Familial palindromic rheumatism: a possible association with HLA.

Palindromic rheumatism is very rare in children. The familial occurrence of the disease has been only briefly reported previously. A family is described here in which the mother and her 3 children suffered from typical palindromic rheumatism, which ran a benign course. All 4 members were seronegative and the HLA types of the children were identical. The HLA genotype of the mother was HLA A2, Cw4, Bw41, Bw6, DR5, MT2/Aw32, CX, Bw44, Bw4, DR1, MT1. HLA DR5 has previously been found to be associated with juvenile rheumatoid arthritis, while DR1 in Jews is significantly associated with adult-onset rheumatoid arthritis. DR5 was shared by the mother and her 3 children. The presence of the antigen DR5 in this sibship suggests that palindromic rheumatism may be a variant of juvenile rheumatoid arthritis with a relatively late onset and a more benign course. Tissue typing of patients with palindromic rheumatism may give a clue to prognosis. The patients' youth and the familial involvement, with identical HLA characteristics, are the outstanding features of this family.     

The association between rheumatoid arthritis and the HLA antigen DR4.

One hundred and forty-two patients with 'definite' or 'classical' rheumatoid arthritis (RA) were studied for the frequency and possible prognostic significance of HLA DR4. Of these, 122 were seropositive, while 20 were negative for rheumatoid factor (RF) in serum. The HLA antigen DR4 was significantly increased in the seropositive group (65%) as well as in the seronegative group (55%) in comparison with a frequency of 27% in 116 healthy controls. Among seropositive patients a higher frequency of DR4 was found in females (73%) than in males (50%), the difference being statistically significant (p less than 0.01). DR4 was more frequent among patients with a family history of RA (74%) than among patients without affected relatives (57%). DR4 appeared to be associated with an early onset of RA. No significant differences in general disease activity or functional capacity between DR4-positive and DR4-negative RA patients were found. Patients without the HLA antigen DR4 had a significantly (p less than 0.05) higher mean titre of RF than those with the antigen.     

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.      

Association of HLA-Aw31 and HLA-DR1 with adult rheumatoid arthritis.

Forty-nine Israeli Jewish patients with rheumatoid arthritis (RA) were studied for their HLA A, B, C, DR antigen frequency. A significant increase in HLA Aw31 and HLA DR1 was observed (p less than 5.10(-5) and p less than 5.10(-3) respectively). 45% of Aw31 positive patients were sero-negative for rheumatoid factor, while most HLA DR1 positive individuals were seropositive. DR5 was found to be significantly decreased (p less than 5.10(-4)). Contrary to previous reports, DRw4 was found to be within the range of antigen frequency of the controls (34.7% vs. 32%). It is suggested that in our population of patients Aw31 and DR1 and not DR4 are highly associated with adult onset of RA.     

HLA antigens in juvenile arthritis. Genetic basis for the different subtypes

Serologic HLA typing was performed in 77 patients with juvenile arthritis (JA). The frequency of the DR4 antigen was significantly increased in the seropositive but decreased in the seronegative patients--53% and 17%, respectively (P less than 0.025)--compared with 27% in healthy Norwegians. An increased frequency of the HLA-DR4 antigens was also found in polyarticular onset JA (50% compared with 27%, P less than 0.05). The frequency of both the HLA-B27 (21%) and the DR5 antigen (21%) was increased in the whole patient group compared with controls (10% and 9%, respectively, P less than 0.01). The DR5 antigen was also increased in the systemic onset patients (40%, P less than 0.05). Both the DR5 and the DR8 antigens were increased in the pauciarticular onset group (P less than 0.05 and P less than 0.01, respectively). The results support the view that seropositive and seronegative JA are different disease entities and also that seropositive JA may be an early form of seropositive rheumatoid arthritis. The association between the DR4 antigen and IgM rheumatoid factor suggests that the HLA-DR4 gene or a closely linked gene may regulate autoimmune responses to self IgG.     

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 and gold toxicity.

One hundred and thirty-two patients with rheumatoid arthritis treated with gold have been studied for possible associations between HLA DR antigens and different adverse reactions occurring during such therapy. Patients possessing HLA DR3 had a significantly greater frequency of side effects than patients lacking this antigen. It was particularly noticed that DR3 positive patients on gold treatment had an 11 times higher risk of getting proteinuria than those without DR3. The lowest frequency of side effects was seen in DR7 positives. No significant differences between the DR antigen groups with respect to skin eruptions, liver reactions, or leucopenia were evident.     

HLA DR4 and rheumatoid arthritis in Japanese people.

