A gain of function polymorphism in the interleukin 6 receptor influences RA susceptibility.

OBJECTIVES: To investigate the possible role of a functional polymorphism in the soluble interleukin 6 receptor (sIL-6R) gene in the genetic background of rheumatoid arthritis (RA). METHODS: An association between disease status and the sIL-6R rs8192284 (A358D) variant was tested in 965 patients with RA and 988 unrelated healthy controls. Odds ratios (ORs) for disease were calculated with asymptotic 95% CI; p values <0.05 were considered statistically significant after adjustment for multiple testing. To determine the relationship between protein levels and IL-6R A358D genotype, the protein levels of sIL-6R in 100 plasma samples from healthy controls were measured using an ELISA and compared across the genotype groups. RESULTS: The allele frequency of the C allele (alanine) was lower in cases than in controls (38.4% vs 41.7%, p=0.04, OR 0.9, 95% CI 0.8 to 1.0), as were the CC/AC genotypes compared with AA genotype frequencies (61.0% in RA cases vs 67.5% in controls, p=0.004, OR 0.8, 95% CI 0.6 to 0.9). Plasma levels of sIL-6R differed significantly according to genotype in the controls: 17.00 + or - 2.03 ng/ml for A/A, 20.08 + or - 1.83 ng/ml for A/C and 21.57 + or - 2.10 ng/ml for C/C (p=0.0001). CONCLUSION: These data suggest a role for genetically determined lower sIL-6R levels as a risk factor for RA. The proinflammatory role of the IL6 system in established RA has been highlighted by the use of anti-sIL-6R antibodies. However, the findings of this study suggest a protective effect of IL6 on the risk of developing RA.

Evidence of epistasis between interleukin 1 and selenoprotein-S with susceptibility to rheumatoid arthritis.

OBJECTIVE: Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1beta and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF. METHODS: Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel-Haenszel (M-H) test and the linkage disequilibrium (LD)-based statistic. RESULTS: No association of SELS -105 genotype and RA susceptibility was detected. Stratification of SELS -105 genotypes by IL1 -511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS -105 locus) in individuals with the GG/AG genotype at the IL1beta -511 locus was significantly lower than that in individuals having the AA genotype at the IL1beta -511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M-H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS -105 and IL6 or TNF variants. CONCLUSION: Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene-gene interactions in the pathogenesis of RA.

TNF +489 polymorphism does not contribute to susceptibility to rheumatoid arthritis.

OBJECTIVES: To determine if a tumour necrosis factor (TNF +489) polymorphism is associated with susceptibility to rheumatoid arthritis (RA). METHODS: Two European populations were studied: 217 controls and 238 patients from the north of England and 145 controls and 179 patients from Spain. HLA-DRB1 and TNF +489 markers were typed using polymerase chain reaction based methods. RESULTS: Strong associations were demonstrated with shared epitope (SE) encoding HLA-DRB1 alleles in the English (OR = 2.9 [2.2-3.9]) and Spanish (OR = 2.3 [1.6-3.3]) populations, however no association was found with TNF +489 alleles. Furthermore carriage of TNF +489A was not associated with the presence of radiological erosions, rheumatoid nodules or rheumatoid factor. CONCLUSION: The role of the TNF locus in the genetic background of RA is unclear, however, our data does not support the previous reported association of the TNF +489A allele with RA susceptibility or severity.

Prevention of bone loss with risedronate in glucocorticoid-treated rheumatoid arthritis patients.

