Etiology and pathogenesis of relapsing polychondritis
- Clement J Michet, MD
Clement J Michet, MD
- Associate Professor of Medicine
- Mayo Clinic
Relapsing polychondritis (RPC) is a systemic inflammatory/degenerative disease with varying clinical manifestations that can include compromise of the structural and functional integrity of cartilage; organs of special sense; and the cardiovascular, renal, and nervous systems (table 1). (See "Clinical manifestations of relapsing polychondritis".)
This topic will review our current understanding of the etiology and pathogenesis of RPC. The pathologic changes in this disorder are described elsewhere. (See "Pathology of relapsing polychondritis".)
The approach to diagnosis and treatment of RPC are presented separately. (See "Diagnostic evaluation of relapsing polychondritis" and "Treatment of relapsing polychondritis".)
The etiology of relapsing polychondritis (RPC) is unknown. Although few clues are evident, there appears to be a genetic susceptibility, an overlap with other disorders associated with immunologic abnormalities, and the potential for multiple inciting events including chemical insults. This hypothesis is supported by a series of observations which imply that RPC is not a primary disease but a syndrome associated with multiple precipitating factors that appear in a genetically susceptible subject. The paraneoplastic myelodysplastic relationship suggests a potential pathophysiologic role for clonally expressed lymphoid stem cells in which functional T cell defects induce both autoimmunity and uncontrolled neoplastic hematopoietic clonal proliferation. However, a report of abrupt onset after recreational drug abuse implies that a direct biochemical insult also can induce the disease. (See 'Genetic susceptibility' below and 'Association with other immunologic diseases' below and 'Induction by toxins' below.)
Genetic susceptibility — No association of RPC with human leukocyte antigen (HLA) class I (HLA-A and HLA-B) antigens has been identified . However, an association has been described between RPC and HLA class II, specifically with HLA-DR4 . Genetic analysis of the frequency of HLA class II histocompatibility antigens was performed in 60 central European Caucasian patients with RPC ; the frequency of HLA-DR4 was 56 percent compared with 26 percent in a healthy control group. Genotyping showed no preferential association of specific DR4 subtype alleles, in contrast to the clear association of rheumatoid arthritis (RA) with DRB1*0401 and DRB1*0404 . These RA-associated alleles have in common a region of highly similar sequence, designated the shared epitope (see "HLA and other susceptibility genes in rheumatoid arthritis"). Further, a novel DR4 allele (DRB1*0421), has been identified in a single patient with RPC . Thus, although RPC and RA may share clinical and immunologic features and, at times, may coexist, the contribution of HLA-DRB1*04 alleles to disease may differ between these two disorders.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Luthra HS, McKenna CH, Terasaki PI. Lack of association of HLA-A and B locus antigens with relapsing polychondritis. Tissue Antigens 1981; 17:442.
- Zeuner M, Straub RH, Rauh G, et al. Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. J Rheumatol 1997; 24:96.
- Gao XJ, Olsen NJ, Pincus T, Stastny P. HLA-DR alleles with naturally occurring amino acid substitutions and risk for development of rheumatoid arthritis. Arthritis Rheum 1990; 33:939.
- Keller E, Yao Z, Volgger A, et al. A novel variant of DR4 (DRB1*0421) identified in a patient with polychondritis. Immunogenetics 1995; 41:171.
- Hue-Lemoine S, Caillat-Zucman S, Amoura S, et al. HLA-DQA1 and DQB1 alleles are associated with susceptibility to relapsing polychondritis: From transgenic mice to humans. Arthritis Rheum 1999; 42:S261.
- Piette JC, Papo T, Chavanon P, et al. Myelodysplasia and relapsing polychondritis. J Rheumatol 1995; 22:1208.
- Hebbar M, Brouillard M, Wattel E, et al. Association of myelodysplastic syndrome and relapsing polychondritis: further evidence. Leukemia 1995; 9:731.
- Berger R. Polychondritis resulting from intravenous substance abuse. Am J Med 1988; 85:415.
