HLA antigens and seronegative rheumatoid arthritis.

HLA antigens and clinical features in a series of 46 Caucasian patients (40 females, 6 males) and definite repeatedly seronegative rheumatoid arthritis (RA) of more than two years' duration (mean 11.6 years) were compared with those in 77 seropositive RA patients and 110 controls of the same ethnic and geographic origin. Seronegative RA appeared to be less often erosive than seropositive RA, and seronegative patients had fewer extra-articular features. The frequency of the HLA antigen DR1 was raised in seronegative patients as compared with controls (p = 0.006, relative risk = 3) and with seropositive patients (p less than 0.05). HLA-DR4 was slightly increased in seronegative patients compared with controls (p less than 0.05) but was clearly less so than in seropositive patients (p less than 0.005). Early onset of disease was very significantly associated with HLA-DR1 in seronegative patients (p = 0.007), whereas HLA-DR4 was present more frequently in seropositive patients with onset prior to age 35 (p less than 0.05). No correlation between HLA antigens and intolerance to drugs was found in seronegative patients, whereas in seropositive patients side effects to gold salts were associated with DR3. These results suggest that seropositive and seronegative RA have distinct HLA-DR associations, especially in disease of early onset, in addition to well established clinical differences.     

HLA-DR versus HLA-B5-CREG antigens in rheumatoid arthritis (RA)

Thirty caucasian patients suffering from classic erosive rheumatoid arthritis (RA), with a condition persisting for more than 8 years, were examined together with 67 healthy control subjects with regard to associations to HLA-DR and HLA-B-CREG antigens (B5-, B8-, B12-, B16- and B27-CREG). We found a significant correlation of seropositive RA (SPRA) with HLA-DR4 (9/14 patients = 64% chi 2 = 11.8, p less than 0.05), and seronegative RA (SNRA) with B5-CREG antigens (14/16 patients = 88%, chi 2 = 7.8, p less than 0.05). This HLA locus-differing association of SPRA and SNRA could, in addition to the known differences in clinicophenomenological parameters, be additional proof of the independent entity of these two forms of illness.     

Lack of influence of non-inherited maternal HLA-DR alleles on susceptibility to rheumatoid arthritis.

OBJECTIVE--To reproduce findings from previous reports that non-inherited maternal HLA class II antigens might contribute to rheumatoid arthritis (RA) susceptibility in the offspring. METHODS--Families were recruited from the Arthritis and Rheumatism Council's National Repository of RA families and HLA-DRB1 alleles were examined in these individuals and their first degree relatives using DNA typing methods. RESULTS--There was no evidence of an increase in either non-inherited maternal HLA-DR4 or the HLA-DRB1 shared epitope as a whole compared with the frequency expected using the non-inherited paternal antigens as controls. CONCLUSIONS--The numbers of probands who were shared epitope negative were small, but we are unable to confirm in these families the findings that non-inherited maternal HLA contributes an additional susceptibility factor to rheumatoid arthritis.     

Epidemiological study of HLA and GM in rheumatoid arthritis and related symptoms in an open Dutch population.

This report deals with the question of whether or not the established association of HLA-DR4 with rheumatoid arthritis (RA) can also be detected in cases of RA as diagnosed in a population survey. For this purpose 6584 persons older than 19 years living in a single community in The Netherlands were investigated for the presence of rheumatoid arthritis and related abnormalities. After five years 83 patients with RA, 30 with only erosive abnormalities on radiological examination (Rad), and 48 with only rheumatoid factor (RF) were reinvestigated and typed for HLA and allotypes of immunoglobulin G heavy chain (GM). On the classification of the initial survey no significant association of HLA-DR4 or GM could be detected in any of the three categories. When the information of the follow-up investigation was taken into account, a reappraisal of the classification resulted in 53 cases with RA, 18 with Rad only, and 35 with RF only. The frequencies of HLA-DR4 and GM in the three categories were also about the same as those in normal controls. However, an increase in the frequency of HLA-DR4 was observed in cases of RA positive for Rad, RF, or both. We found no evidence for an interaction between HLA-DR4 and GM. Our results suggest that rheumatoid arthritis is a heterogeneous disorder, only a fraction of which is associated with HLA-DR4. At present no single determinant of RA such as Rad or RF can characterise the HLA-DR4-associated, and most probably more severe, type of RA.     

