Relapsing polychondritis (RP) is a relatively rare autoimmune disease characterized by recurrent inflammation of cartilage throughout the body. In addition to all cartilaginous tissues including tracheal cartilage, tissues rich in proteoglycans such as the eyes, cardiovascular system, and inner ear are targeted. It commonly occurs in the 40s to 50s, with no sex predilection, though some reports suggest a slight female predominance. It may be associated with myelodysplastic syndrome (MDS), systemic vasculitis, and collagen diseases.
Ocular involvement occurs in 50–65% of patients, with scleritis and episcleritis being the most common3). In some cases, ocular symptoms are the initial manifestation leading to diagnosis8). Relapsing polychondritis is designated as Intractable Disease No. 384.
In cases with ocular involvement, differentiation from Behçet’s disease and HLA-B27-associated uveitis is important. Especially in severe inflammation with hypopyon, it is necessary to actively inquire about subtle systemic symptoms such as saddle nose and tenderness of the auricular cartilage. The Uveitis Clinical Practice Guidelines (2019) classify this disease as uveitis associated with collagen disease, emphasizing the importance of ophthalmic screening1).
It is a rare autoimmune disease that causes recurrent inflammation of cartilage throughout the body, designated as Intractable Disease No. 384. In addition to the auricular, nasal, airway, and joint cartilage, lesions also affect the eyes, cardiovascular system, and inner ear. It commonly occurs in the 40s to 50s and follows a course of remissions and exacerbations. Ocular involvement occurs in 50–65% of patients, with scleritis and episcleritis being the most frequent lesions3).
The following ocular subjective symptoms may appear.
The most common initial systemic symptom is pain, redness, and deformity of the auricle. Other symptoms such as nasal bridge deformity (saddle nose), hoarseness, dyspnea, hearing loss, dizziness, and joint pain may precede or occur concurrently.
Scleritis and Episcleritis
Episcleritis: Presents with redness and mild pain. Can be unilateral or bilateral.
Diffuse scleritis: Redness and tenderness of the entire sclera. Marked dilation of deep vessels.
Nodular scleritis: Formation of red nodules on the sclera. Severe tenderness.
Necrotizing scleritis: The most severe type. Associated with scleral thinning and risk of perforation. Related to peripheral corneal ulcer (corneal melt).
Anterior Segment and Cornea
Anterior uveitis: Mainly anterior chamber flare and cellular infiltration. Severe inflammation with hypopyon (pus accumulation) is seen, requiring differentiation from Behçet’s disease.
Peripheral keratitis/ulcer: Stromal infiltration and ulceration around the limbus. Often secondary to necrotizing scleritis.
Corneal melt (peripheral ulcerative keratitis): In severe cases, there is a risk of corneal perforation. Requires urgent management.
Posterior Segment and Optic Nerve
Retinopathy: Cotton-wool spots, retinal hemorrhages, retinal vascular occlusion, and serous retinal detachment may be seen.
Optic neuritis: Thought to be caused by inflammatory or vascular occlusive ischemia.
Extraocular muscle palsy: Leads to diplopia due to spread of inflammation into the orbit.
Proptosis: Forward displacement of the eyeball due to inflammation of orbital cartilage and orbital tissues.
Recurrent scleritis and episcleritis are important signs of systemic autoimmune diseases including relapsing polychondritis. Especially when accompanied by ear pain, redness, deformity, or nasal deformity (saddle nose), this disease should be actively suspected, and the patient should be referred to an otorhinolaryngologist or immunology/allergy specialist. Even if subjective symptoms are mild, checking for tenderness of the auricle and nasal root during history taking can provide diagnostic clues. Systematic screening is also recommended in the uveitis treatment guidelines 1).
Autoantibodies against type II collagen, which is abundant in the sclera and cartilage tissue, are considered central to the pathology. Approximately 20–50% of patients test positive for type II collagen autoantibodies, and these are reported to be at higher levels than those found in rheumatoid arthritis 4). Additionally, autoantibodies against matrilin-1, specific to airway cartilage, are detected in some patients.
Histopathologically, infiltration of lymphocytes, plasma cells, macrophages, and neutrophils is observed. The destroyed cartilage matrix is replaced by fibrous connective tissue. In scleral lesions, inflammatory cell infiltration and vasculitis are observed, while in episcleritis, basophilic degeneration and fragmentation of elastic fibers are characteristic. The sclera, episclera, and peripheral cornea are proteoglycan-rich tissues with antigenicity similar to cartilage, making them targets for ocular involvement.
An association with HLA-DR4 has been reported. It may occur in association with systemic autoimmune diseases such as MDS, systemic vasculitis, rheumatoid arthritis, and systemic lupus erythematosus (SLE).
VEXAS syndrome, described in 2020, is an autoinflammatory disease caused by somatic mutations in the UBA1 gene on the X chromosome, and has been found to present with symptoms resembling relapsing polychondritis 5). It predominantly affects men over 60 years of age and presents with cytopenia, MDS, recurrent auricular chondritis, skin lesions, and ocular inflammation. Some older male patients previously diagnosed with relapsing polychondritis may actually have VEXAS syndrome, and since treatment strategies differ, detailed examination is important.
There are no specific blood test findings for this disease; diagnosis is based on a comprehensive assessment of clinical symptoms, blood tests, and tissue biopsy. The following two diagnostic criteria are used2)9).
