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Objective: The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies)., Methods: High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method., Results: Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001)., Conclusion: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.

Objective: The presence of certain HLA class II antigens is strongly associated with the progression of joint destruction in rheumatoid arthritis (RA). Such antigens may be more effective than other class II antigens in inducing the formation of autoreactive T cells after presentation of (auto)antigens. We investigated whether early and aggressive treatment with disease-modifying antirheumatic drugs could modify this relationship., Methods: We analyzed data from 2 studies of patients with early RA treated according to different strategies. The first study consisted of 2 cohorts, one (n = 109; median disease duration before treatment 4 months) was treated according to the pyramid strategy (initial nonsteroidal antiinflammatory drugs, followed by chloroquine [CQ] or sulfasalazine [SSZ] when necessary), and the other (n = 97; median disease duration before treatment 2 weeks) was immediately treated with CQ or SSZ. The second study comprised 155 patients (median disease duration 4 months) from the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial, in which patients were randomly assigned to combination treatment with step-down prednisolone, methotrexate (MTX), and SSZ (n = 76) or with SSZ alone (n = 79). Prednisolone and MTX dosages were tapered and stopped after 28 and 40 weeks, respectively. The extent of joint damage was measured by the modified Sharp method., Results: In the pyramid treatment cohort, the median increase in Sharp score after 2 years was 12 in patients positive for the shared epitope (SE) and 1 in SE- patients. In the immediate treatment cohort, the median increase was 3 in SE+ patients and 2 in SE- patients. In the SSZ group of the COBRA study, the median increase in Sharp score after 1 year was 11 in DR4+ patients and 3 in DR4- patients. In the combination treatment group, the median increase was 4 in DR4+ patients and 2 in DR4- patients. Significance was confirmed by multiple regression using log-transformed scores., Conclusion: Early and aggressive antirheumatic drug treatment affects the association of HLA class II alleles with progression of joint damage in RA.

Background: Several studies have reported an association between the presence of the shared epitope (SE) and susceptibility to rheumatoid arthritis (RA). Recent studies have shown that certain HLA-DRB1 alleles in combination with predisposing DQB1 and DQA1 alleles may protect against the development of RA. This model is known as the rheumatoid arthritis protection (RAP) hypothesis., Objective: To determine the distribution of HLA-DRB1 and DQB1/DQA1 alleles in a cohort of patients with RA in remission and to determine the association between these HLA alleles and the persistence of remission., Patients and Methods: HLA-DRB1 and DQB1 typings were performed in 167 patients with RA in remission, defined according to the American College of Rheumatology criteria. The disease course, as defined by the persistence of remission during a follow up of two years, was compared between subgroups. According to the RAP hypothesis patients were divided into three subgroups: patients carrying predisposing DQ alleles, patients carrying predisposing alleles in combination with protective alleles (DQ(RA+)/DERAA phenotype), and patients lacking the predisposing alleles. According to the SE hypothesis, patients were divided into three subgroups based on whether they were carrying two, one, or no predisposing alleles (SE alleles)., Results: Predisposing DQ alleles along with a DERAA-bearing allele were present in 14 (8%) of the 167 patients. At least one SE allele was present in 116 (69%) patients; 34 of them (20%) were carrying two copies. The disease course was not significantly different between the subgroups according to the SE and RAP hypothesis, respectively., Conclusion: The frequency of DQ(RA+)/DERAA combinations and of SE alleles in patients with RA clinically in remission was similar to that found in other RA populations. Persistent remission of RA was not associated with any particular HLA subtypes, indicating that HLA typing is not useful for predicting persistent clinical remission.

Our aim was to examine, using microsatellite (ms) markers, the contribution of the telomeric part of the HLA region to rheumatoid arthritis (RA) predisposition in the Spanish population. We have looked at the distribution of DQB1, DRBI and five ms loci (D6S1014, D6S273, D6STNFa, MIB and C1-2-5) within the HLA region in 147 Spanish RA patients and 202 control subjects. A total of 19 conserved ms configurations were observed, twelve of them in linkage disequilibrium with particular DQB1-DRB1 haplotypes. Interestingly, haplotype c1 (DQB1*0201-DRB1*0301-D6S1014*143-D6S273*139-D6STNFa*99-MIB*350-C1-2-5*196) was significantly associated with RA predisposition. As part of this haplotype, the MIB*350 allele was found to be a risk factor independently of the RA-predisposing haplotypes. The present results along with data from others prove the existence of a second predisposing locus located inside the MHC region, and suggest that might be located within the TNFa-HLA-B region.

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1*0501/DQA1*01 (DQ5) and DQB1*03/DQA1*03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1*03/DQA1*03 (or DRB1*04) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, p = 0.004). These results demonstrate a protective role of (70)DERAA(74)-positive DRB1 alleles against disease severity among RA patients.

