Ethnic variation in the clinical manifestations of rheumatoid arthritis: Role of HLA–DRB1 alleles

Objective

To assess the extent of ethnic variation in the clinical expression of rheumatoid arthritis (RA) and the role of HLA–DRB1 alleles in this variation.

Methods

We assessed consecutive RA patients for joint findings, subcutaneous nodules, laboratory and radiographic findings, and treatment. We typed HLA–DRB1 alleles to identify those that contain the shared epitope (SE). We adjusted ethnic comparisons for age and sex, and tested for ethnic heterogeneity in the effect of the SE.

Results

We studied 777 RA patients, 498 of whom were women (64%), 432 were Hispanic (56%), 272 were non‐Hispanic white (NHW; 35%), 53 were African American (AA; 7%), and 20 were Asian (3%). Compared with NHW, Hispanics had significantly more tender joints (17 versus 11), more swollen joints (8 versus 7), more frequent rheumatoid factor (RF) positivity (93% versus 84%), higher erythrocyte sedimentation rate (ESR; 45 versus 36 mm/hr), and a lower number of lifetime disease‐modifying antirheumatic drugs (1.9 versus 2.5). AA were older at onset (46 versus 44 years), had less frequent subcutaneous nodules (18% versus 28%), and higher ESR (42 versus 36 mm/hour) than did NHW. Hispanics and AA were more likely than NHW to be null for the SE (odds ratio [OR] = 4.59 for AA; and OR = 1.61 for Hispanics), and less likely to have 2 SE‐carrying alleles (OR = 0.59 for Hispanics and OR = 0.25 for AA). The number of SE copies was associated with subcutaneous nodules, ESR, RF, and radiographic changes. Ethnic heterogeneity in the effect of the SE was modest.

Conclusions

There is ethnic variation in the clinical expression of RA and in both the frequency and types of SE‐carrying HLA–DRB1 alleles. Some ethnic variation in clinical findings is associated with differences in SE frequency. However, we found that the effect of the SE on the clinical features of RA varies little between ethnic groups.

     

Occurrence of autoimmune diseases and autoantibodies in multicase rheumatoid arthritis families.

The presence of autoimmune diseases and autoantibodies has been studied in 237 individuals from 17 families with two or more members affected by rheumatoid arthritis (RA). Hyperthyroidism occurred significantly more frequently than in a local control population (p less than 0.05), but if the RA cases were excluded this significance was lost. Thyroid cytoplasmic and microsomal antibodies were significantly more common (p less than 0.001), and this remained true if RA sufferers were excluded (p less than 0.01). The prevalence of both clinical thyroid disease and circulating thyroid autoantibodies was similar in the families where RA was associated with HLA-DR4 and in those where no DR4 association was observed. RA and immune thyroid disease may, therefore, share a common inherited factor, but this is unlikely to be at the HLA-DR locus. Antinuclear factor (ANF) was found in association with RA and with HLA-DR3 within the RA group (p less than 0.02). Relatives of RA sufferers did not show any excess of ANF positivity. The prevalence of pernicious anaemia (PA) and gastric parietal cell antibody did not differ from the expected.     

Hla–drb1 alleles in polymyalgia rheumatica,giant cell arteritis,and rheumatoid arthritis

Objective. Immunogenetic analysis has demonstrated that giant cell arteritis (GCA) and rheumatoid arthritis (RA) are associated with 2 different domains of the HLA–DR4 molecule. The present study was undertaken to evaluate whether polymyalgia rheumatica (PMR) immunogenetically resembles GCA or RA and to determine whether expression of HLA-DRB1 alleles can be used to detect heterogeneity among PMR patients. Methods. Forty-six patients with PMR, 52 with GCA, 122 with seropositive RA, and 72 normal individuals were genotyped for HLA-DRB1 alleles by allele-specific amplification and subsequent oligonucleotide hybridization. Results. The HLA-DRB1^*04 allele was the most frequent among PMR patients (67%). While the expression of allelic variants of the HLA-DR4 family was restricted to HLA-DRB1^*0401 and ^*0404/8 in RA patients, all HLA–DRB1^*04 alleles, including B1^*0402 and B1^*0403, were represented in the PMR group. The distribution of HLA–DRB1 alleles among HLA–DRB1^*04 negative patients was similar in those with PMR and those with GCA, and could be distinguished from that in RA patients. In particular, HLA–DRB1^*01 alleles, which were found in most HLA–DRB1^*04 negative RA patients, were underrepresented in patients with PMR and GCA. Conclusion. The distribution of HLA–DRB1 alleles in PMR resembles that found in GCA. PMR and GCA share the associated sequence polymorphism encoded by the second hypervariable region (HVR) of the HLA–DRB1 gene. The HLA–DRB1 association of PMR and GCA can be distinguished from that of RA, which is linked to a sequence motif in the third HVR of DRB1 alleles. The differential role of distinct domains on HLA-DR molecules suggests that multiple biologic functions are regulated by these molecules and that they contribute differently to disease mechanisms. The similarities in the distribution of HLA–DRB1 alleles in PMR and GCA indicates that HLA–DRB1 alleles are not predictive for progression of PMR to the vasculitic lesions that are pathognomonic for GCA.     

