Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF)

OBJECTIVE: It has been proposed that noninherited maternal HLA-DR antigens (NIMA) might play a role in the susceptibility for rheumatoid arthritis (RA). This hypothesis has not been thoroughly tested in patients with familial RA, in whom genetic factors, either inherited or not, might have stronger influence than in patients with sporadic RA. We investigated the NIMA hypothesis in a large cohort of European patients with familial RA. METHODS: The distribution of NIMA, noninherited paternal antigens (NIPA), and inherited HLA-DR antigens was assessed in patients with familial RA from all family sets collected from 1996 onwards by the ECRAF. HLA-DRB1 oligotyping from patients and all available nonaffected siblings and parents was carried out. Familial RA was defined by the presence of at least 2 affected first-degree relatives in the same family. The frequencies of HLA-DR NIMA and NIPA were compared using odds ratios after stratification for HLA-DR*04, *0401, and/or *0404 and shared epitope (SE) status. NIMA/NIPA that coincided with inherited parental HLA-DR antigens were considered redundant and were excluded from analysis. RESULTS: NIMA and NIPA could be analyzed in 165 RA patients with familial RA and 84 nonaffected siblings. Patients were predominantly female, rheumatoid factor positive, and had erosive disease (81, 75, and 84%, respectively). Possession of HLA-DR*04 and *0401/*0404 alleles tended be more frequent in patients than in nonaffected siblings but this did not reach statistical significance. SE possession was similar in patients and healthy siblings, although the former had a double dose SE more often (37.6 vs 17.8%; p = 0.002). Transmission of SE encoding alleles from parents to offspring was skewed only in patients [OR (95% CI) 3.56 (2.55-4.95) vs 1.16 (0.75-1.79) in nonaffected siblings]. Using the NIPA as control, the frequencies of HLA-DRB1*04, *0401/*0404, and SE positive NIMA were not increased in patients lacking these susceptibility alleles. The frequencies of NIMA encoding susceptibility alleles in DR*04 and *0401/*0404 negative patients were lower than in nonaffected siblings. CONCLUSION: Our results corroborate the association between RA and inherited SE alleles and do not support a role for noninherited HLA-DR maternal antigens in the susceptibility for familial RA.     

HLA antigens in palindromic rheumatism, nonerosive rheumatoid arthritis and classical rheumatoid arthritis

The frequency of HLA antigens has been investigated in patients with definite rheumatoid arthritis (RA) who lacked characteristic erosive radiographic changes that we called nonerosive rheumatoid arthritis ( NERA ). The frequency of HLA-DR4 in patients with NERA was significantly lower than that in classical, erosive RA. A normal frequency of HLA antigens was also found in patients with palindromic rheumatism (PR). Those of the PR patients who however, developed RA during followup, carried HLA-DR4. The patients with PR, NERA and RA who had familial RA demonstrated increased frequency of HLA-DR4.     

Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Results of a followup study

The association between HLA-DR antigens and rheumatoid arthritis (RA) was investigated in a well-characterized cohort of RA patients who were followed from the beginning of the disease (mean followup 6 years). The frequencies of HLA-DR antigens in patients with possible or probable RA (n = 49) were similar to those in controls. In patients with definite RA (n = 134), the frequencies of DR1, DR4, and DRw53 were increased, whereas the frequencies of DR2, DR3, DRw6, DRw13, and DRw52 were decreased, compared with controls. Comparison of HLA-DR frequencies in patients with definite RA subclassified according to the severity of the disease at the end of the followup period revealed a difference only in the frequency of DR4, which was increased in patients with progressive RA (59.2%) compared with those who had mild RA (34.8%). Further analysis showed that, compared with DR4-negative RA patients, DR4-positive patients had more swollen joints, higher scores on the Ritchie articular index, the Health Assessment Questionnaire, and the Steinbrocker functional classification, more radiologic abnormalities, and more use of second-line drugs. Also, the rate of progression of radiologic abnormalities, functional classification, and use of second-line drugs was higher in DR4-positive patients. We conclude that DR4 is associated with a more severe disease course, and is a prognostic marker in early RA.     

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.     

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.     

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 haplotypes in non-familial rheumatoid arthritis.

