C. A., Tobias, A., Costedoat-Chalumeau, N., Launay, D., Mathian, A., Mattews, L., Ponte, C., Toniati, P., Bombardieri, S., Frank, C., Schneider, M., Smith, V., Cutolo, M., Mosca, M., & Arnaud, L. (2018). Relapsing polychondritis: state of the art on clinical practice guidelines. RMD open, 4(Suppl 1), e000788. https://doi.org/10.1136/rmdopen-2018-000788

Petitdemange, A., Sztejkowski, C., Damian, L., Martin, T., Mouthon, L., Amoura, Z., Cutolo, M., Burmester, G. R., Fonseca, J. E., Rednic, S., & Arnaud, L. (2022). Treatment of relapsing polychondritis: a systematic review. Clinical and experimental rheumatology, 40 Suppl 134(5), 81–85. https://doi.org/10.55563/clinexprheumatol/h9gq1o

Terao, C., Yoshifuji, H., Yamano, Y., Kojima, H., Yurugi, K., Miura, Y., Maekawa, T., Handa, H., Ohmura, K., Saji, H., Mimori, T., & Matsuda, F. (2016). Genotyping of relapsing polychondritis identified novel susceptibility HLA alleles and distinct genetic characteristics from other rheumatic diseases. Rheumatology (Oxford, England), 55(9), 1686–1692. https://doi.org/10.1093/rheumatology/kew233

Yoo, J. H., Chodosh, J., & Dana, R. (2011). Relapsing polychondritis: systemic and ocular manifestations, differential diagnosis, management, and prognosis. Seminars in ophthalmology, 26(4-5), 261–269. https://doi.org/10.3109/08820538.2011.588653

Zeuner, M., Straub, R. H., Rauh, G., Albert, E. D., Schölmerich, J., & Lang, B. (1997). Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. The Journal of rheumatology, 24(1), 96–101.