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Relapsing polychondritis
Indian Journal of Rheumatology 2012 September Volume 7, Number 3; pp. 147e152
Review Article
Relapsing polychondritis Aman Sharmaa,*, Abhijai Singhb
ABSTRACT Relapsing polychondritis is a rare, progressive and potentially fatal disease affecting the cartilaginous tissues like ears, nose, laryngotracheal tree and joints. Proteoglycan-rich structures like eyes, heart, blood vessels and inner ear are also affected. The common manifestations are auricular and nasal chondritis and nonerosive arthritis. Due to the rarity of the disease, the diagnosis is often delayed due to lack of awareness. Relapsing polychondritis disease activity index has recently been developed and may help in monitoring disease activity thus resulting in better patient outcomes. The treatment depends on the extent and severity of disease, with minor manifestations requiring only NSAIDS and the organ/life-threatening manifestations requiring immunosuppression with corticosteroids cytotoxic drugs. Newer biological agents may be helpful in refractory disease. Copyright © 2012, Indian Rheumatology Association. All rights reserved.
Relapsing polychondritis (RP) is a rare, episodic, progressive, inflammatory, immune-mediated disorder of uncertain etiology affecting the chondral structures of the nose, ears, tracheobronchial tree, hyaline cartilage of the peripheral joints and fibrocartilage at axial sites.1e6 It also involves the proteoglycan-rich structures like eye, heart, blood vessels and inner ear. The term relapsing polychondritis was introduced in 1960 by Pearson, Kleine and Newcomer, though the first recognizable case was described by Jaksch Wartenhorst in 1923.
EPIDEMIOLOGY Epidemiological data on RP is scarce due to the infrequent nature of this disorder. Data from western population suggests an incidence of 3.5 cases per million population and an equal gender predisposition. The mean age at diagnosis is 40e50 yrs. Indian data, although limited has been largely congruous with its western counterpart.7,8 The only case of placental transmission was reported by Gimovsky and Nishiyama.9
PATHOPHYSIOLOGY RP is an inflammatory autoimmune disorder. It is associated with HLA DR 4 allele. In the largest study on immunogenetic analysis of RP in a multicentric study, a significant susceptibility was demonstrated with HLA DR4.10 Pathogenesis of RP has not been clearly delineated but available evidence implicates exposure of epitopes of connective tissue triggering an inflammatory response. The inciting agent, however stays elusive. Stabler et al in their study of cytokines in a group of patients with relapsing polychondritis demonstrated elevated levels of MIP-1beta (macrophage inflammatory protein-1 beta), MCP (monocyte chemoattractant protein) and IL-8 delineating the role of cell-mediated immunity in the pathogenesis of RP.11 Corroborative evidence for humoral involvement comes from the demonstration of antibodies against type II collagen in some patients of RP with their titers correlating with the severity of the illness. But this is not a universal phenomena and what drives the immune system and the cartilage destruction in the other subgroup stays conjectural.12
a Assistant Professor, Department of Internal Medicine, PGIMER, Chandigarh 160012, India, bDepartment of Internal Medicine, John H. Stroger, Jr. Hospital, Chicago, IL, USA. * Corresponding author. Tel.: þ91 172 275 6681; fax: þ91 172 274 4401, email: [email protected] Available online: 20.7.2012 Copyright Ó 2012, Indian Rheumatology Association. All rights reserved.
http://dx.doi.org/10.1016/j.injr.2012.07.008
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Further, the expression of higher titers of antibodies against native type II collagen compared to those against constituent alpha I chains corroborates primary immunological involvement rather than a consequence of inflammatory destruction.12 Clinical presentation similar to RP can be induced in animal models by immunization against type II collagen.13,14 However anti collagen type II antibodies are not specific to this disease and have also been described in other arthritides like rheumatoid arthritis. Other autoantibodies like antibodies to collagen type IX and XI; and matrilin 1, an extracellular matrix protein predominantly expressed in tracheal cartilage, have also been reported.
DIAGNOSTIC CRITERIA Diagnostic criteria for RP were initially proposed by McAdam et al in 1976 in a study on 23 patients15 and were later modified by Damiani and Levine.15,16 These are given in Table 1.
CLINICAL FEATURES Clinical involvement varies with severity and duration. The manifestations depend on the organ involvement and almost all organs with hyaline cartilage can be affected.15 Males have a higher predisposition to auricular chondritis, episcleritis and scleritis while women are more susceptible to nasal chondritis and subglottic stenosis.16 The patients may present with general symptoms like fever, malaise and myalgias but the striking clinical features are due to cartilaginous inflammation which usually accompany the general symptoms.
AURAL INVOLVEMENT The external ear involvement is the most common manifestation of RP reported in 60e100% of the patients.5,7,8,15,17 Auricular chondritis is the presenting manifestation in Table 1 Clinical diagnostic criteria for relapsing polychondritis (RP). 1. 2. 3. 4. 5. 6.
B/L auricular chondritis Nonerosive seronegative inflammatory polyarthritis Nasal chondritis Ocular inflammation Respiratory tract chondritis Audiovestibular damage
Positive diagnosis requires presence of 3 criteria at the initial presentation OR 2 criteria with remission produced by steroids/dapsone OR 1 criterion with positive histological diagnosis.
Sharma and Singh
39e90% patients and can exhibit an acute to subacute inflammation of the cartilaginous part of the pinna with classical sparing of the lobule. The ear assumes a typical violaceous hue with exquisite tenderness on palpation. Recurrent flares can lead to complete chondral destruction with collapse of the pinna and a floppy ear (“cauliflower like ears”). External auditory meatus and the eustachian tube can be involved by the inflammatory process to cause serous otitis media and/or conductive deafness. Internal ear involvement is uncommon and seen in upto 30% of the patients during the course of the illness. A vasculitic process involving the cochlear branch of the internal auditory artery can cause sensorineural hearing loss, while tinnitus, vertigo and ataxia may ensue due to the vestibular branch vasculitis.18
OCULAR MANIFESTATIONS Ocular involvement at presentation is described in about 20%e32% of the patients which increases to 50e60% during the course of the illness.4,7,8,10,16 All the chambers of the eye can be affected. Episcleritis and scleritis are the most common manifestations followed by nonspecific conjunctivitis, iritis, keratitis or proptosis. The most common adnexal involvement is in the form of periorbital or lid edema. Isolated cases of ischemic optic neuropathy due to systemic vasculitis, retinal detachment, chorioretinitis and retinal infiltrates have been published.19,20 Recurrences and relapses of ocular inflammation are common and generally parallel systemic inflammatory responses. The presence of ocular and musculoskeletal system involvement can mislead a clinician into diagnosing reactive arthritis.