The frequencies of HLA-A, B, C, DR, and BF haplotypes in 44 unrelated Caucasian patients with definite seropositive rheumatoid arthritis (RA) were compared with haplotype frequencies in controls. Overall, the patients had an increased risk for HLA-DR4, DR3, and DR2 antigens, but frequencies of certain DR4 or DR3 haplotypes were not increased, suggesting the importance of other HLA loci for the evaluation of risk. The presence of DR4 alone was not found to produce an increased risk for RA since the frequencies of certain DR4 haplotypes were similar in patients and controls. Increased frequencies of HLA-B18, DR4, HLA-B15, DR4, and HLA-A1, B8, Cw7, DR3 haplotypes were found in patients. RA susceptibility has been found to be associated with the last two haplotypes in some studies of multiple case families, suggesting that similar genetic mechanisms may underlie the disease in familial and sporadic forms.     

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.     

HLA in Singapore Chinese with rheumatoid arthritis.

The HLA-A, B, C, DR and DQ antigens were determined in 50 Singapore Chinese patients with rheumatoid arthritis (RA). There was a significant increase in the prevalence of HLA-Bw46, DRw53 and DQ3 in patients with RA. The linkage disequilibrium between Bw46 and DRw53 explains this association. This major histocompatibility complex association differs from the HLA-DR4 link in Caucasian populations and suggests that RA is an immunogenetically heterogeneous disease.     

HLA-DR antigens and HLA-DQ beta chain polymorphism in susceptibility to rheumatoid arthritis.

Forty four patients with rheumatoid arthritis (RA) were studied for HLA-DR antigens and for HLA-DQ beta chain gene restriction fragment length polymorphism using DNA hybridisation. A significant increase in the prevalence of the DR4 antigen and a tendency towards an increase of DR1 was found in patients with RA. No allelic form of HLA-DQ restriction fragment length polymorphism patterns was increased, but the prevalence of an allele characterised by a combination of 7.5 and 3 kb fragments was decreased among patients with RA. The DQw8 subtype represented by a 12 kb fragment was the most common DR4 associated allele, and a 3.7 kb fragment related to DQw7 was found in only 5/25 (20%) DR4 positive patients and 2/12 (17%) controls. The results support the hypothesis that RA susceptibility factors are primarily located within HLA-DR genes but HLA-DQ genes may have a role in protection from the disease.     

Association of HLA-DR with susceptibility to and clinical expression of rheumatoid arthritis: re-evaluation by means of genomic tissue typing

The clinical expression of rheumatoid arthritis (RA) varies considerably among individual patients. Genetic variations in human leucocyte antigen (HLA) may influence clinical expression. We re- examined the association of HLA-DR with susceptibility to and clinical expression of RA using genomic tissue typing, since most studies were based on (less reliable) serological techniques. Seventy-eight patients with recent-onset RA, all participating in a clinical trial on therapeutic strategies, were HLA-DR typed by means of low-resolution genomic typing. Cumulative disease activity within the first 3 yr of disease was measured. Of the RA patients, 54% expressed DR4 (DR4+) vs 26% of healthy controls. Rheumatoid factor (RF)-positive patients had a higher cumulative disease activity than RF-negative patients. Patients who were either DR1+ or DR4+ had a higher cumulative disease activity than those who expressed neither DR1 nor DR4. This association was less obvious after correction for RF status. The association of DR52+ (DR3, 5, 6) and a lower cumulative disease activity could also not be demonstrated after correction for RF status. Among RF-negative patients, DR51+ (or DR2+) was associated with a higher cumulative disease activity. Other HLA-DR types (including DR1 and DR4 separately) were not associated with the severity of RA. DR4 was associated with susceptibility to RA in our patients; HLA-DR low-resolution genomic tissue typing did not yield additional information to RF status for the clinical identification of individual patients with a poor prognosis.      

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.     

A FAMILY STUDY OF THE PREVALENCE OF ANTIBODIES TO THE RHEUMATOID ARTHRITIS ASSOCIATED NUCLEAR ANTIGEN (RANA)

Sera from families with at least two members suffering fromseropositive rheumatoid arthritis (RA) were examined for theprevalence of antibodies to the RA associated nuclear antigen(RANA). It was found that consanguineous relatives of patientshad a significantly increased prevalence of anti-RANA antibodiescompared to sera from a control group of families. Anti-RANAantibodies were also significantly more prevalent in the seraof familial RA patients who possessed HLA-DR4. No correlationof anti-RANA antibodies with disease associated haplotypes wasobserved in these families.     

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.     