Objective: To evaluate the contributions of HLA-DQ and -DR polymorphisms to susceptibility to rheumatoid arthritis (RA) in a population in southern Spain, and to compare the value of the shared epitope (SE) and RA protection (RAP) models in accounting for the HLA class II region's contribution to RA predisposition., Methods: One hundred sixty RA patients and 153 healthy controls were typed for HLA-DRB1 and -DQB1 using high-resolution DNA techniques. Distributions of predisposing DRB1 alleles in patients and control subjects according to the SE model were compared with distributions of predisposing DQ and protective DERAA-positive DRBI alleles according to the RAP model., Results: DQ3 (DQBI*03 and *04 combined with DQA1*03) and DQ5 (DQB1*0501/DQA1*0101) alleles predisposed individuals to RA independently of SE-positive DRB1 alleles. DQ3/3-homozygous individuals had the strongest risk of developing RA. DQ3 molecules predisposed to RA more than did DQ5 molecules. The weaker predisposition mediated by DQ5 included the DRB1*1001-carrying haplotype; no DRB1*1001-homozygous patients were observed. DRBI*0401 played a unique role in the contribution of DQ3-DR4 haplotypes to RA, in spite of its low frequency in southern Spain., Conclusion: The low prevalences of RA and of mild disease observed in Spain, and in southern Europe in general, can be explained in great part by the low frequency of DQ3-DR4 haplotypes, especially those carrying DRB1*0401. However, the overall distribution of HLA-DQ and -DR alleles in RA patients compared with control subjects is similar to that in other European and North American populations. A model involving both DQ and DR can best account for the contribution of HLA to RA.

Objective: To analyse the distribution of predisposing DQ3 (DQB1*03(*04)/DQA1*03) and DQ5 (DQB1*0501/DQA1*01), shared epitope encoding and protective DRB1 alleles in patients with early rheumatoid arthritis (RA) and undifferentiated arthritis (UA)., Methods: Consecutive patients enrolled in an early arthritis clinic were DNA-typed for HLA-DQ and DR. RA patients (n=195), UA patients (n=160) and controls from the same region (n=306) were sorted according to their DQ-DR phenotypes: DQ3 vs DQ5 and the presence or absence of a protective DERAA-positive DRB1 molecule. The three groups were also sorted according to the shared epitope (SE) hypothesis., Results: We observed the association of both DQ3 and DQ5 with RA. DQ3/3 homozygous individuals had the highest risk of developing disease [odds ratio (OR)=20.00]. Conversely DQ5, but not DQ3, was associated with undifferentiated arthritis (OR=2.15 vs 1.25). Consistent with these differences, DQ3-positive individuals had significantly more active disease at the first visit at the outpatient clinic than DQ5-positive patients. DRB1 alleles encoding a DERAA motif in their third hypervariable region provided a strong dominant protection against RA among DQ5-positive individuals and decreased arthritis activity among DQ3-positive patients. Individuals with SE-positive DR1, DR4 and DR10 alleles were also predisposed to RA, DR4/4 homozygous individuals having the highest risk of developing RA (OR=11.00)., Conclusion: The DQ3-DR4/9 haplotypes are associated with RA. The DQ5-DR1/10 haplotypes are associated with less active disease, i.e. UA, and DERAA encoding DRB1 alleles modulate either predisposition to or the severity of RA. We propose that HLA polymorphism influences not only the initiation or perpetuation of RA but also protection against the disease.

We have evaluated the possible contribution of genes besides DQ and DR to the association of HLA with rheumatoid arthritis (RA). To this end, we have looked at the allele distributions of six microsatellites, D6S1014, D6S2673, TNFalpha, MIB, C1-2-5, and C1-3-2 among 132 RA patients and 254 controls. We have defined 19 microsatellite clusters corresponding to previously described ancestral haplotypes. One of them was D6S1014*143-D6S273*139-TNFalpha*99-MIB*350-C1-2-5*196-C1-3-2*354, often found associated with DQB1*0201-DRB1*0301. As part of this microsatellite cluster, the allele MIB*350 was found to be a RA-predisposing factor, independent of DRB1*0301 and RA-predisposing haplotypes DQB1*03-DRB1*04 and DQB1*0501-DRB1*01. We conclude that the telomeric part of the HLA region contains a locus conferring predisposition to RA independently of HLA class II.

We have reviewed the literature on the association of HLA class II with rheumatoid arthritis (RA). Strong linkage disequilibrium among DQB1, DQA1 and DRB1 alleles makes it difficult to evaluate the individual contribution of each locus. Nonetheless, there is a strong case for the role of DQB1*03 and *04 combined with DQA1*03 in susceptibility to severe RA while DQB1*0501 combined with DQA1*0101 and *0104 weakly predisposes to a mild form of RA. However, it is also clear that DRB1*0401 has a particular role in predisposition to the most severe form of the disease while other DRB1 alleles might provide protection. We would like to propose that in RA, as in type I diabetes, both DQ and DR loci contribute to predisposition to the disease.

Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.

