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Etiology and pathogenesis of relapsing polychondritis

Etiology and pathogenesis of relapsing polychondritis
Literature review current through: Jan 2024.
This topic last updated: Apr 28, 2022.

INTRODUCTION — 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".)

ETIOLOGY — 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, direct trauma, and infections. This hypothesis is supported by a series of observations that imply that RPC is not a primary disease, but a syndrome associated with multiple precipitating factors that appear in a genetically susceptible subject. (See 'Genetic susceptibility' below and 'Association with other immunologic and bone marrow diseases' below and 'Induction by triggers' below.)

Genetic susceptibility — No association of RPC with human leukocyte antigen (HLA) class I (HLA-A and HLA-B) antigens has been identified [1]. However, an association has been described between RPC and HLA class II, specifically with HLA-DR4 [2]. Genetic analysis of the frequency of HLA class II histocompatibility antigens was performed in 60 White Central European patients with RPC [2]; 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 [3].

Subsequent evidence from a Japanese population could not confirm an association with HLA-DR4. However, these investigators identified three HLA class II alleles in linkage disequilibrium with each other and associated with RPC. Two of the alleles are seen predominately in Eastern Asian populations and not thought to be generalizable. HLA-DQB1*05:02, the third allele, is also present in European populations and could be a focus of additional genotyping studies. In the Eastern Asian population, the three alleles did not influence the clinical features of the disease [4].

The RA-associated alleles have in common a region of highly similar sequence, designated the shared epitope. 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. (See "HLA and other susceptibility genes in rheumatoid arthritis".)

Another observation made in one of these studies was a negative association between HLA-DR6 positivity and clinical features of RPC, including extent of organ involvement and specific organ manifestations (such as general symptoms and nasal chondritis) [2]. HLA-DR6-positive patients also had a higher median age at disease onset compared with HLA-DR6-negative patients. The importance of this relationship is unclear and remains speculative.

A role for HLA class II DQ alleles was suggested by one preliminary report of a study that evaluated HLA class II allelic distribution among 64 unrelated White RPC patients compared with 507 unrelated healthy controls [5]. The following allele frequencies were significantly increased in RPC: DQB1*0601 (4.7 versus 0.9 percent), DQA1*0103 (15.6 versus 7.9 percent) and DQA1*0301 (22.7 versus 12.9 percent). In addition, 59 percent of patients expressed the DQA1*0103 or 0301 allele compared with 38 percent of controls. This is further supported by the report that double transgenic mice which express both DQA1*0301/DQB1*0302 and DQA1*0103/DQB1*0601 class II molecules develop severe experimental RPC following immunization with type II collagen. (See 'Genetic predisposition in experimental models' below.)

Association with other immunologic and bone marrow diseases — There is a frequent association of RPC with a diverse array of connective tissue, endocrine, and inflammatory bowel diseases in which immunologic mechanisms are believed to have a prominent role in pathogenesis. These include systemic necrotizing forms of vasculitis, Graves' disease, and ulcerative colitis (table 2). (See "Clinical manifestations of relapsing polychondritis".)

Since the mid-1990s, there has been recognition of a particular subgroup of patients with an overlap of RPC and myelodysplastic syndrome (MDS) [6-8]. These patients were mostly described as older males, with high mortality, an absence of airway chondritis, and a diagnosis of MDS [9]. Subsequently, the description of a newly defined syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, found that somatic mutations in the UBA1 gene caused a disease characterized by an overlap of inflammatory and hematologic features including MDS. In the first description of VEXAS, a high proportion of patients carried a clinical diagnosis of RPC, and patients with VEXAS were older and males, for the most part, due to the mutations being X-linked [10]. Thus, it is very likely that the cause of the previously described subgroup of RPC overlapping with MDS was due to VEXAS syndrome. Another study has found that 7.6 percent of patients with RPC in a prospective observational cohort of RPC patients referred to the US National Institutes of Health (NIH) had VEXAS syndrome [11]. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Autoimmune/inflammatory conditions'.)

