Session Information
Date: Monday, November 9, 2015
Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy Poster II
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Previously published rheumatoid arthritis (RA) trials in which TNFi-MTX and triple therapy (MTX + hydroxychloroquine + sulfasalazine) were included as treatment arms in MTX inadequate responder (MTX-IR) patients did not convincingly demonstrate superiority for TNFi-MTX. This could be due to trials being underpowered to detect true differences.1,2The objective of this study was to estimate the efficacy and radiographic benefits of TNFi-MTX vs. triple therapy in MTX-IRs by conducting a systematic review and network meta-analysis. This is an important, clinically relevant question in MTX-IRs.
Methods: Medline, EMBASE, and the Cochrane Library were searched for randomized controlled trials that used either TNFi-MTX or triple therapy as one of the treatment arms in MTX-IRs with RA. The primary endpoint for this analysis was ACR70 at 6 months. Other endpoints included ACR20, ACR50, DAS28 LDA, DAS28 remission, EULAR good response, and no radiographic progression; and changes in DAS28 score, joint erosion, joint space narrowing, and various versions of Sharp scores from baseline. Endpoints were analyzed at 3 months, 6 months, 1 year, and 2 years from baseline when feasible. Data from direct and indirect comparisons between TNFi-MTX and triple therapy were pooled and quantitatively analyzed using fixed and random effects Bayesian models (FEM and REM) in WinBUGS version 1.4.3. Relative treatment effects were generated as odds ratio [OR] (OR>1 indicated a benefit towards triple therapy) for dichotomous endpoints and mean differences (D<0 indicated a benefit towards triple therapy) for continuous endpoints.
Results: A total of 39 studies met the study eligibility criteria, corresponding to 12,749 randomized patients. MTX-IRs were significantly less likely to achieve ACR70 with triple therapy than with TNFi-MTX at 6 months in both fixed effects models (FEM) (OR=0.35, 95% Credible Interval [CrI]: 0.19, 0.64) and random effects models (REM) (OR=0.36, 95% CrI: 0.16, 0.80). All endpoints except for DAS28 score change from baseline showed a statistically significant benefit of TNFi-MTX relative to triple therapy in FEM but not REM at some point within the 2 years of evaluation from baseline. Across the 27 analyzable endpoint-time scenarios evaluated, 26 numerically favored TNFi-MTX in both FEM and REM.
Conclusion: In this network meta-analysis of MTX-IR patients, triple therapy had a 65% significantly lower odds than TNFi-MTX in achieving an ACR70 at 6 months. The benefits of TNFi-MTX over triple therapy were shown across clinical and radiographic endpoints in the MTX-IR population, supporting the use of biological therapy in this setting.
References: 1. O’Dell JR, Mikuls TR, Taylor TH, et al. N Engl J Med 2013;369:307–18.
2. van Vollenhoven RF, Ernestam S, Geborek P, et al. Lancet 2009;374:459–66.
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Table. Relative treatment effects concerning efficacy and radiographic endpoints in the MTX non-responder population |
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Endpoints |
3 months |
6 months |
1 year |
2 years |
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|
Fixed |
Random |
Fixed |
Random |
Fixed |
Random |
Fixed |
Random |
|
|
ACR70 |
1.27 (0.42, 4.10) |
1.30 (0.17, 10.1) |
0.35 (0.19, 0.64)d* |
0.36 (0.16, 0.80)d* |
0.55 (0.22, 1.31) |
0.56 (0.13, 2.27) |
0.82 (0.41, 1.63) |
0.81 (<0.01, 428.2) |
|
EULAR good response |
0.94 (0.54, 1.63) |
0.94 (<0.01-148.7) |
0.61 (0.35, 1.07) |
0.62 (<0.01, 353.3) |
0.51 (0.29, 0.86)* |
0.50 (<0.01, 249.2) |
NA |
NA |
|
ACR50 |
0.55 (0.27, 1.08) |
0.55 (0.18-1.61) |
0.61 (0.41, 0.90)* |
0.60 (0.13, 2.83) |
0.51 (0.27, 0.96)* |
0.50 (0.07, 3.61) |
0.65 (0.37, 1.14) |
0.65 (<0.01, 347.7) |
|
ACR20 |
0.90 (0.52, 1.57) |
0.90 (0.33, 2.50) |
0.80 (0.57, 1.15) |
0.75 (0.22, 2.52) |
0.54 (0.32, 0.91)* |
0.54 (0.08, 3.46) |
0.75 (0.44, 1.24) |
0.75 (<0.01, 405.1) |
|
DAS28-ESR/CRP LDA |
NA |
NA |
0.62 (0.38, <1.00)* |
0.62 (<0.01, 90.0) |
NA |
NA |
NA |
NA |
|
DAS28-ESR/CRP remission |
NA |
NA |
0.52 (0.28, 0.95)* |
0.52 (0.10, 2.56) |
NA |
NA |
NA |
NA |
|
DDAS28-ESR/CRP |
NA |
NA |
0.27 (-0.02, 0.56) |
0.27 (-1.10, 1.65) |
NA |
NA |
NA |
NA |
|
No radiographic progression |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
|
DmTSS |
NA |
NA |
0.42 (-0.22, 1.06) |
0.42 (-1.37, 2.18) |
2.09 (-0.09, 4.26) |
2.08 (-4.79, 8.90) |
3.23 (0.39, 6.10)* |
3.22 (-3.50, 10.0) |
|
DJoint erosion |
NA |
NA |
0.26 (-0.04, 0.56) |
0.26 (-1.60, 2.17) |
0.90 (-0.16, 1.98) |
0.92 (-5.50, 7.33) |
1.53 (0.05, 2.96)* |
1.54 (-4.90, 7.96) |
|
DJoint space narrowing |
NA |
NA |
0.16 (-0.27, 0.59) |
0.16 (-0.48, 0.81) |
1.29 (0.04, 2.53)* |
1.25 (-4.35, 6.86) |
1.66 (>-0.01, 3.34) |
1.66 (-4.82, 8.10) |
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adata presented as odds ratio (OR) (95% CI) or as mean (95% CI) from either a fixed effects or random effects model bdata presented as mean (95% CI) for all endpoints measuring mean change (D) from baseline cOR<1 and mean>0 indicates a benefit towards the TNFi-MTX group (vs. triple therapy) dpre-specified primary endpoint *p<0.05 |
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To cite this abstract in AMA style:
Fleischmann R, Pope JE, Tongbram V, Tang D, Chung J, Collier D, Urs S, Ndirangu K, Wells GA, van Vollenhoven RF. A Systematic Review and Network Meta-Analysis on the Efficacy of Tumor Necrosis Factor Inhibitor-Methotrexate Combination Therapy Versus Triple Therapy in Methotrexate Inadequate Responders with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-systematic-review-and-network-meta-analysis-on-the-efficacy-of-tumor-necrosis-factor-inhibitor-methotrexate-combination-therapy-versus-triple-therapy-in-methotrexate-inadequate-responders-with-rheum/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-systematic-review-and-network-meta-analysis-on-the-efficacy-of-tumor-necrosis-factor-inhibitor-methotrexate-combination-therapy-versus-triple-therapy-in-methotrexate-inadequate-responders-with-rheum/