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Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Objective

To define the differences in effects on joint destruction in rheumatoid arthritis (RA) patients between therapy with single and combination disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and biologic agents.

Methods

Randomized controlled trials in RA patients, investigating the effects of drug treatment on the percentage of the annual radiographic progression rate (PARPR) were included in a meta-analysis performed with the use of Review Manager 5.0 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol.

Results

Data from 70 trials (112 comparisons, 16 interventions) were summarized in 21 meta-analyses. Compared with placebo, the PARPR was 0.65% smaller in the single-DMARD group (P < 0.002) and 0.54% smaller in the glucocorticoid group (P < 0.00001). Compared with single-DMARD treatment, the PARPR was 0.62% smaller in the combination-DMARD group (P < 0.001) and 0.61% smaller in the biologic agent plus methotrexate (MTX) group (P < 0.00001). The effect of a combination of 2 DMARDs plus step-down glucocorticoids did not differ from the effect of a biologic agent plus MTX (percentage mean difference –0.07% [95% confidence interval –0.25, 0.11]) (P = 0.44).

Conclusion

Treatment with DMARDs, glucocorticoids, biologic agents, and combination agents significantly reduced radiographic progression at 1 year, with a relative effect of 48–84%. A direct comparison between the combination of a biologic agent plus MTX and the combination of 2 DMARDs plus initial glucocorticoids revealed no difference. Consequently, biologic agents should still be reserved for patients whose RA is resistant to DMARD therapy. Future trials of the effects of biologic agents on RA should compare such agents with combination treatments involving DMARDs and glucocorticoids.

During the last 10 years, several effective, but expensive, immunoselective biologic agents have been introduced for the treatment of rheumatoid arthritis (RA). Biologic agents are currently used as second-line drugs, but in clinical trials, they have been used to treat patients who have not previously taken disease-modifying antirheumatic drugs (DMARDs) (1, 2), and some guidelines recommend biologic agents as first-line treatment for selected patients in whom a poor prognosis is suspected (3). In the coming years, new biologic agents for a growing spectrum of diseases may increase the economic challenge. It is therefore important to ensure that the less-expensive drugs of the past are fully exploited.

In RA, many different clinical and biochemical variables and composite measures reflect the degree of inflammation in the joints. Although a dissociation between joint inflammation and joint destruction may exist in some patients, joint inflammation leads to joint destruction in most patients (4, 5). Joint destruction is considered a key outcome in RA and is measured by means of scoring systems applied to interpretations of joint radiographs (6, 7). As RA progresses with time, these scores gradually increase. We previously found that various mathematical functions were suitable for describing radiographic progression in different patients, but we also found that the course of the radiographic scores followed an approximately linear function in ∼90% of the patients (8). It is therefore possible to compare the radiographic progression in groups of RA patients by dividing the changes in radiographic scores by the time between the 2 scorings of the radiographs.

One of the claimed breakthroughs of biologic agents is their potential to arrest radiographic progression. The corresponding ability of DMARDs is less well defined because the effect of DMARDs on radiographic progression has only sporadically been investigated in randomized trials. The purpose of the present meta-analysis of randomized controlled trials was to quantify the effect of approved drugs and treatment methods (DMARDs, glucocorticoids, biologic agents, and combination treatments) on the yearly percentage of progression of radiographic joint destruction in patients with RA.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol, as described elsewhere (9).

Eligibility criteria.

Types of studies.

Full-length studies published in peer-reviewed journals that were performed according to a randomized controlled trial design and that scored joint radiographs as the primary or secondary outcome at 2 separate time points with a time interval of at least 3 months were included, irrespective of sample size and publication year.

Types of participants.

Patients with RA diagnosed according to the 1958 (10) or the 1987 (11) criteria of the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) were included. In studies performed before 1959, the stated study definitions of RA were accepted.

Types of interventions.

A total of 16 interventions and 5 subinterventions were defined in 5 main groups, which were classified as follows.

Group 1 was defined as single DMARD versus single DMARD. In 9 meta-analyses (analyses I–IX), each of the following 9 DMARDs was analyzed in comparison with another DMARD: leflunomide, methotrexate (MTX), sulfasalazine, injectable gold, chloroquine, cyclosporin A, D-penicillamine, oral gold, and azathioprine. Based on the significance levels of these 9 meta-analyses, the DMARDs were primarily classified as effective or less effective.

