C3, Gm, and Pi polymorphisms in rheumatoid arthritis.

This paper reviews the associations between RA and three non-MHS genetic markers: C3, Gm, and Pi. There is no evidence to suggest that genes linked to C3 predispose to RA. However, there is evidence to suggest that genes on chromosome 14, linked to both Gm and Pi, do influence susceptibility to RA and further studies of this chromosome are indicated.

Are major histocompatibility system class III products independent markers for susceptibility to rheumatoid arthritis?

Three components of the complement pathway C2, Factor B, and C4 are coded for by four genes C2, Bf, C4A, and C4B in the class III region of the major histocompatibility system in man. Studies of the polymorphism of these plasma proteins have shown associations of BfS, C2C, and C4B3 (2.9) with RA. Family studies have shown that these markers occur together, usually on DR4 positive haplotypes and in particular on the A2-Cw3-Bw62-C4B3-C4A3-BfS-C2C-DR4 haplotype. It is argued that Class III gene products are unlikely to be independent markers of susceptibility to RA.

Rheumatoid arthritis: inheritance and association with other autoimmune diseases.

This paper reviews the significance of the associations between rheumatoid arthritis (RA) and both diabetes mellitus and autoimmune thyroid disorders (ATD). All three disorders are thought to result from an interaction between genetic susceptibility and environmental factors. There is a probable real but not dramatic aggregation of insulin-dependent diabetes mellitus (IDDM) in the families of RA probands and a significant aggregation of ATD in both first- and second-degree relatives of RA probands. HLA-linked genes predispose to all three disorders while genes linked to Gm have been implicated in predisposition to RA and ATD. Within the HLA region two or more genes may predispose independently to RA; one of these genes is in linkage disequilibrium with HLA-DR4 and a second is in linkage disequilibrium with DR1 and 3. The familial aggregation of RA and IDDM is at least partially attributable to a single gene linked to HLA-DR4 predisposing to both disorders. By contrast, although 'DR4 negative RA' seems more frequent in sibships containing members with ATD, the familial aggregation of RA and ATD cannot be accounted for by a single gene linked to HLA predisposing to both disorders. Neither can this familial aggregation be accounted for by a single gene linked to Gm predisposing to RA and ATD so that any genetic predisposition common to both disorders is likely to involve at least a third locus which is still to be defined. A simple model with an interaction between at least three independent genetic loci and genetic heterogeneity is proposed to account for the known facts concerning the genetic susceptibility to RA.

Immunoglobulin allotypes in rheumatoid arthritis.

The HLA region of chromosome 6 may account for as little as 20% of the genetic contribution to rheumatoid arthritis (RA). Previous studies have shown associations with immunoglobulin heavy chain allotypes (Gm) coded for by genes on chromosome 14. We review evidence that G1m(x)-bearing haplotypes are associated with DR4-positive, but not DR4-negative RA. A differing Gm association has been reported in two studies of RA patients with circulating antibodies to native type II collagen, which might constitute a specific genetic subgroup. A family study has shown no evidence for genetic linkage between Gm allotypes and susceptibility to RA. It is possible that Gm (or linked 14th chromosomal genes) may influence susceptibility to RA by interacting with different genes within the HLA region. Immunoglobulin light chain allotypes (Km) coded by genes on chromosome 2 show no consistent association with RA.

Age and year of onset differences in siblings with rheumatoid arthritis.

Differences in age of disease onset and calendar year of onset were studied in 46 rheumatoid arthritis (RA) sibling pairs and in unrelated pairs of RA patients attending a hospital clinic. Mean age of onset and calendar year of onset differences in each group were similar. These results support the theory that RA is caused by an interaction of genetic and environmental factors and provide evidence against a single environmental transmissible cause.

Rheumatoid arthritis.