Induction by triggers

Toxins – A disease simulating RPC (auricular/nasal cartilage inflammation, scleritis, audiovestibular, and peripheral and axial joint involvement) appeared within 24 hours of an intravenous injection of a preheated multiple substance "cocktail" [12]. This cocktail included hydrochloric acid, carburetor fluid, the waxy internal matrix of a mentholated nasal inhaler, and tap water. This bizarre event is reminiscent of early experimental studies showing that intravenously injected crude papain could induce collapse of the normally rigid ears of young rabbits within four hours of administration, followed in some animals by respiratory distress caused by tracheal and bronchial collapse [13]. There was widespread but reversible diffuse loss of connective tissue metachromasia consistent with proteoglycan depletion.

Trauma – Direct trauma to cartilaginous structures has also been described as a trigger of RPC. The mechanisms associated with this process have been proposed to be due to trauma causing exposure of cartilage matrix protein antigens. These antigens generate an autoimmune response by producing autoantibodies and autoreactive T lymphocytes towards cartilaginous structures that will then generate chondritis in other anatomic locations [14,15].

Infection – Infections have been recognized as a trigger of autoimmunity in other conditions by generating an innate immune response mediated by nucleotide-binding oligomerization domain-like receptor (NLR) and toll-like receptor (TLR) signaling [15]. A few cases of RPC associated with hepatitis C have been reported, suggesting a possible role of infections as a trigger of RPC [16,17].

PATHOGENESIS — Although the inciting cause may vary, increasing evidence derived from human and experimental animal studies has clearly implicated genetically preconditioned phlogistic and immunologic mechanisms that disturb connective tissue structure and cell function. In addition to the association with human leukocyte antigen (HLA) DR4, the following observations are consistent with this hypothesis:

The presence of autoimmunity, both antibody and cell-mediated, to extracellular matrix components of cartilage such as types II, IX and XI collagen, matrilin-1, and proteoglycan constituent fractions [18-20].

Some observations support the contribution of a cell-mediated immune reaction to type II collagen [21]. As an example, T cell clones isolated from a DRB1*0101/0401 heterozygous patient with relapsing polychondritis (RPC) showed specificity to a peptide derived from type II collagen that is an immunodominant epitope in a transgenic mouse model with features of RPC. Of further interest are differences found in the epitope specificity for type II collagen antibody identified in patients with rheumatoid arthritis versus RPC. Response in the rheumatoid patients was directed to an evolutionary conserved type II collagen domain that is also targeted by pathogenic autoimmune responses in murine models of arthritis but not RPC [22].

The prominence of HLA-DR-positive antigen-presenting cells and CD4-positive T lymphocytes at lesional sites [23].

Cartilage destruction may also be mediated by induction of apoptosis in chondrocytes. Chondrocyte expression of matrix metalloproteinase (MMP)–3 and cathepsin-K is strongly associated with this finding [24].

The genetically governed experimental induction of features of RPC following immunization of experimental animals with connective tissue antigens. (See 'Genetic predisposition in experimental models' below.)

Selective decreases in the number and function of natural killer regulatory T cells (NKT cells), a novel lymphocyte lineage distinct from conventional T, B, or NK cells which are believed to be involved in control of expression of autoimmune disease by modulating the balance of cytokine expression [25].

Findings such as these have led to the generation of a unifying hypothesis which takes into account genetic predisposition, the immunogenicity of cartilage, and specific immunologic pathways important in mediating the disease process (algorithm 1).

Immunogenicity of cartilage — Cartilage proteoglycans, collagen types, elastin, and the chondrocyte cell membrane express multiple epitopes capable of eliciting an immune response [26-28]. These epitopes are largely masked in the native state because of their conformational structure.