- McCLUSKEY RT, THOMAS L. The removal of cartilage matrix, in vivo, by papain; identification of crystalline papain protease as the cause of the phenomenon. J Exp Med 1958; 108:371.
- Foidart JM, Abe S, Martin GR, et al. Antibodies to type II collagen in relapsing polychondritis. N Engl J Med 1978; 299:1203.
- Ebringer R, Rook G, Swana GT, et al. Autoantibodies to cartilage and type II collagen in relapsing polychondritis and other rheumatic diseases. Ann Rheum Dis 1981; 40:473.
- Herman JH, Dennis MV. Immunopathologic studies in relapsing polychondritis. J Clin Invest 1973; 52:549.
- Buckner JH, Van Landeghen M, Kwok WW, Tsarknaridis L. Identification of type II collagen peptide 261-273-specific T cell clones in a patient with relapsing polychondritis. Arthritis Rheum 2002; 46:238.
- Burkhardt H, Koller T, Engström A, et al. Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse. Arthritis Rheum 2002; 46:2339.
- Riccieri V, Spadaro A, Taccari E, Zoppini A. A case of relapsing polychondritis: pathogenetic considerations. Clin Exp Rheumatol 1988; 6:95.
- Ouchi N, Uzuki M, Kamataki A, et al. Cartilage destruction is partly induced by the internal proteolytic enzymes and apoptotic phenomenon of chondrocytes in relapsing polychondritis. J Rheumatol 2011; 38:730.
- Takagi D, Iwabuchi K, Iwabuchi C, et al. Immunoregulatory defects of V alpha 24V+ beta 11+ NKT cells in development of Wegener's granulomatosis and relapsing polychondritis. Clin Exp Immunol 2004; 136:591.
- Herman JH, Carpenter BA. Immunobiology of cartilage. Semin Arthritis Rheum 1975; 5:1.
- Baker JR, Caterson B, Christner JE. Immunological characterization of cartilage proteoglycans. Methods Enzymol 1982; 83:216.
- Glant T, Mikecz K. Antigenic profiles of human, bovine and canine articular chondrocytes. Cell Tissue Res 1986; 244:359.
- Stuart JM, Cremer MA, Dixit SN, et al. Collagen-induced arthritis in rats. Comparison of vitreous and cartilage-derived collagens. Arthritis Rheum 1979; 22:347.
- Mörgelin M, Paulsson M, Heinegård D, et al. Evidence of a defined spatial arrangement of hyaluronate in the central filament of cartilage proteoglycan aggregates. Biochem J 1995; 307 ( Pt 2):595.
- Wu JJ, Eyre DR. Matrilin-3 forms disulfide-linked oligomers with matrilin-1 in bovine epiphyseal cartilage. J Biol Chem 1998; 273:17433.
- Poole AR, Pidoux I, Reiner A, et al. Mammalian eyes and associated tissues contain molecules that are immunologically related to cartilage proteoglycan and link protein. J Cell Biol 1982; 93:910.
- van Eden W, Holoshitz J, Nevo Z, et al. Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci U S A 1985; 82:5117.
- Menge T, Rzepka R, Melchers I. Monoclonal autoantibodies from patients with autoimmune diseases: specificity, affinity and crossreactivity of MAbs binding to cytoskeletal and nucleolar epitopes, cartilage antigens and mycobacterial heat-shock protein 60. Immunobiology 2002; 205:1.
- Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 1977; 146:857.
- Yoo TJ, Kim SY, Stuart JM, et al. Induction of arthritis in monkeys by immunization with type II collagen. J Exp Med 1988; 168:777.
- Cremer MA, Pitcock JA, Stuart JM, et al. Auricular chondritis in rats. An experimental model of relapsing polychondritis induced with type II collagen. J Exp Med 1981; 154:535.
- McCune WJ, Schiller AL, Dynesius-Trentham RA, Trentham DE. Type II collagen-induced auricular chondritis. Arthritis Rheum 1982; 25:266.