The results of family and twin studies suggest that RA may result from an interaction between an oligogenic susceptibility and unknown environmental factors. Part of this genetic predisposition is accounted for by genes within the MHC where there is a well-documented association with HLA-DR4. Studies of DR and other MHC variants have shown different associations with particular subgroups. One subgroup is Felty's syndrome where there is a strong association with DR4, as well as associations with DQ-beta and C4B null variants when DR4-matched Felty's and RA subjects are analysed. These DQ-beta and C4B null variants may characterize a single haplotype which is associated with extra-articular disease. A further rheumatoid subgroup characterized by circulating antibodies to native type II collagen, shows an association with HLA-DR3 and 7. Genes on chromosome 14 may also influence susceptibility to RA, probably by interaction with MHC genes and there are different Gm associations for DR4-positive and collagen-antibody-positive rheumatoid subgroups. HLA and Gm markers so far identified only account for a small part of the total genetic predisposition to RA and a third or further loci may also be involved. Possible candidates include T-cell alpha- and beta-chain genes and immunoglobulin light chain genes. One present concept of the genetic predisposition to RA is of several independent immunogenetic pathways each including interactions at two or more loci.

Studies of a C2 DNA polymorphism in RA, Felty's and normal subjects.

A restriction fragment length polymorphism at the C2 locus was studied in rheumatoid arthritis (RA), Felty's and control subjects. No association was found between any C2 variant and either RA itself or within the rheumatoid population with Felty's syndrome. The C2 DNA polymorphism can be used to subdivide Bf*S- as well as Bf*F-bearing haplotypes. The 2.65-kb C2 DNA allele showed allelic association with HLA-B44 and C4B*Q0 and may help to further characterize the haplotype B44-Bf*S-C4A*3-C4B*Q0-DR4, which has previously been described in Felty's syndrome.

Agranulocytosis in rheumatoid arthritis associated with long-term flucloxacillin for staphylococcal osteomyelitis.

Agranulocytosis and septicaemia developing in a patient with rheumatoid arthritis after 3 years' intermittent treatment with diclofenac, cimetidine and flucloxacillin for staphylococcal osteomyelitis is described. Treatment with recombinant granulocyte-colony-stimulating factor and high-dose methylprednisolone had no effect on the neutropenia which resolved on stopping all drug therapy. Relapse of agranulocytosis followed reintroduction of flucloxacillin and cimetidine 3 months later.

Complement C4 null alleles as a marker of gold or D-penicillamine toxicity in the treatment of rheumatoid arthritis.

C4 null alleles and HLA-DR antigens were defined in 48 rheumatoid arthritis (RA) subjects who had developed renal or heamatological side effects to gold or penicillamine, as compared to 33 RA subjects who had received the drugs for similar time periods without developing side effects. A C4A null allele was found in 56% of subjects with and 31% of those without side effects (P = 0.027, relative risk 2.8). A similar but statistically non-significant trend was observed with the C4B null allele (P = 0.64) resulting in a higher risk of drug toxicity in rheumatoid patients bearing either a C4A or C4B null allele (relative risk 5.7). Frequencies of DR3 and DR4 were similar in the two groups.

Genetic variants of complement component 3 (C3) in DR4 positive and DR4 negative rheumatoid arthritis.

C3 allotypes were defined in 86 Caucasoid patients with rheumatoid arthritis living in the north west of England and in 80 local, healthy controls. C3 allotype and phenotype frequencies were similar in RA (whether DR4 positive or negative) and control groups.

alpha 1 Antitrypsin (PI) allotypes in rheumatoid arthritis.

alpha 1 Antitrypsin (PI) phenotypes were defined in 144 patients with rheumatoid arthritis (RA) and in 223 normal controls. The frequencies of the rare F, S, and Z variants were similar in RA and control groups. No relationships were found between PI allotypes and rheumatoid disease severity or autoantibody titre. The PI M1M2 phenotype was increased in frequency in the RA group, and phenotype frequencies in DR4 positive and negative disease were similar. These results support the suggestion that genes on the 14th chromosome which are linked to PI predispose to RA.

Gm and Km allotypes in rheumatoid arthritis.