HLA risk alleles and gut microbiome in ankylosing spondylitis and rheumatoid arthritis

Human leukocyte antigen (HLA) alleles are associated with a variety of autoimmune diseases. The composition of gut microbiome can be influenced by host immunity, which is partially regulated by HLA. In this review, first we provide evidence from animal and human studies on: if and how HLA-B27, HLA-DRB1 (shared epitope (SE)), and other HLA alleles alter the gut microbiome, then we analyzed the data for several hypotheses to explain the mechanism(s) of HLA alleles influences on gut microbiome, and finally, we discussed several potential clinical implications of HLA alleles and microbial data, such as bacterial biomarkers for diagnosis, treatment, and the screening of high-risk population.     

The DERAA HLA–DR alleles in patients with early polyarthritis: Protection against severe disease and lack of association with rheumatoid arthritis autoantibodies

Objective

To define the association of alleles encoding the HLA–DR rheumatoid arthritis (RA) protective epitope (DERAA) with the presence of RA‐associated antibodies at study inclusion and with severe outcome in patients with early polyarthritis (EPA).

Methods

Consecutive EPA patients (n = 210) were evaluated early (mean of 4.8 months after diagnosis) and prospectively (for 30 months). HLA class II typing was performed by polymerase chain reaction using sequence‐specific primers, and HLA–DR alleles DERAA, RA‐associated shared epitope (SE), and non‐SE/non‐DERAA (neither SE nor DERAA) were identified. RA‐associated antibodies identified were anti‐Sa/citrullinated vimentin, anti–cyclic citrullinated peptide 2, and IgM rheumatoid factor. Severe disease was defined according to a preset threshold of joint destruction and/or functional limitation.

Results

DERAA and SE alleles were present in 62 and 110 of the 210 EPA patients, respectively. At 30 months, severe disease was present in 78 patients (37%). In contrast to SE alleles, DERAA alleles were not associated with the production of RA‐associated antibodies, but were strongly protective against severe disease at 30 months (odds ratio 0.30, P < 0.001). DERAA alleles emerged as a strong, independent protective marker on multivariate analysis. The protective effect of DERAA was seen only in patients who did not already have erosions at study inclusion, was independent of the presence of antibodies, but was not associated with spontaneous remission.

Conclusion

In our EPA cohort, the presence of a DERAA sequence was a strong independent predictor of a better prognosis, but only in the absence of erosive disease that was already present at inclusion. Identification of DERAA alleles may help in managing the large subgroup of EPA patients who do not have erosions at baseline.

     

Porphyromonas gingivalis and disease‐related autoantibodies in individuals at increased risk of rheumatoid arthritis

Objective

To examine the relationship of Porphyromonas gingivalis to the presence of autoantibodies in individuals at risk of rheumatoid arthritis (RA).

Methods

Study participants included the following: 1) a cohort enriched in subjects with HLA–DR4 and 2) subjects at risk of RA by virtue of having a first‐degree relative with RA. None of the study subjects satisfied the American College of Rheumatology 1987 classification criteria for RA. Autoantibodies measured included anti–citrullinated protein antibody (ACPA; by second‐generation anti–cyclic citrullinated peptide antibody enzyme‐linked immunosorbent assay [ELISA]) and rheumatoid factor (RF; by nephelometry or ELISA for IgA, IgM, or IgG isotype). Individuals were considered autoantibody positive (n = 113) if they had ≥1 RA‐related autoantibody; individuals were further categorized as high risk (n = 38) if they had ACPA or positive findings ≥2 assays for RF. Autoantibody‐negative individuals (n = 171) served as a comparator group. Antibody to P gingivalis, P intermedia, and F nucleatum were measured. Associations of bacterial antibodies with group status were examined using logistic regression.

