HLA: linkage with rheumatoid arthritis or seropositivity

HLA haplotype sharing was compared in sibships from multicase families with rheumatoid arthritis (RA), subdivided by rheumatoid factor status, to investigate the claim that HLA is linked more to RA severity than susceptibility. Considerable deviation from expected (Mendelian) inheritance towards greater sharing of inherited parental haplotypes was observed in the sibships as a whole and when subdivided according to the serological status of the sibship's members. Further, there was no evidence that linkage was stronger in the seropositive concordant than in the other sibships. Linkage was also demonstrated between HLA and seropositivity even in sibships where not all members expressed clinical RA. These results, therefore, do not support the existence of genetic heterogeneity between seropositive and seronegative RA, a possibility previously suggested from population studies of antigen associations.     

Development of lupus-related side-effects in patients with early RA during sulphasalazine treatment-the role of IL-10 and HLA

OBJECTIVE: The development of systemic lupus erythematosus (SLE)-related syndromes during treatment with sulphasalazine has been described and demonstrated to be influenced by genetic factors. The prevalence of this drug-induced condition and the immunological mechanisms involved are less known. The aim of this study was to determine the prevalence of sulphasalazine-induced lupus-like reactions in a well-defined early rheumatoid arthritis (RA) cohort and to analyse the roles of HLA haplotypes, autoantibodies and the B-cell stimulating cytokine interleukin-10 (IL-10) as possible underlying risk factors. Patients and methods. Forty-one consecutive patients with early RA, in whom sulphasalazine was used as the first disease-modifying anti-rheumatic drug in single therapy and was maintained for at least 6 months, were investigated for the occurrence of lupus-related events. Longitudinal analyses of rheumatoid factor (RF), antinuclear antibodies (ANA), anti-double-stranded DNA antibodies and serum IL-10 (ELISA) and the typing of HLA DR and DQ alleles were performed. RESULTS: Four of the 41 patients developed lupus-like disease. Three of four patients who had lupus-related events vs four of 37 patients without side-effects had an HLA DR 0301 haplotype. The patients developing lupus-related side-effects had increased levels of serum IL-10 and a high frequency of ANA in speckled patterns before the onset of therapy. CONCLUSION: The development of SLE-like symptoms and SLE-related autoantibody production was observed more commonly than expected, with an increased risk in patients with SLE-related HLA haplotypes, increased serum IL-10 levels and ANA in speckled patterns. The data suggest that immunomodulation associated with sulphasalazine treatment may contribute to the development of lupus-related reactions in genetically predisposed individuals.     

HLA Class ii sequence polymorphisms and susceptibility to rheumatoid arthritis in greeks. the hla–drβ shared-epitope hypothesis accounts for the disease in only a minority of greek patients

Objective. In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA–DRβ found notably in the HLA–DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. Methods. We characterized HLA–DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. Results. DNA analysis in the RA patients showed that although individual HLA–DR allelic associations were weak, a relatively conserved HLA–DRβ motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA–DRβ1 of 43.5% of the RA patients versus 15.5% of the controls (unconnected P = 0.00004). Conclusion. Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA–DRβ motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.     

Coexisting rheumatoid arthritis and ankylosing spondylitis discussion of 3 cases with review of the literature

Summary Coexisting rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have rarely been reported. We aim to evaluate such association in our RA and AS hospitalized patients during the 5 past years. We selected 130 RA and 87 AS patients and found 3 genuine associations which are here reported, 3 AS patients with positive rheumatoid factors (RF) and 4 HLA B27 RA patients. HLA B27 frequency in our RA patients (6,6%) and positive RF in our AS patients (8,3%) does not differ from the HLA B27 or RF frequency in a control series of 172 osteoarthritis or fibromyalgia patients (respectively 8%-in the Caucasian-and 9,8% in this control series).Coexisting RA and AS is discussed with regard to these 3 cases; 44 similar cases are found in the literature and reviewed here. The mechanisms leading to this curious association are discussed. Besides these patients, the sacroiliac joint involvement in RA is also analyzed as well as the positivity of RF in AS. The low frequency of coexisting RA with AS suggests that these 2 conditions probably occur by chance. A similar explanation can certainly be advanced for positive RF in AS and HLA B27 in RA patients since the same frequency for B27 and RF has been observed in controls. Finally, these different case reports and unusual biological or roentgenographic features in RA or AS demonstrate the possibility of confusion between these two rheumatic conditions.     