Group 2 was defined as single DMARD versus placebo or analog (i.e., drug known to have no effect on radiographic progression, such as nonsteroidal antiinflammatory drugs, other analgesics, or a minimal dose of an active drug). The meta-analysis included the DMARDs of group 1, with the exception of azathioprine, which has not been investigated in a placebo design, and with the addition of 1 study of cyclophosphamide. In addition to this meta-analysis of all placebo-controlled studies (analysis I), 2 subanalyses were performed: one of effective DMARDs (analysis Ia) and the other of effective DMARDs that excluded studies contributing to heterogeneity (analysis Ib). DMARDs were definitely classified as effective or less effective based on the primary evaluation of the group 1–intervention meta-analyses (analyses I–IX) and a secondary evaluation of the group 2–intervention meta-analysis (analysis I).

Group 3 was defined as combination DMARDs versus single DMARD. Two meta-analyses were performed: one tested intervention with 2 DMARDs versus a single DMARD (analysis I) and the other tested intervention with 3 DMARDs versus a single DMARD (analysis II). In a subanalysis, all combination studies were integrated into 1 meta-analysis (I plus II).

Group 4 was defined as glucocorticoids with or without a DMARD versus placebo or analog with or without a DMARD. Two meta-analyses were performed, one of all studies in this group (analysis I) and the other in which studies contributing to heterogeneity were excluded (analysis Ia).

Group 5 was defined as a combination biologic agent plus MTX versus MTX or other DMARDs with or without glucocorticoids. The following combinations that included a biologic agent were tested against different controls: a biologic agent combined with MTX versus MTX alone (analysis I), a biologic agent combined with MTX versus combination DMARDs after 1 year (analysis II), a biologic agent combined with MTX versus combination DMARDs after 2 years (analysis IIa), and a biologic agent combined with MTX versus combination DMARDs plus glucocorticoids (analysis III).

The following biologic agents were investigated in combination with MTX: tumor necrosis factor antagonists (infliximab, etanercept, adalimumab, and certolizumab), anti-CD20 antibody (rituximab), and a T cell costimulation inhibitor (abatacept). In addition, the interleukin-6 (IL-6) antagonist tocilizumab was tested as single therapy versus MTX, and the IL-1 receptor antagonist anakinra was tested versus placebo. In biologic studies with several arms of different doses of drug, we analyzed the arm with the dose that had been introduced in clinical practice as the dose of choice (i.e., infliximab 3 mg/kg every 8 weeks, etanercept 50 mg/week, adalimumab 40 mg every 2 weeks, certolizumab 200 mg every 2 weeks, rituximab 2,000 mg for the treatment period, abatacept 10 mg/kg every 4 weeks, and tocilizumab 8 mg/kg every 4 weeks). In the anakinra analysis, all 3 treatment arms were included (30, 75, and 150 mg/day).

Types of outcome.

The outcome was the difference in the percentage of the annual radiographic progression rate (PARPR) between 2 randomized groups. The radiographic score (irrespective of scoring system) was standardized by calculating the score as the percentage of the maximum score according to the formula score percentage = (score/maximum possible score) × 100. The score change percentage was calculated as follows: end study score × 100/maximum possible score − baseline study score × 100/maximum possible score. Furthermore, the score change percentage was adjusted for the different durations of the studies to a study duration of 1 year according to the following formula: score change percentage (1 year) = (score change percentage × 52 (weeks)/duration (weeks). Consequently, the formula for the outcome measure per randomized group was as follows: PARPR = [(end study score × 100/maximum possible score) − (baseline study score × 100/maximum possible score)] × 52 (weeks)/duration (weeks).

Data sources.

Studies were identified by searching the electronic databases (the Cochrane database, PubMed, EMBase, and ClinicalTrials.gov) and by scanning the lists of references from the identified meta-analyses and randomized studies through December 30, 2009.

Search for studies.

Previous meta-analyses of RA were searched in the Cochrane database (selecting 14 of 144 reviews) and in PubMed using the search terms “meta-analysis” and “rheumatoid arthritis” (an additional 10 meta-analyses of 373 references) and the search terms “rheumatoid arthritis,” “review,” “combination therapy,” and “DMARD” (an additional 1 review of 709 references). The reference lists of these 25 reviews and of the identified references were searched for eligible trials. Then, PubMed was searched using the medical subject headings (MeSH) terms “rheumatoid arthritis” and “randomized controlled trial” (resulting in 2,161 references) combined with each of the 17 included drugs (resulting in 1,029 references): gold (oral and injectable), chloroquine (including hydroxychloroquine), D-penicillamine, cyclophosphamide, azathioprine, sulfasalazine, MTX, cyclosporin A, leflunomide, anakinra, infliximab, etanercept, adalimumab, certolizumab, tocilizumab, rituximab, and abatacept. The searches were repeated several times during the review period, by both authors by turns. The last search for trials was performed in March 2009. A final search on December 30, 2009 did not reveal any additional trials. A similar search of EMBase did not disclose further studies. A search of ClinicalTrials.gov using the key-words “rheumatoid arthritis” and “radiographic progression” revealed 0 published studies of 11 ongoing studies. We would have included eligible studies in languages other than English, but none were detected.

