Genetics of rheumatoid arthritis: Is there a pattern predicting extraarticular manifestations?
Version of Record online: 11 OCT 2004
Copyright © 2004 by the American College of Rheumatology
Arthritis Care & Research
Volume 51, Issue 5, pages 853–863, 15 October 2004
How to Cite
Turesson, C., Weyand, C. M. and Matteson, E. L. (2004), Genetics of rheumatoid arthritis: Is there a pattern predicting extraarticular manifestations?. Arthritis & Rheumatism, 51: 853–863. doi: 10.1002/art.20693
- Issue online: 11 OCT 2004
- Version of Record online: 11 OCT 2004
- Manuscript Accepted: 2 MAR 2004
- Manuscript Received: 2 OCT 2003
- Lund University
- Swedish Rheumatism Association
- Swedish Society of Medicine
- NIH. Grant Numbers: R01-AI-44142, R01-AR-42527, R01-EY-11916, R01-HL-63919, R01-AG-15043, R01-AR-41974, K24-AR-47578-01A1
Rheumatoid arthritis (RA) is a heterogeneous disease. Most rheumatologists encounter a wide variety of patients—ranging from those with mild, spontaneously remitting, symmetric synovitis to those with aggressive, treatment-resistant disease who become severely disabled and sometimes die at a young age from disease-related complications, including vascular disease. There is a wide variety in disease presentation with respect to clinical and laboratory signs of inflammation, extent and severity of joint damage, and presence of extraarticular disease manifestations. Understanding and managing this heterogeneity is a major challenge for the practicing rheumatologist and the clinical scientist.
Recent surveys have highlighted the major impact of extraarticular manifestations on survival of patients with RA (1, 2). Improved ability to predict such manifestations and improved knowledge of the underlying mechanisms would have a major impact on the management of patients with RA. Suggested predictors of extraarticular RA include clinical, serologic, and genetic factors, such as specific HLA genotypes, cytokine gene polymorphisms, and other genes that regulate immune responses and inflammation. This review discusses the evidence for associations between immunogenetic markers and extraarticular disease features and their importance for our understanding of extraarticular RA; it also suggests a model for the genetic predisposition to extraarticular disease manifestations.
Extraarticular manifestations in RA
Extraarticular features of RA include vasculitis, rheumatoid nodules, pericarditis, rheumatoid lung disease, Felty's syndrome, scleritis and other ophthalmologic manifestations, secondary Sjögren's syndrome, and amyloidosis. These manifestations are likely to differ to a certain extent with respect to pathogenesis and underlying mechanisms, although blood vessel abnormalities have been noted in serositis (3), eye disease (4), and nodules (5), indicating that vascular mechanisms may be shared by most extraarticular RA lesions. The concept of extraarticular RA (ExRA) as a systemic vascular disorder is supported by the demonstration of immunoglobulin deposition in vessels in normal-appearing skin of patients with ExRA (6) and signs of endothelial activation in muscle biopsy specimens from patients with ExRA who are otherwise without clinical and histologic signs of muscle disease (7).
A problem hampering investigation of systemic disease in RA is that there is no uniformity in the definition or usage of the term ExRA in studies of these manifestations. Cross-sectional assessment of extraarticular features of RA patients, retrospective cohort studies, and prospective followup surveys are likely to identify somewhat different subsets of patients with ExRA. To address this problem, a set of criteria for identification of severe ExRA manifestations (pericarditis, pleuritis, cutaneous vasculitis, neuropathy, scleritis, vasculitis involving other organs, and Felty's syndrome) in structured case record reviews has been developed (1, 8) (Table 1). In the community-based cohort of patients with RA from Olmsted County, Minnesota (9), the incidence of severe ExRA according to these criteria is about 1 per 100 years of followup in patients with RA, and approximately 15% of all RA patients develop such manifestations at any time (1). People with this set of severe ExRA have been shown to have increased mortality compared with other RA patients (1, 9, 10). Indeed, in a community based setting, it appears to be the major determinant of excess mortality in RA (1, 2). This is in accordance with other studies indicating an increased mortality in patients with ExRA (11–14).