Differences between female and male patients with familial rheumatoid arthritis

OBJECTIVE: To determine whether there are genetic differences between female and male patients with familial rheumatoid arthritis (RA). METHODS: 45 men and 119 women from 78 families with RA who all had at least one first degree relative with RA were compared. HLA-DRB1 alleles were analysed, including DRB1*04 subtypes and associations of DRB1*04 haplotypes with DQB1*0301 or DQB1*0302 alleles, the age of the patients at disease onset, the presence of rheumatoid factor (RF), joint erosions, and rheumatoid nodules. RESULTS: HLA-DRB1*13 allele (the subtype allele of DR6, reported to be protective against the development of RA) was found in 14/119 (12%) of female but in none of the male patients (p=0.036). The HLA-DR4 allele was found slightly more often in men than women patients with familial RA (31/45 (69%) v 75/119 (63%), NS). Men were also more often RF positive than women (44/45 (98%) v 98/117 (84%); p=0.031). On the other hand, the mean age at onset of RA was significantly lower in the female group (40.4 years) than in men (46.6 years, p=0.0044). CONCLUSION: The results indicate that there is stronger genetic background in familial male than female patients with RA in the genetic susceptibility defined by the studied HLA antigens. However, the earlier age of onset of the disease in female group and the increased proportion of women with RA indicate that there are additional sex related predisposing factors enhanced in familial cases.     

Gm allotypes and HLA in rheumatoid arthritis patients with circulating antibodies to native type II collagen.

HLA antigens and immunoglobulin heavy chain allotypes (Gm) were determined in 166 unrelated patients with rheumatoid arthritis (RA), 44 of whom had circulating antibodies to native type II collagen. Collagen antibody positive patients showed an association with HLA-DR3 and DR7 (68% compared with 39% of collagen antibody negative RA, p less than 0.005), and with the Gm phenotype, Gm(zafngb). This contrasted with the collagen antibody negative RA patients where there was an association with HLA-DR4 and, in DR4 positive disease only, with the Gm allotype, G1m(x). The Gm(zafngb) phenotype was found in 26% of DR3 or DR7 positive patients overall and only 9% of RA patients negative for these DR antigens (p less than 0.005), suggesting an interaction between HLA-DR3/7 and Gm(zafngb). The differing Gm associations for collagen antibody positive and negative RA provide further evidence for genetic heterogeneity in susceptibility to RA.     

Associations of HLA‐DRB1 alleles with anti‐citrullinated protein antibody‐positive and anti‐citrullinated protein antibody‐negative rheumatoid arthritis in northern east part of Turkey

Aim: The aim of this study was to investigate the associations between human leukocyte antigen (HLA)‐DRB1 alleles with genetic susceptibility to rheumatoid arthritis (RA) and production of antibodies against cyclic citrullinated peptide (anti‐CCP antibody) and rheumatoid factor (RF) in Turkish RA patients. Methods: We studied 291 RA patients and 253 controls. Genotyping was performed by polymerase chain reaction with sequence‐specific oligonucleotide probes hybridization method. Serum levels of anti‐CCP antibody, IgM‐RF and high sensitive C‐reactive protein titers were measured by commercial kits using immunological methods. Results: We found that HLA‐DRB1*04 and *09 alleles were associated in anti‐CCP+ and anti‐CCP+ RA patients (P < 0.0001 and P < 0.001, respectively), while DRB1*01 and *04 were determined to be higher in RF+ RA patients (P < 0.001 and P < 0.0001, respectively). Moreover, DRB1*11 and DRB1*13 alleles were determined to be lower in RF and anti‐CCP/RF+ RA patients (P < 0.001 for both). HLA‐DRB1*04 was identified as a common responsible allele for susceptibility to the disease in anti‐CCP, RF and anti‐CCP/RF? RA patients (P = 0.0018, P = 0.0004 and P = 0.0023, respectively). HLA‐DRB1*13 allele alone was found to be protective against to anti‐CCP+ and RF? RA (P = 0.0003 and P = 0.006, respectively). On the contrary, there was no protective allele in anti‐CCP/RF? RA as well as anti‐CCP? RA patients. Conclusion: This study indicates that associate and protective HLA‐DRB1 allele distributions are different in autoantibody (anti‐CCP or RF or anti‐CCP/RF)+ RA and autoantibody? RA patients, with exceptions of DRB1*04 and DRB1*13.     