Results

Anti–P gingivalis concentrations were higher in high‐risk (P = 0.011) and autoantibody positive group (P = 0.010) than in the autoantibody negative group. There were no group differences in anti–P intermedia or anti–F nucleatum concentrations. After multivariable adjustment, anti–P gingivalis concentrations (but not anti–P intermedia or anti–F nucleatum) were significantly associated with autoantibody‐positive and high‐risk status (P < 0.05).

Conclusion

Immunity to P gingivalis, but not P intermedia or F nucleatum, is significantly associated with the presence of RA‐related autoantibodies in individuals at risk of RA. These results support the hypothesis that infection with P gingivalis may play a central role in the early loss of tolerance to self antigens that occurs in the pathogenesis of RA.

     

Gene–environment interaction between the DRB1 shared epitope and smoking in the risk of anti–citrullinated protein antibody–positive rheumatoid arthritis: All alleles are important

Objective

An interaction effect for developing rheumatoid arthritis (RA) was previously observed between HLA–DRB1 shared epitope (SE) alleles and smoking. We aimed to further investigate this interaction between distinct SE alleles and smoking regarding the risk of developing RA with and without anti–citrullinated protein antibodies (ACPAs).

Methods

We used data regarding smoking habits and HLA–DRB1 genotypes from 1,319 patients and 943 controls from the Epidemiological Investigation of Rheumatoid Arthritis, in which 972 patients and 488 controls were SE positive. Subsequently, 759 patients and 328 controls were subtyped for specific alleles within the DRB1*04 group. Odds ratios with 95% confidence intervals (95% CIs) were calculated by means of logistic regression. Interaction was evaluated by calculating attributable proportion due to interaction, with 95% CIs.

Results

A strong interaction between smoking and SE alleles in the development of ACPA‐positive RA was observed for all DRB1*04 SE alleles taken as a group (relative risk [RR] 8.7 [95% CI 5.7–13.1]) and for the *0401 and *0404 alleles (RR 8.9 [95% CI 5.8–13.5]) and the *01 and *10 alleles (RR 4.9 [95% CI 3.0–7.8]) as specific, separate groups, with similar strength of interaction for the different groups (attributable proportion due to interaction 0.4 [95% CI 0.2–0.6], 0.5 [95% CI 0.3–0.7], and 0.6 [95% CI 0.4–0.8], respectively).

Conclusion

There is a statistically significant interaction between distinct DRB1 SE alleles and smoking in the development of ACPA‐positive RA. Interaction occurs with the *04 group as well as the *01/*10 group, demonstrating that regardless of fine specificity, all SE alleles strongly interact with smoking in conferring an increased risk of ACPA‐positive RA.

     

Influence of shared epitope–negative HLA–DRB1 alleles on genetic susceptibility to rheumatoid arthritis

Objective

Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE‐negative HLA–DRB1 alleles influence the development of RA. This study examined the influence of SE‐negative HLA–DR alleles (DRB1*X) on the development of RA in 3 different French populations.

Methods

HLA–DRB1 alleles were defined by polymerase chain reaction with sequence‐specific oligonucleotide hybridization or sequence‐specific primers. SE‐negative alleles were classified according to the electric charge of their P4 pocket. HLA–DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA–DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p.

Results

Among the SE‐negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single‐dose SE–positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients.

Conclusion

The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.

     

Clinical features, autoantibodies and HLA-DR antigens in rheumatoid arthritis

HLA-DR4 was associated with seropositive but not seronegative disease in 105 Caucasians with rheumatoid arthritis (RA). There were no clinical or radiological differences between DR4 positive and negative RA groups, although 7 of 8 patients with early disease onset (less than 30 yr) were DR4 positive. High rheumatoid factor (RF) titers were more frequent in DR4 negative RA. A plot of the frequency distribution of RF titers in DR4 negative disease showed a bimodal distribution with seronegative and high titer groups. HLA-DR3 was not associated with high RF titers but was associated with high titers of antinuclear antibodies.     