|Pericarditis||Clinical judgment and exudation verified by echocardiography|
|Other causes improbable, such as tuberculosis or other infection, metastases, primary tumor, postoperative status, or other trauma|
|Pleuritis||Clinical suspicion and exudation verified by radiograph|
|Other causes improbable, such as tuberculosis or other infection, metastases, primary tumor, postoperative status, or other trauma|
|Felty's syndrome||Splenomegaly (clinically evident or measured by ultrasound) and neutropenia (<1.8 × 109/liter) on 2 occasions|
|Other causes improbable, such as drug side effect or infection|
|Major cutaneous vasculitis||Diagnostic biopsy or clinical judgment by dermatologist|
|Neuropathy||Clinical judgment and signs of mononeuropathy/polyneuropathy at EMG/ENeG|
|Scleritis, episcleritis, or retinal vasculitis||Clinical judgment by ophthalmologist|
|Glomerulonephritis||Clinical judgment by nephrologist and positive biopsy|
|Vasculitis involving other organs||Clinical judgment by organ specialist and biopsy compatible with vasculitis|
ExRA manifestations are more frequent among hospitalized RA patients (8, 11) and seem to occur mainly in patients with severe polyarthritis (11, 15). On the other hand, extraarticular manifestations are sometimes seen in patients without extensive joint damage. Erosive disease and ExRA may thus in part reflect different pathomechanisms, including genetic factors. Although ExRA manifestations can be regarded as the tip of an iceberg of a disease that is in essence systemic, we believe that patients with severe extraarticular disease represent a distinct subgroup, based at least in part on their unique genetic setup. In the conclusion, we discuss a model for the contribution of genetic factors to mechanisms specifically involved in ExRA.
RA and genetics
There is extensive evidence for a genetic component in the etiology of RA (Table 2). Specifically, RA has been associated with the shared epitope (SE) of HLA–DRB1 (23). SE genotypes include the DRB1*1402 and *1406 subtypes, which are found in the vast majority of Yakima and Pima Indians (23), in whom the highest reported prevalence of RA in the world is reported (24, 25). Overall, the SE has been estimated to account for about one-third of the genetic risk in RA (26). Genome-wide searches using microsatellite loci have confirmed linkage between RA and the HLA–DR region in European (27) and US (28, 29) subjects, but not Japanese (30) subjects.
|Increased concordance of RA in MZ versus DZ twins||Concordance rates: ∼15% (MZ) versus ∼4% (DZ)||National studies of twins in Finland and the UK||16, 17|
|Familial clustering of RA, extending beyond the nuclear family||Risk ratio for RA 4.38 in first degree relatives; 1.95 in uncles/aunts||The Icelandic population-based genealogy database||18|
|Estimate of the genetic contribution to RA||Heritability estimate 53–65%||Variance analysis models based on twin studies (15, 16)||19|
|Shared HLA genes in patients with RA, with increased frequency of DR4||Mixed lymphocyte culture reaction patterns||Case control studies (RA versus normals and RA versus SLE)||20, 21|
|Shared epitope in RA-associated HLA–DRB1 genes||DRB1* epitopes sharing the Q(R)K(R)AA amino acid pattern in position 70–74 are more frequent in patients with RA†||Molecular analysis of RA-associated genotypes||22|
The HLA–DR genes are situated on chromosome 6p within the major histocompatibility complex (MHC), which consists of a large number of highly polymorphic genes. There is considerable linkage disequilibrium within the MHC, indicating that other genes, being part of extended SE-associated haplotypes, could in part explain disease associations with HLA genotypes. Linked genes and gene–gene interactions could modify disease expression in SE-positive individuals.