Association of different HLA antigens with various toxic effects of gold salts in rheumatoid arthritis.

An association of gold induced proteinuria with HLA-D(R)3 has been reported. To investigate other possible relationships between gold toxicity and HLA antigens we studied 85 patients with rheumatoid arthritis (RA) divided into four subgroups: patients with gold induced interstitial pneumonitis, mucocutaneous lesions, proteinuria, and patients without gold toxicity. The HLA frequencies in patient groups and 283 healthy controls were compared in different pairwise combinations. Gold induced pneumonitis was associated with HLA-B40 and Dw1. An association between gold induced proteinuria and HLA-Dw3 was also seen. The increased prevalence of Dw4 in RA was observed only in the control patient group without gold induced side effects. The frequencies of HLA-B7 and Dw2 were decreased in all patient groups compared with the control population. These results further support the view of the heterogeneity of RA as manifested by the unique HLA associations with resistance and susceptibility to gold induced side effects characterising different subgroups.     

Concurrence of rheumatoid arthritis and systemic lupus erythematosus: report of 11 cases.

The concurrence of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) has been reported infrequently. Eleven patients are described here with both RA and SLE, in whom the diagnoses were separated by one to 24 years. Because of the difficulty in diagnosing RA occurring subsequent to SLE, only patients with classical RA as their initial diagnosis were included. Further difficulties arise because arthritis is common to both diseases and may be deforming in SLE, antinuclear antibodies (ANA) are not uncommon in RA, and rheumatoid factor (RF) may be seen in SLE. Nonetheless, judicious application of the American Rheumatism Association (ARA) criteria allows both diagnoses to be made in the individual patient. In our patients there was erosive arthritis in nine, rheumatoid nodules in five, and urinary abnormalities in 10. Serological evidence of RA and SLE with positive RF and ANA and raised DNA antibodies was universal, all patients had haematological evidence of SLE, and all but one decreased serum complement levels. These cases suggest that the concurrence of RA and SLE is not as rare as previously considered and may occur more often than expected by chance alone.     

Young age of onset is associated with increased prevalence of circulating IgM rheumatoid factor and antinuclear antibodies at presentation in women with rheumatoid arthritis

In 200 patients, 143 women and 57 men, with rheumatoid arthritis (RA), age at onset was related to the presence of IgM rheumatoid factor (RF) and antinuclear antibodies (ANA) in serum at presentation. The patients were stratified into bands of age at onset: <40 years, 40– 60 years, and >60 years. In women, the prevalences of ANA (1:160) were 63.0%, 45.5%, and 31.1% in the respective age bands (p=0.002), and the prevalences of IgM RF were 85.2%, 72.7% and 66.4%, respectively (p=0.03). The prevalences of ANA and IgM RF among men were, respectively, 35% and 86% with no association with age at onset. The findings may indicate interactive effects between gender and various pathogenetic factors.Abbreviations ANA Antinuclear antibodies - MBL Mannose-binding lectin - RA Rheumatoid arthritis - RF Rheumatoid factor     

Prevalence and clinical significance of antikeratin antibodies and other serological markers in Lithuanian patients with rheumatoid arthritis

