Introduction

Corticosteroids were first shown to be effective in patients with rheumatoid arthritis in 1949 in an uncontrolled study.¹ In 1959, a two year randomised trial showed that an initial dose of prednisolone 20 mg daily was significantly superior to aspirin 6 g daily.² Important adverse effects were also noted, however, and the authors concluded that the highest acceptable dose for long term treatment was probably in the region of 10 mg daily.

Corticosteroids have received renewed interest in recent years because of their possible beneficial effect on radiological progression.³ Tendencies towards such an effect were noted both in the early trials and in a recent report.⁴

These findings are interesting, but oral corticosteroids are still being used mainly for their symptomatic effectfor example, for acute exacerbations of rheumatoid arthritis and as "bridge therapy" before slow acting drugs have taken effect.⁵ The effect of low doses has been variable, however, and was questioned as late as 1995 when the most recent trial of low dose steroids was published.⁶ We therefore performed a systematic review of randomised trials that compared corticosteroids, given at a dose equivalent to no more than 15 mg prednisolone daily, with placebo or with non-steroidal anti-inflammatory drugs. Our review is limited to the short term effectthat is, as recorded within the first weeks of treatment. In an analysis of the adverse effects of steroids, however, we also included long term trials and matched cohort studies.

	Methods

All randomised studies that compared an oral corticosteroid with placebo or a non-steroidal anti-inflammatory drug in patients with rheumatoid arthritis were eligible if they reported clinical outcomes within 1 month after the start of treatment. When there were data from several visits, the data that came closest to 1 week of treatment were used for the analyses. We excluded studies with high dose steroids (exceeding an equivalent of 15 mg prednisolone daily); studies of combination treatmentsfor instance, of a steroid and a non-steroidal anti-inflammatory drug; and studies that used quasi-randomisation methods, such as allocation by date of admission or by toss of a coin (no such studies were actually found). The outcome variables were joint tenderness (usually Ritchie's joint index), pain, and grip strength.

Medline was searched from 1966 onwards and most recently updated in September 1997. We used the Explode option (which searches for a broad term plus related narrower items) for "glucocorticoids" or "glucocorticoids, -synthetic" (for all subheadings) combined with Explode "arthritis-rheumatoid" (for all subheadings) and with "placebos" or "comparative study" in MeSH. The reference lists were scanned for additional trials, and an archive in possession of one of the authors was searched. As most of the retrieved trials were very old and the steroid drugs were non-proprietary ones authors and companies were not asked about possible unpublished studies. We did not handsearch journals for relevant trials as this work is already being organised by the Cochrane Collaboration for all medical journals, including specialist rheumatological journals. The results of these handsearches are made available in the Cochrane Controlled Trials Register in The Cochrane Library,⁷ which we searched with prednisolone and prednisone as text words combined with rheumatoid.

Decisions on which trials to include were taken independently by two observers based only on the methods sections of the trials; disagreements were resolved by discussion. Details on the nature and dose of treatments, number of randomised patients, the randomisation and blinding procedures, and exclusions after randomisation were noted. When an outcome was measured on the same scale in all trials we calculated the weighted mean difference as the summary estimate for the effect. As the outcomes were often measured on different scales, however, even when they referred to the same qualityfor example, tender jointswe also calculated standardised effect measures.⁸ With this method the difference in effect between two treatments is divided by the standard deviation of the measurements. By that transformation the effect measures become dimensionless, and outcomes from trials which have used different scales may therefore often be combined. As an example, the tender joint count may be recorded either as the number of tender joints or as Ritchie's index, in which each joint is scored on a scale from 0 to 3 for pain on firm palpation and the scores added. Often the two types of counts will give similar values, but if the patients have very severe disease Ritchie's index may be higher. The standard deviation will then also be higher, however, and by dividing the counts with their standard deviations (for example, of the baseline measurements) the effect sizes will be of the same magnitude.

The random effects model⁹ was used if P<0.10 for the test of heterogeneity; otherwise a fixed effects analysis was performed. As data from crossover trials were reported in only summary form, as if they had been generated from a group comparative trial, we analysed them accordingly. We therefore assumed that no important carryover effects had occurred.