The RA-associated SE subtypes have been found mainly in patients with severe disease, indicating that they not only affect disease susceptibility but also influence disease severity (31–36), although the utility of DR typing in early RA cohorts (37) and community-based RA samples (38) to predict outcome has been questioned. In a recent study of a large US sample of early RA patients (39), RA was mainly associated with DRB1*0401, but there was no clear association between the presence of SE subtypes and disability.
Extraarticular RA and HLA–DR
ExRA manifestations have mainly been associated with SE DR4 subtypes (40–61) (Table 3). Associations between ExRA manifestations and DR4 tend to be stronger in studies of northern European RA populations (40, 43, 56, 61) than in studies performed in Mediterranean countries (35, 48, 60), where no or weak associations are seen. In Caucasian populations, ExRA has predominantly been associated with HLA–DRB1*0401 (42, 44, 55, 61). DRB1*0401 is less frequent in the general population of southern France (48), Italy (46), and Greece (60) than in the United Kingdom (61), indicating that this is part of the explanation for the differences in these studies, and also for the lower prevalence of ExRA in Mediterranean populations (48). In Asian populations, where *0401 is a rare allele, the most common RA-associated genotype is DRB1*0405 (62). This subtype has also been associated with an increased risk of extraarticular disease in East Asian populations (34, 50).
|Author, year (reference)||Country (setting)||N total (ExRA)||Association (+/−)||Main findings|
|Ollier, 1984 (40)||UK (Clin)||77 (27)||(+)||DR4 frequencies similar in ExRA and non-ExRA patients; increased DR4 in subset with ExRA, RF, and circulating immune complexes|
|Jaraquemada, 1986 (41)||UK (Clin)||440 (35) (nodules: 108)||(+)||Modest increase of DR4 in patients with nodules (NS) and other ExRA (vasculitis, alveolitis, neuropathy) (NS)|
|Lanchbury, 1991 (42)||UK (Clin)||150 (43)||+||Felty's syndrome strongly associated with Dw4|
|Hillarby, 1991 (43)||UK (Clin)||295 (67)||+||Dw14 increased in RA patients with vasculitis|
|Weyand, 1992 (44)||USA (Clin)||81 (18) (nodules: 54)||+||0401/0401 associated with vasculitis, Felty's syndrome, or rheumatoid lung disease; 0401/05/08 with nodules|
|Wordsworth, 1992 (45)||UK (Clin)||230 (46)||(+)||Dw4/Dw14 associated with severe RA, but patients with Felty's syndrome are similar to non-Felty's within this group|
|Salvarani 1992 (46)||Italy (Clin)||141 (52)||+||DR4 increased in patients with ExRA (including nodules and sicca)|
|Agrawal, 1995 (47)||India (Clin)||74 (11)||+||DR4/DR1 heterozygosity associated with ExRA (including sicca)|
|Benazet, 1995 (48)||France (Clin)||73 (4)||−||Low ExRA prevalence in population with SE expression, but low 0401|
|MacGregor, 1995 (49)||UK (Clin)||201 (109)||+||0401/0404 associated with nodules; other ExRA not studied|
|Suarez-Almazor, 1995 (38)||Canada (Comm)||103 (34)||−||DR4 distribution unremarkable in nodular patients|
|Koh, 1997 (34)||Singapore (Clin)||70 (16)||+||ExRA (including nodules, sicca, and amyloidosis) associated with 0405|
|Kim, 1997 (50)||Korea (Clin)||102 (35)||+||ExRA (including sicca and chronic anemia) associated with 0405|
|Hakala, 1997 (51)||Finland (Comm)||88 (28)||−||ExRA associated with DR3 not DR4|
|González, 1997 (52)||Chile (Clin)||129 (43)||+||SE double dose strongly associated with vasculitis and other ExRA|
|Pedigrer, 1997 (53)||France (Clin)||189 (21)||+||SE associated with ExRA, SE double dose (0401/0404 in particular) with vasculitis|
|Voskuyl, 1997 (54)||Netherlands (Clin)||107 (31)||−||No association between vasculitis and DR/DQ genotype, but minor skin vasculitis associated with 0401 and 0404|
|Salvarani 1998 (35)||Italy (Clin)||86 (44)||−||No significant association between ExRA and DR4 or SE gene dose|
|Toussirot, 1999 (55)||France (Clin)||120 (44)||(+)||No influence on ExRA overall, but vasculitis more frequent in patients with 0401|
