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Relapsing Polychondritis

Relapsing Polychondritis

Relapsing polychondritis

Author: Professor Alexandros A. Drosos1 Creation Date: November 2001 Update: October 2004

Scientific Editor: Professor Haralampos M. Moutsopoulos

1Department of Internal Medicine, Section of , Medical School, University of Ioannina, 451 10 Ioannina, GREECE. [email protected]

Abstract Keywords Disease name and synonyms Diagnostic criteria / Definition Differential diagnosis Prevalence Laboratory findings Prognosis Management Etiology Genetic findings Diagnostic methods Genetic counseling Unresolved questions References

Abstract (RP) is a multisystem inflammatory disease of unknown etiology affecting the . It is characterized by recurrent episodes of affecting the cartilaginous structures, resulting in tissue damage and tissue destruction. All types of cartilage may be involved. of auricular, nasal, tracheal cartilage predominates in this disease, suggesting response to tissue-specific antigens such as collagen II and cartilage matrix protein (matrillin-1). The patients present with a wide spectrum of clinical symptoms and signs that often raise major diagnostic dilemmas. In about one third of patients, RP is associated with and autoimmune rheumatic diseases. The most commonly reported types of vasculitis range from isolated cutaneous leucocytoclastic vasculitis to systemic polyangiitis. Vessels of all sizes may be affected and large-vessel vasculitis is a well-recognized and potentially fatal complication. The second most commonly associated disorder is autoimmune rheumatic diseases mainly rheumatoid and systemic erythematosus . Other disorders associated with RP are hematological malignant diseases, gastrointestinal disorders, endocrine diseases and others. Relapsing polychondritis is generally a progressive disease. The majority of the patients experience intermittent or fluctuant inflammatory manifestations. In Rochester (Minnesota), the estimated annual incidence rate was 3.5/million. The peak age for disease onset is the fifth decade, although cases have been reported at both extremes of life. The treatment of choice is prednisone; however, immunosuppressive drugs seem to have an additional value. was found to be an efficacious and well-tolerated steroid sparing drug.

Keywords Relapsing polychondritis; cartilage; chondritis; auricular; nasal; laryngotracheal; collagen type II; matrillin- 1; vasculitis; autoimmune diseases; malignant disorders.

auricular chondritis; Disease name and synonyms nasal chondritis; Relapsing polychondritis; polychondropathia.

Drosos, A.A. Relapsing polychondritis. Orphanet encyclopedia, October 2004. http://www.orpha.net/data/patho/GB/uk-RP.pdf 1