- Griffiths MM, Eichwald EJ, Martin JH, et al. Immunogenetic control of experimental type II collagen-induced arthritis. I. Susceptibility and resistance among inbred strains of rats. Arthritis Rheum 1981; 24:781.
- Wooley PH, Luthra HS, Stuart JM, David CS. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med 1981; 154:688.
- Mauri C, Williams RO, Walmsley M, Feldmann M. Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis. Eur J Immunol 1996; 26:1511.
- Bradley DS, Das P, Griffiths MM, et al. HLA-DQ6/8 double transgenic mice develop auricular chondritis following type II collagen immunization: a model for human relapsing polychondritis. J Immunol 1998; 161:5046.
- Lamoureux JL, Buckner JH, David CS, Bradley DS. Mice expressing HLA-DQ6alpha8beta transgenes develop polychondritis spontaneously. Arthritis Res Ther 2006; 8:R134.
- Taneja V, Griffiths M, Behrens M, et al. Auricular chondritis in NOD.DQ8.Abetao (Ag7-/-) transgenic mice resembles human relapsing polychondritis. J Clin Invest 2003; 112:1843.
- Hansson AS, Heinegård D, Holmdahl R. A new animal model for relapsing polychondritis, induced by cartilage matrix protein (matrilin-1). J Clin Invest 1999; 104:589.
- Buckner JH, Wu JJ, Reife RA, et al. Autoreactivity against matrilin-1 in a patient with relapsing polychondritis. Arthritis Rheum 2000; 43:939.
- Hansson AS, Johansson AC, Holmdahl R. Critical role of the major histocompatibility complex and IL-10 in matrilin-1-induced relapsing polychondritis in mice. Arthritis Res Ther 2004; 6:R484.
- Hansson AS, Johannesson M, Svensson L, et al. Relapsing polychondritis, induced in mice with matrilin 1, is an antibody- and complement-dependent disease. Am J Pathol 2004; 164:959.
- Saxne T, Heinegård D. Serum concentrations of two cartilage matrix proteins reflecting different aspects of cartilage turnover in relapsing polychondritis. Arthritis Rheum 1995; 38:294.
- Hansson AS, Heinegård D, Piette JC, et al. 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; 44:2402.
- Herman JH, Greenblatt D, Khosla RC, Appel AM. Cytokine modulation of chondrocyte proteinase release. Arthritis Rheum 1984; 27:79.
- Saklatvala J. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 1986; 322:547.
- Dingle JT, Page Thomas DP, King B, Bard DR. In vivo studies of articular tissue damage mediated by catabolin/interleukin 1. Ann Rheum Dis 1987; 46:527.
- Herman JH, Nutman TB, Nozoe M, et al. Lymphokine-mediated suppression of chondrocyte glycosaminoglycan and protein synthesis. Arthritis Rheum 1981; 24:824.
- Herman JH, Khosla RC, Mowery CS, Appel AM. Modulation of chondrocyte synthesis by lymphokine-rich conditioned media. Arthritis Rheum 1982; 25:668.
- Goldring MB, Sandell LJ, Stephenson ML, Krane SM. Immune interferon suppresses levels of procollagen mRNA and type II collagen synthesis in cultured human articular and costal chondrocytes. J Biol Chem 1986; 261:9049.
- Goldring MB, Birkhead J, Sandell LJ, et al. Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes. J Clin Invest 1988; 82:2026.
- Stabler T, Piette JC, Chevalier X, et al. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum 2004; 50:3663.
- Herman JH, O'Connor MP, Lieberman MA. Perturbation of a Cartilage Autocrine/Paracrine Basic Fibroblast Growth Factor Metabolic Regulatory Network by Osteoarthritic Synovial Tissue. Am J Ther 1996; 3:52.
- Lazarus DD, Moldawer LL, Lowry SF. Insulin-like growth factor-1 activity is inhibited by interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6. Lymphokine Cytokine Res 1993; 12:219.