Relapsing polychondritis

Definition and diagnostic framework

RP causes recurrent inflammation and damage in cartilage and other proteoglycan-rich tissues. There is no gold-standard biomarker or prospectively validated diagnostic criterion set. The McAdam, Damiani–Levine and Michet frameworks are historical aids; they support pattern recognition but do not replace longitudinal assessment and exclusion of infection, vasculitis, VEXAS and other mimics.[1][3][4][5][6]

[4] [5] [6]

The RP Disease Activity Index (RPDAI) is a preliminary clinician-reported activity instrument, not a diagnostic test or validated treatment threshold. It weights 27 manifestations over the preceding 28 days, with a theoretical maximum of 265; its original validation was limited and it should not be treated as a universal severity rule.[12]

Pathophysiology: what is known and uncertain

Pathogenesis is incompletely understood. Innate and adaptive immune responses probably contribute to perichondrial and cartilaginous inflammation, matrix degradation, fibrosis and structural failure. Type II collagen and other matrix antigens are candidate targets, but anti–type II collagen antibodies are neither consistently present nor disease-specific or diagnostic. A simple antibody-to-cartilage-collapse pathway is therefore not established.[1][7]

Repeated inflammation can produce auricular deformity, saddle-nose change, fixed airway stenosis and tracheobronchomalacia. These are consequences of damage, not inevitable outcomes of every flare.[3][9]

Clinical presentation

Auricular and nasal disease

Auricular chondritis causes abrupt pain, erythema and swelling of the cartilaginous pinna. The non-cartilaginous lobule may be spared. However, infectious perichondritis can also spare the lobule; lobule involvement favours pinna cellulitis but its absence does not prove RP. Recurrent injury may deform the pinna. Nasal chondritis causes bridge pain, swelling or crusting and may eventually cause saddle-nose deformity.[1][3][7]

Airway disease

Laryngeal or tracheobronchial involvement may present with hoarseness, cough, wheeze, exertional dyspnoea, stridor, recurrent infection, fixed stenosis or dynamic collapse. It may be mistaken for asthma. Airway disease is potentially fatal and can be clinically occult; routine inspiratory CT alone can miss expiratory malacia and air trapping.[8][9]

Other clinical domains

• Eyes: episcleritis may be mild, whereas scleritis, keratitis and uveitis can threaten vision; pain, photophobia or reduced vision requires urgent ophthalmic review.[14]
• Audiovestibular: conductive or sensorineural hearing loss, tinnitus and vertigo.[1]
• Joints: acute intermittent, often asymmetric, non-erosive oligoarthritis or polyarthritis; erosions should prompt review for rheumatoid arthritis or another overlap.[1]
• Cardiovascular: valvular disease (especially aortic regurgitation), aortitis or aneurysm, pericardial disease and conduction abnormalities.[13]
• Skin and mucosa: purpura, nodules, neutrophilic dermatosis, aphthosis or vasculitic lesions are non-specific but may point to Behçet disease, VEXAS or another systemic diagnosis.[1]
• Kidney: direct renal involvement is uncommon; haematuria, proteinuria or renal impairment should trigger review for GPA/ANCA-associated vasculitis or another associated disease.[16]

MAGIC syndrome (mouth and genital ulcers with inflamed cartilage) is a descriptive Behçet–RP overlap phenotype, not a laboratory diagnosis.[17]

VEXAS: correct marrow-vacuole teaching

VEXAS is an adult-onset autoinflammatory syndrome caused by somatic UBA1 variants in haematopoietic cells. Clues in a patient labelled as RP include male sex, later onset, fever, neutrophilic skin disease, venous thrombosis, pulmonary infiltrates, macrocytic anaemia, other cytopenias or myelodysplasia.[10][11]

The characteristic vacuoles are described in myeloid and erythroid precursor cells in bone marrow, not as a routine peripheral-blood-film finding. Their presence supports suspicion but does not itself prove VEXAS. A full blood count may show macrocytosis or cytopenias; confirmation requires appropriately performed somatic UBA1 testing, usually on blood-derived myeloid DNA or marrow according to specialist laboratory practice.[10][11]

Differential diagnosis

[1] [3] [10] [17]