Diagnostic criteria / Definition may all lead to perichondritis that can be easily Relapsing polychondritis (RP) was first described misdiagnosed as RP. Auricular involvement must in 1923 by Jaksch-Wartenhorst under the term of also be differentiated from traumatic and “polychondropathia” and was considered as a chemical conditions, such as and insect degenerative disease (1). It is an uncommon bite. Prolonged endotracheal intubation may multisystemic disorder of unknown etiology cause tracheal similar to that of RP (5-8). affecting young adults. It is characterized by Nasal damage may occur in many other recurrent episodes of inflammation affecting the conditions such as local infections from fungi, cartilaginous structures, resulting in tissue , , , Wegener’s damage and tissue destruction. All types of granulomatosis and lethal midline granuloma cartilage may be involved such as: the elastic and should be taken into account (9, 12). Eye cartilage of the and nose, the hyaline involvement in RP can be difficult to differentiate cartilage of peripheral joints, the fibrocartilage of from other conditions like and , the and the cartilage of the which may occur in rhumatoid arthritis, tracheobronchial tree. RP can also affect other Wegener’s granulomatosis, , proteoglycan-rich structures like the eye, heart, Behçet’s disease, and Cogan’s disease (5-7, 11, blood vessels and inner . Thus, patients with 12). RP present with a wide spectrum of clinical symptoms and signs that often raise major Prevalence diagnostic dilemmas (2-5). In Rochester (Minnesota), the estimated annual In the majority of patients, RP has a fluctuating incidence rate was 3.5/million. The peak age for but progressive course in which recurrent bouts disease onset is the fifth decade, although cases of inflammation lead to the permanent have been reported at both extremes of life (5). destruction of the involved structures. Patients Most cases occur in whites. Both pediatric and usually consult primary care physicians, elderly cases have been described with an age otolaryngologists, rheumatologists and range of 6 to 87 years. Pregnancy does not ophthalmologists. On average, it takes 3 years seem to influence the disease course and the between occurrence of the first symptom until majority of pregnancies were successful (13). RP RP is diagnosed. This gap reflects the diagnostic was reported to occur with equal frequency in ambiguities that may encountered. Thus, both sexes. However, some authors found that proposed diagnostic criteria for RP are based on the female/male ratio was about 3:1 (5) (Table characteristic clinical manifestations. 2). Empirical diagnostic criteria have been established by McAdam et al. (6), Michet et al. Table 2. Clinical features of patients with (7) and Damiani et al. (8). The diagnostic criteria relapsing polychondritis in 4 large series Mc proposed by McAdam require three or more Michet Zeuner Adam Trentham clinical features, even without biopsy (7) (10) (6) (5) [1998] [1986] [1997] confirmation (Table 1). Damiani and Levine have [1976] suggested that diagnosis can be considered as Variables: total definitive when one or more of the clinical number of patients N= 159 N= 112 N= 62 N= 66 features are present in conjunction with biopsy followed up Mean age at confirmation. 44 51 47 46 diagnosis (years) Female/male 1/1 1/1 1.8/1 3/1 Table 1. Diagnostic criteria for relapsing polychondritis Mean duration of (6) - 6 - 8 follow up (years) Recurrent chondritis of both auricles Ear involvement Non erosive inflammatory (%) Chondritis of nose cartilage auricular chondritis 27 40 93.5 92 Inflammation of ocular structures auditory 7 9 19 7 keratitis, scleritis, , dysfunction - 4 23 6 Chondritis of the vestibular laryngeal and/or tracheal dysfunction Cochlear and/or vestibular damage causing sensor neural hearing loss, tinnitus and/or vertigo Polyarthritis (%) 24 37 53 48 Nasal chondritis 14 25 56.5 33 (%) Differential diagnosis Ocular 15 20 50 25 Although the clinical features of this disease are inflammation (%) characteristic, diagnosis may be difficult in some Respiratory tract 15 26 31 39 cases. Thus, acute streptococcal infection, inflammation (%) Cardiovascular fungal infection, Hansen disease, and syphilis 9 1 23 1 inflammation (%)

Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004. http://www.orpha.net/data/patho/GB/uk-RP.pdf 2

Skin involvement series in table 2. Disease onset is generally 17 7 - 0.5 (%) sudden and often flagrant. External ear Kidney disease - - 6.5 - involvement is the presenting symptom in (%) almost all patients. RP typically attacks the Nervous system - - 10 - involvement (%) cartilaginous portion of the pinna, sparing the lobe which lacks cartilage. Auricular chondritis

presents with pain, redness or violaceous Clinical description discoloration, swelling and tenderness involving Associated diseases one or both ears. Episodes can last a few days In about one third of patients, RP is associated or weeks and patients recover from these with vasculitis and autoimmune rheumatic episodes with or without treatment. After diseases (Table 3) (14). The most commonly recurrent or persistent inflammation, the disease reported types of vasculitis range from isolated ends in cartilage destruction. The pinna loses its cutaneous leucocytoclastic vasculitis to systemic firmness, becomes soft and flops over or has a polyangiitis. Vessels of all sizes may be affected knobby or cauliflower appearance (5-8, 10-12). and large-vessel vasculitis is a well-recognized Hearing impairment may accompany ear and potentially fatal complication. The MAGIC involvement. This is due to closure of the syndrome (mouth and genital ulcers with external auditory meatus, serous otitis media inflamed cartilage) has also been reported to be and Eustachian tube obstruction. In addition, associated with RP (5). The second most inflammation of the middle ear with sensorineural commonly associated disorder is autoimmune hearing loss and vestibular dysfunction with rheumatic diseases mainly dizziness, , nausea and vomiting may also (RA) and systemic lupus erythematosus (SLE) occur. In table 2, the main clinical features are (5). Other disorders associated with RP are presented from four large series (5-7, 10-12). hematological malignant diseases, The second most common clinical finding of gastrointestinal disorders, endocrine diseases RP is joint pain with or without arthritis. All and others (Table 3). synovial joints may be affected. The most