Immunogenetic differences between patients with familial and non-familial rheumatoid arthritis

OBJECTIVE: To search for possible immunogenetic differencies between the patients with familial and non-familial rheumatoid arthritis (RA). METHODS: The study compared 129 familial RA patients with 217 non-familial patients for the frequencies of HLA-DR antigens including DR4 subtypes, DR4-DQB1*0301 and DR4-DQB1*0302 haplotypes and HLA-B27 antigen as well as the age of disease onset and existence of rheumatoid factor or joint erosions. RESULTS: Two major differences between familial and non-familial groups were found: firstly, familial RA patients had increased frequency of HLA-DR4 as compared with the non-familial RA group (68.2 v. 54.8%; p = 0.019). Secondly, the mean age at onset of RA was significantly lower in the familial than in the sporadic RA patients (42.0 v. 46.5 years; p = 0.0020) and the difference still remained when the DR4 positive and negative subgroups were compared separately. CONCLUSION: These results confirm the more prominent association with HLA-DR4 in familial than in the non-familial cases and suggest that accumulation of HLA risk genes may, at least partly, explain the familial occurrence of the disease. Other susceptibility genes may also be concentrated in multiplex case families as suggested by an earlier age at the onset of RA in both HLA-DR4 positive and negative familial patients.     

Seronegative rheumatoid arthritis: a clinical study with HLA typing

We examined both clinically and by determining HLA-A, -B, -C and -DR antigens 50 patients thought to have seronegative erosive polyarticular rheumatoid arthritis (RA) in Finland and the USSR. All the patients fulfilled at least 4 of the 1987 ARA criteria for RA. According to HLA typing and clinical findings, of which a part was collected by followup, the patients fell into 5 groups: HLA-B27 related diseases, putative psoriatic arthritis, putative juvenile chronic polyarthritis, and seropositive and seronegative RA. Our results indicate that most of the patients with seronegative RA had some other disease. In the remaining cases the presence of rheumatoid factors had not been examined adequately, especially at the early phase of disease. The classification of erosive seronegative polyarticular patients is discussed.     

HLA and disease manifestations in rheumatoid arthritis--a Canadian experience

Forty-eight Canadian patients with rheumatoid arthritis (RA) were tissue typed for class 1 (HLA-A, B, and C) and class 2 (HLA-DR and DQ) antigens in an attempt to identify HLA associations and to relate them to disease manifestations and drug toxicity. HLA-DR4 was found with a significantly higher frequency among patients with RA than in the control population. DR4 correlated with presence of rheumatoid nodules and pulmonary manifestations, and was more frequent among patients who had vasculitis. All 4 patients who died were DR4 positive. DR2 and DR7 were less frequent in our patients. There was no association between the presence of DR3 or DR4 and drug toxicity.     

HLA DR antigens in rheumatoid arthritis

The prevalence and possible prognostic significance of HLA-DR antigens have been studied in 129 patients with seropositive (RF-positive) classical rheumatoid arthritis (RA). HLA-DR4 was increased in RA, whilst HLA-DR2 was decreased, though it was not associated with either low titres of RF or with good prognosis. HLA-DR3-positive patients had the highest prevalence of antibodies to nuclear antigens, and the antigen correlated negatively to the presence of subcutaneous nodules, bony erosions and familial RA. RA patients possessing DR3 thus had some of the characteristics of SLE. HLA-DR5 was not present in male RA patients. An absence of familial RA was observed among DRw8-positive patients.     

A DR4-associated DR-DQ haplotype is significantly associated with rheumatoid arthritis

Forty-three patients with seropositive, erosive rheumatoid arthritis (RA) and 24 members of 5 RA multicase families were studied for HLA class II gene polymorphism, using restriction fragment analysis with complementary DNA probes for DR beta and DQ beta chains. This method generates HLA-DR-DQ haplotypes that are highly correlated with HLA-DR serology. Thirty-five of the 43 RA patients (81%) were positive for one or for both of the DR4-associated DR-DQ haplotypes, 4.1 and 4.2. Among these patients, the 4.1 haplotype was found significantly more often than in DR4+ controls (P less than 0.01). The haplotype segment C3;B15;DR4 was present in all RA patients in 4 of the 5 families, and included the DR-DQ4.1 haplotype.     

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.     

Noninherited maternal antigens do not play a role in rheumatoid arthritis susceptibility in Europe. European Consortium on Rheumatoid Arthritis Families

