Hormone replacement therapy in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is 2-3 times more frequent in women as compared to men. The peak incidence in women coincides with the years around the menopause and the course of RA is also influenced by events associated with hormonal alterations. Animal studies have revealed distinct beneficial effects on arthritis by treatment with estradiol (E2) whereas human studies have been inconclusive. RA is associated with increased prevalence of osteoporosis and fractures related to the reduced bone mineral density (BMD).We have conducted a two-years randomised controlled trial with the aim of evaluating different aspects of HRT in 88 postmenopausal women with RA. All patients received a daily dose of 500 mg calcium and 400 IE vitamin D3 and women in the HRT group were given E2 plus noretisterone acetate. The patients took also part in a cross sectional observational study investigating the frequency of osteoporosis and predictors of reduced BMD and joint destruction.The disease activity, measured by the 28 joint count disease activity score (DAS 28) decreased significantly more in the HRT group as compared to the controls. Erythrocyte sedimentation rate (ESR) and orosomucoid, decreased and hemoglobin (Hb) increased in the HRT group. The improved Hb levels were believed to be secondary to the reduced inflammation as indicated by simultaneously increase in serum iron, total iron binding capacity and saturation of transferrin.The BMD increased significantly in the total hip, lumbar spine and forearm in the HRT group and estimations revealed that the improved BMD in the hip corresponded to a 20 % risk reduction of fractures in the hip in the HRT group. There was no overall difference in the radiographic outcome between the groups but, in the subgroup of patients with increasing joint damage, HRT retarded significantly the progression of destruction.HRT reduced biochemical markers reflecting bone metabolism assessed by decrease in two different fragments of C-terminal telopeptide of type I collagen, CTX-I and ICTP and the C-terminal propeptide of type I procollagen, PICP. The reductions of the markers were associated with improved BMD at two years. CTX-I was the most sensitive of all markers tested. HRT also reduced biochemical markers reflecting cartilage turnover assessed by decrease in urinary levels of collagen type II C-telopeptide degradation fragments, CTX-II and serum levels of cartilage oligomeric matrix protein, COMP.HRT reduced serum levels of soluble interleukin 6 receptor (sIL-6R), an agonist to IL-6, a cytokine involved in both bone remodelling and the inflammatory process in RA. The bone-anabolic factor, insulin-like growth factor 1 (IGF-1) increased significantly in the HRT group. Both of these findings; might be involved in the mechanisms mediating the beneficial effects of HRT in RA. Interestingly, the increase in IGF-1 was modestly connected with decrease in ESR and elevation of serum levels of E2 was associated with reduction of sIL-6R.Fifty-six % of the postmenopausal RA women, not treated with HRT or bisphosphonate, had osteoporosis in at least one measured site. High age, low body weight and severe joint damage were the most important determinants of reduced BMD whereas elevated CRP and long disease duration were the best predictors of high Larsen score found in the multiple stepwise regression analyses.