Glucocorticoids in early rheumatoid arthritis

Abstract

For 50 years, glucocorticoids (GC) are used for symptomatic treatment of rheumatoid arthritis (RA). In the last decade, results from clinical studies of treatment with GC as additional therapy to long-acting antirheumatic drugs in patients with early RA suggested also disease-modifying properties of GC in RA. The aim of this thesis was to investigate disease-modifying properties and side effects of low-dose GC as monotherapy of patients with previously untreated early active RA in relation to clinical efficacy, general wellbeing and glucocorticoid receptors. All 81 consecutive outpatients who participated in the clinical 2-year study had recently been diagnosed as having early RA (disease duration less than a year). According to randomization 41 patients were allocated to 10 mg prednisone orally daily and 40 to placebo. Additional therapies like analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), physiotherapy were allowed in both groups and recorded. After 6 months sulphasalazine 2 gram daily could be prescribed as rescue medication only if clinically necessary. According to the study protocol clinical, biochemical and radiologic parameters were assessed. Furthermore, health assessment questionnaires for disability and general wellbeing were performed regularly and side effects documented. In general, patients in the prednisone group experienced significant but transient clinical improvement in the first months compared to those in the placebo group. However, patients in the placebo group used twice as much additional therapies compared to those in the prednisone group. To put it the other way around, prednisone had a sparing effect on the use of NSAIDs and other additional therapies. From 12 months on, radiological scores showed significantly less progression of joint damage (erosions and joint space narrowing) in the prednisone group compared to the placebo group. No clinically relevant side effects were observed, except for a higher incidence of new osteoporotic vertebral fractures in the prednisone group. At the time of the design of the study, back in 1989, it was considered ethical to study RA patients with an active drug against placebo; nowadays such a study design would be unethical because we know that joint damage is an early feature of the disease and early and aggressive therapy is now advocated. Moreover, suppletion with only 500 mg calcium daily was prescribed; nowadays potent anti-osteoporotic treatment with biphosphonates inhibits the negative effects of prednisone on bone and reduce fracture rate. In our study, a non-significant reduction of bone mineral density (BMD) was observed in the prednisone group as opposed to a higher vertebral fracture rate: changes in bone structure and strength rather than diminished BMD could explain, at least partially, the higher incidence of fractures. From our results, no significant changes were observed in the GR-expression (number and affinity) and serum cortisol levels in both groups. So, it seems unlikely that GR-expression plays a major role in the aethiopatogenesis of RA. Also, no predictive values could be found for the response on GC treatment. No correlations between GR-number, radiological scores and BMD was found. We were able to study a unique group of early DMARD-naïve patients with RA, treated with a low-dose prednisone without bias, an opportunity not likely to recur. We demonstrated a powerful disease-modifying effect of prednisone in the early phase of RA. This is in concordance with results of other recent studies in early RA. There seems to be a ´window of opportunity´ in the first 2 years of the disease in which aggressive therapy limits joint destruction over time. In this treatment we advocate a low dose prednisone, in combination with other DMARDs. Future studies should concentrate on the lowest possible effective dose in combination therapy