Eighty-eight Japanese patients with rheumatoid arthritis and 104 normal Japanese persons were typed for HLA A, B, C, and DR antigens. The frequency of HLA DR4 was 70.5% in patients compared with 46.1% in normal controls (P less than 0.001). However, a sex difference in the frequency of HLA DR4 in patients was noted. HLA DR4 was found in 80.6% of male patients, which was highly significant compared with controls (P less than 0.0005), while only a borderline increase of 60.5% was found in female patients (P less than 0.05). In addition, the frequency of HLA DR2 was remarkably low in male patients. These suggest the possible heterogeneity of rheumatoid arthritis in Japanese.     

HLA-DR4等位基因与类风湿关节炎疗效的关系

目的：探讨对类风湿关节炎（RA）联合使用改善病情抗风湿药（DMARDs）的疗效与易感HLA－DR4基因携带的关系。方法 测定RA患者HLA－DR4携带频率,并作病程、关节功能及红细胞沉降率（ESR）、C反应蛋白（CRP）、类风湿因子（RF）比较分析后,分别于阳性者及阴性者联用甲氨蝶呤（MTX）、柳氮磺吡啶（SASP）及氯奎（CQ）等DMARDs,并观察疗效。结果 HLA－DR4携带使患者ESR、CRP及RF值升高,使RA病情复杂化,给联合治疗带来困难,表现在控制症状及生化指标恢复正常值的时间上,HLA－DR4阳性组比HLA－DR4阴性组显著延迟;在RF值恢复正常方面,HLA－DR4阳性组比HLA－DR4阴性组病例显著减少,上述两方面与RA预后密切相关。在药物的副作用方面,两组差异无显著性。结论 HLA－DR4可作为判断RA治疗的重要预后指标。     

Histocompatibility antigens in psoriasis, psoriatic arthropathy, and ankylosing spondylitis.

Patients with ankylosing spondylitis, psoriatic arthritis, and psoriasis alone were typed for HLA A, B, Cw, and DR antigens, and the antigen frequencies were compared with those in a normal control population and in patients with rheumatoid arthritis. Patients with psoriasis had a significantly raised frequency of Cw6. Those with arthritis in addition to their psoriasis also had raised frequencies of B27 and DR7. Patients with ankylosing spondylitis were characterised by the expected high frequency of HLA B27. Again, those with peripheral arthritis had a higher B27 and DR7 frequency than those without. DR3 is associated with the development of erosions in psoriatic arthritis.     

HLA-DR antigens and disease patterns of rheumatoid arthritis

HLA-DR antigens were determined in 111 patients with classic or definite rheumatoid arthritis. HLA-DR4 was significantly (P corr. less than 10(-6] increased in patients with rheumatoid arthritis (54%) compared with controls (23.2%). HLA-DR 5 was decreased in rheumatoid arthritis (12.6% vs 26.4% of controls); however, the corrected P value was not significant. There were no significant differences with regard to various clinical, radiological and serological parameters between HLA-DR 4 positive and negative patients. However, a milder course of rheumatoid arthritis was observed in DR 7 positive patients: Patients with this antigen were associated significantly with seronegativity and low titers of IgM-rheumatoid factor. Despite a similar disease duration patients with DR 7 had a significantly lower number of joints with inflammatory arthritis (synovitic swelling with limitation of movement) and developed less frequently severe radiological changes as joint ankylosis than DR 7 negative patients. In addition to the well known association between rheumatoid arthritis and HLA-DR 4, our data indicate that HLA-DR 7 may have a protective effect on the course of rheumatoid arthritis.     

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 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.     

Associations between HLA and antibodies to collagen in rheumatoid arthritis.

Associations between HLA types and serum antibodies to native and denatured type II collagen were sought in 105 patients with rheumatoid arthritis (RA). Antibodies were measured using a solid phase radioimmunoassay. There were no significant associations between any HLA antigen (A, B, or DR) and a high antibody titre to native collagen. There were significant associations, however, between HLA antigens and high antibody titres to denatured collagen. Although DR4 did not show an association, the phenotype A2+DR4+ did; this was not related to A2 as A2+DR- was not associated with a high antibody titre. No single B locus antigen showed an association, but several B locus antigens, B12, B15, and B40, were included in phenotypes with A2 and DR4 which were associated with a high antibody titre to denatured collagen. These HLA associations with anticollagen type II are best explained by a gene other than DR4 (but in linkage with it) which may regulate the antibody response to denatured collagen. If so, this would represent an HLA gene in addition to DR4 that is active in RA.     