	Results

Twenty eight randomised trials were initially identified, several of which had been published more than once. Eighteen trials were excluded for various reasons. ^{2 4 5 10-31} Nine trials did not fulfil the inclusion criteria for the meta-analysis: five had studied combinations of drugs ^{10 17-19 27 31} ; two used too high a dose ^{2 20-23} ; in one, 4 mg methylprednisolone was given to all the patients in the placebo group²⁸; and one concerned patients with juvenile rheumatoid arthritis (this trial found prednisolone to be significantly better than placebo).²⁴

The other nine excluded studies were potentially eligible for the meta-analysis. However, one was a five way crossover trial with a grossly unbalanced designfor instance, placebo was given to 9, 13, 3, 6, and 6 patients during weeks 1, 2, 3, 4, and 5, respectively.¹² Because of regression towards the mean we found it inappropriate to include this trial. Another trial was also unbalanced as the steroid group was kept mobile whereas the control group received bed rest and splints for the inflamed joints.²⁵ Two trials were too poorly reported to be usable for the meta-analysis, ^{15 16 26} and one reported only on joint size.²⁹ Three of these four trials found prednisolone or prednisone to be significantly more effective than placebo; the fourth compared prednisolone and indomethacin and gave no numerical data but just reported that there was "no significant difference in response."²⁶ The four other excluded trials were long term studies that did not report short term data. ^{4 5 11 13 14} We contacted the authors of these studies to make sure that no short term data had been recorded without being reported. This was confirmed in two cases ^{4 11} ; we were unable to contact any of the authors of the other two studies or of the study that reported only joint size²⁹ to ensure that no further variables had been recorded.

View larger version (43K): [in this window] [in a new window]   Fig 1.   Results of meta-analysis of low dose prednisolone versus placebo for control of rheumatoid arthritis, according to joint tenderness, pain, and grip strength. *If prednisolone is better than control standardised mean difference is negative for joint tenderness and pain but positive for grip strength. Random effects model was used for joint tenderness and pain, and fixed effects model for grip strength

Ten studies were included in the meta-analysis (table 1). ^{6 32-43} Most of the studies were quite old and rather small. In all but one ^{35 36} the criteria of the American Rheumatism Association for classical or definite rheumatoid arthritis were fulfilled. Age, proportion of women, and duration of disease were reported in only half of the studies but they were typical for studies in rheumatoid arthritis: mean age was 55 years, two thirds were women, and the mean (range) duration of disease was 6 (2.1 to 9.6) years. As expected for patients enrolled in steroid trials the severity of the disease, expressed as number of tender joints or Ritchie's tender joint index, was quite pronounced (see fig 1). Prednisolone was used in six trials and prednisone in four. ^{6 32 34 40 41 43} As prednisone is equipotent with prednisolone and is a pro-drug of prednisolone we have used "prednisolone" as a general term throughout the paper. The doses were 2.5, 3.0, and 7.5 mg in one study each, 10 mg in three studies, and 15 mg in four. The median length of treatment was 1 week.

The randomisation method was not described in any of the trial reports but details were obtained from the authors for one of the studies in which the treatment allocation seemed to have been adequately concealed. ^{6 32} These authors also provided short term data from their long term trial. All studies were double blind apart from a single blind study in which the patients seemed to have been blinded. ^{40 41} Eight of the studies were of a crossover design but only one of them reported having tested for sequence effects.⁴³ Apart from one study⁴³ the tender joint count was recorded as Ritchie's index; pain was recorded on a ranking scale with 4 or 5 classes in two studies, ^{35 36 40 41} on a visual analogue scale in two studies, ^{6 32 33} and as a composite pain index in two studies. ^{38 43}

The results of the meta-analysis are shown in figures 1 and 2. It should be noted that if prednisolone is better than control, the standardised effect size is negative for joint tenderness and pain but positive for grip strength.

View larger version (31K): [in this window] [in a new window]   Fig 2.   Results of meta-analysis of low dose prednisolone versus non-steroidal anti-inflammatory drugs (NSAIDs) for control of rheumatoid arthritis, according to joint tenderness, pain, and grip strength. *If prednisolone is better than control standardised mean difference is negative for joint tenderness and pain but positive for grip strength. Random effects model was used for joint tenderness and pain, and fixed effects model for grip strength

Prednisolone had a clear effect over placebo on joint tenderness (standardised effect size 1.31; 95% confidence interval 1.83 to 0.78), pain (1.75; 2.64 to 0.87), and grip strength (0.41; 0.13 to 0.69). Measured in the original units, in an analysis of the weighted mean difference the difference between prednisolone and placebo was 12 tender joints (95% confidence interval 6 to 18; test for heterogeneity ² 46.42, df=6; P<0.00001). The effect on grip was always measured in mm Hg or in kPa. After conversion of kPa to mm Hg the superiority of prednisolone over placebo was 22 mm Hg (95% confidence interval 5 mm Hg to 40 mm Hg; test for heterogeneity ² 5.47, df=5; P=0.36).