NASAL MANIFESTATIONS Nasal chondritis is reported in 30e70% of the patients with two Indian series reporting more than 50% involvement.7,8 Nasal cartilage inflammation can lead to crusting, epistaxis and rhinorrhea. Chronic and recurrent inflammation accounts for saddle deformity in these patients.3. Nasal and respiratory symptoms in conjunction with arthralgias may mimic granulomatosis with polyangiitis (previously Wegener’s granulomatosis). Nasal chondritis has been shown to be more prevalent in younger (<50 yrs) women and can remit spontaneously.5 Nasal chondritis may result in saddle nose deformity.21
MUSCULOSKELETAL Joint pain is the second most reported symptom with a reported frequency of 50e80%.5,15,17 Nonerosive and
Relapsing polychondritis
noninflammatory arthritis is the classical musculoskeletal presentation in RP. The most common joints involved are the proximal interphalangeal joints, metacarpophalangeal and the knees followed by the ankles and the wrists. Peripheral joint involvement is seen in upto 70% of patients with nonerosive and asymmetric pattern with noninflammatory synovial fluid on analysis.22 A major confounder is the occurrence of RP in association with seropositive, erosive rheumatoid arthritis or spondyloarthropathies.
LARYNGOTRACHEAL INVOLVEMENT Involvement of the respiratory tree can occur in upto 23% of the patients at the time of diagnosis, however over time more than half of the patients tend to develop airway complications.17,23 Lower prevalence of laryngotracheal symptoms has been reported from Indian series.7 Women are at a higher risk of these complications for inexplicable reasons. These patients may be symptomatic in the form of thyroid cartilage, laryngeal or anterior cervical tracheal tenderness. Tracheal and subglottic strictures may be symptomatic with stridor or dysnea and may need tracheostomy. However lower bronchial stenosis are usually asymptomatic and may be incidentally detected on bronchoscopy or spirometry. Tracheomalacia is a rare but potentially fatal outcome of destruction of the cartilaginous rings of the trachea. Several mechanisms have been described to cause airway obstruction. In the early phase of the illness, wall edema can lead to narrowing of the bronchial lumen. Subsequently repeated attacks of inflammation can cause scarring and fibrosis. Accumulation of secretions has also been described in these patients either due to impaired ciliary clearance or ineffective cough due to dynamic airway collapse.
CARDIOVASCULAR Cardiovascular complications are the second leading cause of mortality following pulmonary aberrations.24 They account for almost 40% of mortality over a 10 yrs follow up of these patients.17 Valvular heart diseases e aortic regurgitation (AR) is the most common cardiovascular abnormality occurring in upto 10% of these patients.15 Studies on Indian subjects have been relatively small, nevertheless, have produced results in sync with their western counterparts.7 AR usually occurs late during the course of the illness with a mean of 7 yrs as a result of aortic root dilatation or of cusp retraction. Occasional cases of early, asymptomatic AR have been described, more commonly following cuspal rupture and seldom due to root dilatation23. We have also described
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a successful stabilization of aortic root dilatation with aggressive immunosuppression in an Indian male with asymptomatic AR.25 Mitral regurgitation (MR) occurs with a frequency of 1.8% and a combination of AR and MR can be seen in 1.5% of the patients.24,26 The mechanism of MR has been discretely described as annular dilatation, valvular thickening, anterior leaflet prolapse and chordal rupture from endocarditis.26 Rhythm disturbances e various tachyarrhythmias including sinus tachycardia and atrial fibrillation or atrial flutter occur with a frequency of less than 5%. Involvement of the conduction system leading to varying degrees of heart block is also reported. Pericarditis e pericarditis leading to pericardial effusions without tamponade occur with a reported frequency of 4%. Myocardial infarction can occur due to coronary vasculitis, coronary aneurysms or ostial occlusions. Even angiography can be hazardous in these patients due to vascular wall fragility.
DERMATOLOGIC MANIFESTATIONS Skin is involved in RP with a reported frequency of 17e36% in various large series.5,10,15,17 Indian studies have also been consistent with 30% patients with some form of dermatological involvement.7 There is no specific pattern of dermatological involvement and their occurrence in the various disease associations of RP can further complicate the scenario. Oral aphthous ulcers are the most common manifestation in RP. They can occur as simple or complex aphthae. In some patients they can be associated with genital aphthae, when the term MAGIC syndrome (mouth and genital ulcers with inflamed cartilage), coined by Firestein et al27, is more appropriate. The other frequently reported dermatologic manifestations included nodules, papules or ulcerations on the extremities, superficial phlebitis, livedo reticularis and distal necrosis. Histological evaluation has included vasculitis, neutrophilic infiltrates, thrombosis of skin vessels and panniculitis.28 Skin is the primary site of involvement on presentation at diagnosis in 12% of the patients. Frances et al have reported higher skin involvement (95% vs 36%) in those with myelodysplastic syndrome associate RP.28
RENAL MANIFESTATIONS Urinalysis may reveal microhematuria, proteinuria or abnormal renal function in upto 22% of patients.29 Renal involvement is a harbinger of a worse outcome and is
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commonly seen in older patients, in the presence of arthritis and extrarenal vasculitis. The predominant histopathological lesions include mesangial deposits, IgA nephropathy and crescentic glomerulonephritis.29e31
NEUROLOGICAL INVOLVEMENT It is a rare presentation of RP with no cases reported in the Indian series of patients. Only about 3% of patients have neurological involvement with the most frequent being cranial nerve palsies. Other reported symptoms include headaches, seizures, hemiplegia and rhomboencephalitis.32,33
DISEASE ASSOCIATIONS Various rheumatological and nonrheumatological conditions have been associated with relapsing polychondritis. A comprehensive list for review is presented in Table 2. Table 2 Disease associations. Other Vasculitides 1. Myasthenia gravis 1. PAN 2. Aseptic deep abscesses 2. Granulomatous with 3. Familial Mediterranean 3. Temporal arteritis fever 4. Takayasu arteritis 4. Glomerulonephritis 5. Behcet’s 6. ChurgeStrauss syndrome 7. MAGIC syndrome Gastrointestinal diseases Connective tissue diseases 1. Crohn’s 1. Rheumatoid arthritis 2. Ulcerative colitis 2. SLE 3. Primary biliary cirrhosis 3. Sjogren’s syndrome 4. Mesenteric panniculitis 4. MCTD 5. Ankylosing spondylitis 6. Reiter’s syndrome 7. Systemic sclerosis 8. Juvenile rheumatoid arthritis Hematological diseases Endocrinologic diseases 1. IgA myeloma 1. Thyroid autoimmune 2. Myelodysplastic syndrome diseases 3. Pernicious anemia 2. DM 4. Lymphoma 3. Thymoma 5. Acute leukemia 6. Mixed cryoglobulinemia Skin diseases 1. Psoriasis 2. Vitiligo 3. Lichen planus 4. Atopic dermatitis