|Turesson, 2000 (56)||Sweden (Clin)||74 (35)||(+)||ExRA association restricted to 0401/0401, which is present only in a minority of ExRA patients|
|Mattey, 2001 (57)||Spain (Clin)||181 (35)||−||No association between HLA–DRB1 types and nodules or severe RA|
|McKibbin, 2001 (58)||UK (Clin)||116 (47)||(+)||Trend toward higher frequency of SE/SE in patients with corneal melt or other ExRA (NS)|
|Del Rincon, 2002 (59)||USA (Comm)||777 (214)||+||Nodules more frequent in SE+ patients, other ExRA not studied|
|Ioannidis, 2002 (60)||Greece (Clin)||174 (79)||−||No association between SE and ExRA (including chronic anemia)|
|Mattey, 2002 (61)||UK (Clin)||420 (94)||+||Nodules associated with 0401/0401; other ExRA not studied|
The results from various surveys of HLA–DR4 subtypes in RA patients are highly variable (Table 3), and may be influenced by patient selection. In hospital-based studies, a major proportion of the patients may carry SE genes because of the association between SE and joint damage, whereas community-based samples are likely to be more genetically diverse. In smaller studies, low power is doubtless a limiting factor in assessing the association of potential genetic markers and occurrence of ExRA. Great concern has also been raised about the variations in case definitions of ExRA and their impact on the strength of association with genetic markers (63). Some studies have included severe organ manifestations (but also features such as sicca syndrome and anemia), others concentrate on rheumatoid nodules, and still others are mainly concerned with vasculitis and internal organ disease. Ideally, standardized case definitions, based on clinical, epidemiologic, and pathobiologic data, should be used in scientific studies of ExRA.
Some specific RA manifestations probably have a different genetic background than the shared epitope. HLA–DRB*15, which corresponds to the serotype HLA–DR2, which is infrequent in RA patients, has been associated with secondary Sjögren's syndrome in Spanish patients (64) and with renal involvement in a Japanese study (65). The latter study included patients with various renal pathology—amyloidosis, membranous glomerulonephritis, mesangioproliferative glomerulonephritis, and others. The underlying mechanisms behind these conditions are variable, and include drug reactions. The HLA–DRB1*15 association may thus reflect predisposition to substantial renal damage from, for example, gold-induced nephrotoxicity rather than systemic rheumatoid disease.
A strong association between Felty's syndrome and DRB1*0401 has been reported (42, 44, 56, 66). A gene dosage effect for ExRA with severe organ manifestations has been noted, with patients with RA who have 2 SE copies being at higher risk for these (44). In studies from Minnesota (44) and Sweden (56), the increased risk in SE homozygotes was mainly accounted for by a significant increase in patients with the 0401/0401 genotype. The ethnic background of these populations is to a considerable extent similar, due to Scandinavian and northern European immigration to the midwest United States. In fact, in these 2 studies, 0401/0401 was seen almost exclusively in the subset of patients with severe ExRA. Based on these findings, a model for the impact of DRB1 genotypes on RA disease expression, including ExRA manifestations, has been suggested (Figure 1). Other studies have reported an association between rheumatoid vasculitis and 0401/0404 (54). In a meta-analysis of studies of ExRA manifestations and the SE (67), ExRA overall was found to be associated with double-dose SE heterozygosity (i.e., the presence of 2 different SE subtypes, including DR1 subtypes, but not 2 of the same, e.g., 0401/0401). As pointed out previously, the considerable variety in case definitions and patient selection may account for these apparently conflicting results.
