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.

The WTCCC study identified 49 single nucleotide polymorphisms (SNPs) putatively associated with RA at p=1×10 -4 -1×10 -5 (Tier 3). Here, we show that 3 of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend p = 4×10 -5 , p=4×10 -4 and p=4×10 -4 , respectively) in a validation study of 4,106 RA cases and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in Caucasians.Rheumatoid arthritis (RA) is a common autoimmune disease, affecting an estimated 475,000 adults in the UK, in which inflammation of synovial joints is characteristic. The WTCCC genome wide association screen of 1860 RA case and 2938 healthy control Caucasian samples confirmed association of SNPs with previously identified loci within the HLA region and the PTPN22 gene (Tier1, p<5×10 -7 )1. Nine loci were associated in the next tier of significance (Tier 2, p=1×10 -5 -5×10 -7 ) and association to one, on chromosome 6q23 has been replicated and confirmed in subsequent independent studies2, 3. Forty-nine SNPs were associated at p = 1 × 10 -4 -1 × 10 -5 (Tier 3) and we now describe investigation of these SNPs in an independent cohort of 4,106 RA samples (supplementary methods). Causal variants within this group of SNPs are likely to confer small effect sizes, by virtue of the fact that the evidence for association with them in the original WTCCC study was weaker than for those SNPs in Tiers 1 and 2. In order to maximise power to replicate true associations, genotype data from an independent cohort of 3,599 healthy controls was combined with that Table 1). In addition, we took the opportunity to reevaluate the evidence for association with the Tier 2 SNPs using the expanded reference group for comparison.Of the 49 novel Tier 3 SNPs tested, 3 showed association with RA: rs4750316 (C>G), mapping to chromosome 10p15 (OR minor allele =0.87, 95% CI 0.81-0.93, trend P = 4 × 10 -5 ); rs1678542 (G>C) mapping to chromosome 12q13 (OR minor allele = 0.91, 95% CI 0.86-0.96, trend P = 4 × 10 -4 ) and rs3218253 (C>T) mapping to chromosome 22 (OR minor allele = 1.11, 95% CI 1.05 -1.17, trend P = 4 × 10 -4 ) ( Table 1, supplementary Tables 2 and 3). For all SNPs, the allele frequencies were similar across the control group tested in the WTCCC study and the expanded reference group tested here (rs4750316 minor allele frequency (MAF) 0.20 and 0.20; rs1678542 MAF 0.37 and 0.37; rs3218254 MAF 0.25 and 0.26, respectively) and all satisfied Hardy-Weinberg expectations. Both combined analysis and meta-analysis of the WTCCC data and the validation data provided strong statistical evidence for association between RA and all 3 SNPs (combined analysis: OR rs4750316 = 0.85 95% CI 0.80-0.90, trend P = 1.3×10 -8 ; OR rs1678542 = 0.88, 95% CI 0.85-0.93, trend P = 1.3 × 10 -7 ; OR rs3218253 = 1.13, 95% CI 1.07-1.18, trend P = 1.3 × 10 -6 ) ( Table 1 and supplementary Table 2).RA is characterised by the presence of autoantibodies in some but not all patients. Previo...

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.

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The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 × 10−6, OR (95% CI) 1.22 (1.13–1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95% CI) 0.86 (0.8–0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95% CI) (1.51–2.29)]. This equates to an effect size of 1.50 (95% CI 1.21–1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.