OBJECTIVE: It has been proposed that noninherited maternal antigens (NIMA) (HLA-DR antigens) might play a role in susceptibility to rheumatoid arthritis (RA), especially in patients who are not genetically predisposed, such as those who are HLA-DR4 and/or shared epitope (SE) negative. The present study was undertaken to test the NIMA hypothesis in a large cohort of European RA patients assembled by the European Consortium on RA Families (ECRAF). METHODS: HLA-DRB1 oligotyping was performed in families of European RA patients for whom both parents were alive. These families were consecutively recruited by the ECRAF between 1996 and 1998, for association studies. The frequencies of HLA-DR NIMA were compared with those of the noninherited paternal antigens (NIPA) after stratification for HLA-DR*04, *0401 and/or *0404, and SE status. NIMA or NIPA that coincided with inherited HLA-DR antigens were considered redundant and excluded from analysis. Calculations concerning the whole group and restricted to patients lacking parental RA were performed. RESULTS: One hundred seventy families from France (n = 81), Belgium (n = 23), Spain (n = 24), Italy (n = 19), Portugal (n = 14), and The Netherlands (n = 9) were oligotyped. The group of probands was predominantly female (88%), positive for rheumatoid factor, DR*04, and SE (71%, 58%, and 75%, respectively), and had erosive disease (75%). Parental RA was reported in 21 families. Using the NIPA as control, the frequency of HLA-DRB1*04, *0401 and/or *0404-, or SE-positive NIMA was not found to be increased in patients lacking these susceptibility alleles. The same was true when the 21 probands with parental RA were excluded from analysis. In DRB1*04-positive patients, we found no evidence of a relevant effect of HLA-DR3 or DR6 in the NIMA. CONCLUSION: Our results do not support the notion that noninherited maternal antigens have a role in susceptibility to RA in the offspring.     

HLA and rheumatoid arthritis: a combined analysis of 440 British patients.

Four hundred and forty unrelated British Caucasoid patients with rheumatoid arthritis (RA) have been HLA typed for class I and class II antigens. Analyses of HLA antigen associations were performed on the overall group and in patient subsets selected according to particular disease parameters or sex, or both. The results confirm previously reported positive associations of HLA-DR4, Dw4, and DRw53 and negative associations of HLA-DR2 and DR7 with RA. Patients subsets with severe erosions, seropositivity, and features of extra-articular disease showed a stronger association, also confirming earlier reports. The link between HLA and disease severity was emphasised by a significant trend of increased Dw4 frequency with increasing severity of radiological erosions. In addition, a positive association of RA with HLA-A2 was observed and a strong negative association with DR3. The frequency of HLA-B27 was significantly increased in patients with subluxation of the spine. Differences were observed between male and female patients in relation to the HLA association. In men an increase in the frequency of the haplotype HLA/Dw4/DR4/Bw62/Cw3/A2 was observed. This showed no relationship with parameters of disease severity other than extra-articular disease. In women only class II antigens (DRw53/Dw4/DR4) showed an increased frequency. This increase was strongly associated with disease severity. A significant decrease of this class II association was observed with increasing age of disease onset; this was not seen in men.     

HLA associations with rheumatoid arthritis in African blacks

The HLA-A, B, C and DR antigens were determined in a group of 100 blacks with classical or definite rheumatoid arthritis (RA) in Durban, South Africa. Fifty-six of these patients were also tested for the DQ antigens. There was a significant association of HLA-DR4 with RA (chi 2 = 77.2; p less than 0.0001). The frequency of DR4 in RA was 44% in comparison with 10% in controls (relative risk 7.4). An unusual finding was a significant increase in the frequency of HLA-B8 in 35% of patients with RA compared to 12.5% of controls (p less than 0.001; relative risk 3.8). There was no linkage disequilibrium between DR4 and B8 to explain the latter association.     

HLA DR4 and B27 antigens in familial and sporadic rheumatoid arthritis

We studied HLA antigens in 105 unrelated American Caucasian patients with rheumatoid arthritis (RA), 70 of them with familial disease. HLA-DR4 was observed in 71% of familial RA, 63% of non-familial RA, and 27% of normal controls, confirming the already well-established association between HLA-DR4 and both familial and non-familial RA. HLA-B27 was present in 14.3% of patients, versus 8% of normal controls (p = 0.04), and was not more common in familial (10 of 70, or 14.3%) versus non-familial (5 of 35, or 14.3%) disease. These results are compared with those observed in Scandinavian patients.     

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.     

Association of immunomodulators and HLA antigens in rheumatoid arthritis

We studied the association between HLA antigens and clinical response to immunomodulators or the toxic effects of immunomodulators in 191 patients with rheumatoid arthritis (RA). All patients received nonsteroidal anti-inflammatory drugs. Fifty-seven patients were treated with auranofin, 61 patients with penicillamine and 45 patients with lobenzarit. We found that HLA-Cw 1 is significantly (p less than 0.05) associated with a substantial clinical response to auranofin in RA patients (65% vs 33% of Cw 1-negative patients). We observed that HLA-DR 4 is a risk factor for the occurrence of toxic reactions to penicillamine (45% vs 21% of DR 4-negative patients: p less than 0.05) and that HLA-DRw 9 is a risk factor in the case of lobenzarit (62% vs 32% of DRw 9-negative patients: p less than 0.05). HLA-A 24-positive patients with RA experienced a low frequency of side effects from auranofin (16% vs 37% of A 24-negative patients: p less than 0.05). HLA-A 2 or Cw 7-positive patients with RA experienced a low frequency of side effects from penicillamine (12% vs 49% of A 2-negative patients: p less than 0.01, 17% vs 46% of Cw 7-negative patients: p less than 0.05). Our data demonstrated that HLA antigens are significantly associated with a clinical response to immunomodulators and the toxic effects of immunomodulators in patients with RA.     

