Relapsing polychondritis (RP) is a rare systemic autoimmune disease characterized by episodic, progressive inflammatory destruction of cartilage. It can occur as an overlap syndrome in patients with other rheumatologic conditions. The disease usually follows an indolent relapsing-remitting course, but occasionally it can progress rapidly and even cause death. Although auricular or nasal chondritis or peripheral arthritis without other significant organ involvement are usually treated with low-dose corticosteroids, other more severe disease manifestations may require treatment with high-dose corticosteroids or other immunosuppressive agents. Biological targeted therapies might prove to be effective treatments of this condition.
Key points
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Relapsing polychondritis (RP) is a rare systemic autoimmune disease characterized by episodic, progressive inflammatory destruction of cartilage.
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RP can be primary or exist as an overlap syndrome with other rheumatologic conditions such as rheumatoid arthritis, spondyloarthropathies, and vasculitis, or as a paraneoplastic manifestation of myelodysplastic syndromes.
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No specific laboratory test is diagnostic for RP, but increased levels of acute phase reactants may indicate the presence of systemic inflammation. The diagnosis is confirmed by showing characteristic histologic features of RP on biopsy of affected tissues.
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Systemic immunosuppression is the mainstay of treatment of RP, but recent case reports suggest efficacy of tumor necrosis factor inhibitors and of the anti–interleukin-6 receptor monoclonal antibody tocilizumab.
Introduction
Relapsing polychondritis (RP) is an infrequently occurring systemic autoimmune disease that is characterized by episodic, progressive inflammatory destruction of cartilage. The cartilaginous structures most often involved include the elastic cartilage of the ears, the hyaline cartilage of the tracheobronchial tree and the joints, and the fibrocartilage of the axial skeleton. Immune-mediated damage can spread to involve noncartilaginous tissues that are rich in proteoglycans, such as that of the eyes, the inner ear, the heart, blood vessels, and the kidney. RP may occur alone (primary RP) or in association with other diseases. It follows a fluctuating, but progressive, course that may result in significant morbidity and sometimes death.
History
Rudolf Jaksch von Wartenhorst, an Austrian internist, first described this disease in 1923. His patient was a 32-year-old male brewer who presented with fever, asymmetric polyarthritis, and pain, swelling, and deformity of the ears and nose. Biopsy of nasal cartilage revealed loss of the cartilage matrix and a hyperplastic mucous membrane. Jaksch von Wartenhorst characterized it as a degenerative disease of cartilage and named it polychondropathia. Taking his patient’s occupation into consideration, he related the cause to excessive alcohol intake.
Since then, the disease has also been called diffuse perichondritis, chondromalacia, chronic atrophic polychondritis, diffuse chondrolysis, and dyschondroplasia. The current name, RP, was introduced by Pearson and colleagues in 1960 to emphasize the episodic course of the disease.
Epidemiology
RP occurs predominantly in white people but has also been described in people of African, Asian, or Hispanic ancestry. It occurs with equal frequency among men and women. At the Mayo Clinic, the annual incidence has been estimated to be 3.5 cases per million. Although RP may develop at any age, most reported cases have had onset between the ages of 20 and 60 years, with the highest incidence occurring between the ages of 40 and 50 years. One case has been reported of a pregnant woman with RP whose baby was similarly affected at birth, but no other cases suggest maternal-fetal transmission or a genetic predisposition to developing RP.
Cause and pathogenesis
The specific cause of RP is unknown, but the proposed pathogenesis involves both humoral and cellular immunity. Autoantibodies to collagen have been shown in the sera of patients with RP. Circulating antibodies to type II collagen were identified in 33% of patients with RP and acute cartilage inflammation. Antibodies to type IX and type XI collagen also have been identified in patients with RP. Antibodies to other cartilaginous proteins, including matrilin-I and cartilage oligomeric matrix proteins, have been identified in patients with RP. Type II collagen neoepitope (TIINE), a 45-mer peptide fragment of type II collagen, has been detected in the urine of patients with RP and might be useful to follow as a biomarker of collagen destruction reflecting RP disease activity.