commonly involved joints are Table 3. Conditions associated with relapsing metacarpophalangeal, proximal interphalangeal polychondritis joints, wrists and mimicking RA. Mono or Vasculitis Hematological diseases involving peripheral large joints also Leucocytoclastic Myelodysplastic syndromes Wegener’s granulomatosis Hodgkin’s disease occur. Arthritis is non-deforming and non- Polyarteritis nodosa Non Hodgkin’s lymphoma erosive. Tests for rheumatoid factor are negative Churg-Strauss Acute lymphoblastic in affected patients (5-8, 10). MAGIC syndrome leukemia Involvement of the nasal cartilage may present Behçet’s disease Pernicious anemia Mixed cryoglobulinemia with nasal pain, redness and swelling. Repeated Endocrine disorders attacks may cause destruction of the nasal mellitus type I bridge creating the characteristic “saddle-nose” Hashimoto thyroiditis Autoimmune rheumatic deformity (5-7, 10, 12,15). Graves disease diseases Hypothyroidism Ocular manifestations, occur in approximately Rheumatoid arthritis 60% of reported patients with RP. The most Systemic lupus Dermatological disorders erythematosus common are scleritis, episcleritis, keratitis and Sjögren’s syndrome conjuctivitis, which may occur early. Pyoderma gangrenosum Mixed connective tissue Recurrences and exacerbations are very disease Panniculitis common. Scleritis and episcleritis usually parallel inflammation elsewhere, most commonly of the nose and joints (16). Uveitis occurs in about 25% Seronegative Other diseases of RP patients and 15 most often either an spondylarthophathies Myasthenia gravis anterior uveitis or a sclerouveitis (16). Additional Familiar mediterranian ocular manifestations include proptosis, corneal Thymoma Reiter’s syndrome perforation, and Gastrointestinal diseases leading to blindness (5-7, 13,16). Crohn’s disease Respiratory symptoms are common and can Primary biliary cirrhosis be lethal. At disease onset, approximately 25% Retroperitonial fibrosis of the patients present with respiratory symptoms, while during disease course, this Clinical features precentage increases to 50%. Inflammation The demographic and clinical features of occurs in the laryngeal, tracheal and bronchial patients with RP are summarized in 4 large cartilages which is accompanied by complaints

Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004. http://www.orpha.net/data/patho/GB/uk-RP.pdf 3