Antibodies to type II collagen and HLA disease susceptibility markers in rheumatoid arthritis

OBJECTIVE: To seek associations between antibodies to native and denatured type II collagen (NCII and DCII) and HLA in rheumatoid arthritis (RA). METHODS: One hundred fourteen patients with clinically well-defined RA were HLA-DR and DQ typed. Those who were DR4 positive were subtyped for DRB1*0401-*0408 alleles by polymerase chain reaction using allele-specific oligonucleotide probes. Antibodies to human NCII and DCII (heat-denatured) were measured by enzyme-linked immunosorbent assay. The frequency of HLA alleles was compared in patients grouped according to the presence and absence of antibodies to NCII and DCII. RESULTS: Twenty-seven patients (24%) were positive for antibodies to NCII. There was a significant increase in the frequency of HLA-DR7 in anti-NCII-positive patients compared with anti-NCII-negative patients (30% versus 9%; P = 0.019) and a significant decrease in HLA-DR3 (7% versus 28%; P = 0.044). Repeating the analyses after excluding the 16 patients who were DR7 positive revealed a significant increase in the frequency of HLA-DR1 in anti-NCII-positive patients compared with anti-NCII-negative patients (63% versus 27%; P = 0.045). Moreover, antibodies to NCII were associated with the third hypervariability region susceptibility sequence QRRAA that is present in DRB1*0101, *0404, *0405, and *0408 (84% versus 47%; P = 0.0085); 24 of 27 anti-NCII-positive patients were positive for either DR7, DR1, or DRB1*0404 or *0408. Thirty patients (26%) were positive for antibodies to DCII. There was a significant increase in the frequency of HLA-DR3 in anti-DCII-positive patients compared with anti-DCII-negative patients (40% versus 18%; P = 0.028). CONCLUSION: The genetic associations between HLA-DR alleles and antibodies to CII in RA patients is in keeping with the collagen-induced arthritis model and implicates autoimmunity to CII as a major component in the multifactorial pathogenesis of RA.     

Longterm followup of treatment with D-penicillamine for rheumatoid arthritis: effectivity and toxicity in relation to HLA antigens

To assess therapeutic effect and toxicity of D-penicillamine in relation to HLA antigens, 111 consecutive patients with rheumatoid arthritis (RA) were followed for a period of 7-9 years. Side effects occurred in 60% and were the main reason for withdrawal in 52%. HLA typing was performed in 86; overall frequencies were comparable with those found in other studies in patients with RA. Drug induced proteinuria (5 patients) was associated with HLA-B8/DR3 (60 vs 9%), and thrombocytopenia (23 patients) with HLA-DR4 (94 vs 67%). Therapeutic effect was good in 26 (23%), and moderate in 30 (27%). No single variable, including HLA antigens, was predictive of effectiveness. It is concluded that although some of the side effects were associated with HLA antigens, HLA typing is not useful in predicting the outcome of treatment with D-penicillamine.     

HLA antigens and toxic reactions to sodium aurothiomalate in patients with rheumatoid arthritis

HLA typing studies were performed on 60 consecutive patients with seropositive definite or classical rheumatoid arthritis (RA). Patients were treated with gold and were followed for a minimum of 18 months for identification of adverse reactions to gold therapy. HLA-DR3 was increased significantly in patients who developed gold induced rash, proteinuria or thrombocytopenia. On the other hand, the incidence of HLA-DR4 was lower in patients with these adverse reactions. Our results demonstrate that patients with RA carrying DR3 are at a higher risk of developing adverse reactions to gold. The most interesting finding was the low incidence of DR4 in patients who developed adverse reactions to gold, suggesting that DR4 positive patients may have some degree of protection against gold toxicity.     

HLA-antigens in patients with rheumatoid arthritis

109 patients with rheumatoid arthritis (RA) from the north of the GDR were HLA typed and the antigen frequencies compared with those of a control group. Even in our patients the HLA-DR4 association was demonstrable. But in all studies DR4 association is not strong enough for taking HLA typing as a diagnostic test for RA. There was an immunogenetic heterogeneity in correlation to side effects of therapy with sodium aurothiomalate or D-penicillamine. HLA-DR5 was significantly increased in patients with side effects in comparison to patients without side effects in therapy. Before recommending HLA-DR typing for selection of high risk patients in D-penicillamine therapy these results should be proven in a large patient group or in a second study.