Sharma and Singh
DISEASE ACTIVITY ASSESSMENT Relapsing polychondritis disease activity index (RPDAI), a preliminary scoring system for assessing disease activity in RP has been developed and validated with the help of 27 international experts from all over the world including India. This may help in improving the care of patients with this disease.34
LABORATORY EVALUATION No laboratory test is pathognomonic for this disease. Complete blood counts may show normocytic anemia, mild leukocytosis, thrombocytosis, hypergammaglobulinemia. About 10% of the patients have eosinophilia. No specific autoantibodies have been reported in these patients. Anti collagen type II antibodies were initially reported to be specific but further studies did not corroborate this.12 Antibodies to matrilin 1, a cartilage specific protein present mainly in the tracheal cartilage, correlate with inflammation of tracheobronchial cartilage.35 Pulmonary function testing can demonstrate inspiratory or expiratory obstruction.36 Bronchoscopy is reserved for high-risk patients with substantially compromised airways. Doppler echocardiography is used for evaluation of cardiovascular involvement and valvular inflammation. The role of imaging has evolved in the last few decades. A plain X ray can demonstrate tracheal narrowing, calcification of the tracheal and laryngeal cartilage along with various infectious complications. Dynamic expiratory CT has been recommended as a part of routine assessment of all patients with RP. Lee et al demonstrated that 94% patients tend to have expiratory CT abnormalities while inspiratory CT was abnormal only in 50% of those patients.37 MRI can be useful adjunct for characterization of RP-related changes in the cartilaginous tissues.
PATHOLOGY RP is characterized by widespread, inflammatory, destructive and degenerative lesions. The biopsy specimen has the highest yield during active inflammatory phase. Initially pleomorphic lymphocytic (mainly CD4 helper T cells) predominant inflammatory infiltrate is present. This is admixed with other cells including neutrophils, monocytes, macrophages with TNF-alpha expression and plasma cells. Chondrocytes are vacuolated and undergo necrosis. Loss of basophilic staining of the matrix may signify significant proteoglycan depletion.6,15 Immunofluorescence studies have demonstrated deposition of immunoglobulins and C3 at the chonofibrinous junction.38
Relapsing polychondritis
In the chronic phase, there is extensive degeneration and fibrosis which may ultimately lead to calcification or even ossification.
TREATMENT No standardized protocol of treatment exists due to sheer uncommon nature, unpredictable manifestations and course of the illness. Mild cases of RP with nasal or aural chondritis but no organ involvement can be treated with NSAIDS alone with close monitoring of symptoms.39 Failure of resolution should prompt the clinician to initiate steroids in a dose of 0.5e1 mg/kg. Prednisone is the fundamental component of treatment of all types of organ involvement with methylprednisolone reserved for presence of progressive sensorineural hearing loss, systemic vasculitis and acute respiratory flares. No definite guidelines for duration of steroid therapy exist. However, the general consensus is to maintain clinical and laboratory remission for atleast 3 months before attempting tapering or a steroid sparing agent in case of intolerable side effects. Immunosuppressive agents are considered in case of severe organ involvement, lack of satisfactory clinical response on several weeks of steroids or prohibitive adverse events due to steroids. The commonly used ones include cyclophosphamide, azathioprine, cyclosporine and methotrexate.40 Methotrexate has a distinct advantage of no secondary prolonged hematological toxicity unlike other agents. However, no one therapy has been proven superior to the other.5,7,15,17,25,41 Use of agents including leflunomide, anakinra, etanercept, infliximab, rituximab and tocilizumab and adalimumab have been limited to isolated reports.42e45
PROGNOSIS The commonest cause of death in RP is infection either as a complication of disease or immunosuppressive therapy. Other common causes include cardiovascular with progressive aortic regurgitation, aortic aneurysmal rupture or dissection, acute respiratory failure or renal failure associated with glomerulonephritis.17 Predictors of poor survival in patients younger than 50 yrs of age include anemia, saddle nose deformity, arthritis, laryngotracheal strictures, vasculitis and microhematuria.
CONFLICTS OF INTEREST All authors have none to declare.
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REFERENCES 1. Pearson CM, Kline HM, Newcomer VD. Relapsing polychondritis. N Engl J Med. 1960;263:51e58. 2. Letko E, Zafirakis P, Baltatzis S, Voudouri A, LivirRallatos C, Foster CS. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum. 2002;31:384e395. 3. Kent PD, Michet Jr CJ, Luthra HS. Relapsing polychondritis. Curr Opin Rheumatol. 2004;16:56e61. 4. Yoo JH, Chodosh J, Dana R. Relapsing polychondritis: systemic and ocular manifestations, differential diagnosis, management, and prognosis. Semin Ophthalmol. 2011;26:261e269. 5. Trentham DE, Le CH. Relapsing polychondritis. Ann Intern Med. 1998;129:114e122. 6. Lahmer T, Treiber M, von Werder A, et al. Relapsing polychondritis: an autoimmune disease with many faces. Autoimmun Rev. 2010;9:540e546. 7. Sharma A, Bambery P, Wanchu A, et al. Relapsing polychondritis in North India: a report of 10 patients. Scand J Rheumatol. 2007;36:462e465. 8. Ananthakrishna R, Goel R, Padhan P, Mathew J, Danda D. Relapsing polychondritis e case series from South India. Clin Rheumatol. 2009;28(suppl 1):S7eS10. 9. Gimovsky ML, Nishiyama M. Relapsing polychondritis in pregnancy: a case report and review. Am J Obstet Gynecol. 1989;161:332e334. 10. Zeuner M, Straub RH, Rauh G, Albert ED, Scholmerich J, Lang B. Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. J Rheumatol. 1997;24:96e101. 11. Stabler T, Piette JC, Chevalier X, Marini-Portugal A, Kraus VB. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum. 2004;50:3663e3667. 12. Foidart JM, Abe S, Martin GR, et al. Antibodies to type II collagen in relapsing polychondritis. N Engl J Med. 1978;299:1203e1207. 13. Boissier MC, Feng XZ, Carlioz A, Roudier R, Fournier C. Experimental autoimmune arthritis in mice. I. homologous type II collagen is responsible for self-perpetuating chronic polyarthritis. Ann Rheum Dis. 1987;46:691e700. 14. Boissier MC, Roudier R, Carlioz A, Fournier C. Induction of arthritis in mice by injection of homologous type II collagen. C R Acad Sci III. 1986;302:665e668. 15. McAdam LP, O’Hanlan MA, Bluestone R, Pearson CM. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore). 1976;55:193e215. 16. Damiani JM, Levine HL. Relapsing polychondritis e report of ten cases. Laryngoscope. 1979;89:929e946. 17. Michet Jr CJ, McKenna CH, Luthra HS, O’Fallon WM. Relapsing polychondritis. Survival and predictive role of
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18.