Study selection.

Eligibility assessments were performed independently by both authors, and disagreements were resolved by consensus. Titles were screened, possible abstracts were read, and possible papers were retrieved. Studies fulfilling the eligibility criteria were included in the meta-analysis.

Data collection process.

Both authors independently extracted data as published in the original articles. Disagreements were resolved by discussion between the authors. Only the first publication of studies with repeated publications of followup data was included, with the exception of 1 study, which was analyzed both at 12 months (2) and at 24 months (12), because this was the only study to compare the combination of a biologic agent plus MTX with a combination of 2 DMARDs. Four studies were substudies that included only radiographic data. The basic studies were also retrieved for supplementary information.

The outcome was recorded in the Review Manager (RevMan) computer program, version 5.0 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2008; online at www.cochrane.dk). Additional data on the study characteristics and quality were recorded on a standardized extraction form using StatView 5.0 software (SAS Institute).

Data items.

Radiographic scorings at baseline and at followup were recorded. Most studies reported 1 radiographic followup and scoring. If serial radiographic scorings were reported, the one with most complete data was recorded. The recorded non-outcome data are shown in Appendix Table A (available online at www.niels-graudal.dk).

Risk of bias in individual studies.

The quality of the studies that were included in our meta-analysis was ensured by requiring randomization and by using the Cochrane risk of bias tool to assess sequence generation, allocation concealment, blinding, and incomplete outcome data at the level of the individual study (13). In addition, blinding was evaluated at the outcome level. The analysis of incomplete outcome data included recording of the following 6 features: 1) dropout frequency (total number of patients dropping out after randomization), 2) dropout frequency due to lack of effect (number of patients dropping out after randomization because of a lack of efficacy of treatment), 3) treatment persistence (number of patients adhering to incipient treatment during the study), and 4) side effects (most gave information on the total number of side effects and the number of serious side effects resulting in dropout, hospital admission, or treatment change; we recorded the latter frequency), 5) change of treatment strategy (change of DMARD, addition of DMARD or glucocorticoids, change of placebo to DMARD), and 6) use of intent-to-treat principle. In addition, we recorded the use of step-up therapy, initial full-dose therapy, and glucocorticoids.

Since each of the 5 main groups contained a single-DMARD group and because the PARPR expresses disease severity, differences in disease severity across meta-analyses could be evaluated by comparing the PARPRs of the single-DMARD groups. We did not exclude any studies due to bias, but summarized the data for each of the 5 main groups in order to be able to evaluate whether there were differences between these groups concerning sources of bias (Appendix Table A; available online at www.niels-graudal.dk).

Summary measure.

Since the primary outcome consisted of continuous data, which were standardized to the same scale, the weighted mean difference was used as the effect measure.

Methods of synthesis.

The inverse variance method was used to synthesize the results by means of the RevMan computer program (version 5.0). In articles where the median instead of the mean was used to describe the radiographic score, this median value was used as a substitute for the mean value in the statistical software. If a standard deviation was not given, it could be calculated from a 95% confidence interval, a standard error of the mean, a P value and a T table, a range, individual data, or from data estimated from a figure or calculated as the weighted mean standard deviation of studies from the corresponding group (13).

Heterogeneity between studies was examined by I2 test (13). In cases of homogeneity, a fixed-effects model was used, and in cases of heterogeneity, a random-effects model was used.

Five different treatment principles were investigated (groups 1–5). Since these were not thought to be mutually independent, we did not correct the significance level of 0.05 for multiple comparisons. Application of the Bonferroni correction would have changed the significance level to 0.05 ÷ 5 = 0.01.

Risk of bias across studies.

For each trial, the effect was plotted according to its standard error in a funnel plot. The possibility of publication bias was assessed by evaluating the funnel plots for asymmetry, which can result from nonpublication of small trials that yielded negative results, from differences in trial quality, or from true study heterogeneity. When possible, subgroup analyses were performed after the elimination of studies contributing to heterogeneity as well as asymmetric funnel plots.

