Balancing the benefits and risks of low-dose glucocorticoid in rheumatoid arthritis.

Glucocorticoids have potent anti-inflammatory and immunomodulatory effects and are widely use in the management of rheumatoid arthritis in combination with other synthetic and with biological disease-modifying anti-rheumatic drugs. Concerns about the risk of adverse effects of glucocorticoids, especially if they are given at higher dosages and for a longer time, hamper their use despite the clear symptomatic and disease modifying benefits. However, the evidence base for these concerns for low dose glucocorticoid therapy is quite limited due to the scarcity of quality literature on its safety in rheumatoid arthritis. This review discusses the current understanding about their disease-modifying effects, toxicity data from recent trials and observational studies, recommendations for their management and the current efforts to improve the therapeutic ratio of glucocorticoid through the development of new formulations, such as modified-release prednisone. Introduction With over 60 years of experience, the number of patients treated with glucocorticoids (GCs), and the range of clinical applications are more extensive than with any other treatment. GCs represent a true anchor treatment for rheumatoid arthritis (RA). This is supported by data indicating that up to 60% of all patients with RA in Germany are treated with GCs at some time during the course of their disease (1). Similarly, 34 to 93% of all patients entering recent clinical trials of biologics, and thus with active disease, were receiving GCs at baseline (2). Such data are in contrast with the literature predominantly addressing the risks of these agents and the caution advised by every treatment recommendations. Clinicians, and presumably patients, seem thus to value the anti-inflammatory, immunosuppressive and disease-modifying therapeutic effects of GCs. In contrast, both the literature and the medical community seem to be split between those in favour and those against the use of low-dose GCs in RA. This contention cannot be resolved without a clear understanding of the potential risks of adverse effects of these drugs. Unfortunately, currently available evidence is limited, but the need to optimize benefit-risk ratio of GCs represents a continuous challenge to the practicing clinician. This review reinforces the need for balancing risks and benefits of GCs use in RA, with a focus on chronic oral therapy. First, we address the rapid effect of GCs on disease activity and their long-term effects on radiographic damage, followed by their prolonged use in controlled disease. Next, we discuss the toxicity of low-dose GC therapy. Finally, we describe strategies and recommendations for its safe use and new therapeutic approaches, including chronotherapy, which may improve our ability to tailor treatment to the individual patient’s needs. A. Benefits Symptomatic benefit In active RA, prednisone is frequently added for a short period to the treatment regimen to rapidly minimize disease activity while awaiting a clinical response to a slower-acting disease-modifying antirheumatic drugs (DMARD). A review (3) provided evidence of short-term benefit in RA: a dose below prednisolone 15 mg/day is more effective than either placebo or a nonsteroidal anti-inflammatory drugs (NSAID), with a large effect size of 1.75 on pain. In 2000, a Cochrane meta-analysis (4) including 7 studies (253 patients in total) evaluating the symptomatic effect of GCs treatment in RA, concluded that prednisone (or a comparable GC preparation) at a mean dosage of less than or equal to 15 mg/day for a period of 6 months, was significantly more effective than placebo controls, with an effect size for pain of 0.43. Significant improvement was also documented in other outcomes measures: standardized mean difference for tender joints = -0.37 (95%CI: -0. 59 to -0.14), swollen joints = -0.41 (-0.67 to -0.16) and functional status = -0.57 (-0.92 to -0.22). Another meta-analysis of short-term (median length of treatment was one week in the ten studies included) found that prednisolone (<15 mg/day) had a clear superior effect on pain compared to placebo (standardized effect size 1.75; 0.87 to 2.64) and compared to NSAIDs (1.25; 0.26 to 2.24) (3). Recently, numerous clinical trials in early RA have demonstrated significant symptomatic benefit and clinical improvement, already at 3 months after start of therapy, which is maintained at all time points thereafter, until 2 years of follow-up (5-7) - Table 1. In the Arthritis Research Council (ARC) trial (8), the patients in the prednisolone group had greater reductions than the patients in the placebo group in scores on an articular index and for pain and disability at 3 months; for pain at 6 months; and for disability at 6, 12, and 15 months (all p < 0.05). In 2002, van Everdingen et al. (5) found a greater clinical improvement in multiple measures particularly in the first 6 months in the 10 mg/day prednisone treated group. However, this additional benefit was sustained only for joint tenderness at 24 months. The Better Anti-Rheumatic FarmacOTherapy (BARFOT) study (6) compared the addition of 7.5mg/day prednisolone to methotrexate (MTX) or sulfasalazine (SSZ) with DMARD alone in 250 patients with a disease duration of less that one year. The patients treated with DMARD plus prednisolone had a significant reduction of DAS28 and HAQ score. These differences were already seen at 3 months, and were present at all time points thereafter during the 2-years of follow-up. In the prednisolone group, the mean (SD) DAS28 decreased from 5.3 (1.1) to 2.7 (1.5) versus 5.4 (1.0) to 3.3 (1.5), (p<0.001) after 1 year, and to 2.7 (1.3) versus 3.2 (1.4), (p<0.005) after 2 years. After 1 year, 51% of patients in the prednisolone group had achieved disease remission compared with 39% of patients in the no-prednisolone group (P = 0.06). After 2 years, this difference had increased to 56% in the prednisolone group compared with 33% in the placebo group (P = 0.0005). The Computer Assisted Management in Early Rheumatoid Arthritis trial-II (CAMERA-II) (7) evaluated the effect of prednisolone 10 mg/day from start added to an MTX-based strategy with computer-assisted dose adjustments based on the level of disease activity versus the effect of the MTX-based strategy with placebo-prednisone in 236 patients with a symptom duration <1 year. Also this treat-to-target (target was remission) study (7) confirmed the efficacy of prednisone 10 mg/day added to DMARD in reducing disease activity and physical disability at 24 months. The patients treated with prednisone at 10 mg/day had more symptomatic benefit during the first three months - mean difference of DAS28 was -1.56 (CI, -1.88 to -1.25). This difference was sustained but was not significantly different anymore at the end of two years: -0.26 (CI, -0.68 to 0.16), because both step-up strategy arms were aimed at remission. The response rates after 1 year of treatment for the MTX-based strategy plus prednisone and the MTX-based strategy plus placebo were respectively for the ACR20 70% versus 66% (P = 0.45); for the ACR50 56% versus 43% (P= 0.037), and for the ACR70 27% versus 26% (P = 0.82). Similar differences were seen at 2 years: these response rates were 65% versus 61% (P = 0.56) for the ACR20, 53% versus 42% (P =0.091) for the ACR 50, and 38% versus 19% (P =0.002) for the ACR70.