HLA-DR3 and HLA-DR5 associated thyrotoxicosis--two different types of toxic diffuse goiter

One hundred fifty patients with toxic and scintigraphically diffuse goiter were HLA typed (A, B, C, DR). One group consisted of 101 patients with concomitant Graves' ophthalmopathy and/or TSH-binding inhibiting antibodies (TBIAb). Forty nine patients had neither ophthalmopathy nor TBIAb. The former group showed a higher prevalence of HLA-B8 and DR3 compared to a normal control group. The latter group showed a higher frequency of HLA-DR5, whereas the HLA-B8 and DR3 antigens were slightly below normal prevalence. These data indicate an immunogenetic heterogeneity in patients with toxic diffuse goiter. A group of 47 hyperthyroid patients with single autonomous thyroid adenoma had no increased prevalence of any HLA-antigens. Patients with long term remission did not show an altered prevalence of any of the HLA antigens compared to controls. In contrast, patients with Graves' ophthalmopathy and/or TBIAb activity who relapsed had a significantly higher prevalence of HLA-B8 DR3, whereas patients without TBIAb and eye signs who relapsed had a significantly higher prevalence of HLA-DR5 than the control group.     

What factors distinguish probands from multicase rheumatoid arthritis same sex sibships from sporadic disease?

Thirty-two of 243 same sex sibships in which the proband had rheumatoid arthritis (RA) had at least one same sex sibling with RA ("familial" RA) and 211 did not ("sporadic" RA). The most important factors accounting for familial RA were the sibship size, and the proportion of siblings sharing both HLA haplotypes with the proband. Demographic and clinical details, autoantibodies and HLA-DR status were similar between the 2 groups, with the exceptions of regular use of artificial teardrops, and involvement of distal interphalangeal joints, which were both more prevalent in familial RA. The extrapolation of results from familial to sporadic RA appears to be justified.     

Is rheumatoid arthritis in Indians associated with HLA antigens sharing a DR beta 1 epitope?

HLA class II antigens were identified in a group of 44 patients with rheumatoid arthritis (RA) originating largely from the north or northeast of the Indian subcontinent and resident now in east London. Compared with 67 locally typed east London Asian controls, the prevalence of three HLA-DR antigens was raised in the patients: DR1 18.2% v 6.0% chi 2 = 3.99, DR4 20.5% v 11.9% chi 2 = 1.48, and DRw10 27.3% v 8.9% chi 2 = 6.56. These differences were also found when the patients with RA were compared with a larger control group of 110 northern Indians: DR1 18.2% v 7.2% chi 2 = 4.02, DR4 20.5% v 7.2% chi 2 = 5.56, and DRw10 27.3% v 8.1% chi 2 = 9.7. Twenty five (57%) of the patients expressed at least one of these antigens. All patients were also characterised for HLA-Dw types by mixed lymphocyte culture typing. The prevalence of the HLA-DR4 associated Dw types in the patients was: Dw4 2.3%, Dw10 0%, Dw14 11.4%, and Dw15 6.8%. The DR beta 1 chains of DR1 and DRw10 together with the Dw types of DR4 other than Dw10 share amino acid residues in a region of the third hypervariable region considered to be critical in antigen presentation. It is concluded that RA in Indians is associated with these HLA antigens, and data from this study support the hypothesis of a cross reactive epitope common to HLA specificities associated with RA.     

Characterization of T cells bearing HLA-DR antigens in rheumatoid arthritis

It has been demonstrated that T cells bearing HLA-DR antigens on their surface are actively involved in an immune response. In diseases of disordered immunoregulation, including rheumatoid arthritis (RA), there are elevated numbers of circulating HLA-DR+ T cells. In this study, we examined the cellular physiology of these T cells in RA patients. Using tritiated thymidine incorporation, we found that, in most patients, HLA-DR+ cells do not account for a significant amount of spontaneous proliferation found in peripheral blood T cells. RNA hybridization studies, using a cloned HLA-DR alpha chain gene probe, indicate that the T cells actively synthesize HLA-DR antigens rather than passively adsorbing them. The cell surface phenotype of the HLA-DR+ T cells was analyzed using double immunofluorescence and a variety of monoclonal antibodies. The expression of T cell differentiation antigens T4, T6, T8, and T10 varied markedly from patient to patient. In some patients, a significant number of cells expressed both T4 and T8 antigens. Most HLA-DR+ cells also express antigens defined by the following antibodies: anti-Tac (the interleukin-2 receptor), J2 (a glycoprotein found on T cell blasts), and ILR-1 (a class II major histocompatibility complex antigen). Activated T cells bearing HLA-DR antigens may play a role in the development of RA. Our data demonstrate that although these cells are not lymphoblasts, they possess a distinct cell surface phenotype.     

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.     

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.