The effect of treatment on radiological progression in rheumatoid arthritis: a systematic review of randomized placebo-controlled trials

G. Jones, J. Halbert1, M. Crotty1, E. M. Shanahan2, M. Batterham1 and M. Ahern2

Menzies Centre for Population Health Research, GPO Box 252-23, Hobart, Tasmania 7000,
1 Department of Rehabilitation and Aged Care and
2 Department of Medicine, Flinders University, Bedford Park, South Australia 5042, Australia


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To undertake a systematic review of randomized placebo-controlled trials to assess and rank the efficacy of pharmacological interventions in preventing radiological progression of rheumatoid arthritis.

Methods. The two outcome measures were the weighted standardized mean difference and the odds of progression of X-ray scores pooled as close to 12 months as possible to minimize heterogeneity.

Results. A total of 38 trials were identified. Of these, 13 were excluded, leaving data on 3907 subjects. Infliximab, cyclosporin, sulphasalazine, leflunomide, methotrexate, parenteral gold, corticosteroids, auranofin and interleukin 1 receptor antagonist were statistically better than placebo in terms of change in erosion scores. All agents were equivalent statistically, with the exception of infliximab (which was superior to the last five agents). There were similar findings for the odds of progression, with the exception of auranofin (P=0.06) and the infliximab–methotrexate comparison (P=0.07). Other agents did not reach statistical significance in either outcome measure. With the exception of the antimalarials, the magnitude of the effect was consistent with the effect seen in short-term disease activity trials.

Conclusion. There is published evidence which supports the efficacy of nine agents in decreasing radiological progression in rheumatoid arthritis.

KEY WORDS: Rheumatoid arthritis, Meta-analysis, Therapy, Radiographic, Trial, Placebo.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Rheumatoid arthritis is a common and serious inflammatory arthritis of unknown cause with a prevalence of 0.3–1.5% of the population [1]. Assessment of both outcomes and response to therapy with rheumatoid arthritis is multifaceted. Most studies are short-term in nature and concentrate on a combination of subjective and objective variables which assess disease activity. However, while short-term benefits are well demonstrated for a number of therapeutic agents [2], the long-term significance of these remains unclear. Longer-duration studies can measure disability but it is clear that factors apart from disease severity impinge on disability [3]. Arguably the most unambiguous method to assess rheumatoid arthritis activity over time is by change in X-ray scores, and accurate and reproducible methods for assessing this have been developed, such as the Larsen and Sharp scores [4, 5]. Reviews about the effect of therapeutic agents on radiological progression have been inconclusive [6]. This has been due to the small numbers of trials, often small numbers of subjects and the widely varying methods of reporting X-ray changes, making it difficult to combine studies and estimate overall effects. In this study, we used the technique of meta-analysis to calculate two directly comparable outcomes and rank the various treatments for rheumatoid arthritis in terms of their effect on radiological progression.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Search strategy
We identified trials by a systematic search of the Cochrane controlled trials register, Medline (1966–2000) and Embase. The search was supplemented by manually searching bibliographies of previously published reviews and papers as well as conference proceedings of the American College of Rheumatology. Trials were identified using the Cochrane optimal search strategy for randomized trials [7], including terms for rheumatoid arthritis, pharmacological interventions and X-ray outcomes. We also contacted pharmaceutical companies and authors for unpublished data.

Inclusion criteria
For inclusion in this meta-analysis, studies had to be randomized trials examining the effectiveness of one or more pharmacological interventions in adult rheumatoid arthritis. All pharmacological interventions were eligible. The studies needed to have a placebo (or equivalent) control group, radiographic scoring of erosions as a reported outcome, and a minimum of 24 weeks between the start of the trial and the last X-ray, even if treatment ceased before 24 weeks. Trials in which the placebo group were given aspirin (or other non-erosion-affecting medications) were included, as were trials that allowed other disease-modifying anti-rheumatic drugs (DMARDs) or corticosteroids, both before and after randomization, if the dose remained constant. Trials that allowed these to be modified after randomization were excluded.