It has been postulated that cell-mediated immunity may perpetuate cartilage inflammation. CD4+ T lymphocytes, plasma cells, immunoglobulin, and complement have been isolated from RP lesions in cartilage. Incubation of lymphocytes obtained from patients with RP with cartilage mucopolysaccharides resulted in transformation of the lymphocytes into lymphoblasts. Increased levels of chemokines, including monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1β, and interleukin (IL)-8, indicating activation of macrophages, have been observed in rodent models of RP. In patients with RP, serum levels of macrophage inhibitory factor (MIF) were significantly increased compared with healthy controls. This finding might account for the in vitro observation that migration of guinea pig macrophages to human laryngeal proteoglycan was inhibited when the macrophages were mixed with lymphocytes from patients with RP, compared with when they were mixed with lymphocytes obtained from healthy controls. Tumor necrosis factor (TNF) α expression also is increased in patients with RP.
The frequency of human leukocyte antigen (HLA) DR4 is significantly increased among patients with RP. However, oligonucleotide-based genotyping failed to show a predominance of any single HLA-DR4 subtype. In contrast, the frequency of HLA-DR6 is decreased among patients with RP.
Classification
It has been proposed that RP be considered as a syndrome, with the primary form occurring in isolation and the secondary form in association with one of the diseases listed in Table 1 . Associated autoimmune diseases are present in 30% to 37% of patients with RP. RP has occasionally developed following mechanical injury to cartilage, such as after piercing of the cartilaginous portion of the pinna of the ear.
| Cutaneous | |
| Atopic dermatitis | Cutaneous leukocytoclastic vasculitis |
| Dermatitis herpetiformis | Lichen planus |
| Panniculitis | Psoriasis |
| Vitiligo | |
| Endocrine | |
| Diabetes mellitus | Graves’ disease |
| Hashimoto’s thyroiditis | Hypothyroidism |
| Gastrointestinal | |
| Inflammatory bowel disease | Primary biliary cirrhosis |
| Hematologic | |
| Acute lymphocytic leukemia | Cryoglobulinemia |
| Hodgkin’s disease | MALT lymphoma |
| Myelodysplastic syndromes | Pernicious anemia |
| Genitourinary | |
| Glomerulonephritis | Retroperitoneal fibrosis |
| Rheumatologic | |
| Behçet’s syndrome | Familial Mediterranean fever |
| Juvenile chronic arthritis | Rheumatoid arthritis |
| Spondyloarthropathies | Systemic vasculitis |
Clinical features
Auricular chondritis and arthritis are the most common presenting symptoms of RP, each of which is present in about 20% to 30% of patients at the time of diagnosis. Another 10% to 15% of patients present with nasal chondritis, ocular inflammation, and/or respiratory tract involvement. The diagnosis of RP may be delayed in patients who present only with nonspecific symptoms of fever, weight loss, fatigue, or lethargy and no signs of cartilage inflammation.
Auricular Manifestations
Auricular chondritis is the most characteristic presenting sign of RP. The pinna of the ear becomes painful, red, and swollen, but the earlobe is spared ( Fig. 1 ). Attacks typically occur with subacute onset and follow a relapsing-remitting course. After recurrent attacks of inflammation, the pinna of the ear may become floppy and contorted, resembling the florets of a cauliflower. Nearly all patients with RP eventually develop auricular chondritis; it involves both ears in all but a few patients. Stenosis of the external auditory canal, eustachian tube chondritis, and serous otitis media each can result in conductive hearing loss. Vasculitis of the internal auditory artery may cause acute sensorineural hearing loss, with or without vestibular dysfunction.