OBJECTIVES: To assess the clinical value of several serological markers in Lithuanian patients with rheumatoid arthritis (RA) compared with control patients with rheumatic disease and age matched healthy controls. METHODS: Serum samples from 96 patients with RA of approximately 8 years' duration, 90 rheumatic disease controls, and 37 healthy subjects were tested. Antikeratin antibody (AKA), antineutrophil cytoplasmic antibody (ANCA), and antinuclear antibody (ANA) titres were estimated by indirect immunofluorescence (IIF) and serum samples positive for ANA and ANCA were further studied by enzyme linked immunosorbent assay (ELISA). IgA and IgM rheumatoid factors (RF) were measured by ELISA. RESULTS: A positive AKA test was highly specific for RA (diagnostic specificity 97%), being found in 44% of the patients. Although both RF tests had a higher sensitivity, they were less specific for RA. ANCA was detected in 33% of patients with RA but lacked diagnostic specificity. AKA and ANCA were associated with more erosive disease and the presence of extra-articular manifestations. Positivity for AKA, IgA RF, and ANCA was significantly associated with disease activity and worse functional capacity. However, in multiple regression analysis only positivity for AKA was significantly correlated with functional disability (p=0.0001), evaluated by the Steinbrocker functional classification, and no single marker had any relation with radiological damage. CONCLUSION: Although AKA showed the highest disease specificity, all serological markers studied except ANA exhibited interesting associations with important clinical and paraclinical parameters of RA.     

The genetic epidemiology of rheumatoid arthritis.

This review considers the epidemiological aspects of the genetic investigation of rheumatoid arthritis (RA). Problems both of disease definition and disease heterogeneity render studies difficult to undertake and interpret. The selection of individuals both in population and family studies can explain divergent results. Despite the insights into the immunopathogenesis of RA afforded by the demonstration of an association between the disease and HLA class II genes, the latter have only a limited role in explaining differences, both between individuals and between populations, in susceptibility to RA.     

HLA-DRB1 and HLA-DQB1 allele associations in an Albanian patient population with rheumatoid arthritis: correlations with the specific autoantibody markers and inter-population DRB1 allele frequency variability

The prevalence of rheumatoid arthritis and its specific autoantibodies varies in different populations. This variability depends on the genetic polymorphism of the immune response genes among which the HLA system plays a major role. In this context, we studied the HLA-DRB1 and HLA-DQB1 first-level allele frequencies in 100 Albanian patients with rheumatoid arthritis (RA), and taking into account their rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA) serologic subgroups, we compared them with the respective frequencies in a population of 191 Albanian individuals without known pathology. No differences were found between the controls and the RA patient group as a whole, but three statistically significant differences were found: an increase in DRB1*04 among ACPA+, RF+ and ACPA+/RF+ patients, a significant decrease in DRB1*11 among ACPA+/RF+ and also a decrease in DRB1*13 among RF+ patient subgroups. Comparing allele frequencies of putatively associated RA alleles in different European populations revealed a significant negative correlation between the RA predisposing DRB1*04 and protective DRB1*11 allele frequencies. A statistically significant correlation was also found between RA prevalence rates and DRB1*04 as well as DRB1*11 frequencies. The relatively low frequencies of DRB1*04 and high DRB1*11 in the Albanian population might explain the rather low positivity rate of ACPA and RF antibodies among the Albanian RA patients. These specific association patterns suggest that this first study of RA in an Albanian population should be followed up to include second level or higher definition of HLA alleles and to compare RA patterns among European populations.     

The genetics of rheumatic disease in man

This article reviews the current knowledge of genetic factors conferring susceptibility to several major rheumatic disorders, in particular, rheumatoid arthritis (RA), juvenile chronic arthritis (JCA), systemic lupus erythematosus (SLE), and Sj?gren's syndrome. Emphasis is given to major histocompatibility complex associations with these diseases, particularly rapidly evolving knowledge of class II HLA genes and disease-conferring "epitopes." Non-MHC-linked genes, such as T cell receptor and immunoglobulin genes, also may be involved.     

HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks. The HLA-DR beta shared-epitope hypothesis accounts for the disease in only a minority of Greek patients.

OBJECTIVE. In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. METHODS. We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. RESULTS. DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR beta 1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004). CONCLUSION. Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.     

Association between HLA-DR antigens and rheumatoid arthritis in Arabs.