We have recently proposed a new hypothesis to explain the association of Human Leukocyte Antigen (HLA) with rheumatoid arthritis (RA) predisposition. In this model, which challenges the Shared Epitope (SE) hypothesis, HLA-DQ predisposes while HLA-DR protects. In the present study, we have compared these two models in an Early Arthritis Clinic started in 1993 in the Department of Rheumatology at the Leiden University Medical Centre. Out of 524 patients who enrolled this programme in the period 1993-1998 and completed the one year follow-up, 155 have been classified as RA. These patients along with 306 consecutive cadaveric renal organ donors have been typed for HLA-DR and -DQ. The distributions of predisposing DR alleles according to SE, and predisposing DQ and protective DR according to our model were analysed. We found that two doses of predisposing DQ alleles strongly predisposed to RA, even in individuals with a single dose of SE while DRB1 alleles carrying the motif DERAA confered a dominant protection in DQ5-positive individuals. We conclude that the present findings are consistent with our previously described model of HLA and RA association. Using this new model, we have been able to characterise two novel groups of individuals on the basis of their HLA typing: one strongly predisposed to RA and one protected. Knowing the mechanism of HLA-related dominant natural protection may help in designing novel treatment modalities for RA.

In the present study, we tested our hypothesis on the role of a DQ-DR haplotype in rheumatoid arthritis (RA) predisposition. Using two groups of patients and controls, one from The Netherlands and one from Switzerland, we found that DQA1*0301-homozygous and DQA1*0301//DQA1*0101/04-heterozygous individuals are highly predisposed to RA in both populations, while DQA1*0101/04-homozygous are not. The DQA1*0301-DRB1*0403/06/07 and DQA1*0301-DRB1*0901 haplotypes are not associated with RA by themselves but strongly increase the risk of developing disease in DQA1*0301- and DQA1*0101/04-heterozygous. DRB1 alleles carrying the motif DERAA in their third hypervariable region, i.e., *0103, *0402, *1102, *1103, *1301, and *1302, provide a long-lasting protection against RA in DQA1*0101/04- but not in DQA1*0301-positive individuals. These data show that considering both DQ and DR gives a better distinction between patients and controls than the shared epitope hypothesis.

Recently, we have proposed that the combination of HLA-DQ and -DR alleles is responsible for the association of the HLA class II region with rheumatoid arthritis (RA). According to this model, some HLA-DQ alleles, namely DQ4, DQ7, DQ8, and DQ9, predispose carriers to severe RA, but a self peptide of sequence KDILEDERAAVDTYC from the third hypervariable (HV3) region of some DRB1 alleles, including DRB1*0402, can protect from the disease if presented by DQ molecules. This model implies that DQ4, DQ7, DQ8, and DQ9 should be able to present a set of common peptides, despite polymorphisms in their Ag binding groove. In the present study, we have further analyzed the immunogenicity of the DRB1*0402 HV3 peptide in DQ8-transgenic mice. We found that the motif DERAA guarantees DQ8-restricted immunogenicity, and that R is the main anchor residue for binding of the DRB1*0402 peptide to DQ. Interestingly, the p1 pocket that probably controls binding of the R residue is identical in all four RA-associated DQ molecules. Our results imply that the association of RA with some DR subtypes can be explained by their linkage with DQ alleles displaying a binding site for similar "arthritogenic" peptides.

The major histocompatibility complex class II genes play an important role in the genetic predisposition to many autoimmune diseases. In the case of rheumatoid arthritis (RA), the human leukocyte antigen (HLA)-DRB1 locus has been implicated in the disease predisposition. The "shared epitope" hypothesis predicts that similar motifs within the third hypervariable (HV3) regions of some HLA-DRB1 alleles are responsible for the class II-associated predisposition to RA. Using a line of transgenic mice expressing the DQB1*0302/DQA1*0301 (DQ8) genes in the absence of endogenous mouse class II molecules, we have analyzed the antigenicity of peptides covering the HV3 regions of RA-associated and nonassociated DRB1 molecules. Our results show that a correlation exists between proliferative response to peptides derived from the HV3 regions of DRB1 chains and nonassociation of the corresponding alleles with RA predisposition. While HV3 peptides derived from nonassociated DRB1 molecules are highly immunogenic in DQ8 transgenic mice, all the HV3 peptides derived from RA-associated DRB1 alleles fail to induce a DQ8-restricted T-cell response. These data suggest that the role of the "shared epitope" in RA predisposition may be through the shaping of the T-cell repertoire.

Extensive studies in different ethnic groups have associated the susceptibility to development of rheumatoid arthritis (RA) with the third hypervariable region of the major histocompatibility complex (MHC) HLA-DR beta 1 molecule. On the basis of recent findings in the experimental mouse model of collagen-induced arthritis, Eric Zanelli, Miguel Gonzalez-Gay and Chella David propose that the HLA-DRB1 locus is associated with protection to RA and that the actual arthritogenic peptide-presenting molecule is HLA-DQ. Thus, the development of RA would depend upon the expression of the susceptible DQ allele and the nonprotective DRB1 alleles, along with environmental factors that trigger the autoimmune process.