Hla antigens in yakima indians with rheumatoid arthritis. lack of association with hla–dw4 and hla–dr4

Women of the Yakima Indian Nation, a northwest Native American population, are known to have an increased prevalence of a rheumatoid arthritis–like disease characterized by erosive arthritis, frequent involvement of metacarpophalangeal and wrist joints, and positive rheumatoid factor. These patients are frequently positive for antinuclear antibodies and often demonstrate adverse reactions to gold therapy. HLA antigens were determined for 29 Yakima Indians with this disease, but there was no increased frequency of either HLA–Dw4 or HLA–DR4, in contrast to other populations with rheumatoid arthritis. There was, however, a trend toward an increase in HLA–B40 and a decrease in HLA–DR8. The relative risk for rheumatoid arthritis in Yakima Indians was 2.53 in the presence of B40 and 0.28 in the presence of DR8.     

Increased expression Of HLA—DQ antigens by interstitial cells and endothelium in the synovial membrane of rheumatoid arthritis patients compared with reactive arthritis patients

We investigated cellular phenotypes and expression of class II major histocompatibility complex antigens on endothelium and cellular infiltrates in synovium from patients with rheumatoid arthritis (RA) or reactive arthritis, using an indirect immunoperoxidase technique. The RA specimens showed synovial lining layer hypertrophy and several focal accumulations of lymphocytes, both of which were absent in the reactive arthritis synovium. The percentage of cells expressing monocyte/macrophage markers was significantly higher in RA specimens. The percentages of cells expressing B and T cell markers were similar in both diseases. There was no significant difference in the expression of HLA–DR or DP by endothelium in the 2 diseases, but a marked increase in expression of HLA–DQ by endothelium was observed in the RA synovium versus that from patients with reactive arthritis. This overexpression of HLA–DQ was also seen in the interstitial cells of RA patients compared with reactive arthritis patients. In the reactive arthritis synovium, a significant population of cells (30%) was noted to be HLA–DR positive, and negative for macrophage and lymphocyte markers. Some of these cells had a dendritic morphology. The coexpression of HLA–DQ and HLA–DR may play an important role in antigen presentation and disease chronicity in RA.     

Serum IgG anti-native type II collagen antibodies in rheumatoid arthritis: association with HLA DR4 and lack of clinical correlation

Serum anti-type II collagen antibodies were measured in 85 rheumatoid arthritis patients before and after treatment with disease modifying drugs. These patients were also serotyped for HLA class II antigens. High anti-type II collagen antibodies (anti-CII) were detected in 35% and 29% of patients at onset and completion of study, respectively. Eighty percent of patients with high anti-CII initially had HLA DR4 (p less than 0.05). There was no correlation of anti-CII levels with severity of disease or response to treatment.     

The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations

Thirty-two patients with the Felty syndrome, defined by the presence of rheumatoid arthritis, splenomegaly, and neutropenia, have been studied in comparison with 32 patients with rheumatoid arthritis matched for age, sex, and disease duration, and 9 patients with rheumatoid arthritis and idiopathic neutropenia. Patients with the Felty syndrome had severe destructive arthritis, which progressed during follow-up despite little evidence of objective synovitis, and a higher frequency of extra-articular manifestations, including vasculitis. Bacterial infection tended to occur in patients with the lowest neutrophil count but continued to occur in some despite normalization of the WBC. Prognosis was poor and 8 deaths occurred, predominantly from sepsis. Serologic features were prominent. High titers of IgG rheumatoid factor and circulating immune complexes characterized patients with persistent neutropenia. A family history of rheumatoid arthritis was more common in patients with the Felty syndrome. The association with HLA DR4 was very strong; in addition there was an increased frequency of the DQw3 variant, 3b, suggesting that HLA Class II genes in linkage with DR4 may contribute to disease expression.     

HLA haplotypes in multiple case families with rheumatoid arthritis

Summary In 9 families of which at least two members were affected by rheumatoid arthritis (RA), no specific combination of HLA genes, i.e., HLA haplotype was found to be associated with transmission of disease susceptibility. The results suggested an important role of HLA-DR4 in the etiology of RA, irrespective of other HLA markers. In addition, it may be concluded that genetic markers other than DR4 may act together with this HLA antigen in determining which individuals are at risk of developing this rheumatic disorder.     

Clinical and immunogenetic studies in rheumatoid arthritis from northern India

A total of 258 patients with classic rheumatoid arthritis seen over a 7-year period were included in this study. The majority of the patients had relatively mild disease at the time of presentation. The incidence of extraarticular manifestations such as subcutaneous nodules, vasculitis, amyloidosis and pulmonary involvement was low although one or two pulmonary function test parameters were abnormal in some. Seventy patients were tested for all three subclasses of rheumatoid factors - IgM, IgG and IgA. Of these, 23 patients had all three whilst four had only IgG. The 62 patients who had most typical and severe manifestations were typed for four major HLA loci A, B, C and DR. Of these 42 (67.7%) had DR4 antigen while DR3 antigen was detected in 14 (22.6%).