The aim of the study was to assess risedronate's effect on bone mineral density in postmenopausal women with rheumatoid arthritis receiving glucocorticoids. We carried out a two center, 2 year, double-masked, placebo-controlled trial with a third year of nontreatment follow-up. We studied 120 women requiring long-term glucocorticoid therapy at > 2.5 mg/day prednisolone randomized to treatment with daily placebo; daily 2.5 mg risedronate; or cyclical 15 mg risedronate (2 out of 12 weeks). At 97 weeks, bone mineral density was maintained at the lumbar spine (+1.4%) and trochanter (+0.4%) in the daily 2.5 mg risedronate group, while significant bone loss occurred in the placebo group (-1.6%, p = 0.03; and 4.0%, p < 0.005, respectively). At the femoral neck, there was a nonsignificant bone loss in the daily 2.5 mg risedronate group (-1.0%) while in the placebo group bone mass decreased significantly (-3.6%, p < 0.001). The difference between placebo and daily 2.5 mg risedronate groups was significant at the lumbar spine (p = 0.009) and trochanter (p = 0.02) but did not reach statistical significance at the femoral neck. Although not significantly different from placebo at the lumbar spine, the overall effect of the cyclical regimen was similar to that of the daily 2.5 mg risedronate regimen. Treatment withdrawal led to bone loss in the risedronate groups that was significant at the lumbar spine. A similar number of patients experienced adverse events (including upper gastrointestinal events) across treatment groups and risedronate was generally well tolerated. Thus risedronate preserves bone mass in postmenopausal women with rheumatoid arthritis receiving glucocorticoids while patients receiving a placebo have significant bone loss.

Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis.

OBJECTIVES: To determine the prevalence of vertebral fracture in postmenopausal women with steroid treated rheumatoid arthritis (RA), and whether the risk of vertebral fracture could be predicted from measurements of bone mineral density (BMD). METHODS: Vertebral deformities were defined from spine radiographs in 76 postmenopausal women with steroid treated RA (aged 50-79 years) and 347 age matched women from a population based group, using a morphometric technique. Lumbar spine (LS) BMD was measured by dual energy x ray absorptiometry. RESULTS: The odds ratio for vertebral fracture in the women with RA was 6.2 (95% confidence interval 3.2 to 12.3). The decrease in LS-BMD was less than expected for the observed prevalence of vertebral fracture and, among the women with RA, LS-BMD was not lower in those with vertebral fractures. CONCLUSIONS: We conclude that patients with steroid treated RA may have abnormal bone quality, and that LS-BMD cannot be used to predict the risk of vertebral fracture in these patients.

Bone mineral density of the hand in rheumatoid arthritis.

OBJECTIVE: To determine the reproducibility, accuracy, and linearity of hand bone mineral content (BMC) measurements, and to evaluate the influence of hand posture; to determine the relationship of hand bone mineral density (BMD) to generalized osteopenia in rheumatoid arthritis (RA); and to determine the relationship between hand BMD and disease severity in early RA. METHODS: Hand BMD was measured by dual-energy x-ray absorptiometry (DXA). We studied 70 postmenopausal women with steroid-treated RA (established RA), ages 49-79, and 20 age-matched healthy controls to determine the relationship to generalized osteoporosis; we also studied 20 patients aged 23-74 years with early RA to determine the relationship between disease severity and hand BMD. RESULTS: Reproducibility of hand BMD was to within 1%. In established RA, there was a greater decrease in juxtaarticular BMD (23% at the hand) than in generalized BMD (16% at the femoral neck, 11% at the lumbar spine, and 11% total body) compared with that in age-matched controls. Hand BMD correlated with skeletal size and BMD at other skeletal sites. In established RA, there was no effect of disease duration, disability, or steroid therapy. In early RA, hand BMD correlated with age and disease activity. CONCLUSION: Measurement of hand BMD by DXA is accurate and precise. Hand BMD reflects BMD at other skeletal sites in patients with RA, and is a marker of disease severity in patients with early disease. It may be a sensitive marker of disease progression and response to therapeutic intervention.

Arthritis artefacta: factitious disease in rheumatology.

Self-induced disease can be difficult to diagnose and costly of time and money to investigate. The key is to think of the possibility. Five patients in whom the evidence for factitious rheumatological illness was strong are discussed and their histories, physical signs and family backgrounds are explored in relationship to factitious disease presenting in other fields. Young immature individuals seem most at risk and the discrepancy between physical signs and understandable pathological mechanisms may suggest the diagnosis. The outlook seems frequently poor.

