Insufficient Data on Glucocorticoid Use in RA Trials

Rieke H. E. Alten

Disclosures

Nat Rev Rheumatol. 2011;7(6):318-319. 

Abstract and Introduction

Abstract

Glucocorticoids, such as prednisone, are often administered concomitantly with biologic agents for the treatment of rheumatoid arthritis. An evaluation of the main studies of biologic agents reveals that information about such therapy is insufficiently reported, which could have important consequences.

Introduction

Comparing the safety and efficacy of biologic agents in rheumatoid arthritis (RA) is complicated by the limits of trial design. In order to draw firm conclusions, careful analysis of data from several trials, with heterogeneous designs, is often required. But what happens when a study of a biologic agent does not report the use of a concomitant medication, such as glucocorticoids? How are conclusions about the effects of the biologic therapy to be reached? In their article published in Joint Bone Spine, André et al.[1] assessed the reported information on the use of the glucocorticoid prednisone in patients with RA enrolled in the main studies of biologic agents published between 1994 and 2010. They found that the status (whether the drug was used or not) of concomitant prednisone therapy was specified in only 56 (85%) of the 66 publications reviewed. In addition, the percentage of patients who received concomitant prednisone treatment ranged from 34% to 93% across the studies, and varied across biologic drugs (abatacept, 74.4%; golimumab, 67.9%; infliximab, 60.6%; certolizumab 57.5%; rituximab, 57.5%; etanercept, 54.4%; tocilizumab, 52.8%; adalimumab, 50.4%). Owing to a lack of head-to-head comparison studies, the reasons for this variation across drugs cannot be explained on the basis of available data.

Regarding the dose of glucocorticoids specifically, data needed to calculate the mean daily dose of prednisone in patients receiving this agent were available for only 12% (8/66) of the studies, and in these studies the mean dosage ranged from 5–9 mg per day. Moreover, the maximum allowed prednisone dosage was indicated in just 39 (59%) of the evaluated studies. Only 42 of the 66 (64%) reports specified that the prednisone dosage remained the same during the study. It is noteworthy that barely any (3%) of these studies contained information on all the following items: mean prednisone dose (mg per day), the maximum dosage of prednisone allowed and the proportion of patients administered >10 mg of prednisone per day.

Despite the introduction of new biologic agents, glucocorticoids remain an important class of drug in the treatment armamentarium against RA. Goekoop-Ruiterman et al.[2] showed in the BeSt trial that in patients with recent-onset RA, concomitant treatment with prednisone (at a maintenance dose of 7.5 mg per day) and three DMARDs (either ciclosporin, azathioprine or gold) resulted in clinical improvements comparable to those in patients receiving infliximab in conjunction with methotrexate. The results of a meta-analysis published in 2010 that analyzed the effects of various antirheumatic treatment regimens (including combinations of different drugs) on radiographic progression showed that in a direct comparison there was no difference between the combination of a biologic agent in conjunction with methotrexate and the combination of two DMARDs plus initial glucocorticoids.[3]

Nevertheless, it is well known that continued glucocorticoid treatment in conjunction with biologic agents is associated with several adverse effects, mainly infections. Only a few studies, however, have investigated the increased risk of infections related to glucocorticoid therapy in combination with a biologic agent. The results of the most recent meta-analysis of glucocorticoid-induced adverse effects (published in 2009),[4] which included data from 1,066 German patients with RA, showed that the frequency of a number of different adverse events was lower in patients who received prednisone at a dose <7.5 mg per day compared with those who received dosages >7.5 mg per day.[4] However, the frequency of certain adverse events, including mycosis, shortness of breath and leg edema, increased with an increase in the glucocorticoid dose. Whereas mycosis developed in only 4.5% of patients who had not been given glucocorticoids in the past 12 months, this adverse event was reported in 20.6% of those who had received glucocorticoid treatment for more than 6 months (5.8% of patients receiving <5 mg per day, 6.6% of patients receiving 5–7.5 mg per day and 8.2% of patients receiving >7.5 mg per day). Nonetheless, André et al.[1] found that only a few studies indicated that a proportion of patients received prednisone at a dose of >10 mg per day, and in many studies the data on mean daily dose and/or maximum dosage were not available. This lack of information makes it difficult to assess the effects of glucocorticoid treatment on the adverse events reported in most studies of biologic agents in RA.

Given the effects of glucocorticoids on patient outcomes, the use of concomitant glucocorticoids could have an effect on the results of studies of biologic agents in patients with RA. The additional administration of glucocorticoids reflects increased disease activity in the study populations that receive them. Nevertheless, glucocorticoid therapy can result in clinical improvement. This notion was confirmed in a trial that included patients with recent-onset RA (n = 150) where the 2-year remission rate in patients receiving prednisone at a dose of 7.5 mg daily (in addition to initial DMARD therapy) was nearly double that in patients who were administered DMARD therapy but no prednisone (55% versus 30%, respectively).[5] In another trial in patients with RA, the probability of being in remission was four times higher in individuals who received treatment with 5.0–7.5 mg of prednisone daily in addition to a biologic agent (n = 105) than in those who were not given prednisone (n = 105).[6] These findings suggest that the variation in response and remission rates seen across biologic agents could be caused by, among other factors, differences in the concomitant glucocorticoid regimen; therefore, it is important to take this information into account in the design and reporting of studies.

Awareness regarding disease flares in RA is growing. However, limited data are available from randomized clinical trials on the incidence of flares in RA after changes to the dose of and tapering of glucocorticoids. Two randomized, double-blind, placebo controlled trials were conducted in patients with RA to monitor the effects of prednisone withdrawal.[7,8] In these studies, disease flares were repeatedly documented following withdrawal of glucocorticoids, confirming the beneficial effect of prednisone in RA therapy. However, the definition of disease flare varied across these studies. Pincus et al.[7] defined stable status as an absolute change of less than 3 units (on a 0–30 scale) over 12 weeks on the RAPID3 (routine assessment of patient index data 3) index, whereas an increase of more than 3 units was considered a flare. By contrast, Tengstrand et al.[8] defined an increase in disease activity as worsening in the 28-joint Disease Activity Score and the Health Assessment Questionnaire score. The OMERACT (Outcome Measures in Rheumatology Clinical Trials) RA Flare Definition Working Group[9] developed a definition of a disease flare as "any worsening of disease activity that would, if persistent, in most cases lead to initiation or change of therapy; and a flare represents a cluster of symptoms of sufficient duration and intensity to require initiation, change, or increase in therapy." Given these discrepancies, the development of a questionnaire to assess the frequency of disease flares in patients with RA might help to better elucidate the effect of the administration of prednisone on disease activity.

In summary, the study conducted by André et al.[1] showed that most reports on the efficacy and safety of biologic agents in patients with RA provided inadequate information on concomitant prednisone therapy. This lack of reporting of prednisone use has consequences for the interpretation of the original studies themselves as well as being a confounding factor in existing meta-analyses. In order to assess the efficacy and safety of biologic agents in an unbiased manner it should be mandatory for all future studies to provide information on whether the patients enrolled receive any concomitant glucocorticoid treatment and if they do, detailed information regarding the medication (duration; dosage and change of dosage or other modifications) should be reported.

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