Furthermore, ethnic differences influence the impact of genetic markers. A genotype that has one effect in a population with a certain genetic background may have a different impact in another genetic setting. For example, in a survey of RA patients in Finland (where the population is ethnically distinct from other European populations), extraarticular manifestations were associated with HLA–DR3 rather than DR4 (51).
The results from these studies suggest that the genetic predisposition is somewhat different for various ExRA manifestations, and that genetic factors other than HLA–DRB1 are likely to be important determinants of these manifestations.
An association between HLA–DQ polymorphisms and Felty's syndrome has been suggested (68). Subsequent research has shown that the serotype HLA–DQw7 (corresponding to the genetic subtype DQB1*0301) is increased in Felty patients (43), and that this pattern is apparent even when stratifying for the presence of DR4 (69). Others have demonstrated that this association is mainly due to the strong linkage disequilibrium between HLA–DRB1*0401 and DQB1*0301 (42, 66). The DQB1*0301–DRB1*0401 extended haplotype includes several other potentially important genes, including the C4B null allele (43, 69). DQB1*0301 could also be associated with other extraarticular manifestations (56). The power to discriminate between DR effects, DQ effects, and haplotype effects is limited in most studies.
An alternative model for explaining the MHC class II association with RA has been suggested (70, 71). In this model, the main genes associated with increased susceptibility to RA are HLA–DQ genotypes, e.g., DQB1*0301 and DRB1 alleles that do not express the SE have a protective effect. This has been labeled the “RA protection model.” Other authors have not found data to support this model (72). It is unknown to what extent such DQ–DR interaction influences the susceptibility to ExRA.
Suggested explanations for the MHC class II associations
The main function of HLA–DR and DQ molecules is to present antigens to CD4+ T cells (73). It has therefore been suggested that the association between DR or DQ genotypes and RA susceptibility and severity could be due to presentation of disease-specific peptides, triggering a T-cell dependent immune response (74, 75). To date, no such RA-specific antigen has been isolated.
Another possibility is that the RA-associated SE sequence crossreacts with a similar sequence on a microbial antigen—so called molecular mimicry. Some experimental data indicate that such potentially important similarities exist (76, 77). According to the RA protection model, HLA–DR-derived peptides are presented by HLA–DQ molecules. The presentation of peptides containing the amino acid sequence DERAA instead of the SE would decrease the risk of RA. Neither of these models, however, account for the gene dosage effect on the risk of severe ExRA observed in several studies of patients homozygous for certain SE subtypes (44, 47, 53, 56).
HLA–DR- and DQ-restricted antigen recognition is also involved in T-cell maturation in the thymus. The T-cell repertoire is shaped by negative and positive selection based on T-cell interaction with antigen-presenting cells. Genotype-specific differences in this process could be the basis for associations between HLA genes and autoimmune disease. Indeed, T-cell receptor (TCR) gene usage has been shown to be to a great extent determined by HLA–DR genes (78, 79). There appears to be a stoichiometric relationship between the MHC molecules on the cell surface and the positive selection mechanisms in thymic maturation of T lymphocytes (80). It has thus been suggested that the explanation for the gene dosage effect seen in ExRA is its effect on the diversity of the T-cell repertoire (44, 81).
This model of HLA-determined selection of T cells and the concept of presentation of HLA-derived peptides are not mutually exclusive. It has been demonstrated that peptides including the HLA–DRB1*0401-specific SE amino acid sequence QKRAA can induce tolerance (82) and proliferation (83) in T cells. This indicates that DRB1*0401-derived peptides could be involved in the thymic selection of T cells (84).
The T-cell repertoire in RA patients is markedly contracted, with less diversity and emergence of dominant T-cell clonotypes (85). TCR usage is distorted in RA patients compared with HLA-matched healthy controls, indicating that this is in part due to non–HLA-dependent mechanisms (78). Expansion of particular T-cell clones, such as CD4+ CD28− cells (86) and CD8+ large granular lymphocytes (87), have been demonstrated in patients with ExRA. This suggests that the HLA–DR/DQ genotype predisposes to extraarticular disease through effects on thymic selection of T lymphocytes, but that other mechanisms are involved in the events that lead to clonal lymphocyte expansions.
