An independent role of protective HLA class II alleles in rheumatoid arthritis severity and susceptibility

OBJECTIVE: To prospectively investigate the effect of the DERAA-encoding HLA alleles on disease susceptibility and severity in a large cohort of patients with rheumatoid arthritis (RA), and to differentiate protective effects from non-predisposition by comparing subgroups of patients with an equal amount of predisposition alleles. METHODS: HLA class II alleles were determined in 440 patients with early RA and in 423 healthy controls. In order to study the effect of HLA on disease severity, radiographic joint destruction was evaluated, using the modified Sharp/van der Heijde method, during 4 years of followup. RESULTS: The presence of DERAA-encoding HLA-DRB1 alleles conferred a lower risk of developing RA for both the presence and absence of SE alleles (odds ratio 0.6). At all time points, radiographic destruction was significantly less severe in DERAA-positive patients with 1 SE allele compared with DERAA-negative patients with 1 SE allele. Additionally, a protective effect of DERAA was detected in the groups of patients who were prone to having more severe disease because of the presence of anti-cyclic citrullinated peptide antibodies or because of smoking. CONCLUSION: DERAA-encoding HLA-DRB1 alleles independently protect against RA and are associated with less severe disease.     

Evidence for a protective role of the human leukocyte antigen class II region in early rheumatoid arthritis

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.     

Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity

Methods: Cross sectional analysis of a cohort of patients with RA randomly selected from the clinical databases of 34 centres. Standard definitions and measurements were used, and radiographs read centrally. Estimates and confidence intervals were adjusted to sampling. Results: Data were available for 788 patients. Extra-articular RA was present in 285 (36.2%) patients. Cumulative prevalence and 95% confidence intervals of extra-articular manifestations were estimated: nodules 24.5% (21.5 to 27.5), Sjögren''s syndrome 17.0% (14.4 to 19.6), atlantoaxial subluxation 12.1% (9.8 to 14.4), carpal tunnel syndrome 10.7% (7.8 to 13.6), interstitial lung disease 3.7% (2.4 to 5.0), serositis 2.5% (1.4 to 3.5), eye disease 2.5% (1.1 to 3.9), vasculitis 1.3% (0.5 to 2.1), amyloidosis 0.6% (0.1 to 1.2), and Felty''s syndrome 0.3% (<0.6). Mean (SD) activity/progression indexes were: DAS28-3 3.4 (1.2), HAQ 1.6 (0.4), Larsen score 54.7 (26.4). Less than 5% of the patients were in remission. 205 (72%) patients were receiving disease modifying antirheumatic drugs (DMARDs). Conclusion: Spanish patients with RA ever seen by a rheumatologist have, on average, a moderate degree of activity, despite widespread use of DMARDs. Measures of the degree of progression do not show a benign disease. The proportion of extra-articular manifestations in Spanish patients with RA is similar to that found in other Mediterranean populations, and lower than that reported in Anglo Saxon countries.     

Cloning of the HLA class II region in yeast artificial chromosomes.

Yeast artificial chromosomes (YACs) have been applied to clone the entire class II region of the human major histocompatibility complex (MHC), including its flanking regions, in a contig over 1.5 million base pairs (bp) long. The human DNA inserts in the YACs have a size between 60 and 1300 kbp and were isolated from two EcoRI partial digest libraries. The gaps between DRA and DRB, DRB and DQA, and DOB and DPA, which had not been cloned by other means, have been bridged with YAC clones. The contig extends through the 400 kpb of DNA between the DRA and C4 genes, thus linking the class II region with the complement gene cluster in the class III region. The cloning in YACs has been supported by a conventional cosmid walk of 290 kbp in the C4-DRA region. Restriction enzyme sites in the YAC clones were compared to the sites in the cosmid walk, to published cosmid clones, and to the already existing physical maps, leading to a detailed characterization of a region of the human genome over 1500 kbp. The YAC clones will be valuable for functional analysis of the MHC.     

HLA class I and class II antigens associated with multiple myeloma in southern Africa

While the exact aetiology of myeloma is unknown, genetic factors feature among the potential risk factors. The HLA phenotypes in African blacks with myeloma (the commonest haematopoietic malignancy in this group) have not been characterized. The purpose of this study was to determine the HLA class I and class II phenotypes of patients with multiple myeloma and to compare the findings to an ethnically matched control group of 100 individuals. Analysis of the HLA class I and class II phenotypes in 62 myeloma patients revealed: (i) a corresponding statistically significant association with HLA B18 [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.013-39.727; P < 0.005]; (ii) no statistically significant association with HLA B13, Cw2, Cw6 or the DR and DQ antigens; and (iii) a statistically significant negative (protective) association with HLA Cw7 (OR 0.4; 95% CI 0.21-0.87; P < 0.005). This study suggests that although genetic factors may play a role in the multifactorial aetiology of multiple myeloma, with the exception of HLA B18, there is no specific association between HLA types and multiple myeloma in South African blacks.     