of hoarseness, non productive cough, dyspnea, by nodules on the limbs with an erythema wheezing and inspiratory stridor (5-8, 12,15). nodosum appearance (19). Other skin Early in the disease, patients may have manifestations included: purpura, sterile tenderness over the cartilage and pustules, superficial phlebitis and livedo trachea. Involvement of laryngeal and epiglottal reticularis. Limb ulcerations, urticarial papules, cartilage may lead to upper airway collapse, bluish red papules, distal necrosis and erythema which may require emergency tracheostomy. elevatum diutinum were seen less frequently Strictures usually appear in the subglottic region, (19). Biopsy specimens often show causing increased susceptibility to secondary leucocytoclastic, nercotizing or even infections. Mortality from respiratory granulomatosus vasculitis (5,19). complications varies from 10 to 50%. Additional symptoms, such as fatigue and Cardiovascular involvement, although , are common in RP and fever uncommon, is the second most frequent cause frequently accompanies acute flares (5). of death in patients with RP. Aortic regurgitation and mitral regurgitation occur in about 2 to 6% of Laboratory findings the patients. Aortic regurgitation is more often During acute flares, patients may present with attributable to progressive dilation of the aortic markers of inflammation, such as elevated root of the ascending aorta than to inflammation erythrocyte sedimentation rate, and C-reactive of the valve leaflets. Rarely, dilation of the protein, anemia, leucocytosis and annulus of both mitral and tricuspid valves may thrombocytosis. Serum antibodies to collagen II cause mitral and tricuspid regurgitation (5-8, 17). have been found in about 40% to 50% of the Other manifestations include thoracic and patients with RP (20). Urinary abdominal aneurysm, myocarditis, pericarditis, glycosaminoglycans levels may be elevated. silent myocardial infection, paroxysmal atrial Recently, a serum 148-kDa noncollageneous tachycardia, and first-degree or even complete cartilage matrix protein has been identified in heart block. patients with RP and RA. In patients with RP, Renal involvement can occur in RP in the tests for rheumatoid factor, antinuclear absence of other associated diseases such as antibodies or antineutrophil cytoplasmic SLE or . Although rare, renal antibodies are negative, unless an associated disease indicates worse prognosis. The most occurs. Conventional common histopathologic finding is mild radiographs and computed tomography identified mesangial proliferation, followed by focal and laryngotracheal lesions and thin section segmental necrotizing with computed tomography defines abnormalities in crescents. Other abnormalities include lobar and segmental bronchi. Three-dimensional glomerulosclerosis, IgA nephropathy and or spiral magnetic resonance imaging may tubulointertitial nephritis. Immunofluorescence provide better resolution. Pulmonary function studies most often reveal faint deposits of C3, tests are useful tools for monitoring changes IgG or IgM primarily in the mesangium (5, 15). over time. Finally, biopsy from ear cartilage or Neurological abnormalities, not due to other inflamed areas may be useful to confirm infection, rarely occur in patients with RP. The the diagnosis. most common manifestations are cranial nerve palsies, cerebral aneurysms and aseptic Prognosis meningitis (5-8). The pathogenesis of these Relapsing polychondritis is generally a symptoms is presumed to be vasculitis, but progressive disease. The majority of the patients definite vasculitis is experience intermittent or fluctuant inflammatory rarely documented. Magnetic resonance imaging manifestations. Many have persistent symptoms of the brain may show multifocal areas of between acute flares. Most of them develop enhancement consistent with cerebral vasculitis some degree of disability over the time. It (11, 12). includes bilateral deafness, impaired vision, Skin manifestations, RP causes many non- phonation difficulties and respiratory problems. specific skin disorders, which may proceed the In 1986, the overall survival rates were 74% at 5 disease onset (chondritis) by 10 days to 20 years and 55% at 10 years. However, recent years. Dermatologic symptoms are present in studies showed a better outcome with a survival 50% of patients with RP. The frequency of skin rate of 94% at 8-year follow-up (5-8). involvement in the absence of an associated is the most common cause of death related to disease is about 35% but doubles in the RP. These cases are often associated with presence of another systemic illness. In a recent airway stricture and long-term steroid use. Other study of 200 cases of RP, oral aphthous ulcers causes of death include respiratory failure from were the most frequent manifestation, followed airway collapse or obstruction and complications

Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004. http://www.orpha.net/data/patho/GB/uk-RP.pdf 4

of valvular heart disease and vasculitis (5-8, 10- than 30% of the patients with valvular 12). regurgitation need valve replacement (5).