19.
20. 21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
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early disease manifestations. Ann Intern Med. 1986;104: 74e78. Clark LJ, Wakeel RA, Ormerod AD. Relapsing polychondritis e two cases with tracheal stenosis and inner ear involvement. J Laryngol Otol. 1992;106:841e844. Isaak BL, Liesegang TJ, Michet Jr CJ. Ocular and systemic findings in relapsing polychondritis. Ophthalmology. 1986;93:681e689. Cody DT, Sones DA. Relapsing polychondritis: audiovestibular manifestations. Laryngoscope. 1971;81:1208e1222. Sharma A, Bambery P, Wanchu A, Singh S, Panda N. A woman with abnormal ears and unusual voice. Med J Aust. 2007;186:424. Balsa A, Expinosa A, Cuesta M, MacLeod TI, Gijon-Banos J, Maddison PJ. Joint symptoms in relapsing polychondritis. Clin Exp Rheumatol. 1995;13:425e430. Lee-Chiong Jr TL. Pulmonary manifestations of ankylosing spondylitis and relapsing polychondritis. Clin Chest Med. 1998;19:747e757. Mainguene C, Bouhour JB, De Lajartre AY, Dupon H. Cardiovascular complications in chronic atrophic polychondritis. A patho-clinical case history literature review. [Les complications cardiovasculaires de la polychondrite chronique atrophiante: a propos d’un cas anatomo-clinique. revue de la littérature]. Annales de cardiologie et d’angéiologie. 1991;40:97. Sharma A, Mittal T, Kumar S, et al. Successful treatment of aortic root dilatation in a patient with relapsing polychondritis. Clin Rheumatol (in press). Lang-Lazdunski L, Hvass U, Paillole C, Pansard Y, Langlois J. Cardiac valve replacement in relapsing polychondritis. A review. J Heart Valve Dis. 1995;4:227e235. Firestein GS, Gruber HE, Weisman MH, Zvaifler NJ, Barber J, O’Duffy JD. Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome. Five patients with features of relapsing polychondritis and Behcet’s disease. Am J Med. 1985;79:65e72. Frances C, el Rassi R, Laporte JL, Rybojad M, Papo T, Piette JC. Dermatologic manifestations of relapsing polychondritis. A study of 200 cases at a single center. Medicine (Baltimore). 2001;80:173e179. Chang-Miller A, Okamura M, Torres VE, et al. Renal involvement in relapsing polychondritis. Medicine (Baltimore). 1987;66:202e217. Satoh F, Kohno M, Ohmoto A, Ieko M. A case of relapsing polychondritis with IgA nephropathy. Nihon Rinsho Meneki Gakkai Kaishi. 1998;21:41e47. Dalal BI, Wallace AC, Slinger RP. IgA nephropathy in relapsing polychondritis. Pathology. 1988;20:85e89.
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32. Stewart SS, Ashizawa T, Dudley Jr AW, Goldberg JW, Lidsky MD. Cerebral vasculitis in relapsing polychondritis. Neurology. 1988;38:150e152. 33. Sundaram MB, Rajput AH. Nervous system complications of relapsing polychondritis. Neurology. 1983;33:513e515. 34. 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 (in press). 35. Hansson AS, Heinegard D, Piette JC, Burkhardt H, Holmdahl R. The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis. Arthritis Rheum. 2001;44:2402e2412. 36. Krell WS, Staats BA, Hyatt RE. Pulmonary function in relapsing polychondritis. Am Rev Respir Dis. 1986;133: 1120e1123. 37. Lee KS, Ernst A, Trentham DE, Lunn W, Feller-Kopman DJ, Boiselle PM. Relapsing polychondritis: prevalence of expiratory CT airway abnormalities. Radiology. 2006;240:565e573. 38. Valenzuela R, Cooperrider PA, Gogate P, Deodhar SD, Bergfeld WF. Relapsing polychondritis. Immunomicroscopic findings in cartilage of ear biopsy specimens. Hum Pathol. 1980;11:19e22. 39. Park J, Gowin KM, Schumacher Jr HR. Steroid sparing effect of methotrexate in relapsing polychondritis. J Rheumatol. 1996;23:937e938. 40. Svenson KL, Holmdahl R, Klareskog L, et al. Cyclosporin A treatment in a case of relapsing polychondritis. Scand J Rheumatol. 1984;13:329e333. 41. Seymour MW, Home DM, Williams RO, Allard SA. Prolonged response to anti-tumour necrosis factor treatment with adalimumab (Humira) in relapsing polychondritis complicated by aortitis. Rheumatology (Oxford). 2007;46:1738e1739. 42. Vounotrypidis P, Sakellariou GT, Zisopoulos D, Berberidis C. Refractory relapsing polychondritis: rapid and sustained response in the treatment with an IL-1 receptor antagonist (anakinra). Rheumatology (Oxford). 2006;45:491e492. 43. Handler RP. Leflunomide for relapsing polychondritis: successful longterm treatment. J Rheumatol. 2006;33:1916. author reply 1916e7. 44. Kawai M, Hagihara K, Hirano T, et al. Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxford). 2009;48:318e319. 45. Leroux G, Costedoat-Chalumeau N, Brihaye B, et al. Treatment of relapsing polychondritis with rituximab: a retrospective study of nine patients. Arthritis Rheum. 2009;61: 577e582.