Rheumatoid arthritis: Evolving recognition of a common disease

Rheumatoid arthritis (RA) is a highly prevalent autoimmune disease and the most common form of autoimmune inflammatory arthritis. Studies of RA pathogenesis have contributed significantly to understanding the basis for complex immune-mediated disease, identified key steps in the development of autoimmune activation and joint damage in RA, and led to the development of targeted therapies that opened up the era biologic therapy. Current studies are linking differences in gene expression to abnormalities in cellular function that will help optimize therapy for individual patients and advance the goal of personalized medicine. Our evolving understanding and current important issues in RA are highlighted.     

Gold induced nephropathy in rheumatoid arthritis and HLA class II genes.

OBJECTIVES--To elucidate the role of HLA-DRB, -DQA, and -DQB genes in patients with rheumatoid arthritis (RA) who developed gold induced nephropathy. METHODS--Southern blot analysis of HLA-DRB, -DQA, and -DQB genes was performed on DNA from 27 patients with RA with gold induced nephropathy, 37 patients with RA who were treated with gold but did not develop nephropathy, and 122 ethnically matched normal subjects. RESULTS--The 4.7 kb DQA1/Taq I band associated with DQA1*0501 and DR3 and DR5 was found in 16 (59%) patients with gold induced nephropathy compared with five (14%) patients without gold induced nephropathy. CONCLUSION--It is concluded that HLA-DQA region genes may be an important susceptibility factor for the development of gold induced nephropathy in patients with RA.     

Rheumatoid arthritis: a disease associated with accelerated atherogenesis

OBJECTIVES: Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with an increased prevalence of coronary heart disease and a high cardiovascular (CV) mortality. In this article, a review of mechanisms implicated in the development of accelerated atherogenesis in RA was performed. The potential role of treatment to reduce the incidence of CV events in RA was also discussed. METHODS: Retrospective review of the literature. The potential mechanisms implicated in the development of accelerated atherogenesis in RA, information on carotid ultrasonography, and the potential implication of treatment to prevent accelerated atherogenesis in individuals with RA were examined. RESULTS: Endothelial dysfunction, which is an early step in the development of atherosclerosis, has been observed in patients with RA. Deleterious effects resulting from persistent chronic inflammation may lead to endothelial dysfunction, insulin resistance, and a dyslipidemic pattern in these patients. Other mechanisms different from those related to classic atherogenesis risk factors, such as hyperhomocysteinemia and increased oxidative stress, are considered to be implicated in the pathogenesis of atherosclerosis in RA. Increased carotid intima-media thickness and carotid plaques have been found in RA patients compared with matched controls. Active MTX treatment of the disease has been associated with decreased CV mortality. Additional drugs such as statins may be considered in the management of these patients. CONCLUSIONS: The increased prevalence of CV mortality rate in RA cannot only be explained by the presence of traditional atherosclerotic risk factors. A chronic inflammatory response may promote the development of accelerated atherogenesis in these patients. Active treatment of the disease is required to reduce the risk of developing CV complications in individuals with RA.     

HLA class II gene frequencies in Crohn's disease: a population based analysis in Germany.

BACKGROUND--Ulcerative colitis is the only known inflammatory bowel disease associated with particular HLA alleles. Whereas the association with the HLA-DRB1*15 allele has been described in several independent studies for ulcerative colitis, no contribution of HLA alleles to susceptibility in Crohn''s disease has yet been shown. AIM--This study was designed to study the strength of association of HLA class II alleles as risk markers for Crohn''s disease in a homogenous population in Germany. PATIENTS--A total of 4251 randomly selected control subjects, and 162 unrelated subjects with Crohn''s disease were studied. Subjects were studied for their HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles. METHOD--HLA DNA typing was performed after locus specific amplification with the polymerase chain reaction and reverse dot blot hybridisation. RESULTS--The HLA-DRB1*07 was the only HLA class II allele found to be significantly associated with Crohn''s disease (relative risk (RR) = 1.9, 95% CI: 1.66 to 2.14; p = 0.0001). This association remained significant after correction for the number of DRB1 alleles compared. In patients with disease onset before 35 years the RR for the disease in HLA-DRB1*07 positive subjects was found to be higher (RR = 3.1, 95% CI: 2.44 to 3.76). The HLA-DRB1*03 was significantly decreased in frequency in Crohn''s disease (RR = 0.5, 95% CI: 0.39 to 0.61; p = 0.0028). CONCLUSION--The HLA-DRB1*07 allele provides risk for the disease especially in patients with younger ages of onset. These data also provide indirect evidence for an immunogenetically based heterogeneity of the disease.     