Management Etiology Patients with mild signs of acute inflammation The cause of RP remains unknown. Specimens are usually treated with non-steroidal anti- of inflamed cartilage may show distinctive inflammatory drugs and small doses of features. There is a loss of basophilic staining of prednisone. Patients with severe manifestations, the cartilage matrix accompanied by such as airway compromise may require high perichondral inflammation of the cartilage. doses of prednisone (1 mg/kg/day) or even Perivascular mononuclear and intravenous pulse methyl-prednisone in doses of polymorphonuclear cell infiltrates are present. 1 g/day (5-8, 10-12). The doses are then tapered The chondrocytes become vacuolated and to the lowest amounts that can prevent relapses. necrotic and are eventually replaced by fibrous Whether steroid therapy should be continued tissue (23). during clinical remission periods remains Experimental studies in rabbits have shown that unclear. Several immunosuppressive drugs have the intravenous injection of papain causes been used in patients who developed resistance collapse of the external ear within a few hours. In to steroids and in patients who benefit from addition, cartilage tissue shows loss of steroid sparing regimens. , metachromatic staining without inflammation. In cyclosporine-A and plasmapheresis have all humans, cartilage destruction results from the been used as adjunctive therapies. Methotrexate release of degradative enzymes, including matrix has been an efficacious and well-tolerated metalloproteinases and reactive oxygen steroid sparing medication. Trentham et al. metabolites from inflammatory cells, reported 23 out of 31 patients receiving chondrocytes and other cellular elements. The methotrexate, at an average dose of 17.5 release of these enzymes is likely to be mg/week, responded very well and were able to secondary to immune mediated activation of taper their prednisone dose from 19 mg/day to 5 chondrocytes and other inflammatory cells by mg/day (5). Dapsone (50 to 200 mg/day) has cytokines including interleukin-1 (IL-1)and tumor been advocated as an effective therapy for necrosis factor alpha (TNF-a). Pathogenesis of patients without cardiopulmonary involvement RP is unknown. However, is (5). Other approaches include the use of D- involved in several ways: penicillamine, or even combination 1) Tissue inflammation is composed of therapy such as dapsone and steroids, macrophages, CD4+ lymphocytes and B cells. In methotrexate, steroids and cyclosporine-A. addition, deposition of immunoglobulins and In patients with signs and features of systemic complement components are found in tissue vasculitis, may be useful. lesions of patients with RP. More recently, anti-CD4 monoclonal antibody 2) Antibodies to type II collagen, as well as type was reported to be effective in two patients with IX and XI collagen are found in the sera of RP. Oral minocycline, as used for treating RA, patients with RP (20). T cell clones isolated from was associated with improvement in a patient a patient with RP were found to be specific for who had developed methotrexate toxicity (5). type II collagen peptide 261-273 (24). A recent report describes a child successfully 3) Immunization of rodents with collagen II and treated with daily oral fetal bovine type II immunization of rats with cartilage matrix protein collagen. Although, this is only a case report, the (matrillin-1) results in the development of favorable safety profile of oral type II collagen auricular chondritis and tracheal cartilage makes it deserving of further study (21). Several inflammation respectively (25-27). biological therapies have been tried in RP. An 4) Association with autoimmune diseases and anti-CD4 chimeric monoclonal antibody has HLA class II molecules (DR4) have been been successful as a salvage therapy. reported. has been reported to induce remission in some 5) The tissue specificity of RP suggests that cases (22). When other treatments fail, antigens derived from cartilage play an important autologus stem cell transplantation may induce role in driving and propagating the disease. Thus remission in RP patients (11, 12). the following hypothesis may emerge. Patients who develop cardiorespiratory In a genetically predisposed individual, an complications despite medical therapy may unknown x factor may cause immunological require surgery. Tracheostomy or stenting may response to tissues rich in type II collagen and be required to alleviate localized or extensive matrillin-1 (25-27). This leads to an inflammatory trancheobronchial disease. In addition, more process of the cartilage, which causes cytokine and autoantibody production and immune

Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004. http://www.orpha.net/data/patho/GB/uk-RP.pdf 5