Review Article
Relapsing polychondritis Aman Sharmaa,*, Abhijai Singhb
ABSTRACT Relapsing polychondritis is a rare, progressive and potentially fatal disease affecting the cartilaginous tissues like ears, nose, laryngotracheal tree and joints. Proteoglycan-rich structures like eyes, heart, blood vessels and inner ear are also affected. The common manifestations are auricular and nasal chondritis and nonerosive arthritis. Due to the rarity of the disease, the diagnosis is often delayed due to lack of awareness. Relapsing polychondritis disease activity index has recently been developed and may help in monitoring disease activity thus resulting in better patient outcomes. The treatment depends on the extent and severity of disease, with minor manifestations requiring only NSAIDS and the organ/life-threatening manifestations requiring immunosuppression with corticosteroids cytotoxic drugs. Newer biological agents may be helpful in refractory disease. Copyright © 2012, Indian Rheumatology Association. All rights reserved.
Relapsing polychondritis (RP) is a rare, episodic, progressive, inflammatory, immune-mediated disorder of uncertain etiology affecting the chondral structures of the nose, ears, tracheobronchial tree, hyaline cartilage of the peripheral joints and fibrocartilage at axial sites.1e6 It also involves the proteoglycan-rich structures like eye, heart, blood vessels and inner ear. The term relapsing polychondritis was introduced in 1960 by Pearson, Kleine and Newcomer, though the first recognizable case was described by Jaksch Wartenhorst in 1923.
EPIDEMIOLOGY Epidemiological data on RP is scarce due to the infrequent nature of this disorder. Data from western population suggests an incidence of 3.5 cases per million population and an equal gender predisposition. The mean age at diagnosis is 40e50 yrs. Indian data, although limited has been largely congruous with its western counterpart.7,8 The only case of placental transmission was reported by Gimovsky and Nishiyama.9
PATHOPHYSIOLOGY RP is an inflammatory autoimmune disorder. It is associated with HLA DR 4 allele. In the largest study on immunogenetic analysis of RP in a multicentric study, a significant susceptibility was demonstrated with HLA DR4.10 Pathogenesis of RP has not been clearly delineated but available evidence implicates exposure of epitopes of connective tissue triggering an inflammatory response. The inciting agent, however stays elusive. Stabler et al in their study of cytokines in a group of patients with relapsing polychondritis demonstrated elevated levels of MIP-1beta (macrophage inflammatory protein-1 beta), MCP (monocyte chemoattractant protein) and IL-8 delineating the role of cell-mediated immunity in the pathogenesis of RP.11 Corroborative evidence for humoral involvement comes from the demonstration of antibodies against type II collagen in some patients of RP with their titers correlating with the severity of the illness. But this is not a universal phenomena and what drives the immune system and the cartilage destruction in the other subgroup stays conjectural.12
a Assistant Professor, Department of Internal Medicine, PGIMER, Chandigarh 160012, India, bDepartment of Internal Medicine, John H. Stroger, Jr. Hospital, Chicago, IL, USA. * Corresponding author. Tel.: þ91 172 275 6681; fax: þ91 172 274 4401, email: [email protected] Available online: 20.7.2012 Copyright Ó 2012, Indian Rheumatology Association. All rights reserved.
http://dx.doi.org/10.1016/j.injr.2012.07.008
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Further, the expression of higher titers of antibodies against native type II collagen compared to those against constituent alpha I chains corroborates primary immunological involvement rather than a consequence of inflammatory destruction.12 Clinical presentation similar to RP can be induced in animal models by immunization against type II collagen.13,14 However anti collagen type II antibodies are not specific to this disease and have also been described in other arthritides like rheumatoid arthritis. Other autoantibodies like antibodies to collagen type IX and XI; and matrilin 1, an extracellular matrix protein predominantly expressed in tracheal cartilage, have also been reported.
DIAGNOSTIC CRITERIA Diagnostic criteria for RP were initially proposed by McAdam et al in 1976 in a study on 23 patients15 and were later modified by Damiani and Levine.15,16 These are given in Table 1.
CLINICAL FEATURES Clinical involvement varies with severity and duration. The manifestations depend on the organ involvement and almost all organs with hyaline cartilage can be affected.15 Males have a higher predisposition to auricular chondritis, episcleritis and scleritis while women are more susceptible to nasal chondritis and subglottic stenosis.16 The patients may present with general symptoms like fever, malaise and myalgias but the striking clinical features are due to cartilaginous inflammation which usually accompany the general symptoms.
AURAL INVOLVEMENT The external ear involvement is the most common manifestation of RP reported in 60e100% of the patients.5,7,8,15,17 Auricular chondritis is the presenting manifestation in Table 1 Clinical diagnostic criteria for relapsing polychondritis (RP). 1. 2. 3. 4. 5. 6.
B/L auricular chondritis Nonerosive seronegative inflammatory polyarthritis Nasal chondritis Ocular inflammation Respiratory tract chondritis Audiovestibular damage
Positive diagnosis requires presence of 3 criteria at the initial presentation OR 2 criteria with remission produced by steroids/dapsone OR 1 criterion with positive histological diagnosis.
Sharma and Singh
39e90% patients and can exhibit an acute to subacute inflammation of the cartilaginous part of the pinna with classical sparing of the lobule. The ear assumes a typical violaceous hue with exquisite tenderness on palpation. Recurrent flares can lead to complete chondral destruction with collapse of the pinna and a floppy ear (“cauliflower like ears”). External auditory meatus and the eustachian tube can be involved by the inflammatory process to cause serous otitis media and/or conductive deafness. Internal ear involvement is uncommon and seen in upto 30% of the patients during the course of the illness. A vasculitic process involving the cochlear branch of the internal auditory artery can cause sensorineural hearing loss, while tinnitus, vertigo and ataxia may ensue due to the vestibular branch vasculitis.18
OCULAR MANIFESTATIONS Ocular involvement at presentation is described in about 20%e32% of the patients which increases to 50e60% during the course of the illness.4,7,8,10,16 All the chambers of the eye can be affected. Episcleritis and scleritis are the most common manifestations followed by nonspecific conjunctivitis, iritis, keratitis or proptosis. The most common adnexal involvement is in the form of periorbital or lid edema. Isolated cases of ischemic optic neuropathy due to systemic vasculitis, retinal detachment, chorioretinitis and retinal infiltrates have been published.19,20 Recurrences and relapses of ocular inflammation are common and generally parallel systemic inflammatory responses. The presence of ocular and musculoskeletal system involvement can mislead a clinician into diagnosing reactive arthritis.