Ocular Manifestations
The eye is involved in about 20% of patients with RP at the time of initial presentation; ocular involvement, most often episcleritis or scleritis, eventually develops in up to 65% of patients. Inflammation with reactive lymphoid hyperplasia resulted in a mass similar to a salmon-patch on the conjunctiva of a patient with long-standing RP. Recurrent or long-standing inflammation may cause thinning of the sclera, allowing the darker underlying choroid to appear as bluish discoloration through the thinned sclera. Keratoconjunctivitis sicca, keratitis, corneal perforation, iritis, retinopathy, and optic neuritis may occur in RP; each can result in blindness. Inflammation external to the globe may present as orbital pseudotumor, lid edema, or extraocular muscle palsy.
Respiratory Tract Manifestations
Nasal chondritis is present in 10% to 15% of patients at the time of their initial presentation and eventually develops in 50% to 70% of patients with RP. It presents with the acute onset of nasal swelling, warmth, and erythema, predominantly affecting the distal cartilaginous portion of the nasal septum. Patients experience a sensation of fullness of the nasal bridge and surrounding tissues. Recurrent episodes may result in a saddle nose deformity.
Chondritis of the laryngotracheal cartilage causes respiratory tract symptoms in more than half of patients with RP. These symptoms include dyspnea, wheezing, cough, and, occasionally, a sensation of choking. Laryngeal inflammation can also cause vocal cord edema or paralysis, resulting in dysphonia or aphonia. The thyroid cartilage and anterior cervical trachea are tender to palpation. In later stages, ventilatory complications have been observed in half of patients with RP. These complications include fixed subglottic and bronchial stenosis with airway obstruction, thickening and calcification of the airways, obstructive bronchiectasis, and tracheal/bronchial collapse.
Pulmonary function testing, including flow-volume curves, should be performed in all patients with RP to detect occult airway disease. If respiratory tract symptoms or abnormalities on pulmonary function testing are present, the patient should be imaged by computed tomography (CT) scanning of the chest. Although bronchoscopy may help to distinguish active inflammation from changes caused by previous inflammation, this procedure may result in ventilatory decompensation and thus is not recommended.
Musculoskeletal Manifestations
Patients with RP may experience arthralgias in the absence of objective evidence of joint inflammation. Inflammatory arthritis develops at some time during the disease course in 70% to 80% of patients with RP. This seronegative arthritis typically presents with an asymmetric and migratory pattern of joint involvement, often involving the sternoclavicular, costochondral, and sternomanubrial joints, with intermittent flares. Aspiration of involved joints usually yields noninflammatory synovial fluid. Joint cartilage space narrowing and osteopenia may be observed on plain radiographs of appendicular joints, but bone erosion usually does not occur unless rheumatoid arthritis coexists. In severe cases, the clavicles and ribs may become dislocated and lysis of costochondral cartilage may result in a flail chest wall.
Mucocutaneous Manifestations
Mucocutaneous signs and symptoms are present in half of patients with RP. Skin is involved in 20% to 30% of patients with primary RP and in as many as 90% of patients with the combination of RP and a myelodysplastic syndrome (MDS). Oral aphthous ulceration is the most common mucocutaneous manifestation associated with RP. The mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome represents an overlap between Behçet’s syndrome and RP. Other cutaneous manifestations of RP include erythema nodosum, purpura, livedo reticularis, urticaria, angioedema, erythema multiforme, and panniculitis. Histologic examination of skin biopsies from patients with RP most commonly reveals leukocytoclastic vasculitis, as well as thrombosis of cutaneous vessels, septal panniculitis, and neutrophilic dermatosis. The presence of mucocutaneous findings in a patient with RP should prompt a thorough evaluation for underlying myelodysplasia.
Hematologic Manifestations
Despite its infrequent occurrence, RP presents in combination with MDS more frequently than would be expected by chance. Thus, RP might be considered to be a paraneoplastic manifestation of MDS. Similar to those with a MDS alone, patients with the combination of RP and a MDS are typically men between the ages of 60 and 70 years. Older patients with newly diagnosed RP should therefore undergo a hematologic evaluation for a MDS.