Trials were excluded when the published report did not state that the allocation to intervention was random, a placebo group was absent, or the follow-up period was shorter than 24 weeks. Trials were also excluded if the published report did not contain adequate data for inclusion and these data could not be obtained from the original authors. Only articles published in English were included, due to the necessity for a full-text evaluation to assess study quality. Participants must have had adult rheumatoid arthritis according to the American College of Rheumatology criteria or, in the case of older trials, active rheumatoid disease.

Data extraction
Efficacy data were extracted from the published reports by two authors independently. Disagreements were resolved by discussion involving a third investigator. In trials where the results were not expressed in a form allowing extraction of data, we approached the investigators by letter for more information. Seven investigators were approached; four responded and three provided data. This was not attempted for older trials.

Descriptive information was also collected, including the methodology of the trial, total number of participants randomized, number of participants who completed the trial, age and gender of the participants, duration of disease, length of treatment, dosage of treatment, description of control group activities, length of follow-up, intention-to-treat analysis, and type of radiological outcome measured.

Quality assessment
The methodological quality of the studies reviewed was assessed using a scheme described previously [8], which was modified by us for use in rheumatology clinical trials [9]. For this purpose, ‘quality’ is defined in terms of the measures taken by the investigators to minimize bias in each trial. The trials were scored independently of the method of data extraction and were rated in the range 0–3 on each of the following features: (i) the degree to which randomization was truly blind; (ii) the inclusion of data from subjects who subsequently withdrew from the study (intention to treat); (iii) the degree to which assessors of outcome were blind to treatment allocation; and (iv) the comparability of treatment and control groups at entry. Scores for individual quality outcomes were summed for the purpose of analysis. The total possible score was 12 points.

Outcome measures and statistics
The principal outcome measure examined by this review was radiographic scoring of bone erosion in joints. A number of scoring systems were accepted, including Larson, Sharp, erosion counts, and progression. Intention-to-treat analyses were preferred where available. To allow direct comparison and pooling between studies, we calculated two dimensionless outcome measures: the standardized mean difference and the odds of worsening X-ray scores.

Standardized mean difference (SMD)
This measure compares treatment and placebo in terms of a standardized score. The difference is converted to standard deviation units for that particular measure [10], which is directly analogous to the disease activity index derived by Goldsmith et al. [11]. Thus, a treatment that is 1 unit better than placebo is 1 standard deviation better in terms of the original units for that erosion score. A large effect is equivalent to 1 unit, a moderate effect to 0.5 and a small effect to 0.3 units [12]. The SMD was calculated as the difference between the mean change in erosion score (baseline minus final value) in both the intervention and control groups divided by the standard deviation of the difference. The variance of this difference is best calculated using the paired baseline and final erosion scores for each individual. However, none of the trials presented sufficient information to allow this. Consequently, we adopted a conservative approach and calculated the variance of the difference between means, which required us to assume that the baseline and final erosion scores were unpaired.Go



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FIG. 1. Efficacy of therapy for preventing radiological progression in rheumatoid arthritis. There is statistical evidence of efficacy for eight agents. Infliximab is superior to methotrexate and all agents below it in the figure. Summary data are presented as the weighted SMD and 95% confidence interval.

 

Odds of worsening X-ray scores
Progression of erosions was calculated as the number of patients in each treatment group whose erosions worsened at follow-up divided by the number of patients remaining in that group at follow-up. The effect was then measured as the odds of worsening erosions in the intervention compared with the control group. It was not possible to calculate the odds of worsening erosions on an intention-to-treat basis due to the often substantial dropout rate of most included trials.