It remains to be explained why the described DR4/DR4 patterns vary in different studies. Although this may in part be explained by differences in the overall frequency of individual alleles (e.g., 0401), it could be that 0401/0401 is more important in some ExRA subsets, such as vasculitis and severe internal organ disease, and 0401/0404 in others, such as nodules (44). The only difference between 0401 and 0404 is the Lys-Arg substitution in position 71, which has been suggested to be particularly important in peptide binding (88) and in direct HLA–DR–TCR interaction (89). This could lead to a different T-cell repertoire after thymic maturation in 0401/0404 patients compared with those with 0401/0401. Another possibility is that there are important differences in peripheral activation. Gebe et al have shown that DRB1*0401-restricted T cells in vitro can also recognize the same antigen when presented by a 0404-encoded DR molecule, but that, for some T-cell clones, the cytokine expression pattern upon activation is then altered (90). This may indicate that TCR cross recognition in 0401/0404 heterozygotes leads to a functionally different immune response, which affects extraarticular organ involvement.
In addition, some data indicate that SE expressing HLA–DR4 and DR1 molecules are overexpressed on the cell surface of antigen-presenting cells in RA patients compared with HLA–DR-matched controls, and it has been suggested that this facilitates T-cell activation with low-affinity peptides (91). This overexpression could thus lower the threshold for T-cell activation, which would increase the risk of extensive organ involvement in RA. Various combinations of SE subtypes could interact with different sets of T-cell clones under such circumstances.
Other MHC genes
Apart from the class II genes (DR and DQ, but also DP, DO, and DM), the MHC contains the class I genes HLA–A, B, and C. In contrast to class II molecules, which are found only on professional antigen-presenting cells, the class I molecules are expressed on all nucleated cells, and present antigen to CD8+ T cells rather than CD4+ cells. In addition to this, class I molecules also interact with killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells and NK T cells. HLA–A/B/C gene polymorphism could thus be important in regulating various immunologic phenomena, including activation of cytotoxic cells, and could play a role in the development of systemic rheumatoid disease.
In a recent study by Yen et al, the genotypes HLA–C*03 and HLA–C*05 were found to be significantly more frequent in patients with rheumatoid vasculitis than in those without vasculitis (92). These results were not explained by linkage disequilibrium with DR4 genotypes. Interestingly, when a comparison with a healthy reference group was made, HLA–C*03 was not associated with RA in general, whereas C*05 was. This may indicate that the genetic background contributed by HLA–C could differ for ExRA and for RA limited to the joints.
In Pima Indians, who have a high frequency of SE carriers and one of the highest rates of RA prevalence in the world, the distribution of HLA–C genes in patients with RA has been shown to be significantly different from that in non-RA controls (23). Taken together, these 2 studies suggest that HLA–C genes influence the rheumatoid disease process.
The class III region, which is situated between the class I and II domains, includes the complement factor genes C2, C4A, C4B, and factor B, the 21-hydroxylase gene, and the genes encoding tumor necrosis factor α (TNFα) and lymphotoxin α and β. TNFα has been shown to be important in the pathogenesis of RA (93, 94), and treatment with TNFα blocking agents leads to amelioration of joint symptoms and reduction of structural joint damage in many patients (95, 96). Several studies have reported increased serum levels of TNFα in patients with ExRA compared with patients without ExRA (7, 97).