Supplementary analyses.

Subgroup analyses were performed for each of the radiographic scoring methods (Sharp, Larsen, and other methods) to investigate whether the scoring system that was used had any influence on the final outcome estimate. Subgroup analyses were also performed for studies in which the second radiographic scoring was performed at 12 months and for studies in which the time of the second radiographic scoring was different from 12 months to investigate the possible significance of the duration correction of the PARPR on the outcome measure.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Study selection.

The first identified paper was from 1955, and the last was from 2009. The trial flow was as follows. From 11 of the 25 reviews, 123 potential trials were identified, and from the PubMed MeSH-term search of 1,029 PubMed references, an additional 27 potential trials were selected. Of these 150 (123 + 27) potentially relevant trials, radiographic outcome was not estimated in 50 of them, and these were excluded. The 100 that estimated radiographic outcome were evaluated in detail. Fifteen of those were excluded because radiographic data were insufficient to calculate a radiographic progression rate, 5 were excluded because they were extension studies of otherwise included studies, and 10 were excluded because they investigated the effects of unapproved treatments (especially bisphosphonates).

Study characteristics and risks of bias.

A total of 71 references (refs.1, 2, 12, and14–81), including 112 comparisons, were identified. Two references (refs.2 and12) contained data from the same study. We categorized the details of the trial characteristics and risks of bias at baseline (Appendix Table A, part 1; available online at www.niels-graudal.dk) and during the study period (Appendix Table A, part 2) according to the 5 main groups. There was no difference between the 5 defined interventions in the frequency of reporting of sequence generation (P = 0.65), but allocation concealment was reported less frequently in the studies of biologic agents (P = 0.01).

Meta-analyses of the 5 groups.

Group 1, single DMARD versus single DMARD (Table 1, group 1, analyses I–IX, refs.14–33).

In analyses I–IX, we found that injectable gold, sulfasalazine, MTX, D-penicillamine, leflunomide, and cyclosporin A all had effects that were not different from those of the control DMARDs. Chloroquine, oral gold, and azathioprine, in contrast, were less effective than the control DMARDs.

Table 1. Primary outcome of treatment versus control in rheumatoid arthritis: results of meta-analyses of the effect on the difference in the PARPR*
Group, treatment type, specific treatments analyzedNo. of compari- sonsNo. of partici- pantsModelDifference in PARPR, treatment vs. control group (95% CI)ZPPARPR in control groupRelative effect, % DP/CPEffect- ive- nessReference
  • *

    A placebo analog was defined as a drug known to have no effect on radiographic progression (such as nonsteroidal antiinflammatory drugs, other analgesics, or a minimal dose of an active drug). PARPR = percentage of the annual radiographic progression rate; DP = difference in the PARPR between the treatment group and the control group; CP = PARPR in the control group; DMARD = disease-modifying antirheumatic drug; E = effective; LE = less effective; GCs = glucocorticoids.

Group 1, single DMARD vs. single DMARD          
 I. Leflunomide vs. DMARD31,173Fixed−0.06 (−0.33, 0.20)0.470.63E14–16
 II. Methotrexate vs. DMARD132,239Random−0.32 (−0.70, 0.05)1.680.09E15–27
 III. Sulfasalazine vs. DMARD4468Fixed−0.13 (−0.45, 0.19)0.790.43E14, 17, 27, 28
 IV. Injectable gold vs. DMARD5857Random−0.70 (−2.60, 1.20)0.720.47E23–24, 30–32
 V. Chloroquine vs. DMARD4610Fixed1.04 (0.65, 1.42)5.30<0.001LE23, 28–31
 VI. Cyclosporin A vs. DMARD4748Fixed−0.63 (−1.31, 0.05)1.830.07E19, 22, 32–33
 VII. D-penicillamine vs. DMARD2174Fixed−0.04 (−2.01, 1.93)0.040.97E29, 31
 VIII. Oral gold vs. DMARD4508Random1.15 (−0.07, 2.36)1.850.06LE21, 25, 30, 31
 IX. Azathioprine vs. DMARD290Fixed1.31 (0.62, 2.00)3.73<0.001LE18, 20
Group 2, single DMARD vs. placebo/analog          
 