The prognosis of RP occurring with a MDS is worse than that for primary RP. It depends primarily on the severity of the hematologic disease and whether the MDS undergoes leukemic transformation. In a patient with RP and a MDS that presented with a refractory anemia, the hematologic disease transformed to chronic myelomonocytic leukemia without the development of acute leukemia. A case of pernicious anemia has been reported in association with RP.
Cardiovascular Manifestations
Cardiovascular manifestations of RP typically occur in the setting of long-standing disease, even when patients have been receiving immunosuppressive therapy. Aortic regurgitation is the most common cardiovascular complication of RP, occurring in 4% to 10% of patients. Mitral regurgitation has been observed in 2% of patients with RP, more often in men. Other cardiovascular manifestations of RP include aortitis, abdominal and thoracic aortic aneurysms with aneurysmal dilatation of the aortic root, cystic medial necrosis of the aorta, cardiac ischemia, cardiac conduction abnormalities, pericarditis, and thrombophlebitis. Arterial thromboses have occurred in patients with secondary RP, typically in the setting of underlying antiphospholipid antibody syndrome.
Biochemical analysis of diseased valves removed from patients with RP has revealed decreased amounts of hydroxyproline and glycine, which are amino acid constituents of collagen, suggesting that the valvular damage occurred as a result of chronic inflammation. All patients with RP who present with a heart murmur or with otherwise unexplained dyspnea should have both an electrocardiogram and echocardiogram performed to investigate possible cardiovascular involvement.
Neurologic Manifestations
Neurologic involvement occurs in less than 3% of patients with RP and can present with either subacute or acute onset. Cranial nerves are frequently involved, most commonly the second (manifesting as optic neuritis), the sixth (manifesting as lateral rectus palsy), the seventh (manifesting as facial weakness), and the eighth (manifesting as audiovestibular dysfunction). Headaches, seizures, cerebellar dysfunction with ataxia, confusion, cerebral aneurysms, and aseptic meningitis have all been described in patients with RP. As long as renal function is not impaired, gadolinium-containing contrast-enhanced magnetic resonance imaging (MRI) of the brain should be performed to evaluate a neurologic deficit that develops in a patient with RP. Multiple foci of gadolinium enhancement on brain MRI suggests the presence of active cerebral vasculitis.
Renal Manifestations
The kidney is infrequently involved in RP, with renal involvement occurring in 6% to 10% of patients with primary RP. Renal abnormalities observed in patients with secondary RP are more often related to the associated disease, such as glomerulonephritis caused by systemic lupus erythematosus. Patients with RP with renal involvement typically have more severe systemic disease, including more severe arthritis and extrarenal vasculitis, which results in poorer survival. Because an abnormal urinalysis was detected in about 25% of patients with RP and serum creatinine levels were increased in 10%, the urine of patients with RP should be examined regularly to assess for the development of hematuria or worsening proteinuria that might herald the development of renal involvement ( Table 2 ).
| Organ or Organ System | McAdam et al, 1976 n = 159 (%) | Michet et al, 1986 n = 112 (%) | Zeuner et al, 1997 n = 62 (%) | Trentham and Le, 1998 n = 66 (%) |
|---|---|---|---|---|
| Ear | 89 | 85 | 94 | 95 |
| Musculoskeletal | 81 | 52 | 51 | 85 |
| Nose | 72 | 54 | 57 | 48 |
| Eye | 65 | 51 | 56 | 57 |
| Laryngotracheal and pulmonary | 56 | 48 | 30 | 67 |
| Mucocutaneous | 17 | 28 | 24 | 83 |
| Cardiovascular | 9 | 6 | 23 | 8 |
| Neurologic | NR | NR | 10 | NR |
| Renal | NR | NR | 6 | NR |
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