Assessment and investigations

Immediate assessment

1. Record airway symptoms, voice change, stridor, work of breathing, oxygenation and haemodynamic state.
2. Examine both pinnae and lobules, nasal bridge, eyes, joints, skin, pulse symmetry and heart sounds.
3. If unstable, stabilise first and activate the multidisciplinary airway or organ-emergency pathway.[3][9]

Baseline and phenotype-directed tests

• Blood: full blood count and indices, CRP/ESR, renal and liver profiles. Macrocytosis/cytopenias redirect evaluation toward VEXAS or marrow disease; inflammatory markers are non-specific.
• Urine: urinalysis and creatinine; active sediment or renal dysfunction should trigger a vasculitis/secondary-disease work-up.[16]
• Immunology/microbiology: ANCA, RF/anti-CCP and other tests only as differential-directed evidence. ANCA is not a rule-out test; culture suspected infection.
• Airway: CT covering the larynx/cervical trachea and chest with inspiratory and dynamic expiratory acquisitions, plus pulmonary-function tests with flow-volume loops when the patient is stable. ENT laryngoscopy is selected according to symptoms and expertise.[8][9]
• Bronchoscopy: reserve for selected specialist indications after risk–benefit assessment; manipulation can provoke airway injury, bronchospasm or respiratory deterioration.[9]
• Cardiovascular: ECG and echocardiography at assessment; aortic imaging is symptom- and phenotype-directed. Observational literature supports surveillance but no universally validated interval.[13]
• Eye/hearing: urgent ophthalmology for painful or vision-changing disease; audiology when hearing or vestibular symptoms occur.[14][1]
• Biopsy: supportive but non-specific and usually reserved for atypical or consequentially uncertain presentations; it does not replace exclusion of infection or vasculitis.[1][3]
• VEXAS pathway: haematology review, marrow assessment when clinically indicated and somatic UBA1 testing for the compatible phenotype.[10][11]

Management

1. Stabilise organ threats

A threatened airway takes priority over diagnostic imaging: involve anaesthesia, ENT, respiratory medicine and ICU; prepare the safest expert-led airway approach. Urgent ophthalmic, cardiac or vascular involvement requires the relevant emergency specialist pathway. Systemic glucocorticoid treatment is commonly used concurrently for severe active inflammation, but it must not substitute for mechanical airway rescue when obstruction or collapse is present.[3][9]

2. Match anti-inflammatory treatment to severity

• Mild disease limited to ear, nose or joints: an NSAID, colchicine or a short oral glucocorticoid course may be considered after infection is excluded; choice is individualised.[3]
• Organ-, vision- or life-threatening active disease: systemic glucocorticoids are the usual induction treatment. A narrative review reports oral prednisone-equivalent ranges of 0.25–1 mg/kg/day and IV methylprednisolone 500–1,000 mg/day for rapid effect in severe disease, but these are empirical reported ranges—not an RP trial protocol or a universal prescription. Dose, duration and taper require specialist individualisation and comorbidity review.[7]
• Relapsing or glucocorticoid-dependent disease: add a steroid-sparing agent. Methotrexate has the most robust conventional-agent signal in the available review; azathioprine or mycophenolate are alternatives. Cyclophosphamide is generally reserved for selected severe refractory organ-threatening disease.[2][3]

3. Refractory disease and evidence limits

TNF inhibitors, tocilizumab, abatacept, rituximab, anakinra and other targeted agents have been used. The 2022 systematic review found no randomised controlled trial: 11 observational reports included 177 patients and 247 treatment lines, with heterogeneous populations, outcomes and confounding. Pooled signals favoured abatacept, tocilizumab and TNF inhibition, but small samples—especially for abatacept—and non-randomised designs prevent a reliable comparative hierarchy or individual response prediction.[2]

4. Airway procedures and supportive care

Balloon dilatation, tracheostomy, stenting or reconstructive procedures are individualised by expert airway teams. Stents are generally reserved for severe refractory stenosis or malacia because granulation and mucostasis are common; retrospective comparisons are strongly confounded by baseline severity.[15]

Prevent and monitor glucocorticoid/immunosuppressant toxicity, vaccination and infection risk; arrange audiology, ophthalmology, cardiology and respiratory follow-up by phenotype. Delay elective nasal reconstruction until inflammation is controlled.[3]

Complications and prognosis

Complications include fixed laryngotracheal stenosis, tracheobronchomalacia, recurrent respiratory infection, irreversible auricular or nasal deformity, visual loss, hearing loss, valvular/aortic disease and treatment-related infection or metabolic/bone toxicity. VEXAS or myelodysplasia changes both prognosis and treatment strategy.[1][3][11]