Fundamental to an understanding of the immunopathologic significance of such connective tissue constituents in RPC is an awareness of their tissue distribution, since the lesions in RPC usually involve the trachea, nose, and outer ears, and the sharing of antigenicity.

Although type II collagen is transiently present in many tissues during embryogenesis, it is subsequently expressed at only two sites: the fibrillar scaffolding of cartilage matrix, and the vitreous of the eye [29].

Type IX collagen, a fibril-associated form with interrupted triple helices, has proteoglycan properties. It is a molecular coupler that organizes and anchors type II collagen fibrils in a defined three-dimensional pattern within connective tissue matrix.

Type XI collagen, which regulates fibril size, is uniformly distributed in cartilage and dominantly concentrated in pericellular regions.

Although matrilin-1 is a matrix protein unique to fetal epiphyseal cartilage, it is only expressed in adults in auricular, nasal, tracheal, and costochondral cartilages [30,31]. In animal models, immunization to matrilin-1 can induce an RPC-like syndrome. (See 'Matrilin-1' below.)

Proteoglycan-shared epitopes are diversely distributed and can be found in a variety of tissues including connective tissue of aortic media and intima, the anterior uveal tract, heart valves, the endoneurium and perineurium of the optic nerves, the tracheal submucosal basement membrane, endothelial cells, glomerular and tubular basement membranes, myocardial sarcolemma, and synoviocytes [26-29,32].

Of speculative interest is the antigenic crossreactivity between cartilage proteoglycans, streptococcal peptidoglycans, and the purified protein derivative of Mycobacterium tuberculosis [33]. In this context, a monoclonal antibody derived from peripheral blood B cells of a patient with RPC reacted with a purified cytoskeletal antigen (desmin), type II collagen, and proteoglycans [34]. Crossreactivity of this antibody to heat shock protein 60 obtained from M. tuberculosis was also shown. The possibility that an exogenous antigen induces an antibody capable of cross-reacting with autoantigens and thus contributing to the pathogenic process cannot be dismissed.

Genetic predisposition in experimental models — Rodents and primates immunized with native type II or XI cartilage collagen may develop a major histocompatibility complex (MHC)-restricted destructive arthropathy which correlates both with the expression of antibodies specific for conformational determinants of collagen and cell-mediated immune responses which lack conformational or collagen type specificity [35,36]. It is unclear as to whether T cells alone can induce arthritis, although they are likely to have a major role in sustaining the process. An auricular chondritis may develop later in the postimmunization period, independent of the expression of arthritis [37,38].

These responses appear to be under multiple gene control which is, in part, linked to the Ir region of the MHC [39,40]. This region is thought to be responsible for regulation of the expression, severity, and rate of progression of disease. An imbalance of T-helper cell subsets may play an important role in the development of cartilage destruction in this model [41]. However, there are no ocular, laryngotracheobronchial, or cardiovascular lesions in collagen-induced arthritis, as there are in human RPC.

The role of DQ class II molecules in the antigenic presentation of type II collagen and subsequent initiation of collagen-induced arthritis has been studied using transgenic mice lacking endogenous HLA class II molecular expression [42]. These HLA molecules, which are expressed on the cell surface, can positively select CD4+ T cells expressing various V beta T cell receptors. Transgenic mice that express DQ8 develop severe arthritis in response to collagen immunization; by comparison, DQ6 mice are unresponsive. Double transgenic mice expressing both DQ6 and DQ8 develop severe RPC following type II collagen immunization, exhibiting both polyarthritis and auricular chondritis. Older mice bearing both DQ6 and DQ8 develop chondritis spontaneously (in the absence of collagen immunization or adjuvant administration) [43].

Expression of DQ8 in mice with a nonobese diabetic (NOD) genotype and lacking endogenous class II molecules is also associated with a susceptibility to type II collagen-immunization-induced chondritis [44]. In this transgenic strain, immunization with type II collagen produces auricular cartilage inflammation in a larger proportion of animals and also produces an antibody response to both type II and type IX collagen. Immunization of this mouse strain with type IX collagen frequently leads to chondritis.