I. All studies (Figure 1)

171,541Random−1.24 (−1.96, −0.53)3.400.00072.56−4814, 15, 34–46
 Ia. Effective DMARDs vs. placebo/analog9861Random−1.38 (−2.05, −2.72)4.070.00011.91−7214, 15, 35, 38, 40, 42, 45
 Ib. Effective DMARDs vs. placebo/analog (symmetric funnel plot)7762Random−0.65 (−1.05, −0.25)3.160.0020.96−6814, 15, 35, 42, 45
Group 3, combination DMARDs vs. single DMARD          
 

I. 2 DMARDs vs. 1 DMARD (Figure 2)

121,384Random−0.62 (−1.00, −0.24)3.180.0011.25−502, 17, 21, 29, 47–53
 II. 3 DMARDs vs. 1 DMARD3392Random−1.24 (−2.18, −0.30)2.600.0091.56−7953–55
 I + II. 2−3 DMARDs with or without GCs vs. 1 DMARD171,967Random−0.71 (−1.03, −0.40)4.440.000011.23−582, 17, 21, 29, 47–57
Group 4, GCs with or without DMARD vs. placebo/analog with or without DMARD          
 

I. All studies (Figure 3)

141,750Random−0.70 (−1.12, −0.29)3.360.00081.43−492, 52, 58–68
 Ia. Homogeneous studies101,414Fixed−0.54 (−0.71, −0.38)6.360.000011.07−502, 52, 58, 59, 61, 63–66
Group 5, combination biologic agent plus MTX vs. MTX or other DMARDs with or without GCs          
 

I. Biologic agent plus MTX vs. MTX alone (Figure 4)

124,965Fixed−0.61 (−0.72, −0.51)11.860.000010.73−841, 2, 69–78
 II. Biologic agent plus MTX vs. 2 DMARDs (1 year)1241−0.68 (−1.01, −0.35)3.990.00010.93−732
 IIa. Biologic agent plus MTX vs. 2 DMARDs (2 years)12360.03 (−0.34, 0.40)0.160.870.18+1712
 III. Biologic agent plus MTX vs. 2 DMARDs plus GCs1254−0.07 (−0.25, 0.11)0.780.440.32−162
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Figure 1. Forest plot of the findings of the meta-analysis of studies of treatment with a single disease-modifying antirheumatic drug (DMARD) versus treatment with placebo (pl) or a placebo analog (defined as a drug known to have no effect on radiographic progression, such as nonsteroidal antiinflammatory drugs, other analgesics, or a minimal dose of an active drug). The DMARDs that were used in the studies reported in reference 46 were chloroquine, injectable (ij) gold, and methotrexate. 95% CI = 95% confidence interval; po = per os; NSAID = nonsteroidal antiinflammatory drug.

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Figure 2. Forest plot of the findings of the meta-analysis of studies of 2 disease-modifying antirheumatic drugs (DMARDs) versus 1 DMARD. The DMARDs that were used in the studies reported in reference 53 were methotrexate (Mt) and/or sulfasalazine (Su) and/or chloroquine (Cl) versus methotrexate or sulfasalazine or chloroquine. 95% CI = 95% confidence interval; Au = gold; po = per os; Dp = D-penicillamine; Cs = cyclosporin A; ij = injectable.

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Figure 3. Forest plot of the findings of the meta-analysis of studies of glucocorticoids (Gc) with or without a disease-modifying antirheumatic drug (DMARD) versus placebo (pl) or a placebo analog (defined as a drug known to have no effect on radiographic progression, such as nonsteroidal antiinflammatory drugs [NSAIDs], other analgesics, or a minimal dose of an active drug) with or without a DMARD. The DMARDs used in the studies reported in references 2, 59, 61, 63, 64, and 68 were as follows: for reference 2, methotrexate (Mt) and/or sulfasalazine (Su) and/or other DMARD versus methotrexate and/or sulfasalazine and/or chloroquine (Cl); for references 59 and 61, any DMARD versus any DMARD; for reference 63, gold (Au) or D-penicillamine or sulfasalazine or methotrexate; for reference 64, methotrexate or sulfasalazine; and for reference 68, methotrexate or gold. 95% CI = 95% confidence interval; Cs = cyclosporin A; An = analgesics; ij = injectable.

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Figure 4. Forest plot of the findings of the meta-analysis of studies of biologic agents plus methotrexate (Mt) versus methotrexate alone. All studies except that reported in reference 2 were placebo-controlled studies. 95% CI = 95% confidence interval; Et = etanercept; In = infliximab; Ad = adalimumab; Cz = certolizumab; Rt = rituximab; Ab = abatacept.