RP is chronic and unpredictable. Airway, cardiovascular and VEXAS-associated phenotypes have worse outcomes, but survival estimates vary across historical and contemporary cohorts. Do not repeat old cohort percentages as a current individual prognosis. The 1986 Michet series did not establish airway disease as the leading cause of death or early respiratory involvement as a universal survival predictor; infection, systemic vasculitis and malignancy were important causes in that cohort.[6][1]

Exam synthesis

[2] [8] [9] [10]

Key takeaways

1. Diagnose RP clinically using recurrent multisite pattern recognition and exclusion of mimics; historical criteria are aids, not gold standards.[1][3]
2. A painful cartilaginous pinna with a spared lobule is a clue, not proof of RP.[1]
3. Hoarseness prompts urgent airway assessment; stridor or distress prompts immediate stabilisation and expert airway control.[9]
4. Correct airway imaging includes inspiratory and dynamic expiratory CT; bronchoscopy is selected cautiously.[8][9]
5. Correct VEXAS teaching separates marrow precursor vacuoles from peripheral-blood macrocytosis/cytopenias and confirms the diagnosis with somatic UBA1 testing.[10][11]
6. Treatment must be severity-led and individualised because the comparative evidence remains observational.[2][3]

References

1. [1]Mertz P, Costedoat-Chalumeau N, Ferrada MA, et al. Relapsing polychondritis: clinical updates and new differential diagnoses Nat Rev Rheumatol, 2024.PMID 38698240
2. [2]Petitdemange A, Sztejkowski C, Damian L, et al. Treatment of relapsing polychondritis: a systematic review Clin Exp Rheumatol, 2022.PMID 35238756
3. [3]Arnaud L, Costedoat-Chalumeau N, Mathian A, et al. French practical guidelines for the diagnosis and management of relapsing polychondritis Rev Med Interne, 2023.PMID 37236870
4. [4]McAdam LP, O'Hanlan MA, Bluestone R, et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature Medicine (Baltimore), 1976.PMID 775252
5. [5]Damiani JM, Levine HL Relapsing polychondritis--report of ten cases Laryngoscope, 1979.PMID 449538
6. [6]Michet CJ Jr, McKenna CH, Luthra HS, et al. Relapsing polychondritis. Survival and predictive role of early disease manifestations Ann Intern Med, 1986.PMID 3484422
7. [7]Borgia F, Giuffrida R, Guarneri F, et al. Relapsing Polychondritis: An Updated Review Biomedicines, 2018.PMID 30072598
8. [8]Lee KS, Ernst A, Trentham DE, et al. Relapsing polychondritis: prevalence of expiratory CT airway abnormalities Radiology, 2006.PMID 16801364
9. [9]de Montmollin N, Dusser D, Lorut C, et al. Tracheobronchial involvement of relapsing polychondritis Autoimmun Rev, 2019.PMID 31323366
10. [10]Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease N Engl J Med, 2020.PMID 33108101
11. [11]Ferrada MA, Sikora KA, Luo Y, et al. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS Arthritis Rheumatol, 2021.PMID 33779074
12. [12]Arnaud L, Devilliers H, Peng SL, et al. The Relapsing Polychondritis Disease Activity Index: development of a disease activity score for relapsing polychondritis Autoimmun Rev, 2012.PMID 22771427
13. [13]Yin R, Zhao M, Xu D, et al. Relapsing polychondritis: focus on cardiac involvement Front Immunol, 2023.PMID 37771578
14. [14]Gallagher K, Al-Janabi A, Wang A The ocular manifestations of relapsing polychondritis Int Ophthalmol, 2023.PMID 36856986
15. [15]Handa H, Ooka S, Shimizu J, et al. Evaluation of airway involvement and treatment in patients with relapsing polychondritis Sci Rep, 2023.PMID 37221366
16. [16]Chang-Miller A, Okamura M, Torres VE, et al. Renal involvement in relapsing polychondritis Medicine (Baltimore), 1987.PMID 3574118
17. [17]Firestein GS, Gruber HE, Weisman MH, et al. Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome. Five patients with features of relapsing polychondritis and Behçet's disease Am J Med, 1985.PMID 4014306