Immunoglobulin heavy chain (Gm) and kappa light chain (Km) allotype and phenotype frequencies were compared in 173 patients with rheumatoid arthritis (RA) and in 798 controls. No significant differences were found between allotype or phenotype frequencies in overall RA and control groups. However, the Gm(zaxfngb) phenotype and G1m(x) allotype were increased in HLA-DR4 positive RA patients compared with DR4 negative patients and controls, suggesting that immunoglobulin heavy chain genes interact with HLA in the pathogenesis of RA. All four patients with pulmonary fibrosis were Km(1) positive suggesting a possible role for immunoglobulin kappa light chain genes in the pathogenesis of pulmonary fibrosis found in rheumatoid patients.

HLA haplotype sharing by siblings with rheumatoid arthritis: evidence for genetic heterogeneity.

HLA haplotype sharing was studied in 35 sibships in which there were two or more members with rheumatoid arthritis (RA). Haplotype sharing RA siblings was random in 15 sibships which included members with clinical or immunological features of autoimmune thyroid disease. In the remaining 20 'non-thyroid' sibships the frequencies of RA siblings sharing 0, 1, or 2 haplotypes were 0.04, 0.48, and 0.48 respectively (p = 0.006). 67% of RA probands in the 'thyroid' families and 90% in the other families were HLA-DR4 positive. It is suggested that there is genetic heterogeneity in the pathogenesis of RA with at least two independent genes within the major histocompatibility complex (MHC) predisposing to RA. One gene is in linkage disequilibrium with HLA-DR4, while results of comparison of DR antigen frequencies in DR4 negative RA and control groups suggest that the other is in linkage disequilibrium with HLA-DR1 and 3. In the thyroid disease families both genes are frequently present and as either may predispose to arthritis, HLA haplotype sharing is random. The frequencies of HLA haplotype sharing in the 'non-thyroid' families suggest that there is a dominant susceptibility gene in linkage disequilibrium with HLA-DR4, whose frequency is 5% and penetrance about 20%.

Articular disease severity in rheumatoid subjects with and without Felty's syndrome.

Articular disease severity as measured by a radiographic score of hands and feet was compared in rheumatoid subjects with (21) and without (170) Felty's syndrome. Disease duration was a major determinant of joint destruction. When this was taken into consideration radiographic scores were no higher in the Felty's group than in rheumatoid subjects without Felty's syndrome. Immunogenetic associations previously described in Felty's syndrome are unlikely therefore to represent non-specific markers of disease severity and more likely to represent markers of extra-articular disease.

Soluble L-selectin in the connective tissue diseases.

Plasma levels of the leucocyte adhesion molecule L-selectin were measured by ELISA in 41 patients with rheumatoid arthritis, 18 with ankylosing spondylitis, 18 with systemic sclerosis and 27 with vasculitis together with 42 age- and sex-matched controls. Low levels of soluble L-selectin were found in systemic sclerosis (797 +/- 302 ng/ml, P < 0.05) and vasculitis (941 +/- 329 ng/ml, P < 0.05) relative to controls (1244 +/- 269 ng/ml). The exact reasons for low levels of soluble L-selectin are unclear, but may reflect reduced shedding from leucocytes and/or strong binding to its cell membrane ligand(s). An approximate inverse relationship between soluble L-selectin and disease severity may have clinical relevance.

A case-control study examining the role of physical trauma in the onset of rheumatoid arthritis.

OBJECTIVE: To investigate whether physical trauma may precipitate the onset of rheumatoid arthritis (RA). METHOD: In a case-control study comparing RA out-patients with controls attending non-rheumatology out-patient clinics, 262 patients and 262 age- and sex-matched controls completed a postal questionnaire or were interviewed about any physical trauma in the 6 months before the onset of their symptoms. RESULTS: Fifty-five (21%) of the RA patients reported significant physical trauma in the 6 months before the onset of their disease, compared with only 17 (6.5%) of the controls (P<0.00001). A preceding history of physical trauma was significantly more common in RA patients who were seronegative for rheumatoid factor (P=0.03), but was not significantly associated with sex (P=0.78), age (P=0.64), a family history of RA (P=0.07) or type of occupation, defined as manual or sedentary (P=0.6). CONCLUSION: Physical trauma in the preceding 6 months is significantly associated with the onset of RA.