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Group 2, single DMARD versus placebo/analog (Table 1, group 2, analyses I–Ib).

Analysis I included all group 2 studies (refs.14, 15, and34–46). The results are shown in Table 1 and in Figure 1.

Analysis Ia consisted of the effective DMARDs identified in the group 1 analyses (refs.14, 15, 35, 38, 40, 42, and45). In this analysis, the less-effective DMARDs identified in the group 1 analyses were excluded (oral gold, chloroquine, and azathioprine). Azathioprine, however, was not tested against placebo. Since D-penicillamine was only tested in 2 smaller studies (versus gold and versus chloroquine), had no effect as compared with placebo (Figure 1, study 36), and is rarely prescribed, D-penicillamine was also excluded. The analysis of the individual studies showed that cyclophosphamide was without effect (Figure 1, study 43). Consequently, the analysis of effective DMARDs excluded cyclophosphamide, D-penicillamine, oral gold, and chloroquine, as well as azathioprine. Finally, 1 study that tested 3 DMARDs (ref.46) was excluded because 1 of the tested DMARDs was chloroquine. The findings of this analysis of the 9 comparisons of effective DMARDs are shown in Table 1.

Group 3, combination DMARDs versus single DMARD (Table 1, group 3, analyses I, II, and I plus II).

Analysis I consisted of studies of 2 DMARDs versus a single DMARD (refs.2, 17, 21, 29, and47–53). A total of 12 comparisons with a balanced use of glucocorticoids that tested the effect of adding 1 DMARD to 1 DMARD were included. The results of this analysis are shown in Table 1 and Figure 2. The PARPR in the single-DMARD–treated patients was 1.25% (Appendix Table A, part 2; available online at www.niels-graudal.dk).

Analysis II consisted of 3 DMARDs versus a single DMARD (refs.53–55). The triple DMARDs consisted of MTX, sulfasalazine, and chloroquine, as well as combinations including cyclosporin A, gold, and D-penicillamine (ref.54). The results of this analysis are shown in Table 1.

Analysis I plus II consisted of all studies in this group, the above comparisons as well as 2 additional trials, one in which the control DMARD was different from the combination DMARDs (ref.56), and one in which patients in the combination DMARD arm were also treated with glucocorticoids (ref.57). The results of this analysis are shown in Table 1.

Group 4, glucocorticoids with or without DMARD versus placebo with or without DMARD (Table 1, group 4, analyses I and Ia).

Analysis I consisted of all studies in this group (refs.2, 52, and58–68). The results of this analysis are shown in Table 1 and Figure 3.

Group 5, combination biologic agent plus MTX versus MTX or other DMARDs with or without glucocorticoids (Table 1, group 5, analyses I–III).

Analysis I consisted of studies of a biologic agent plus MTX versus MTX alone (refs.1, 2, 69–78). The results are shown in Table 1 and Figure 4.

Analyses II–III consisted of studies of a biologic agent plus MTX versus a combination of DMARDs with or without glucocorticoids (refs.2 and12). In 1 study, infliximab plus MTX was more effective than a step-up combination of DMARDs during the first year of treatment (Table 1, group 5, analysis II), but not during the second year (Table 1, group 5, analysis IIa) and was not better than the initial use of combination DMARDs plus glucocorticoids (Table 1, group 5, analysis III).

Risk of bias across studies.

Group 1.

In all of the 9 meta-analyses of the studies in group 1, few individual studies were included. Thus, it was meaningless to analyze for publication bias (13).

Group 2.

Strong evidence of heterogeneity (I2 = 93%, P < 0.00001) was observed in the analysis of all studies in this group of placebo-controlled studies. In the analysis of the most-effective DMARDs (n = 9 studies), there was still heterogeneity (I2 = 86%, P < 0.00001). A funnel plot of these 9 studies showed asymmetry of 2 small studies, with extreme effects (refs.38 and40). When these were excluded, there was still heterogeneity (I2 = 58%, P < 0.03), but no asymmetry of the funnel plot. The results of this analysis are shown in Table 1, group 2, analysis Ib. The PARPR in the placebo-treated patients was 0.96% and was 0.31% in the DMARD-treated patients (Appendix Table A, part 2; available online at www.niels-graudal.dk).

Group 3.

The funnel plot of the 12 comparisons included in analysis I was not asymmetric. Consequently, publication bias could not explain the significant heterogeneity in this group.

Group 4.