Opposing effects of HLA–DRB1*13 alleles on the risk of developing anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

Objective

The effect of non–shared epitope HLA–DRB1 alleles on rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate the effects of several HLA–DRB1 alleles, independent of the shared epitope, on the risk of developing anti–citrullinated protein antibody (ACPA)–positive or ACPA‐negative RA in a large case–control study.

Methods

HLA typing for the DRB1 gene was performed in 1,352 patients with RA and 922 controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated.

Results

DRB1*13 was found to protect against ACPA‐positive RA when stratifying for the shared epitope and using a dominant genetic model (RR 0.41 [95% CI 0.26–0.64]). Furthermore, DRB1*13 neutralized the effect of the shared epitope in ACPA‐positive RA (RR 3.91 [95% CI 3.04–5.02] in patients who had the shared epitope but not DRB1*13, and RR 1.22 [95% CI 0.81–1.83] in patients with both the shared epitope and DRB1*13, as compared with patients negative for both the shared epitope and DRB1*13). However, we did not replicate the previous published risk of ACPA‐negative RA conferred by DRB1*03 when a dominant genetic model was used (RR 1.29 [95% CI 0.91–1.82]). Similarly, no significant effect of DRB1*03 on RR for ACPA‐negative RA was seen using the recessive genetic model (RR 1.18 [95% CI 0.6–2.4]). In contrast, the combination of DRB1*03 and DRB1*13 was significantly associated with increased risk of developing ACPA‐negative RA (RR 2.07 [95% CI 1.17–3.67]).

Conclusion

Our findings indicate that the DRB1*13 allele plays a dual role in the development of RA, by protecting against ACPA‐positive RA but, in combination with DRB1*03, increasing the risk of ACPA‐negative RA.

     

Physician ability to assess rheumatoid arthritis disease activity using an electronic medical record–based disease activity calculator

Objective

To assess physicians' concordance with Disease Activity Score in 28 joints (DAS28) categories calculated by an electronic medical record (EMR)–embedded disease activity calculator, as well as attitudes toward this application.

Methods

Fifteen rheumatologists used the EMR‐embedded disease activity calculator to predict a rheumatoid arthritis (RA) DAS28 disease activity category at the time of each clinical encounter.

Results

Physician‐predicted DAS28 disease activity categories ranged from high (>5.1, 15% of cohort, 66 of 429 patient visits) to moderate (>3.2–5.1, 21% of cohort, 90 of 429 patient visits) to low (2.6–3.2, 29% of cohort, 123 of 429 patient visits) to remission (<2.6, 35% of cohort, 150 of 429 patient visits). Overall concordance between calculated DAS28 results and physician‐predicted RA disease activity was 64%. Using either the physician‐predicted or the calculated DAS28 category as the gold standard, accuracy was greatest for patients in remission (75% and 88% accuracy, respectively) and those with high disease activity (68% and 79% accuracy, respectively), and less for patients with moderate (48% and 62% accuracy, respectively) or low disease activity (62% and 31% accuracy, respectively).

Conclusion

Accurate physician prediction of DAS28 remission and high disease activity categories, even without immediate availability of the erythrocyte sedimentation rate or the C‐reactive protein level at the time of the visit, may be used to guide quantitatively driven outpatient RA management. This article was published online on March 30, 2009. An error was subsequently identified in Figure 4. This notice is included in the online and print versions to indicate that both have been corrected.     

Infliximab,but not etanercept,induces IgM anti–double‐stranded DNA autoantibodies as main antinuclear reactivity: Biologic and clinical implications in autoimmune arthritis

Objective

To analyze the clinical and biologic correlates of autoantibody induction during longer‐term tumor necrosis factor α (TNFα) blockade with either the monoclonal antibody infliximab or the soluble receptor etanercept.

Methods

Thirty‐four patients with spondylarthropathy (SpA) and 59 patients with rheumatoid arthritis (RA) were treated with infliximab for 2 years. Additionally, 20 patients with SpA were treated with etanercept for 1 year. Sera were blindly analyzed for antinuclear antibodies (ANAs), anti–double‐stranded DNA (anti‐dsDNA) antibodies, anti–extractable nuclear antigen (anti‐ENA) antibodies, and antihistone, antinucleosome, and anticardiolipin antibodies (aCL). The anti‐dsDNA antibodies were isotyped.

