Infliximab for RA

Team: Infliximab for RA, aka “Flexing our way in with Infliximab”

Region: TNF Takedown

Base article: Maini R, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999 Dec 4;354(9194):1932-9. PMID: 10622295.

Authors: University of California San Diego Rheumatology Fellowship Program. Rashmi Dhital, MBBS, second year rheumatology fellow; Neha Singh, DO, first year rheumatology fellow; Manmeet Kaur, MD, first year rheumatology fellow; Brian A. Pedersen, MBBS, Rheumatologist, Assistant Professor of Medicine; Arthur Kavanaugh, MD, Rheumatologist, Professor of Medicine

Team Overview

Imagine a world of rheumatoid arthritis (RA) with only methotrexate (MTX) and no tumor necrosis factor alpha inhibitors (anti-TNFα). Yup, it’s like being on the bubble on Selection Sunday. The first anti-TNFα to have ever been trialed in human patients with RA and the first anti-TNFα to have obtained FDA approval in any disease was infliximab, a drug we proudly share on the court with our gastroenterology colleagues.

Before the publication of the ATTRACT Trial, MTX had become a standard disease-modifying antirheumatic agent (DMARD) for the treatment of RA. But many patients did not respond to treatment with MTX or other agents available at the time (e.g. sulfasalazine, hydroxychloroquine, gold injections),1 either alone or in combination. TNFα was increasingly being recognized as a key, central inflammatory mediator in RA based on ex vivo analyses showing that neutralization of TNFα in vitro reduced the production of other pro-inflammatory cytokines (e.g. IL-1), leading to a novel concept of affecting multiple cytokines through a single cytokine blockade. After demonstration of notable improvement in arthritic mice, a chimeric human-murine monoclonal antibody was genetically engineered to create what we know now as infliximab.2 The first trial of an anti-TNFα in RA using this novel agent was conducted in 1992 and proved to be successful with demonstrable clinical and serological improvements.3 This led to a paradigm shift in the use of biologics with far-reaching influence beyond RA as companies refocused their efforts from sepsis and put the full-court press into anti-TNFα therapy for RA and other inflammatory diseases such as Crohn disease and psoriasis.

Shortly thereafter, investigators began to fiddle with the concept of MTX and Infliximab combination therapy. Our base article highlights the results of the ATTRACT trial, which enrolled 428 from 37 international centers from 1997 – 1998, was a large multinational study that paved way for what has now become the standard for conducting clinical trials.4 This phase III trial comparing infliximab to placebo in patients already on MTX was a game changer.


Now what makes our article an all-star? Patients enrolled in this trial had advanced and recalcitrant disease, as evidenced by mean duration of 7.2 to 9.0 years, significant disease activity with failure of over three DMARDs and incomplete response to methotrexate at a median dose of 15 mg/week (range 10–35), and a history of joint surgery in 1/3 of patients. Over 72% of the patients were receiving ≥ 15mg MTX weekly! Despite enrolling very severe and active patients, the primary endpoint as measured by ACR-20 response at 30 weeks was met with even the lowest dose 3mg/kg q8 weeks. This dosing is still being followed to this day. In addition, this article provided reassurance surrounding the low immunogenicity of the chimeric antibody in combination with MTX eventually leading to its FDA approval for RA in combination with MTX in 1999. Not only did the ATTRACT trial prove the efficacy of infliximab as measured by ACR 20 response, but it also showed that infliximab therapy halted radiographic progression of disease (the findings later published in NEJM in 2000).5 This was quite impressive considering that there was no evidence of MTX or other DMARDs doing this despite being called “disease modifying.” We can say that this trial was the first to use x-ray vision to assess disease response and monitor disease progression in the TNF realm!  After over two decades of anti-TNFs, they still remain on the forefront of therapy for RA with a well-established efficacy/safety profile.

Chances in the Tournament

Like a slam dunk in the paint, we feel infliximab is the most ATTRACTive option! With infliximab, we have an infusion option (which neither MTX nor etanercept offers!) and dose flexibility (several effective doses and frequencies recognized as early as in this trial: 3-10 mg/kg every 4-8 weeks). This means ease for patients who have difficulty self-administering injections and difficulty with medication adherence—a benefit for both providers and patients. Infliximab remains an ATTRACTive anti-TNFα option among rheumatologists (as the trial name suggests!) and deserves another “One Shining Moment.”

Next scouting report: TEAR Triple Rx

Back to the full list of scouting reports.

See the Q&A on for the TNF Takedown Region: Do you use conventional DMARDs aside from methotrexate to prevent anti-drug antibody development for patients on infliximab?


  1. O’Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med. 1996;334(20):1287-1291. doi:10.1056/NEJM199605163342002
  2. Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol. 1993;30(16):1443-1453. doi:10.1016/0161-5890(93)90106-l
  3. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993;36(12):1681-1690. doi:10.1002/art.1780361206
  4. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet Lond Engl. 1999;354(9194):1932-1939. doi:10.1016/s0140-6736(99)05246-0
  5. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594-1602. doi:10.1056/NEJM200011303432202

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