Trials were pooled as close to 12 months as possible to minimize possible heterogeneity associated with different trial durations. Both SMD and odds ratio calculations were weighted according to the inverse of the standard error of each individual trial. Ninety-five per cent confidence intervals were calculated for the pooled effect size, using fixed-effect models on Revman 3.1 [7], although, in the current study, identical results were obtained with random effect models. Tests of heterogeneity were performed using the Mantel–Haenszel method [13]. Standard t-tests were used for comparison of mean treatment effects between X-ray trials and disease activity trials (derived from [2]). A P value <0.05 (two-tailed) or a 95% confidence interval not including the null point was regarded as statistically significant. Superiority of a particular treatment over another was defined as the point estimate of the inferior agent not including the 95% confidence interval of the superior agent.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Description of studies
A total of 38 relevant trials were identified. The 25 included trials had a total of 3907 patients (Table 1Go). There were five trials examining corticosteroids [1418], three for parenteral gold [1921], two for sulphasalazine [22, 23], leflunomide [23, 24], auranofin [25, 26], hydroxychloroquine [27, 28], chloroquine [29, 30] and pamidronate [31, 32], and one each for cyclosporin [33], minocycline [34], methotrexate [24], cyclophosphamide [35], D-penicillamine [36], interleukin 1 (IL-1) receptor antagonist [37] and infliximab [38]. There were no placebo-controlled trials of combination therapy, azathioprine or etanercept with radiological outcomes. Radiological scoring of erosions included Larsen, Sharp, counts, progression, narrowed joints and new erosions and a grading of severity (Table 1Go).


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TABLE 1. Characteristics of included trials: therapeutic agents in rheumatoid arthritis with X-ray outcomes

 

Concomitant DMARD/NSAID use
Thirteen studies allowed the concomitant use of corticosteroids [2226, 30, 3238]. While four trials allowed doses up to 10 mg/day of prednisolone equivalent [23, 34, 37, 38], the remaining studies used 7.5 mg/day or less. Of the studies trialling corticosteroids, one allowed any DMARD other than systemic corticosteroids [18] and one trial put all subjects on 150 mg daily of penicillamine [17]. Five trials excluded the use of non-interventional DMARDs [15, 19, 21, 29, 38]. In one trial, all patients were on gold [27] while in another all were on methotrexate [38]. Only two trials did not allow non-steroidal anti-inflammatory drugs (NSAIDs) [29, 35] and one trial used daily prednisolone to reduce the use of NSAIDs [25].

Methodological quality of included studies
In 10 trials the method of assignment was blinded [1721, 23, 24, 27, 29, 38]. Only two trials [16, 32] reported no patients lost over the course of the study. For the other trials, the mean number of participants lost at final follow-up was 45 (S.D. 44) with a range of 3–136. For these trials, the total number of participants lost as a percentage of participants randomized was on average 24% with a range of 9–51%. Only two trials [15, 22] lost fewer than 10% of randomized patients. In five trials, the dropout rates were>10% different between the intervention and control groups, three trials [19, 27, 36] losing more patients from the intervention group and two [33, 38] losing more from the controls. Ten trials analysed data on an intention-to-treat basis (Table 1Go); with the exception of one trial [20], they reported all dropouts and reasons for dropout. Sixteen trials [1619, 2123, 2628, 31, 33, 34, 3638] reported that the study personnel responsible for measuring outcomes were blinded to the allocation of the participants. With the exception of one trial [32], trials reported good comparability between the intervention and control groups at entry. There was no significant association between quality score and efficacy (data not shown).

The 13 excluded studies involved 985 subjects (Table 2Go). Of these trials, three were of cyclophosphamide [3941], two each of auranofin [42, 43], hydroxychloroquine [44, 45], parenteral gold [42, 46], and D-penicillamine [47, 48], and one each of sulphasalazine [46], prednisone [49], pamidronate [50], and calcitonin. Three of these trials were excluded due to switching of treatment [42, 50, 51] and the rest had non-extractable data.