NASAL MANIFESTATIONS Nasal chondritis is reported in 30e70% of the patients with two Indian series reporting more than 50% involvement.7,8 Nasal cartilage inflammation can lead to crusting, epistaxis and rhinorrhea. Chronic and recurrent inflammation accounts for saddle deformity in these patients.3. Nasal and respiratory symptoms in conjunction with arthralgias may mimic granulomatosis with polyangiitis (previously Wegener’s granulomatosis). Nasal chondritis has been shown to be more prevalent in younger (<50 yrs) women and can remit spontaneously.5 Nasal chondritis may result in saddle nose deformity.21
MUSCULOSKELETAL Joint pain is the second most reported symptom with a reported frequency of 50e80%.5,15,17 Nonerosive and
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noninflammatory arthritis is the classical musculoskeletal presentation in RP. The most common joints involved are the proximal interphalangeal joints, metacarpophalangeal and the knees followed by the ankles and the wrists. Peripheral joint involvement is seen in upto 70% of patients with nonerosive and asymmetric pattern with noninflammatory synovial fluid on analysis.22 A major confounder is the occurrence of RP in association with seropositive, erosive rheumatoid arthritis or spondyloarthropathies.
LARYNGOTRACHEAL INVOLVEMENT Involvement of the respiratory tree can occur in upto 23% of the patients at the time of diagnosis, however over time more than half of the patients tend to develop airway complications.17,23 Lower prevalence of laryngotracheal symptoms has been reported from Indian series.7 Women are at a higher risk of these complications for inexplicable reasons. These patients may be symptomatic in the form of thyroid cartilage, laryngeal or anterior cervical tracheal tenderness. Tracheal and subglottic strictures may be symptomatic with stridor or dysnea and may need tracheostomy. However lower bronchial stenosis are usually asymptomatic and may be incidentally detected on bronchoscopy or spirometry. Tracheomalacia is a rare but potentially fatal outcome of destruction of the cartilaginous rings of the trachea. Several mechanisms have been described to cause airway obstruction. In the early phase of the illness, wall edema can lead to narrowing of the bronchial lumen. Subsequently repeated attacks of inflammation can cause scarring and fibrosis. Accumulation of secretions has also been described in these patients either due to impaired ciliary clearance or ineffective cough due to dynamic airway collapse.
CARDIOVASCULAR Cardiovascular complications are the second leading cause of mortality following pulmonary aberrations.24 They account for almost 40% of mortality over a 10 yrs follow up of these patients.17 Valvular heart diseases e aortic regurgitation (AR) is the most common cardiovascular abnormality occurring in upto 10% of these patients.15 Studies on Indian subjects have been relatively small, nevertheless, have produced results in sync with their western counterparts.7 AR usually occurs late during the course of the illness with a mean of 7 yrs as a result of aortic root dilatation or of cusp retraction. Occasional cases of early, asymptomatic AR have been described, more commonly following cuspal rupture and seldom due to root dilatation23. We have also described
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a successful stabilization of aortic root dilatation with aggressive immunosuppression in an Indian male with asymptomatic AR.25 Mitral regurgitation (MR) occurs with a frequency of 1.8% and a combination of AR and MR can be seen in 1.5% of the patients.24,26 The mechanism of MR has been discretely described as annular dilatation, valvular thickening, anterior leaflet prolapse and chordal rupture from endocarditis.26 Rhythm disturbances e various tachyarrhythmias including sinus tachycardia and atrial fibrillation or atrial flutter occur with a frequency of less than 5%. Involvement of the conduction system leading to varying degrees of heart block is also reported. Pericarditis e pericarditis leading to pericardial effusions without tamponade occur with a reported frequency of 4%. Myocardial infarction can occur due to coronary vasculitis, coronary aneurysms or ostial occlusions. Even angiography can be hazardous in these patients due to vascular wall fragility.
DERMATOLOGIC MANIFESTATIONS Skin is involved in RP with a reported frequency of 17e36% in various large series.5,10,15,17 Indian studies have also been consistent with 30% patients with some form of dermatological involvement.7 There is no specific pattern of dermatological involvement and their occurrence in the various disease associations of RP can further complicate the scenario. Oral aphthous ulcers are the most common manifestation in RP. They can occur as simple or complex aphthae. In some patients they can be associated with genital aphthae, when the term MAGIC syndrome (mouth and genital ulcers with inflamed cartilage), coined by Firestein et al27, is more appropriate. The other frequently reported dermatologic manifestations included nodules, papules or ulcerations on the extremities, superficial phlebitis, livedo reticularis and distal necrosis. Histological evaluation has included vasculitis, neutrophilic infiltrates, thrombosis of skin vessels and panniculitis.28 Skin is the primary site of involvement on presentation at diagnosis in 12% of the patients. Frances et al have reported higher skin involvement (95% vs 36%) in those with myelodysplastic syndrome associate RP.28
RENAL MANIFESTATIONS Urinalysis may reveal microhematuria, proteinuria or abnormal renal function in upto 22% of patients.29 Renal involvement is a harbinger of a worse outcome and is
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commonly seen in older patients, in the presence of arthritis and extrarenal vasculitis. The predominant histopathological lesions include mesangial deposits, IgA nephropathy and crescentic glomerulonephritis.29e31
NEUROLOGICAL INVOLVEMENT It is a rare presentation of RP with no cases reported in the Indian series of patients. Only about 3% of patients have neurological involvement with the most frequent being cranial nerve palsies. Other reported symptoms include headaches, seizures, hemiplegia and rhomboencephalitis.32,33
DISEASE ASSOCIATIONS Various rheumatological and nonrheumatological conditions have been associated with relapsing polychondritis. A comprehensive list for review is presented in Table 2. Table 2 Disease associations. Other Vasculitides 1. Myasthenia gravis 1. PAN 2. Aseptic deep abscesses 2. Granulomatous with 3. Familial Mediterranean 3. Temporal arteritis fever 4. Takayasu arteritis 4. Glomerulonephritis 5. Behcet’s 6. ChurgeStrauss syndrome 7. MAGIC syndrome Gastrointestinal diseases Connective tissue diseases 1. Crohn’s 1. Rheumatoid arthritis 2. Ulcerative colitis 2. SLE 3. Primary biliary cirrhosis 3. Sjogren’s syndrome 4. Mesenteric panniculitis 4. MCTD 5. Ankylosing spondylitis 6. Reiter’s syndrome 7. Systemic sclerosis 8. Juvenile rheumatoid arthritis Hematological diseases Endocrinologic diseases 1. IgA myeloma 1. Thyroid autoimmune 2. Myelodysplastic syndrome diseases 3. Pernicious anemia 2. DM 4. Lymphoma 3. Thymoma 5. Acute leukemia 6. Mixed cryoglobulinemia Skin diseases 1. Psoriasis 2. Vitiligo 3. Lichen planus 4. Atopic dermatitis