Haplotypes bearing HLA-A, -B, and -DR: Bf and C4 genes in rheumatoid arthritis families.

We have compared haplotypes bearing HLA-A, -B, -DR; Bf and C4 genes in 54 rheumatoid arthritis (RA) and 24 control families. There was no statistically significant differences in C4A or C4B gene frequencies between RA and control groups, although there were trends for C4B*Q0 to be reduced and C4B2 to be increased in DR4 positive RA compared with DR4 positive controls. The lack of any strong association between C4 variants and RA overall makes it unlikely that the association between RA and genes within the MHS represents a direct effect of variants within the C4A or C4B loci themselves. On comparison of DR4-bearing haplotypes, the haplotype B15-BfS-DR4 was increased fourfold and the B44-Bfs-DR4 haplotype was less frequent in the RA group. When C4 variants were also considered, the haplotype B44-C4B*Q0-C4A3-BfS-DR4 was nine times less frequent in RA patients than in controls. The observation that different DR4 bearing haplotypes may confer either increased or decreased susceptibility to RA suggests either that it is unlikely that DR4 itself is involved in the disease process or that specific haplotypic combinations are important. Thirty-two RA patients were HLA-DR4 negative. No single DR4 negative haplotype was found to confer significantly increased susceptibility to RA.

Immunoglobulin lambda light chain genes in rheumatoid arthritis.

Restriction fragment length polymorphisms (RFLPs) obtained by hybridisation of an immunoglobulin lambda constant region probe to Eco RI digests of genomic deoxyribonucleic acid (DNA) obtained from rheumatoid arthritis (RA) and control subjects have been compared. Polymorphic bands of 8, 13, 18, and 23 kb (kilobases) were shown. The 8/8 genotype and 8 kb allele were increased and the 8/18 genotype and 18 kb allele decreased in the RA group. This effect was independent of HLA and Gm. These findings suggest that genes linked to the loci for the immunoglobulin lambda constant region may influence susceptibility to RA.

A comparison of clinical and immunogenetic features in familial and sporadic rheumatoid arthritis.

Clinical and immunogenetic factors were compared in 214 patients with sporadic rheumatoid arthritis (RA) and 117 patients from 52 multiplex families. Sex distribution, articular disease severity and seropositivity for rheumatoid and antinuclear factors were similar in familial and sporadic disease. There was a trend for Sjögren's and Felty's syndromes to be more frequent in familial RA but extraarticular disease features were otherwise similar in the 2 RA disease groups. Mean age of onset was 41.1 years in familial and 46.5 years in sporadic RA (p less than 0.0006); 67% of family probands, 74% of affected relatives and 57% of sporadic patients were HLA-DR4 positive (p less than 0.05 affected relatives vs sporadic). The similarity of clinical features found in familial and sporadic RA justifies the use of families with RA to study aspects of disease pathogenesis.

Immunogenetic studies in families with rheumatoid arthritis and autoimmune thyroid disease.

HLA and Gm typing were carried out in 16 families. Seven families included 10 sib pairs with rheumatoid arthritis (RA) and autoimmune thyroid disease (ATD) respectively, and nine families included 16 sib pairs with RA and circulating thyroid autoantibodies respectively. Eight, 11, and seven sib pairs with either RA or clinical or immunological evidence of ATD shared none, one, and two HLA haplotypes respectively, and two, seven, and two informative sib pairs shared none, one, and two Gm haplotypes respectively. This random haplotype sharing of HLA and Gm haplotypes suggests that non-HLA, non-Gm linked genes are likely to be involved in any genetic predisposition common to RA and ATD.