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TABLE 2. Characteristics of excluded placebo-controlled trials greater than 24 weeks' duration with X-ray outcomes

 

Effect of pharmacological treatments on erosion scores (Table 3Go)
In rank order, cyclosporin, infliximab, sulphasalazine, leflunomide, methotrexate, parenteral gold, corticosteroids, auranofin and IL-1 receptor antagonist were statistically better than placebo in terms of changes in erosion scores. All agents were equivalent statistically, with the exception of infliximab, which was superior to the last five agents. No difference was observed with varying doses of corticosteroids. No agents exhibited statistical heterogeneity. Non-significant and generally smaller effects were observed for pamidronate, chloroquine, hydroxychloroquine, minocycline and cyclophosphamide.


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TABLE 3. Standardized mean difference for change in erosion scores ranked by effect size

 

Effect of pharmacological treatments on progression of erosions (Table 4Go)
In rank order, infliximab, leflunomide, methotrexate, parenteral gold, sulphasalazine and corticosteroids were statistically superior to placebo in terms of the odds of progression. For this outcome, infliximab was superior to parenteral gold, corticosteroids, auranofin and IL-1 receptor antagonist. Non-significant and generally smaller effects were observed for auranofin (P=0.06), D-penicillamine, chloroquine, low-dose corticosteroids and hydroxychloroquine.


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TABLE 4. Odds of progression of radiographic damage ranked by effect size

 

Comparison with disease activity scores (Table 5Go)
While the magnitude of the effect appeared consistently less with erosion outcomes, the SMDs obtained from this overview were statistically equivalent to the pooled treatment effects from short-term trials, with the notable exception of antimalarials.


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TABLE 5. Relationship between summary measures of disease activity and erosion scores for treatment vs placebo in rheumatoid arthritis

 


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This is the first statistical review of therapeutic trials in rheumatoid arthritis with radiological outcomes. It provides evidence of efficacy for infliximab, cyclosporin, sulphasalazine, leflunomide, methotrexate, parenteral gold, corticosteroids, auranofin and IL-1 receptor antagonist. Current published data do not provide efficacy for D-penicillamine, hydroxychloroquine, pamidronic acid, minocycline, chloroquine and cyclophosphamide, although, with the exception of cyclophosphamide, all agents showed a trend to improvement compared with placebo. There were no published placebo-controlled data for azathioprine or etanercept. With the exception of antimalarials, these results parallel the short-term effects on disease activity measures.

It has previously been very difficult to combine trials with radiological outcomes in rheumatoid arthritis due to the different methods of assessment. In this study we were able to convert the various measures of erosive disease into dimensionless units to allow direct pooling and comparison between agents. Of note, while effect sizes varied from -0.74 to +0.37 for SMDs and from 0.22 to 0.69 for the odds ratios, the confidence limits for virtually all the agents that were statistically superior to placebo overlapped. This indicates that, with the possible exception of infliximab (both outcome measures) and high-dose corticosteroids (odds of progression), all agents are similar in terms of radiological progression as single-agent treatments in rheumatoid arthritis. The apparent superiority of infliximab was due to the narrow confidence intervals around the point estimate. This would suggest that any decision on which agent to use will depend on patient acceptance, compliance, toxicity and cost rather than superior efficacy, although one caveat to this is that the dose of methotrexate trialled was lower than is currently commonly used in rheumatoid arthritis with only 61% of the patients being on 15 mg per week. In addition, with the exception of antimalarials, the effect size in terms of standard deviation units was very comparable to those reported for disease activity [2], suggesting that short-term trials may be predictive of longer-term disease modification. The magnitude of the effect was small to medium rather than large [12]. However, by partitioning by percentage progressing we were able to determine that effective treatments could decrease the odds of progression by 53–78%, which is substantial, although the absolute reduction in progression is less in milder disease. The two outcome measures led to similar conclusions with the exception of auranofin, which was significant for one but not the other, for which it was of borderline significance (P=0.06), suggesting that the SMD may be more sensitive to change than the odds ratio, as the data for both came from the same two trials.