Matrilin-1 — Other models have used cartilage matrix protein (matrilin-1) as the immunogen in an attempt to replicate the tissue distribution of lesions in RPC [45,46]. Matrilin-1 is primarily expressed in skeletal growth cartilage during development but is limited to the nasal septum, trachea, auricular, and xiphisternal cartilage in adulthood [30,31]. Immunization of rats with this protein produces severe inspiratory stridor due to tracheal involvement, nasal swelling, and/or epistaxis [45]. Female rats were more susceptible than males. All strains mount a strong IgG anti-matrilin-1 response, but only some strains develop disease. Using congenic mouse strains, the likelihood of developing disease appears to be governed by both MHC and non-MHC genes, and is dependent upon alpha beta T cells [47]. Mice devoid of interleukin (IL)-10 through gene deletion develop a significantly more severe disease with earlier onset.

Further studies using the matrilin-1 model have shown both an antibody- and complement-dependent basis for RPC development. Neither specific antibody nor disease could be induced in matrilin-1 immunized mice deficient of B cells [48]. B-cell deficient mice injected with matrilin-1 specific antibody developed erosive respiratory tract chondritis. Respiratory distress occurred significantly less in matrilin-1 immunized mice congenic at complement factor 5, indicating the potential importance of, although not an absolute requirement for, functional C5.

The applicability of these findings to humans is uncertain. Matrilin-1 fragments have been identified in the serum of a patient with RPC during active inflammation [46], and both humoral and cell-mediated immune responses were documented in other patients [46,49]. Anti-matrilin antibodies are present in a minority of patients with RPC. This was illustrated by a study of the sera of 97 patients obtained at a single time point in their disease course; 13 of 97 had IgG and/or IgM anti-matrilin-1 antibody; positive responses correlated with respiratory symptoms in 69 percent of the cases [50]. However, 40 percent of patients having clinical evidence of laryngotracheal involvement did not have an anti-matrilin-1 antibody response.

Immunologic pathways mediating cartilage degradation — The immune response and subsequent release of cytokines may be responsible for cartilage destruction in RPC. Immune complexes, formed in situ and/or localized by affinity to polyanionic proteoglycans, bind to the surface of cartilage. Attempted removal by scavenger cells facilitates release of matrix degrading metalloproteinases, oxygen metabolites and/or cytokines [42].

Cytokines such as IL-1 and tumor necrosis factor (TNF) induce chondrocyte production of matrix-degrading metalloproteinases, plasminogen activator and prostanoids [51-53]. They may also reversibly downregulate chondrocyte collagen and/or proteoglycan synthesis [54-57].

A major role for cell-mediated immune responses in the pathophysiology of RPC is suggested by serum cytokine profile studies [58]. A set of circulating cytokines levels were contrasted between patients with active RPC, patients with rheumatoid arthritis, and healthy control subjects. Mean serum levels of monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 beta (MIP-1 beta), and IL-8 were significantly higher in patients with RPC than controls. The profile in rheumatoid arthritis differed, showing a more generalized pattern of upregulation of multiple cytokines rather than the more discrete elevations observed in RPC. Each of the three cytokines increased in RPC is a proinflammatory chemokine; MCP-1 and MIP-1 beta function to recruit and activate circulating monocyte/macrophages. IL-8 is produced by activated monocyte/macrophages, acting in part to attract neutrophils. Chondrocytes constitutively express and store these cytokines and their receptors are found on activated T cells.

Cartilage contains a constitutive and inducible growth factor/cytokine metabolic regulatory network, which may function in an autocrine/paracrine manner to modulate normal cartilage growth and metabolism. It may also serve a pathophysiologic role, contributing to altered chondrocyte metabolism and ineffectual tissue repair [59]. As an example, basic fibroblast growth factor, an integral part of this network, upregulates IL-1 and TNF receptors. Insulin-like growth factor-1 activity, which is essential for optimal chondrocyte anabolic function, is inhibited by these cytokines [60].