The elimination of 2 studies (refs.67 and68) eliminated the heterogeneity, and elimination of a further 2 studies (refs.60 and62) eliminated the asymmetry of the funnel plot. The result of this analysis of 10 homogenous comparisons is shown in Table 1, group 4, analysis Ia. The PARPR in 8 control groups treated exclusively with DMARDs was 1.05% (Appendix Table A, part 2).

Group 5.

In the analysis of a biologic agent plus MTX versus MTX, the funnel plot was symmetric, and there was therefore no heterogeneity.

Supplementary analyses.

Scoring methods.

Separate analyses of studies scored according to the Larsen system, the Sharp system, as well as other systems showed statistically significant results for all methods, consistent with the findings of the main analyses. In relation to the effect in the control group, the contributions to the effect sizes were similar for all scoring methods (Appendix Table B, group 2, analyses III–V, group 3, analyses I and II, and group 4, analyses I–III; available online at www.niels-graudal.dk).

Duration of the interval between radiographic examinations 1 and 2.

Seventy-five of the 112 radiographic estimations of disease progression were performed at 12 months. Separate analyses of the 12-month comparisons did not change the overall result, and in relation to the effect in the control population, the contributions to the effect sizes were similar for both 12-month comparisons and non–12-month comparisons (Appendix Table B, group 2, analyses VI–VII, group 3, analyses III–IV, and group 4, analyses IV–V; available online at www.niels-graudal.dk)

Studies of biologic agents.

Subanalyses of patients with MTX-resistant and nonresistant RA, treatment with a single biologic agent versus MTX (refs.79 and80), and treatment with 3 different doses of anakinra (ref.81) are shown in Appendix Table B, group 5, analyses I–V (available online at www.niels-graudal.dk).

In all 12 studies in which a biologic agent was combined with MTX, the Sharp score was used as the assessment of radiographic progression. In 11 of the 12 studies, radiographic progression was estimated at 12 months. Consequently, the possible influence of the scoring method and the time between radiographic assessments were not investigated for the studies of biologic agents.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

The development toward a less restricted indication for the use of biologic agents led Bertele' et al (82) to review the field, and they concluded that “recently approved anti-RA products should be a therapeutic option only for patients refractory to conventional drugs.” In the present meta-analysis, a broader perspective is taken because this meta-analysis comprises an evaluation of the average effect of a class of drugs by combining the results from trials that evaluated the effects of a different drug from the class. This is methodologically acceptable because there is no attempt to rank the different drugs (13). Furthermore, it is the first meta-analysis to include all of the antirheumatic drug treatment principles in a single review, including the effects of different combinations of drugs.

The present meta-analysis showed that treatment with a single DMARD or glucocorticoids significantly reduced radiographic evidence of joint destruction, with a relative effect of 48–72% as compared with placebo and that aggressive combination therapy with 2–3 DMARDs, a DMARD plus glucocorticoids, or a DMARD plus a biologic agent reduced radiographic joint destruction, with a relative effect of 50–84% as compared with single-DMARD therapy. The findings of our meta-analyses are robust, with small P values. Sensitivity analyses in which studies using unauthorized radiographic scoring methods, outlier studies with extreme results contributing to heterogeneity, or small studies contributing to possible publication bias were excluded did not diminish the clinical or statistical significance of the findings. Finally, 1 study showed in a direct comparison that a biologic agent combined with MTX was not better than the initial full-dose combination therapy of 2 DMARDs combined with initial step-down glucocorticoids (2). An extension of this study confirmed that between year 1 and 2, the combination of a biologic agent with MTX was not better than either of the 2 tested DMARD combination treatments (PARPR of 0.21% versus 0.18% for one combination and 0.23% versus 0.20% for the other) (12).

Although the evaluation of radiographic progression is only one of several aspects of assessing disease severity, it is the most important measure of structural outcome in RA. Different radiographic scoring systems are robust to pooling in meta-analyses (83). This was confirmed in our analysis in which we found that the use of different scoring systems did not influence the overall results. Radiographic progression was used as an outcome measure in 2 previous limited meta-analyses, one that included placebo-controlled DMARD studies (84) and one that included studies of the effects of glucocorticoids (85). The first was an analysis of 25 studies that, in addition to DMARD studies, included studies of bisphosphonates and used a weighted standardized mean difference of the radiographic scores as the outcome (84), whereas the latter included 15 studies and used a weighted mean difference of the score divided by the maximum score (85), as was used in our meta-analysis, but did not correct for the duration of the intervention. In general, our results are consistent with the results of the 2 previous meta-analyses.