The design of this study does not allow assessment of combination therapy as there were no placebo-controlled studies and the pooling of interdrug comparisons has significant methodological shortcomings, particularly given the marked heterogeneity evident in progression rates in the placebo groups included in this overview. This heterogeneity is due partly to the marked variation in the definition of progression used in the original studies, but does not appear to have affected the comparisons across groups. However, this variation means that it is not possible to hypothesize whether these benefits would be additive with multiple treatments, which would need to be assessed in separate trials. Lack of benefit with azathioprine may possibly be inferred from three recent trials all suggesting that it is inferior to methotrexate in terms of radiological progression [5254]. Etanercept, however, was recently demonstrated to be superior to methotrexate, suggesting that it is also superior to placebo [55].

There are a number of potential limitations in this review, stemming from the methodological shortcomings of the primary trials. In general, the trial sizes were small and had insufficient statistical power. Often, there was only one trial of an agent included in the review and a significant result with one trial can be easily offset by one unpublished negative trial [56]. However, it should be noted that most of the studies included in this review were considered inconclusive by their authors, suggesting that this bias may be less likely in longer-term trials in rheumatoid arthritis. Many of the studies did not perform intention-to-treat analysis, which is especially relevant given the often substantial dropout rates in these longer-term trials. In addition, quality scores varied greatly and inclusion criteria varied somewhat between trials, particularly with regard to other DMARDs permitted and disease duration. This would appear to result in subjects with milder disease being included in the later studies. For example, in the leflunomide trials 12–16% of the placebo group progressed radiologically [23, 24], compared with much higher rates in earlier trials, e.g. 92% for parenteral gold [20]. However, pooling of the data did not introduce any statistical heterogeneity. This might have been expected if this bias had an effect on disease outcome and suggests that treatments are effective regardless of disease duration and severity. Lastly, radiographic data in rheumatoid arthritis trials are often skewed, which may invalidate the use of parametric statistics. Of note, however, is the concordance between the two outcome measures, only one of which is parametric, suggesting both outcome measures are valid in this case.

Many trials were excluded due to clear-cut issues which will not affect the validity of this meta-analysis, such as lack of a placebo group, non-random treatment allocation, study duration or lack of an X-ray measure. However, trials that were excluded for non-extractable data may have biased this study. There were 13 trials in this category. These included three placebo (or equivalent) trials of cyclophosphamide. Two low-dose trials concluded there was no benefit [40, 41] while a high-dose trial did show a significant benefit on radiological progression, but this was associated with very high toxicity [39]. One of the two auranofin studies also showed a significant benefit, which would strengthen the position of this agent [43], while another could not be included due to switching of treatment [42]. The missing data on D-penicillamine and hydroxychloroquine may have strengthened their respective positions, although the effect size we report with the latter was very small. The excluded corticosteroid trial showed no absolute difference between prednisolone and placebo [49] and its inclusion would have weakened the position of corticosteroids, although one of the included studies showed a larger benefit at 2 yr, partially offsetting this effect [18]. The last excluded trial on pamidronate also suggested a benefit with this agent that was obscured by variation in DMARD use [50]. This may be worth further trials, given that the magnitude of benefit is similar to that for the IL-1 receptor antagonist. Calcitonin, on the other hand, was clearly ineffective [51].

In conclusion, there is published evidence which supports the efficacy of nine agents in decreasing radiological progression in rheumatoid arthritis. Most of these agents are equivalent statistically and it remains to be seen if combination therapy is synergistic. Lastly, with the notable exception of the antimalarials, the magnitude of the effect is consistent with the effect seen in short-term disease activity trials.


    Acknowledgments
 
We would like to thank Stephen Blair and Associate Professor J. W. G. (Hans) Jacobs for the provision of data not contained in the original papers.


    Notes
 
Correspondence to: G. Jones. E-mail: g.jones{at}utas.edu.au Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 9 February 2001; Accepted 16 May 2002