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DISEASE ACTIVITY ASSESSMENT Relapsing polychondritis disease activity index (RPDAI), a preliminary scoring system for assessing disease activity in RP has been developed and validated with the help of 27 international experts from all over the world including India. This may help in improving the care of patients with this disease.34
LABORATORY EVALUATION No laboratory test is pathognomonic for this disease. Complete blood counts may show normocytic anemia, mild leukocytosis, thrombocytosis, hypergammaglobulinemia. About 10% of the patients have eosinophilia. No specific autoantibodies have been reported in these patients. Anti collagen type II antibodies were initially reported to be specific but further studies did not corroborate this.12 Antibodies to matrilin 1, a cartilage specific protein present mainly in the tracheal cartilage, correlate with inflammation of tracheobronchial cartilage.35 Pulmonary function testing can demonstrate inspiratory or expiratory obstruction.36 Bronchoscopy is reserved for high-risk patients with substantially compromised airways. Doppler echocardiography is used for evaluation of cardiovascular involvement and valvular inflammation. The role of imaging has evolved in the last few decades. A plain X ray can demonstrate tracheal narrowing, calcification of the tracheal and laryngeal cartilage along with various infectious complications. Dynamic expiratory CT has been recommended as a part of routine assessment of all patients with RP. Lee et al demonstrated that 94% patients tend to have expiratory CT abnormalities while inspiratory CT was abnormal only in 50% of those patients.37 MRI can be useful adjunct for characterization of RP-related changes in the cartilaginous tissues.
PATHOLOGY RP is characterized by widespread, inflammatory, destructive and degenerative lesions. The biopsy specimen has the highest yield during active inflammatory phase. Initially pleomorphic lymphocytic (mainly CD4 helper T cells) predominant inflammatory infiltrate is present. This is admixed with other cells including neutrophils, monocytes, macrophages with TNF-alpha expression and plasma cells. Chondrocytes are vacuolated and undergo necrosis. Loss of basophilic staining of the matrix may signify significant proteoglycan depletion.6,15 Immunofluorescence studies have demonstrated deposition of immunoglobulins and C3 at the chonofibrinous junction.38
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In the chronic phase, there is extensive degeneration and fibrosis which may ultimately lead to calcification or even ossification.
TREATMENT No standardized protocol of treatment exists due to sheer uncommon nature, unpredictable manifestations and course of the illness. Mild cases of RP with nasal or aural chondritis but no organ involvement can be treated with NSAIDS alone with close monitoring of symptoms.39 Failure of resolution should prompt the clinician to initiate steroids in a dose of 0.5e1 mg/kg. Prednisone is the fundamental component of treatment of all types of organ involvement with methylprednisolone reserved for presence of progressive sensorineural hearing loss, systemic vasculitis and acute respiratory flares. No definite guidelines for duration of steroid therapy exist. However, the general consensus is to maintain clinical and laboratory remission for atleast 3 months before attempting tapering or a steroid sparing agent in case of intolerable side effects. Immunosuppressive agents are considered in case of severe organ involvement, lack of satisfactory clinical response on several weeks of steroids or prohibitive adverse events due to steroids. The commonly used ones include cyclophosphamide, azathioprine, cyclosporine and methotrexate.40 Methotrexate has a distinct advantage of no secondary prolonged hematological toxicity unlike other agents. However, no one therapy has been proven superior to the other.5,7,15,17,25,41 Use of agents including leflunomide, anakinra, etanercept, infliximab, rituximab and tocilizumab and adalimumab have been limited to isolated reports.42e45
PROGNOSIS The commonest cause of death in RP is infection either as a complication of disease or immunosuppressive therapy. Other common causes include cardiovascular with progressive aortic regurgitation, aortic aneurysmal rupture or dissection, acute respiratory failure or renal failure associated with glomerulonephritis.17 Predictors of poor survival in patients younger than 50 yrs of age include anemia, saddle nose deformity, arthritis, laryngotracheal strictures, vasculitis and microhematuria.
CONFLICTS OF INTEREST All authors have none to declare.
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REFERENCES 1. Pearson CM, Kline HM, Newcomer VD. Relapsing polychondritis. N Engl J Med. 1960;263:51e58. 2. Letko E, Zafirakis P, Baltatzis S, Voudouri A, LivirRallatos C, Foster CS. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum. 2002;31:384e395. 3. Kent PD, Michet Jr CJ, Luthra HS. Relapsing polychondritis. Curr Opin Rheumatol. 2004;16:56e61. 4. Yoo JH, Chodosh J, Dana R. Relapsing polychondritis: systemic and ocular manifestations, differential diagnosis, management, and prognosis. Semin Ophthalmol. 2011;26:261e269. 5. Trentham DE, Le CH. Relapsing polychondritis. Ann Intern Med. 1998;129:114e122. 6. Lahmer T, Treiber M, von Werder A, et al. Relapsing polychondritis: an autoimmune disease with many faces. Autoimmun Rev. 2010;9:540e546. 7. Sharma A, Bambery P, Wanchu A, et al. Relapsing polychondritis in North India: a report of 10 patients. Scand J Rheumatol. 2007;36:462e465. 8. Ananthakrishna R, Goel R, Padhan P, Mathew J, Danda D. Relapsing polychondritis e case series from South India. Clin Rheumatol. 2009;28(suppl 1):S7eS10. 9. Gimovsky ML, Nishiyama M. Relapsing polychondritis in pregnancy: a case report and review. Am J Obstet Gynecol. 1989;161:332e334. 10. Zeuner M, Straub RH, Rauh G, Albert ED, Scholmerich J, Lang B. Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. J Rheumatol. 1997;24:96e101. 11. Stabler T, Piette JC, Chevalier X, Marini-Portugal A, Kraus VB. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum. 2004;50:3663e3667. 12. Foidart JM, Abe S, Martin GR, et al. Antibodies to type II collagen in relapsing polychondritis. N Engl J Med. 1978;299:1203e1207. 13. Boissier MC, Feng XZ, Carlioz A, Roudier R, Fournier C. Experimental autoimmune arthritis in mice. I. homologous type II collagen is responsible for self-perpetuating chronic polyarthritis. Ann Rheum Dis. 1987;46:691e700. 14. Boissier MC, Roudier R, Carlioz A, Fournier C. Induction of arthritis in mice by injection of homologous type II collagen. C R Acad Sci III. 1986;302:665e668. 15. McAdam LP, O’Hanlan MA, Bluestone R, Pearson CM. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore). 1976;55:193e215. 16. Damiani JM, Levine HL. Relapsing polychondritis e report of ten cases. Laryngoscope. 1979;89:929e946. 17. Michet Jr CJ, McKenna CH, Luthra HS, O’Fallon WM. Relapsing polychondritis. Survival and predictive role of
152
18.