A drawback of the combination DMARD meta-analysis is that 6 of 12 comparisons involved the rarely used cyclosporin A. Thus, there is a need for more studies involving the more commonly used DMARDs (MTX, sulfasalazine, chloroquine, and leflunomide). Concerning the individual DMARDs (Table 1 and Figure 1), injectable gold, sulfasalazine, MTX, leflunomide, and cyclosporin A appeared to have similar effects, which were superior to the remaining DMARDs examined. Due to clinical heterogeneity between studies, as determined by differences in the various characteristics, such as RA severity, the drugs, and the drug doses, it is inappropriate to rank the DMARD treatments based on the placebo-controlled studies. Larger effects may be obtained by individual DMARDs than has previously been shown. For example, it was recently found that significantly more patients treated with subcutaneous MTX than with oral MTX showed an ACR20 response (i.e., 20% improvement in disease activity according to the ACR criteria) and an ACR70 response (86). Variations in the effects also seemed to exist across the studies of biologic agents (Figure 4). However, as for the DMARDs, an attempt to rank the biologic agents according to their effectiveness would be an exaggerated initiative. In a study using a mixed treatment comparison meta-analysis, no differences between the effects of biologic agents on the ACR50 response could be demonstrated (87). Until direct comparisons are available, the biologic agents, with the exception of the less-effective anakinra (87) (Appendix Table B; available online at www.niels-graudal.dk), should be considered equal.

As mentioned above, the finding of no difference between a combination of DMARDs plus step-down glucocorticoids and a combination of a biologic agent plus MTX is based on only 1 study and its extension (2, 12). The reason for this limitation is that all other newer biologic agents have been investigated in unbalanced designs comparing a combination of a biologic agent plus MTX versus single-DMARD therapy (usually, MTX). However, the indirect evidence from our meta-analyses also indicates that the differences between the different principles of combinations are small. In order to learn more about the effect of combination DMARDs in relation to treatment with biologic agents, public authorities should consider requiring all future studies of a biologic agent plus MTX (or other DMARD) to be compared with a combination of 2–3 DMARDs plus supplementation with glucocorticoids during the initial phase of the treatment.

In conclusion, due to various biases, it was deemed inappropriate to rank the individual DMARDs and the individual biologic agents. Consequently, we do not believe that the necessary evidence exists to judge which individual treatment is to be preferred. The findings of this study, however, remove any previous doubt that may have existed about the efficacy of single-DMARD treatment on radiographic progression in RA. Furthermore, our meta-analysis confirms that aggressive treatment with combination DMARDs does reduce structural joint damage as compared with less-aggressive treatment with a single DMARD and that combination-DMARD treatment, especially when combined with periodic glucocorticoids, may be as effective as a biologic agent plus MTX. The recommendation that treatment with a DMARD is the first choice for RA is therefore still valid. Biologic agents should be reserved for patients whose RA is not sufficiently controlled with a combination of DMARDs (82). A more intensive use of DMARDs and periodic glucocorticoid treatment may reduce the number of patients in whom biologic agents are needed. In the future, trials of the effects of biologic agents should be compared with combination treatments involving DMARDs and glucocorticoids in balanced designs.

Addendum.

Since the time this article was accepted for publication, the revised European League Against Rheumatism (EULAR) recommendations for the treatment of RA were posted online to coincide with the EULAR Congress in Rome (June 2010). The recommendations state that, following a systematic review of the literature, combination-DMARD treatment has no additional effect beyond that of single-DMARD treatment (88). Therefore, it is recommended that in patients whose RA is not sufficiently responsive to therapy with a single DMARD, biologic agents should be initiated without first trying therapy with a combination of DMARDs. Our findings, which were based on a meta-analysis of published articles between 1955 and 2009, are in sharp contrast to the EULAR recommendations, which were based on a conventional systematic review of only a fraction of the published studies. Based on our findings, we believe that biologic agents should be reserved for patients whose RA is not sufficiently responsive to treatment with a combination of DMARDs.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Drs. Graudal and Jürgens drafted the article, revised it critically for important intellectual content, and approved the final version to be published. Dr. Graudal had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Graudal, Jürgens.

Acquisition of data. Graudal, Jürgens.

Analysis and interpretation of data. Graudal, Jürgens.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

The A. P. Møller Foundation for the Advancement of Medical Science is a nonprofit funding source. It had no role in the study design or in the collection, analysis, or interpretation of the data, the preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by the A. P. Møller Foundation for the Advancement of Medical Science.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES
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