McAdam 1976 criteria (6 items) used for the diagnosis of relapsing polychondritis:
| Item | Description |
|---|---|
| 1 | Bilateral auricular chondritis |
| 2 | Non-erosive polyarthritis |
| 3 | Nasal chondritis |
| 4 | Ocular inflammation (conjunctivitis, keratitis, scleritis, episcleritis, uveitis) |
| 5 | Respiratory chondritis (laryngeal and tracheal cartilage) |
| 6 | Cochlear/vestibular dysfunction (hearing loss, tinnitus, vertigo) |
McAdam criteria (1976)2): Meeting 3 or more of the above 6 items.
Damiani-Levine modified criteria (1979)9): Meeting any of the following:
Diagnosis based solely on ocular findings is difficult. Suspect this disease when recurrent episcleritis/scleritis is accompanied by pain, redness, or deformity of the auricle, and refer to an otolaryngologist or immunology/allergy specialist.
There is no specific confirmatory test; clinical diagnosis is based on McAdam criteria (≥3 of 6 items) or Damiani-Levine revised criteria2)9). In ophthalmology, slit-lamp, fundus, OCT, FA, and B-mode ultrasound are performed. Systemic tests include CRP, ESR, type II collagen antibodies, ANCA, and CT. Ultimately, multidisciplinary collaboration with otorhinolaryngology and rheumatology is necessary for comprehensive assessment.
Treatment strategy is determined by severity and location of lesions. Local treatment for ocular lesions and systemic control of inflammation are performed concurrently.
| Severity | Target lesions | Drugs and doses |
|---|---|---|
| Mild | Episcleritis, mild arthritis | NSAIDs (loxoprofen, diclofenac, etc.) |
| Moderate | Scleritis, anterior uveitis | Prednisolone 0.5–1 mg/kg/day, tapered |
| Severe | Necrotizing scleritis, laryngotracheal chondritis, cardiovascular lesions | Methylprednisolone 1 g/day × 3 days (pulse therapy) |
| Refractory | Steroid-dependent, difficulty tapering | Immunosuppressants + biologic agents |
Immunosuppressants are added for relapses during steroid tapering or steroid-dependent cases.
Efficacy has been reported in multiple case reports and case series6).
A French multicenter study by Moulis et al. (2018) reported that biologic agents including infliximab, adalimumab, and tocilizumab are useful for managing refractory relapsing polychondritis6). No randomized controlled trials have been conducted, and all are used off-label.
Episcleritis and mild scleritis
Diffuse and nodular scleritis
Severe/circumferential scleritis
Uveitis
Peripheral corneal melting (emergency)
If ocular involvement is mild (episcleritis, mild anterior uveitis), local ophthalmic treatment alone may be sufficient. However, severe scleritis, necrotizing scleritis, and refractory uveitis require systemic steroids and immunosuppressants. Additionally, collaboration with internal medicine is essential to avoid overlooking life-threatening systemic lesions such as laryngotracheal and cardiovascular involvement.
The cause of relapsing polychondritis is unknown, but an autoimmune mechanism against type II collagen is suspected. The sclera, episclera, and peripheral cornea are tissues rich in proteoglycans and have antigenicity similar to cartilage, making them major targets for ocular involvement.
Coordinated autoimmune reactions of T cells (CD4+) and B cells trigger immune responses to cartilage-specific antigens (such as type II collagen and matrilin-1). Activated lymphocytes and macrophages infiltrate tissues, producing inflammatory cytokines (TNF-α, IL-6, IL-1β) that drive tissue destruction. The destroyed cartilage matrix is eventually replaced by fibrous connective tissue.
In episcleritis, basophilic decrease and fragmentation of elastic fibers, and infiltration of lymphocytes and plasma cells are observed. In scleritis, infiltration of inflammatory cells and vasculitis are observed. In cartilage, infiltration of neutrophils, plasma cells, and macrophages causes destruction of the cartilage matrix, ultimately leading to fibrosis and calcification.
VEXAS syndrome is a disease caused by somatic mutations in the UBA1 gene (ubiquitin-activating enzyme E1) on the X chromosome, leading to impairment of the ubiquitin-proteasome pathway and autophagy function, resulting in strong activation of the innate immune system5). Pathologically, it presents with overlapping relapsing polychondritis, MDS, and refractory skin lesions. Genetic testing is recommended for differential diagnosis in newly diagnosed men over 60 years of age.
Complications such as respiratory infections, cardiovascular lesions, systemic vasculitis, and central nervous system lesions are poor prognostic factors. The main causes of vision loss due to ocular lesions themselves include corneal perforation secondary to necrotizing scleritis, optic neuritis, and retinal vascular occlusion.
The discovery of VEXAS syndrome by Beck et al. in 2020 revealed that some elderly male patients previously diagnosed with relapsing polychondritis actually have a different condition5). Retrospective studies have shown therapeutic effects of JAK inhibitors (ruxolitinib, tofacitinib), with ruxolitinib potentially showing higher efficacy than other JAK inhibitors7). Curative cases with bone marrow transplantation have also been reported, but evidence on indications and efficacy is limited.
In a systematic review by Petitdemange et al. (2022), multiple cases and small studies have accumulated suggesting that tocilizumab may be effective in controlling ocular inflammation (scleritis, uveitis)3). No randomized controlled trials have been conducted, and accumulation of prospective evidence remains a future challenge.
Tracheal stenosis due to airway chondritis can lead to acute respiratory failure. Regular monitoring of respiratory and cardiac function in parallel with ophthalmologic management is important, and a multidisciplinary care system involving otorhinolaryngology, respiratory medicine, rheumatology, and ophthalmology is required10).
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Petitdemange A, et al. Treatment of relapsing polychondritis: a systematic review. Clin Exp Rheumatol. 2022;40(Suppl 134):81-85.
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Moulis G, et al. Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study. Ann Rheum Dis. 2018;77:1172-1178.
Heiblig M, et al. Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study. Blood. 2022;140:927-931.
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