19.
20. 21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
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early disease manifestations. Ann Intern Med. 1986;104: 74e78. Clark LJ, Wakeel RA, Ormerod AD. Relapsing polychondritis e two cases with tracheal stenosis and inner ear involvement. J Laryngol Otol. 1992;106:841e844. Isaak BL, Liesegang TJ, Michet Jr CJ. Ocular and systemic findings in relapsing polychondritis. Ophthalmology. 1986;93:681e689. Cody DT, Sones DA. Relapsing polychondritis: audiovestibular manifestations. Laryngoscope. 1971;81:1208e1222. Sharma A, Bambery P, Wanchu A, Singh S, Panda N. A woman with abnormal ears and unusual voice. Med J Aust. 2007;186:424. Balsa A, Expinosa A, Cuesta M, MacLeod TI, Gijon-Banos J, Maddison PJ. Joint symptoms in relapsing polychondritis. Clin Exp Rheumatol. 1995;13:425e430. Lee-Chiong Jr TL. Pulmonary manifestations of ankylosing spondylitis and relapsing polychondritis. Clin Chest Med. 1998;19:747e757. Mainguene C, Bouhour JB, De Lajartre AY, Dupon H. Cardiovascular complications in chronic atrophic polychondritis. A patho-clinical case history literature review. [Les complications cardiovasculaires de la polychondrite chronique atrophiante: a propos d’un cas anatomo-clinique. revue de la littérature]. Annales de cardiologie et d’angéiologie. 1991;40:97. Sharma A, Mittal T, Kumar S, et al. Successful treatment of aortic root dilatation in a patient with relapsing polychondritis. Clin Rheumatol (in press). Lang-Lazdunski L, Hvass U, Paillole C, Pansard Y, Langlois J. Cardiac valve replacement in relapsing polychondritis. A review. J Heart Valve Dis. 1995;4:227e235. Firestein GS, Gruber HE, Weisman MH, Zvaifler NJ, Barber J, O’Duffy JD. Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome. Five patients with features of relapsing polychondritis and Behcet’s disease. Am J Med. 1985;79:65e72. Frances C, el Rassi R, Laporte JL, Rybojad M, Papo T, Piette JC. Dermatologic manifestations of relapsing polychondritis. A study of 200 cases at a single center. Medicine (Baltimore). 2001;80:173e179. Chang-Miller A, Okamura M, Torres VE, et al. Renal involvement in relapsing polychondritis. Medicine (Baltimore). 1987;66:202e217. Satoh F, Kohno M, Ohmoto A, Ieko M. A case of relapsing polychondritis with IgA nephropathy. Nihon Rinsho Meneki Gakkai Kaishi. 1998;21:41e47. Dalal BI, Wallace AC, Slinger RP. IgA nephropathy in relapsing polychondritis. Pathology. 1988;20:85e89.
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32. Stewart SS, Ashizawa T, Dudley Jr AW, Goldberg JW, Lidsky MD. Cerebral vasculitis in relapsing polychondritis. Neurology. 1988;38:150e152. 33. Sundaram MB, Rajput AH. Nervous system complications of relapsing polychondritis. Neurology. 1983;33:513e515. 34. 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 (in press). 35. Hansson AS, Heinegard D, Piette JC, Burkhardt H, Holmdahl R. The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis. Arthritis Rheum. 2001;44:2402e2412. 36. Krell WS, Staats BA, Hyatt RE. Pulmonary function in relapsing polychondritis. Am Rev Respir Dis. 1986;133: 1120e1123. 37. Lee KS, Ernst A, Trentham DE, Lunn W, Feller-Kopman DJ, Boiselle PM. Relapsing polychondritis: prevalence of expiratory CT airway abnormalities. Radiology. 2006;240:565e573. 38. Valenzuela R, Cooperrider PA, Gogate P, Deodhar SD, Bergfeld WF. Relapsing polychondritis. Immunomicroscopic findings in cartilage of ear biopsy specimens. Hum Pathol. 1980;11:19e22. 39. Park J, Gowin KM, Schumacher Jr HR. Steroid sparing effect of methotrexate in relapsing polychondritis. J Rheumatol. 1996;23:937e938. 40. Svenson KL, Holmdahl R, Klareskog L, et al. Cyclosporin A treatment in a case of relapsing polychondritis. Scand J Rheumatol. 1984;13:329e333. 41. Seymour MW, Home DM, Williams RO, Allard SA. Prolonged response to anti-tumour necrosis factor treatment with adalimumab (Humira) in relapsing polychondritis complicated by aortitis. Rheumatology (Oxford). 2007;46:1738e1739. 42. Vounotrypidis P, Sakellariou GT, Zisopoulos D, Berberidis C. Refractory relapsing polychondritis: rapid and sustained response in the treatment with an IL-1 receptor antagonist (anakinra). Rheumatology (Oxford). 2006;45:491e492. 43. Handler RP. Leflunomide for relapsing polychondritis: successful longterm treatment. J Rheumatol. 2006;33:1916. author reply 1916e7. 44. Kawai M, Hagihara K, Hirano T, et al. Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxford). 2009;48:318e319. 45. Leroux G, Costedoat-Chalumeau N, Brihaye B, et al. Treatment of relapsing polychondritis with rituximab: a retrospective study of nine patients. Arthritis Rheum. 2009;61: 577e582.