Unifying hypothesis — A hypothetical scheme for the pathogenesis of RPC begins with insult-induced exposure of connective tissue or cell membrane epitopes, leading to an inflammatory and genetically conditioned immune response (algorithm 1).

Cartilage may be viewed as an immunologically "privileged" tissue because of both the conformational structure of its basic connective tissue constituents and its avascular and alymphatic milieu. Privileged refers to failure of development of immunologic tolerance to self-components.

The integrity of cartilage in RPC can speculatively be compromised by multiple inciting factors including:

An insult, irrespective of cause, to nutrient vasculature at sites contiguous to cartilage, with an ensuing inflammatory cell exudate being responsible for tissue injury

A direct traumatic, toxic, infectious, or chemical insult

A systemic or localized process which directly or indirectly perturbs chondrocyte metabolism by modulating exposure to essential hormones and growth factors

An infectious agent having a cytotropic propensity for chondrocytes

Antigenic mimicry between an infectious agent and a given connective tissue antigen as noted above

The ensuing matrix compromise may lead to release of or in situ exposure to native or modified connective tissue antigens. Genetically conditioned host sensitization would facilitate generation of both humoral and cell-mediated immune responses. Pathologic consequences, in part representing in situ complex formation, may be widespread because of epitope sharing with matrix constituents. Alternatively, cartilage and other connective tissue sites may serve as innocent bystanders, reflecting an affinity-associated adsorption of preformed complexes.

The ensuing inflammatory response would perpetuate enzymatic and oxygen metabolite-mediated connective tissue degradation. Cytokines released into the milieu can further contribute to the pathologic process by inducing chondrocyte and connective tissue fibroblast proteinase release, perturbing matrix repair, and inciting constitutional symptoms and an acute phase response.

SUMMARY

Etiology – The etiology of relapsing polychondritis (RPC) is unknown, and multiple inciting events have been postulated. Genetic susceptibility is suggested by the association between RPC and human leukocyte antigen (HLA) DR4 or other HLA class II alleles. (See 'Genetic susceptibility' above and 'Etiology' above.)

Associated disorders – There is a frequent association of RPC with a diverse array of immune-mediated connective tissue, endocrine, and inflammatory bowel diseases, including systemic necrotizing forms of vasculitis, Graves' disease, and ulcerative colitis. A high proportion of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome meet a clinical diagnosis of RPC. (See 'Association with other immunologic and bone marrow diseases' above.)

Role of autoimmunity and immune cell dysfunction in pathogenesis – There is evidence of autoimmunity, both antibody- and cell-mediated, to extracellular matrix components of cartilage, including types II, IX and XI collagen; matrilin-1; and proteoglycan constituent fractions. (See 'Immunogenicity of cartilage' above and 'Matrilin-1' above.)

Findings include the prominence of HLA-DR-positive antigen-presenting cells and CD4-positive T lymphocytes at lesional sites and selective decreases in the number and function of natural killer regulatory T cells (NKT cells). (See 'Pathogenesis' above.)

Experimental induction of features of RPC following immunization of experimental animals with connective tissue antigens is genetically regulated. (See 'Genetic predisposition in experimental models' above.)

Unifying hypothesis for mechanisms of cartilage injury – RPC is hypothesized to result from exposure of modified or immunologically privileged connective tissue or cell membrane epitopes by an unknown inciting event, leading to an inflammatory and genetically conditioned immune response. The response to injury may perpetuate enzymatic and oxygen metabolite-mediated connective tissue degradation and subsequent release of cytokines, which may be responsible for cartilage destruction. (See 'Immunologic pathways mediating cartilage degradation' above and 'Unifying hypothesis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Clement J Michet, MD, who contributed to an earlier version of this topic review.

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Topic 5604 Version 21.0

References

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