Results

High numbers of infliximab‐treated patients with SpA or RA had newly induced ANAs (61.8% and 40.7%, respectively) and anti‐dsDNA antibodies (70.6% and 49.2%, respectively) after 1 year, but no further increase between year 1 and year 2 was observed. In contrast, induction of ANAs and anti‐dsDNA antibodies was observed only occasionally in the etanercept‐treated patients with SpA (10% of patients each). Isotyping revealed almost exclusively IgM or IgM/IgA anti‐dsDNA antibodies, which disappeared upon interruption of treatment. Neither infliximab nor etanercept induced other lupus‐related reactivities such as anti‐ENA antibodies, antihistone antibodies, or antinucleosome antibodies, and no clinically relevant lupus‐like symptoms were observed. Similarly, infliximab but not etanercept selectively increased IgM but not IgG aCL titers.

Conclusion

The prominent ANA and anti‐dsDNA autoantibody response is not a pure class effect of TNFα blockers, is largely restricted to short‐term IgM responses, and is not associated with other serologic or clinical signs of lupus. Similar findings with aCL suggest that modulation of humoral immunity may be a more general feature of infliximab treatment.

     

Associations of HLA-DR 4, DR 2, DRw 9 with clinical findings in rheumatoid arthritis

HLA-DR antigens were determined in 128 patients with classical or definite rheumatoid arthritis (RA) according to American Rheumatism Association criteria (1957). HLA-DR 4 was significantly (p less than 0.01) increased in patients with RA (60%) compared with Japanese control (40%). In radiological changes, the frequency of stage II to IV were significantly greater in DR 4 positive patients (87.1% (67/77)) than in negative patients (70.6%) (36/51)). An early onset of disease was significantly (p less than 0.05) associated with DR 4 positive patients with duration of 4 years or more. Erythrocyte sedimentation rate was significantly (p less than 0.05) less in DR 2 positive patients (8.0% +/- 8.6 (39)) than DR 2 negative patients (12.2 +/- 11.9 (84)). Frequency of Sjogren's syndrome was more in DR 2 positive patients (41.3% (12/29)) than in DR 2 negative (29.2% (19/65)), and less in DR 4 positive (25.4% (15/59)) than in DR 4 negative (45.7% (16/35)), so the complication of Sjogren's syndrome showed a trend against the severity of RA. There were no associations between rheumatoid factor and HLA-DR phenotypes, but the frequency of anti-nuclear anti-nuclear antibody was significantly (p less than 0.01) lower in DRw 9 positive patients (38.4% (15/39)) than in DRw 9 negative (62.7% (54/86)). In both DR 4 and DRw 9 positive patients (16 cases), onset of disease (38.9 years-old +/- 15.9 (16)) was significantly earlier and frequency of Sjogren's syndrome (10.0% (1/10)) was significantly lower than those in DR 4 negative patients (48.5 years-old +/- 12.5 (51): 45.7% (15/35) respectively). The frequency of HLA-DRw 9 was greater in Japanese than people in the other countries and there was the close association between pathogenesis of RA and HLA-DRw 9 as well as DR 4 and DR 2 in Japan.     

New classification of HLA–DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility

Objective

The shared epitope hypothesis was formulated to explain the involvement of HLA–DRB1 in rheumatoid arthritis (RA). However, several studies, which considered only the HLA–DRB1 alleles shown to be associated with RA risk, rejected this hypothesis. In this report, we propose that a different classification of HLA–DRB1 alleles be considered, based on the amino acid sequence at position 70–74.

Methods

The fit of both HLA–DRB1 classifications was tested in 2 groups of RA patients. All subjects were recruited through the European Consortium on Rheumatoid Arthritis Families, and included 100 patients with isolated RA and 132 patients with at least 1 affected sibling.

Results

The new classification produced risk estimates that fit all of the observed data, i.e., the distribution of the HLA–DRB1 genotype in the 2 patient groups, and the distribution of parental alleles shared by affected sibpairs. The risk of developing RA under this new classification depends on whether the RAA sequence occupies position 72–74 but is modulated by the amino acid at position 71 (K confers the highest risk, R an intermediate risk, A and E a lower risk) and by the amino acid at position 70 (Q or R confers a higher risk than D).

Conclusion

A new classification based on amino acid sequence allows us to show that the shared epitope RAA sequence at position 72–74 explains the data, with the risk of developing RA modulated by the amino acids at positions 70 and 71.