response perpetuation. This may cause and predictive role of early disease chondrocyte damage, release of proteolytic manifestations. Ann Intern Med 1986; 104: 74-8. enzymes, cartilage destruction and disease 8. Damiani JM, Levine HL. Relapsing expression. polychondritis-report of ten cases. Laryngoscope 1979; 89: 929-44. Genetic findings 9. Valestini G, Priori R, Conti F. in Recent studies revealed significant association relapsing polychondritis: a problem of differential of RP with HLA-DR4 antigen. There was no diagnosis. N Engl J Med 1995; 333: 525. predominance of any of the DRB1*04 subtype 10. Zeuner M, Straub RH, Rauh G, Albert ED, alleles in these patients (10). Additionally, no Schölmerich J. Lang B. Relapsing polychondritis: HLA-DR1 association was found. This contrasts clinical and immunogenetic analysis of 62 with RA, where clear association with DRB1- patients. J Rheumatol 1997; 24: 96-101. *0401 and DRB1*0404 has been established. 11. Letko E, Zafirakis P, Baltatzis S, Voudouri A, Therefore, the shared epitope hypothesis, as Livir-Rallatos C, Foster CS. Relapsing postulated for RA, is not likely to be true for RP. polychondritis: a clinical review. Semin Arthritis Rheum 2002; 31: 384-95. Diagnostic methods 12. Kent PD, Michet CJ Jr, Luthra HS. Relapsing No specific diagnostic tools are required for the polychondritis. Curr Opin Rheumatol 2004; 16: diagnosis of RP. Serum autoantibodies to 56-61. collagen II and to 148-kDa noncollageneous 13. Papo T, Wechsler B, Bletry O, Piette AM, cartilage matrix protein may be helpful. Chest Godeau P, Piette JC. Pregnancy in relapsing conventional radiographs, pulmonary function polychondritis. Arthritis Rheum 1997; 40: 1245-9. test and chest CT tomography may be useful for 14. Kronborg IJ. Autoimmune disturbances in diagnosis. Finally, cartilage biopsy from ear or relapsing polychondritis and primary alopecia. other inflamed tissues may be useful to confirm Arthritis Rheum 1981; 24: 862. the diagnosis. 15. Sane DC, Vidaillet HJ Jr, Burton CS 3d. Saddle nose, red ears, and fatal airway collapse. Genetic counseling Relapsing polychondritis. Chest 1987; 91: 268- Genetic counseling is not available. 70. 16. Isaak BL, Liesegang TJ, Michet CJ Jr. Ocular Unresolved questions and systemic findings in relapsing polychondritis. Origin of the unknown etiological factor. Ophthalmology 1986; 93: 681-9. Role of collagen II and matrillin-1 in disease 17. Marshall DA, Jackson R, Rae AP, Capell HA. pathogenesis. Early aortic valve cusp rupture in relapsing Perpetuation and activation of the immune polychondritis. Ann Rheum Dis 1992; 51: 413-5. system. 18. Mestres CA, Igual A, Botey A, Revert L, References Murtra M. Relapsing polychondritis with 1. Jaksch-Warnenhorst R. Polychondropathia. glomerulonephritis and severe aortic Wien Arch F Inn Med 1923; 6: 33-100. insufficiency surgically treated with success. 2. Pearson CM, Kline HM, Newcomer VD. Thorac Cardiovasc Surg 1983; 31: 307-9. Relapsing polychondritis. N Engl J Med 1960; 19. Frances C, el Rassi R, Laporte JL, Rybojad 263: 51-8. M, Papo T, Piette JC. Dermatologic 3. Kaye RL, Sones DA. Relapsing polychondritis: manifestations of relapsing polychondritis. A clinical and pathologic features in fourteen study of 200 cases at a single center. Medicine cases. Ann Intern Med 1964; 60: 653-64. 2001; 80: 173-9. 4. Clayton RN, Hoffemberg R. Relapsing 20. Foidart JM, Abe S, Martin GR, Zizic TM, polychondritis: an autoimmune disease? BMJ Barnett EV, Lawley TJ, et al. Antibodies to type II 1978; ii: 999-1000. collagen in relapsing polychondritis. N Engl J 5. Trentham DE, Le CH. Relapsing Med 1978; 299: 1203-7. polychondritis. Ann Intern Med 1998; 129: 114- 21. Navarro MJ, Higgins GC, Lohr KM, Myers 22. LK. Amelioration of relapsing polychondritis in a 6. McAdam LP, O’Hanlan MA, 5-Bluestone R, child treated with oral collagen. Am J Med Sci Pearson CM. Relapsing polychondritis: 2002; 324: 101-3. prospective study of 23 patients and a review of 22. Mpofu S, Estrach C, Curtis J, Moots RJ. the literature. Medicine (Baltimore) 1976; 55: Treatment of respiratory complications in 193-215. recalcitrant relapsing polychondritis with 7. Michet CJ Jr, McKenna CH, Luthra HS, infliximab. Rheumatology 2003; 42: 1117-8. O’Fallon WM. Relapsing polychondritis: survival 23. Valenzuela R, Cooperrider PA, Gogate P. Relapsing polychondritis; immunomicroscopic

Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004. http://www.orpha.net/data/patho/GB/uk-RP.pdf 6

findings in cartilage ear biopsy specimens. Hum auricular chondritis. Arthritis Rheum 1982; 25: Pathol 1980; 11: 19-22. 266-73. 24. Buckner JH, Van Landeghen M, Kwok WW, 26. Hansson AS, Heinegárd D, Holmdahl R. A Tsarknaridis L. Identification of type II collagen new animial model for relapsing polychondritis, peptide 261-273-specific T cell clones in a induced by cartilage matrix protein (matrillin-1). J patient with relapsing polychrondritis. Arthritis Clin Invest 1999; 104: 589-98. Rheum 2002; 46: 238-44 27. Buckner JH, Wu JJ, Reife RA, Terato K, Eyre 25. McCune WJ, Schiller AL, Dynesius-Trentham DR. Autoreactivity against matrillin-1 in a patient RA, Trentham DE. Type II collagen-induced with relapsing polychondritis. Arthritis Rheum 2000; 43: 939-43.

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