HLA and Behçet's disease in Northern Spain: Their lack of correlation with arthritis pattern

Summary We have studied the characteristics of arthritis present in 32 patients with Behçet's disease (BD), and how this arthritis is related to the HLA markers class I. 84% of the patients presented arthritis, the most common being monoarthritis as the initial presentation, and oligoarthritis in subsequent episodes. In 63% of the cases, the development was in episodes of acute/subacute arthritis. We found statistically significant association between antigens B-5 and B-51, and the group with BD, with a relative risk of 3.89 and 4.71 respectively. The attempt to relate markers B-5, B-51 and B-27 to the presence of arthritis as well as to its manifestation and further development was not conclusive.     

HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region

Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common to the HLA-DR beta chains of several RA-associated haplotypes. We have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR beta chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals (P less than 0.0001). Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR beta molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.     

Rheumatoid arthritis in a patient with sickle cell disease

Sickle cell disease has various articular manifestations. Coexistent rheumatoid arthritis (RA) and sickle cell disease has been reported rarely. We present a patient with sickle cell disease and seropositive erosive RA demonstrating characteristic radiographic findings of the 2 entities.     

Rheumatoid arthritis and cardiovascular disease: the role of systemic inflammation and evolving strategies of prevention

PURPOSE OF REVIEW: The incidence and mortality of cardiovascular disease are increased in the context of rheumatoid arthritis. The purpose of this review is to examine our evolving understanding of the pathogenesis of cardiovascular disease in rheumatoid arthritis and to underscore the importance of tailored prevention of cardiovascular disease in this select population. RECENT FINDINGS: Recent reports have highlighted the shared pathobiology of cardiovascular disease and rheumatoid arthritis, both of which represent inflammatory disorders. Several reports have also provided much-needed insight into the deleterious impact that select therapies (including cyclo-oxygenase-2-specific inhibitors) may have in terms of the risk of cardiovascular disease in rheumatoid arthritis. Although further study is warranted, preliminary investigations also suggest that aggressive anti-inflammatory therapy, including the adjunctive use of statins, may play important cardioprotective roles in rheumatoid arthritis. SUMMARY: The pathogenesis of cardiovascular disease in rheumatoid arthritis is complex and involves several intermediate factors, including dyslipidemia, elevations in serum homocysteine, impaired insulin sensitivity, and endothelial dysfunction. Given the burden of cardiovascular disease in this population, it is important that health care providers caring for rheumatoid arthritis patients adopt a treatment course that is both comprehensive and individualized to address specific risk factors for cardiovascular disease.     

Linkage disequilibrium between HLA class II region and autoimmune hepatitis in pediatric patients

BACKGROUND/AIMS: Susceptibility HLA class II alleles associated with autoimmune hepatitis (AIH) were only described in case-control studies. METHODS: The transmission/disequilibrium test was used in 50 simplex families with AIH, to determine if affected offspring received the disease-associated allele more frequently than its alternate. HLA-DRB1 and DQB1 allele genotyping and autoimmune regulator (AIRE) polymorphisms located in exons 6, 8 and 10 were investigated by PCR-based methods. RESULTS: HLA-DRB1*03 allele was significantly transmitted from heterozygous parent to affected offspring (81.5%) with type 1 AIH compared to random expected frequency (50.0%; P=0.004) or to unaffected offspring (42.8%; P=0.03). HLA-DRB1*1301 allele showed an excess transmission to affected children (100%) than expected frequency (P<0.0001) or unaffected offspring (P=0.001). The transmission of DQB1*201 or DQB1*0603 alleles showed significant deviation in patients compared to random frequencies: (84.8%; P<0.0001 for DQB1*0201 or 100%; P<0.0001 for DQB1*0603). HLA-DQB1*0201 showed a strong association with type 2 AIH in children (100.0%, P=0.0005). CONCLUSIONS: HLA-DRB1 gene is the major genetic determinant in HLA class II region for children with type 1 AIH. Type 2 AIH is associated with the HLA-DQB1gene. Finally, AIRE gene abnormality does not contribute to the development of isolated AIH.