Leucopenia in rheumatoid arthritis: relationship to gold or sulphasalazine therapy.

Leucopenia is one of the most worrying of the many toxic effects of second-line drug therapy for rheumatoid arthritis, and much time and energy is expended in screening for it. Sulphasalazine (SASP) is generally claimed to be safer than some alternative second-line drugs but the reported incidence of leucopenia has varied widely. We have examined, retrospectively, all records of blood counts before, during and after treatment in 326 SASP treated patients and in 213 on gold. Leucopenia on at least one occasion occurred in up to 10% of patients on both drugs but usually recovered spontaneously in spite of continued therapy. 'Serious' leucopenia leading directly to drug withdrawal was a rare event occurring in only one SASP patient and in two patients receiving gold treatment. Most episodes of leucopenia do not require drug withdrawal and may not be drug related.

Sulphasalazine for rheumatoid arthritis: toxicity in 774 patients monitored for one to 11 years.

Sulphasalazine is being used increasingly to treat rheumatoid arthritis, though its long term safety profile has not been established in this condition. The incidence and nature of adverse effects occurring in 774 patients with rheumatoid arthritis treated with sulphasalazine for periods ranging from one to 11 years were therefore noted. Altogether 205 of the patients stopped treatment permanently due to an adverse effect. One hundred and fifty six (76%) of these events occurred within three months and few beyond the first year. Most events were trivial and were self limiting after withdrawal of the drug; of the potentially more serious adverse effects, 33 (66%) occurred within three months of treatment. None of the patients died or suffered lasting ill effects. It is concluded that adverse effects of treatment with sulphasalazine are generally seen within three months; though regular monitoring is desirable during that period, thereafter few worrying problems occur.

Sulphasalazine for rheumatoid arthritis: relationship between dose, acetylator phenotype and response to treatment.

Sulphasalazine is an effective treatment for rheumatoid arthritis but the response in any individual is unpredictable. We have sought to establish a relationship between dose (in mg/kg body weight) and metabolism of the drug in 79 patients selected for an extremely good response (43) or no response (36) to treatment with sulphasalazine. The dose of sulphasalazine in relationship to body weight showed no difference between the two treatment outcome groups. The distribution of acetylator phenotype showed only a trend for slow acetylators to occur more frequently in the group of good responders to treatment. There is no advantage in the routine assessment of acetylator phenotype as a predictor of response to treatment with sulphasalazine.

Sulphasalazine in rheumatoid arthritis: desensitising the patient with a skin rash.

Sulphasalazine has been shown to be useful in the management of rheumatoid arthritis. However, its use may be complicated by a skin rash. Eight patients with a rash have undergone desensitisation, the aim of which was to achieve a daily dose of 2 g sulphasalazine. This was successful in five patients, partially successful in two, and failed in one patient. Desensitisation to sulphasalazine is a simple outpatient procedure, which subsequently allows the majority of patients developing a skin rash to continue treatment.

Sulphasalazine in the long term management of rheumatoid arthritis.

The clinical outcome of rheumatoid arthritis patients treated long term with sulphasalazine or parenteral gold was studied. The rate of withdrawal from gold because of inefficacy was less frequent than that for patients receiving sulphasalazine. However, patients on sulphasalazine withdrew less frequently because of adverse reactions.

Sulphasalazine: a safe, effective agent for prolonged control of rheumatoid arthritis. A comparison with sodium aurothiomalate.

The place of sulphasalazine in the management of rheumatoid arthritis over prolonged periods of time has been compared and contrasted with that of sodium aurothiomalate. One hundred and forty-three patients (59 on sulphasalazine, 84 on sodium aurothiomalate) have been treated for periods of up to 42 months. Sulphasalazine is highly effective for some patients, though probably less frequently than sodium aurothiomalate. However, its safety profile is far superior, and very long-term treatment with sulphasalazine is a safe option for treatment of rheumatoid arthritis.