Eighty five Arab patients with classical and definite rheumatoid arthritis were typed to determine the prevalence of HLA A, B, C, and DR antigens. A significant increase in the prevalence of HLA-A10, B8, B21, and DR3 was found in comparison with a control population matched for age and sex. HLA-DR5 was significantly decreased in the patient group. The classical association of HLA-DR4 with rheumatoid arthritis could not be confirmed in the Arab patients resident in Kuwait, supporting reported observations in different ethnic groups of associations with HLA antigens other than HLA-DR4 and indicating a heterogeneous genetic susceptibility to rheumatoid arthritis.     

Failure to find disease similarity in sibling pairs with rheumatoid arthritis.

Clinical and laboratory measures of disease expression were compared within and between 33 families with two or more affected siblings with rheumatoid arthritis (RA). None of the variables studied--age and calendar year of disease onset, pattern of joint involvement, the presence of rheumatoid nodules, Sjögren''s syndrome, a positive latex or antinuclear antibody (ANA) titre--showed a greater concordance within the families than between them. The families were then divided into those in which the affected sibling pairs were and were not HLA identical. Such a division did not alter the conclusion, with the possible exception of a positive latex titre. These results suggest that genetic or unique environmental factors within families may have only a limited role in explaining disease heterogeneity in RA. Conversely, the absence of homogeneity within the families justifies their use in genetic linkage studies and the extrapolation of results obtained from affected siblings to the commoner sporadic disease.     

A controlled study of ana+ rf- arthritis

Thirty (7.5%) of 401 adult rheumatoid arthritis (RA) patients were antinuclear antibody positive (ANA+) and rheumatoid factor negative (RF-), and 15 of 16 patients who were followed for a year or longer remained so. Clinical, other laboratory, and radiographic parameters were compared among this group and 90 matched RA controls divided into ANA+RF+, ANA-RF+, and ANA-RF- groups. All groups were identical, except the ANA-RF- group, which had significantly fewer nodules and less destructive disease than the other three.     

Rheumatoid factor,HLA–DR4, and allelic variants of DRB1 in women with recent-onset rheumatoid arthritis

Objective. To examine the relationship of rheumatoid factor (RF) to HLA–DR4 and alleles of DRB1 in women with recent-onset rheumatoid arthritis (RA). Methods. Incident cases of RA were identified as part of a prospective, population-based case–control study. HLA typing was completed for 246 cases meeting criteria for definite or classic RA. Results. One hundred thirty-six patients (55%) were positive for DR4, and 130 (53%) were RF positive. DR4 was found to be strongly associated with seropositivity (odds ratio 4.1, P < 0.0001). Patients with a shorter interval from RA onset to RF testing had a higher frequency of seropositivity than those with a longer interval (≤18 months 60%, >18 months 33%). Further analysis of patients who had RF testing within 18 months of RA onset showed that the frequency of seropositivity was significantly greater among DR4-positive patients who had the shared sequence stretch of DRβ1 associated with RA susceptibility (76% RF positive) than among DR1-positive patients who had this sequence (45% RF positive) (odds ratio 3.8, P = 0.01). Moreover, the frequency of seropositivity among DR1-positive patients with the sequence did not differ from that among all patients without the shared sequence (47%) (odds ratio 0.9, P = 0.8). Conclusion. HLA–DR4 is strongly associated with seropositivity in women with recent-onset RA. The amino acid sequence of DRβ1 that is associated with susceptibility to RA and is shared between DR4 and DR1 appears not to be the primary determinant of seropositivity in these women.     

Collagen antibodies in Ross River virus disease (epidemic polyarthritis)

Summary Antibody activity against collagen was measured in 53 samples of serum from 48 patients with active signs of epidemic polyarthritis (EPA) following infection with Ross River virus. Activity was higher against denatured collagen than against native collagen, but was within the normal range for each. Determination of HLA phenotypes permitted a search for any relationship between HLA type and differences in collagen antibody levels within the normal range. No relationship was detected with HLA antigens predominating in EPA or with HLA antigens that are associated with high collagen-antibody levels in rheumatoid arthritis (RA), which suggests that the latter associations may represent failure to control collagen antibody levels after the onset of RA. The findings also provide evidence against a role for nonspecific enhancement of humoral immune responses in the pathogenesis of EPA, and constitute a further point of distinction between EPA and RA.