A Systematic Review and Network Meta-Analysis on the Efficacy of Tumor Necrosis Factor Inhibitor-Methotrexate Combination Therapy Versus Triple Therapy in Methotrexate-Naïve Patients with Rheumatoid Arthritis

Roy Fleischmann¹, Janet E. Pope², Vanita Tongbram³, Derek Tang⁴, James Chung⁵, David Collier⁵, Shilpa Urs³, Kerigo Ndirangu³, George A. Wells⁶ and Ronald F. van Vollenhoven⁷, ¹University of Texas Southwestern Medical Center, Dallas, TX, ²University of Western Ontario, London, ON, Canada, ³ICON Plc., Morristown, NJ, ⁴Amgen, Inc., Thousand Oaks, CA, ⁵Amgen Inc., Thousand Oaks, CA, ⁶Cardiovascular Research Reference Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada, ⁷Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, Sweden

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Biologic agents, Clinical, combination therapies, meta-analysis and radiography

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: Several published randomized head-to-head trials in rheumatoid arthritis (RA) have compared TNFi-MTX with triple therapy (MTX + hydroxychloroquine + sulfasalazine) in MTX-naive patients (MTX-Ns) where most were designed as non-inferiority studies.¹Pooled analyses of multiple trials through network meta-analysis may improve the precision of point estimates and allow more accurate interpretation of results with more power to determine between-groups differences. Thus, the objective of this study was to estimate the efficacy and radiographic benefits of TNFi-MTX vs. triple therapy in MTX-Ns by conducting a systematic review and network meta-analysis.

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-Ns 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, 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 21 studies met the study eligibility criteria, corresponding to 8,118 randomized patients. MTX-Ns were not statistically different in achieving ACR70 with triple therapy than with TNFi-MTX at 6 months in both the FEM (OR=0.76, 95% credible interval [CrI]: 0.36, 1.50) and REM (OR=0.77, 95% CrI: 0.31, 1.76). The following endpoints showed a statistically significant benefit in FEM but not REM: ACR70 at two years (FEM: OR=0.44, 95%CrI: 0.22, 0.82; REM: OR=0.43, 95% CrI: 0.14, 1.28), and proportion with no radiographic progression (FEM: =0.48, 95%CrI: 0.25, 0.90; REM: OR=0.47, 95%CrI: 0.15, 1.41). Across the 15 analyzable endpoint-time scenarios evaluated, 11 numerically favored TNFi-MTX in both FEM and REM.

Conclusion: In this network meta-analysis of MTX-N patients, most endpoints numerically favored TNFi-MTX but with no statistically significant differences between triple therapy and TNFi-MTX. At the group level the two treatment strategies appear similar.

References: 1. Moreland LW, O’Dell JR, Paulus HE, et al. Arthritis Rheum 2012;64:2824–35.

Table. Relative treatment effects concerning efficacy and radiographic endpoints in the MTX naïve population^a-c
Endpoints	3 months		6 months		1 year		2 years
Endpoints	Fixed	Random	Fixed	Random	Fixed	Random	Fixed	Random
ACR70	NA	NA	0.76^d (0.36, 1.50)	0.77^d (0.31, 1.76)	NA	NA	0.44 (0.22, 0.82)*	0.43 (0.14, 1.28)
ACR50	NA	NA	0.92 (0.60, 1.40)	0.92 (0.52, 1.58)	NA	NA	0.79 (0.48, 1.31)	0.76 (0.15, 4.05)
ACR20	NA	NA	1.03 (0.70, 1.52)	1.02 (0.56, 1.77)	NA	NA	0.82 (0.53, 1.25)	0.82 (0.16, 3.99)
DAS28 LDA	NA	NA	NA	NA	NA	NA	NA	NA
DAS28 remission	NA	NA	NA	NA	NA	NA	1.12 (0.73, 1.73)	1.10 (0.50, 2.52)
DDAS28	0.14 (-0.10, 0.37)	0.18 (-0.61, 0.98)	0.09 (-0.15, 0.33)	0.07 (-1.00, 1.10)	-0.10 (-0.37, 0.17)	-0.10 (-0.82, 0.62)	-0.10 (-0.45, 0.26)	-0.11 (-5.35, 4.91)
No radiographic progression	NA	NA	NA	NA	NA	NA	0.48 (0.25, 0.90)*	0.47 (0.15, 1.41)
DmTSS	NA	NA	NA	NA	NA	NA	1.40 (-2.23, 4.97)	1.42 (-5.58, 8.35)
DJoint erosion	NA	NA	NA	NA	NA	NA	0.30 (-1.10, 1.70)	0.31 (-4.82, 5.41)
DJoint space narrowing	NA	NA	NA	NA	NA	NA	0.79 (-1.72, 3.27)	0.82 (-4.36, 6.01)
^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

Disclosure: R. Fleischmann, Amgen Inc., 2,Amgen Inc., 5; J. E. Pope, Amgen Inc., 2,Amgen Inc., 5; V. Tongbram, Amgen Inc., 5; D. Tang, Amgen Inc., 3,Amgen Inc., 1; J. Chung, Amgen Inc., 1,Amgen Inc., 3; D. Collier, Amgen Inc., 1,Amgen Inc., 3; S. Urs, Amgen Inc., 5; K. Ndirangu, Amgen Inc., 5; G. A. Wells, Amgen Inc., 5; R. F. van Vollenhoven, AbbVie, Amgen, BMS, GSK, Pfizer, Roche, UCB, 2,AbbVie, Biotest, BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Vertex, 5.

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-Naïve Patients 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-naive-patients-with-rheumatoid-a/. 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-naive-patients-with-rheumatoid-a/