TNFi-Methotrexate Combo Increases Odds of Achieving ACR70 in RA

Rheumatoid arthritis patients who fail previous methotrexate therapy respond better to tumor necrosis factor inhibitor plus methotrexate, or TNFi–methotrexate, compared to triple therapy including methotrexate, hydroxychloroquine, and sulfasalazine, a new review finds.

This review appears in the January 3 online issue of RMD Open.

The finding is based on a systematic review of EMBASE, MEDLINE and Cochrane library databases, followed by a network meta-analysis of randomized controlled trials where TNFi–methotrexate or triple therapy was one of the treatment arms for patients with rheumatoid arthritis. In total, 19 studies of patients who were methotrexate naive and 33 studies of patients who had inadequate responses to methotrexate were included in the analysis. For the purposes of this study, “inadequate response” to methotrexate was defined by the existence of active rheumatoid arthritis even with current use of methotrexate. The primary outcome was the American College of Rheumatology’s 70 percent response criteria (ACR70) at six months. 

Led by Roy Fleischmann, M.D., of the University of Texas Southwestern Medical Center, the primary goal of this study was to compare TNFi-methotrexate combination therapy with triple therapy with regard to efficacy, safety, radiographic outcomes and patient-reported outcomes. 

“Our results suggest that the addition of a TNFi to methotrexate after inadequate response to methotrexate could result in better outcomes compared with the addition of sulfasalazine and hydroxychloroquine, chiefly with ACR70 at six months. Our finding is therefore applicable to most patients who do not achieve a good response with methotrexate monotherapy,” wrote Fleischmann and researchers. 

With regard to efficacy, in patients with inadequate response to methotrexate, a 65 percent lower odds of achieving ACR70 with triple therapy compared to TNFi-methotrexate at six months was observed. In terms of safety, patients with inadequate response to methotrexate had lower odds of infection for triple therapy. Mean differences between TNFi–methotrexate and triple therapy did not favor either therapy with regard to radiographic outcomes including joint space narrowing, mTSS, or joint erosion. Moreover, patient reported outcomes favored TNFi–methotrexate in terms of mean differences in patients’ overall assessments.

In patients who were methotrexate naive, efficacy findings suggest that TNFi–methotrexate outperforms triple therapy. Regarding safety, there was no difference between TNFi-methotrexate and triple therapy for infections or aspartate aminotransferase elevation, nor were there differences between the two therapies for patient reported outcomes. Lastly, there were no differences in radiographic endpoints between TNFi–methotrexate and triple therapy. 

Previous studies have suggested that initial combination therapy is more optimal compared to methotrexate monotherapy; however, it remains clear if methotrexate plus TNFi is superior to other forms of conventional synthetic DMARDs. Network meta-analysis is a powerful model that allows for network comparisons of interventions by using both direct and indirect evidence. The result is greater precision of point estimates as well as between-group differences with regard to inpidual clinical trials or classical pair-wise meta-analyses.  

Despite the recommendation of the American College of Rheumatology and European League Against Rheumatism to use methotrexate as first-line therapy for patients with active rheumatoid arthritis, only about 30 percent of these patients reach full remission. The other 70 percent of patients require step-up therapy with additional conventional synthetic DMARDs or biologic DMARDs. Some studies have reported that TNFi–methotrexate and triple therapy work equally well in rheumatoid arthritis patients; however, it is possible that these studies were not adequately powered to detect differences between the therapies. 

“Our results suggest that the addition of a TNFi to methotrexate after inadequate response to methotrexate could result in better outcomes compared with the addition of sulfasalazine and hydroxychloroquine, chiefly with ACR70 at 6 months. Our finding is therefore applicable to most patients who do not achieve a good response with methotrexate monotherapy,” wrote Fleischmann and colleagues. 

Disclosures:

This research was funded by Amgen Inc. 

Roy Fleischmann has received grants and non-financial support from Amgen. Vanita Tongbram, Shilpa Urs, and Kerigo Ndirangu are employees of ICON plc, which received grants and consulting fees from Amgen. Ronald van Vollenhoven has received grants from Abbvie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche and Union Chimique Belge, and personal fees from Abbvie, Amgen, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche, Union Chimique Belge and Vertex. Derek Tang, James Chung and David Collier are employees and stockholders of Amgen. Janet Pope received grants from Amgen and received consulting fees from Abbvie, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche and Union Chimique Belge.

References:

Roy Fleischmann, Vanita Tongbram, Ronald van Vollenhoven, et al. “Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor–methotrexate combination therapy versus triple therapy in rheumatoid arthritis,” RMD Open. Published online January 3, 2017. DOI: 10.1136/rmdopen-2016-000371.