By Annette M. Boyle

WEST HAVEN, CT—The development of multiple biologic agents for the treatment of rheumatoid arthritis (RA) in recent years has given patients and clinicians more options for therapy. These alternatives are particularly important, as many patients develop resistance to the first-line therapy for rheumatoid arthritis, methotrexate, over time. Questions remain about when to add conventional disease-modifying anti-rheumatic drugs (DMARD) and when biologic DMARDs should be added to the mix.

Officially, VA guidelines have answered the question. VA policy requires a three-month trial of two conventional DMARDs before the use of a biologic DMARD, unless there are contraindications to use of conventional DMARDs. Research presented at the recent American College of Rheumatology annual meeting, though, indicates that many clinicians add biologics without giving conventional DMARDs a trial—and that a veteran’s likelihood of receiving biologics varies significantly by geographical location.1

The VA policy has a strong evidence-based foundation. “The American College of Rheumatology Guidelines recommend initial use with a conventional DMARD prior to starting biologic therapy. Conventional DMARDs have a long safety record, are effective, and much less expensive than biologics,” said lead author John A. McDougall, MD, a VA scholar with VA Health Services Research and a National Clinician Scholar at the Yale School of Medicine.

In addition, a VA-led study published in the New England Journal of Medicine previously found that triple therapy with methotrexate, sulfasalazine and hydroxychloroquine performed as well as the biologic etanercept added to methotrexate for patients with active disease.2 That study enrolled 353 participants at 16 VA hospitals, 12 rheumatoid arthritis investigational network sites and eight Canadian medical centers who were randomized to receive either triple therapy or methotrexate plus etanercept.

Etanercept is a tumor necrosis factor (TNF) inhibitor. While a number of DMARDs can be used when methotrexate alone does not control rheumatoid arthritis, “the option most often preferred by clinicians is to add a tumor necrosis factor (TNF) inhibitor to methotrexate,” according to the NEJM study.

Patients in both groups had significant improvement in the first 24 weeks. DAS-28 and ACR 70 response rates were higher in the etanercept group at this point. About 27% from each group switched to the other group at 24 weeks. At 48 weeks, the groups were similar in ACR measures, DAS-28 response and radiographic results. Serious adverse events occurred in both groups at similar rates, but serious infections occurred three times more often in the etanercept group, resulting in one death.

Another study recently found that conventional DMARDs, biologics and tofacitinib, a JAK1 inhibitor, are equally effective based on rates of nonadherence, switching or adding a new biologic or tofacitinib, switching or adding a new DMARD, increasing the dose, using glucocorticoid joint injections or increasing the dose of oral glucocorticoid.3

As “randomized clinical trial data have demonstrated that triple therapy using three conventional DMARDs is as effective as biologics, it is rational to try this approach before using a biologic treatment,” McDougall told U.S. Medicine.

High Inter-VISN Variation

But, research by McDougall and his colleagues at the VA Connecticut Healthcare System in West Haven, CT, found that 15% of veterans with newly identified rheumatoid arthritis received a biologic as the initial, second-line DMARD prescription.

The researchers identified 4,823 patients who had been in the VA Musculoskeletal Disorder cohort for at least one year prior to diagnosis with rheumatoid arthritis. All VISNs were represented. All patients had received at least 90 days of methotrexate therapy.

About 40%, 1911 patients, continued on methotrexate therapy alone. Another 45% (2,164) received conventional DMARD as their initial, nonmethotrexate prescription, and 15% (748) received a biologic DMARD (bDMARD) as their next therapy after methotrexate.

The researchers found “a three-fold variation by VISN in the prescription of biologic versus conventional DMARDs.” VISNs in the South and Northeast were the most likely to add a biologic before a trial of conventional DMARDs. Veterans in VISNs 1, 4, 7, 8, 11, 16 and 18 were twice as likely as those in VISN 23 to receive a biologic DMARD after 90 days of methotrexate, while those in VISN 22 were three times as likely. The researchers said they plan to study the causes and impact of this difference.

Perhaps of greater concern than which DMARDs veterans are prescribed is whether they take them at all. Another study of 4,364 veterans who were prescribed either a TNF inhibitor and methotrexate or triple therapy found that only 24.2% of patients in the first group, and only 17.3% in the second group were fully adherent. Among those receiving the biologic TNF inhibitor and methotrexate, adherence rates were 48% for the TNF inhibitor and 40.4% for methotrexate. For those on triple therapy, adherence rates for the components were 48.6% for methotrexate, 48% for hydroxychloroquine and 29.8% for sulfasalazine.4

Triple therapy may have benefits beyond disease control in veterans with rheumatoid arthritis. Men with rheumatoid arthritis tend to experience a more severe disease course and are more likely to “have extra-articular manifestations, which are known to contribute to worse outcomes” than women with the disease, according to VA Rheumatoid Arthritis Registry (VARA) researchers.5

Research suggests that rheumatoid arthritis doubles men’s mortality risk compared to other males without the disease. Methotrexate use reduces all-cause mortality by 40% in men with rheumatoid arthritis, evidently as a result of its cardioprotective properties, according to the study, which notes that major coronary events are associated with greater disease activity in rheumatoid arthritis.

Another component of the triple therapy, hydroxychloroquine (HCQ) also appears to have cardioprotective benefits. VARA participants who used “HCQ were far more likely to achieve target lipid goals than were participants not using HCQ, including total cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio and HDL-C to low-density lipoprotein cholesterol ratio,” the VARA researchers said. The lipid changes occur shortly after HCQ initiation and disappear within a year of discontinuation. HCQ may also improve insulin resistance and prevent diabetes, they noted.

  1. McDougall J, Brandt C, Skanderson M, et al. Variation in DMARD Therapy Following Methotrexate Failure for Newly Identified Rheumatoid Arthritis in a National Veterans Health Administration Cohort. Abstract 1058. 2017 ACR/ARHP Annual Meeting. Sept. 18, 2017.
  2. O’Dell JR, Mikuls TR, Taylor TH, Ahluwalia V, Brophy M, Warren SR, Lew RA, Cannella AC, Kunkel G, Phibbs CS, Anis AH, Leatherman S, Keystone E; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013 Jul 25;369(4):307-18. Epub 2013 Jun 11.
  3. Moura C, Machado M, Behlouli H, et al. SAT0149: Comparative effectiveness of tofacitinib, biologic drugs and traditional disease-modifying antirheumatic drugs in rheumatoid arthritis. Annals of the Rheumatic Diseases. 2017;76:825-826.
  4. Sauer BC, Teng CC, Tang D, Leng J, Curtis JR, Mikuls TR, Harrison DJ, Cannon GW. Persistence With Conventional Triple Therapy Versus a Tumor Necrosis Factor Inhibitor and Methotrexate in US Veterans With Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2017 Mar;69(3):313-322.
  5. Mikuls TR, Remold A, Kerr GS, Cannon GW. Insights and Implications of the VA Rheumatoid Arthritis Registry. Fed Pract. 2015 May;32(5):24-29.