In vitro studies of cytokine production by mitogen-stimulated peripheral blood mononuclear cells revealed that TNF inducibility varied depending on the donor's HLA–DR/DQ pattern (98). Further studies have explored genetic polymorphism in the TNF region in itself. A number of biallelic single nucleotide polymorphisms (SNPs) and 5 microsatellite markers have been identified (99). Several of the SNPs are located in the enhancer/promoter region, but there is no clear evidence indicating that these polymorphisms explain individual variation in TNF expression (100). Suggested associations between the extent of joint damage in RA and the –238 GG genotype (101–103), may instead be due to linkage disequilibrium with other neighboring genes (104).
An association between certain TNFα microsatellite markers and susceptibility to RA, independent of RA-associated haplotypes, has been found in most (104–108), but not all, studies (109). Although microsatellite markers do not seem to affect disease severity by themselves, interactions between the markers TNFa6 (110) and TNFa11 (111) and SE genotypes have been reported to be associated with radiographic damage and disability. The TNFa6–SE interaction may also predict the development of rheumatoid nodules (61). Such interactions could indicate that polymorphisms that influence TNF expression or function are only important in the presence of an immune system shaped by certain class II genes. Alternatively, the interactions could be attributed to other, linked MHC genes. It has recently been demonstrated that various HLA–DRB1*04 subtypes are associated with specific TNF lymphotoxin haplotypes (112), suggesting that these issues can be resolved only through detailed typing of the MHC class II and III regions.
Overall, the role of TNFα gene polymorphisms in RA is unclear. In particular, their importance in modifying disease expression, including extraarticular disease, requires further study.
A number of other proinflammatory and antiinflammatory cytokines have been implicated in rheumatoid arthritis and systemic inflammatory disease. Microsatellite markers mapping near a range of different cytokines were analyzed in a study of RA-affected sib pair families (113). There was no evidence for a strong linkage to RA for any of the genes studied, although weak linkage was found for interleukin-5 receptor, interferon-γ, and interleukin-2 (IL-2) genes. Considerable heterogeneity in the cytokine gene patterns was evident after stratification of patients for age at RA onset, sex, disease severity, and sib-pair HLA concordance. This could indicate that these genes modify disease expression but are not major RA susceptibility genes.
The genes for interleukin-1α (IL-1α), interleukin-1β (IL-1β), and the interleukin-1 receptor antagonist (IL-1Ra) are located in a cluster on chromosome 2q. Polymorphisms in these genes have been associated with disease severity rather than RA susceptibility (114–116). In a study of patients from northern Sweden, restriction fragment length polymorphisms (RFLPs) of IL-1β genes and variable number of tandem repeats (VNTR) polymorphisms of the IL-1Ra gene were investigated (117). The Taq1 RFLP IL-1β genotype A2A2 was associated with higher cumulative disease activity score. Although no association with ExRA was seen in this limited sample, the combination of IL-1β A1 and the IL-1Ra VNTR A2 genotype was less prevalent in patients with cardiovascular comorbidity.
Dewberry et al have demonstrated intracellular expression of IL-1Ra in human coronary artery endothelial cells, and have suggested that the level of expression may in part be genetically determined (118). The findings of widespread, spontaneous arteritis in one of the IL-1Ra knockout mouse strains (119) and of increased systemic endothelial expression of IL-1α in patients with ExRA (7) are compatible with an importance for the IL-1 family in vascular complications in RA. The potential genetic basis for this should be further studied.
Circulating protease inhibitors, which regulate inflammation and prevent organ damage, could be important in extraarticular rheumatoid organ disease. The alpha-1-antitrypsin (α1-AT) deficiency allele PiZ is associated with pulmonary emphysema (120, 121) and liver cirrhosis (122, 123). Some, but not all, studies have reported PiZ to be more prevalent in RA patients than in controls (124–127). There is conflicting data on PiZ and interstitial lung disease in RA (128–130). Steers et al, who excluded patients in whom pulmonary fibrosis could be attributed to other causes, did not find an association with PiZ (130). This underscores the importance of careful characterization of the disease phenotype, with strict case definitions, in the study of ExRA. Although α1-AT deficiency has been shown to be associated with antineutrophil cytoplasmic antibody-positive vasculitis (131), a study of patients with severe ExRA did not reveal any increased prevalence of PiZ in this RA subset (Turesson C and Elzouki AN, unpublished observations).