Prednisolone also had a greater effect than non-steroidal anti-inflammatory drugs on joint tenderness (0.63; 1.16 to 0.11), pain (1.25; 2.24 to 0.26), and grip strength, although the difference in grip strength was not significant (0.31; 0.02 to 0.64). Measured in the original units the difference between prednisolone and non-steroidal anti-inflammatory drugs was 9 tender joints (5 to 12; test for heterogeneity ² 4.06, df=3; P=0.26). The effect on grip strength showed a non-significant superiority of prednisolone over non-steroidal anti-inflammatory drugs of 12 mm Hg (6 mm Hg to 31 mm Hg; test for heterogeneity ² 3.03, df=3; P=0.39).

	Discussion

Our meta-analysis has shown that low dose prednisolone is not only highly effective but also significantly more effective than non-steroidal anti-inflammatory drugs. The point estimate for the difference in effect between prednisolone and non-steroidal anti-inflammatory drugs on grip strength was 12 mm Hg. It is interesting that the point estimate for the difference in effect between non-steroidal anti-inflammatory drugs and placebo was also found to be 12 mm Hg in an earlier meta-analysis.⁴⁴ It was not surprising that the difference in effect on grip strength between prednisolone and non-steroidal anti-inflammatory drugs was not significant as this effect measure is considerably less sensitive to change than pain and joint tenderness.⁴⁵

We used a random effects model for some of the analyses because of heterogeneity. Which model to use is a matter of dispute among statisticians, but the results were not too different if analysed with a fixed effects model, which gave standardised effect sizes for prednisolone versus placebo of 1.23 (1.51 to 0.95) for joint tenderness and 1.35 (1.63 to 1.08) for pain, and for prednisolone versus non-steroidal anti-inflammatory drugs of 0.61 (0.95 to 0.27) for joint tenderness and 0.97 (1.32 to 0.63) for pain.

Heterogeneity
It is always important to try to explain heterogeneity. Our attempts to do so, however, have been rather unsuccessful. As most of the studies were done more than 20 years ago an obvious reason for the heterogeneity could be that the earlier trials had overestimated the effectfor instance, because of insufficiently concealed randomisation methods.⁴⁶ The methodological quality of the trials was acceptable in the whole time span of nearly 30 years, however, and it was, for example, similar to the quality of comparative non-steroidal anti-inflammatory drug trials.⁴⁷ In accordance with this there were no time trends for the differences in joint tenderness and pain between prednisolone and placebo. There was marginal heterogeneity (P=0.08) for the difference between prednisolone and non-steroidal anti-inflammatory drugs in joint tenderness, but the heterogeneity disappeared when the analysis was performed in the original units (P=0.26).

Included trials
The titles of the included trials were generally quite uninformative and some of the them were not easy to find as they were performed within experiments designed to study other factors. Several of the studies were retrieved from an archive in possession of one of the authors assembled during work on a thesis⁵⁰ before the electronic data searches were performed. The authors of the most recent study in this topic ^{6 32} had found only one of five trials comparing steroids with placebo in long term studies and none of the nine short term trials included in our review. These short term trials were described in 11 reports that were all indexed in Medline with the term for rheumatoid arthritis; in addition, all but one³⁸ contained the terms for clinical trial or comparative study. Further, all nine trials were identifiable by using the search term "placebo*" and ("prednisone" or "prednisolone"). This illustrates the value of a systematic and careful search of the literature before starting new clinical trials, and funding bodies and ethical review committees should demand a systematic review of the relevant literature before approving of new clinical research.⁵¹

Adverse effects
It is not easy to get a clear picture of the adverse effects of low dose steroids. Five of our short term studies did not report on side effects; one study reported that no side effects occurred³⁸; two patients on prednisone had "subjective reactions" in one study³⁴; and one patient developed acute psychosis while on prednisone in one study. ^{40 41} The two remaining studies were moderate term studies from which we extracted short term efficacy data. ^{6 32 43} These studies did not report short term side effects but are included in the analysis of moderate or long term adverse effects below.