The mechanisms underlying vascular damage are beginning to be characterized. There has been particular interest in the genetic mechanisms underlying the emergence of clonally expanded CD4+ CD28− T cells in patients with ExRA (86, 132). CD4+ CD28− cell levels appear to be stable over time, and the increased concordance of such clonal expansions in monozygotic twins indicate that they may be genetically controlled (133). CD4+ CD28− T cells lack the CD28-dependent costimulatory pathway and is characterized by high production of interferon-γ (134), cytotoxic capabilities, and expression of NK cell markers, including KIRs (135, 136). This unusual T-cell phenotype has also been implicated in coronary artery disease (137, 138) and Wegener's granulomatosis (139). A cytotoxic effect of these cells on endothelial cells has been demonstrated in vitro (140), and taken together, this indicates that they are likely to be a major pathogenetic factor in vascular disease.
KIRs are encoded in a polymorphic region on chromosome 19q. The expression of various KIR molecules has been shown to be highly variable (141). Triggering of some members of the KIR family has an inhibitory effect on NK cells and NK T cells, whereas others, such as the KIR2DS2, are stimulatory (142). In a recent study, KIR2DS2 molecules were found to be preferentially expressed on CD4+ CD28− cells, and the KIR2DS2 gene was significantly enriched among patients with rheumatoid vasculitis compared with other RA patients and healthy controls (92).
KIR molecules interact with MHC class I molecules (143), and the KIR2D subfamily has specificity for HLA–C. In the same study (92), Yen et al found an association between rheumatoid vasculitis and HLA–C*03, discussed above. Binding of KIR2DS2 to HLA–C*03-encoded molecules may be pathogenetically important, and this interaction could be influenced by HLA–C-bound peptides.
Treatment most likely affects the risk of ExRA, although this may be hard to sort out because treatment per se often is different in patients with a complicated disease course. Some manifestations may be more frequent in male patients (144, 145), suggesting that hormones or other sex-specific factors may be important. Smoking has been shown to predict severe ExRA (15, 146) and nodule formation (147). This may be due to immunomodulatory effects of smoking (148) or to endothelial damage that predisposes to vascular inflammatory disease. Infections and other exposure may also play a part in extraarticular disease, although data on such associations are lacking.
A model for genetic predisposition to extraarticular RA
T cells are important in the pathogenesis of RA and its extraarticular manifestations. This is reflected by the association between extraarticular RA and MHC class II genotypes, and by the emergence of abnormal T-cell clonotypes in such patients. Other genes specifically regulate interaction between T cells and endothelial cells, and vascular pathology in RA is further influenced by cytokine gene polymorphisms. Genes interact with treatment and other environmental exposures in determining the presence and extent of extraarticular involvement in RA. The relative contribution of each of these factors is variable for different ExRA disease manifestations, and probably also variable in populations of differing ethnic background (Table 4 & 5).
|Felty's syndrome||DRB1*0401-DQB1*0301 haplotype||(41, 72)|
|Vasculitis||KIR2DS2 and HLA–C*03||(95)|
|Cardiovascular comorbidity||IL-1β and IL-1 receptor antagonist||(120)|
|Rheumatoid lung disease||PiZ α1-antitrypsin deficiency allele||(127, 128)|
|Rheumatoid nodules||TNFa6–DRB1 shared epitope interaction||(43)|
|Secondary Sjogren's syndrome||DRB1*15||(66)|
|Renal involvement, including drug toxicity||DRB1*15||(67)|
|HLA–DR/DQ||Regulation of T-cell maturation|
|HLA–C||Activation of T cells and NK cells|
|KIR||Activation of T cells and NK cells|
|IL-1 family†||Endothelial activation and vascular damage|
|TNF enhancer/promoter region||Modification of TNF inducibility|
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