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5 Articles in this Series
ACR Releases Updated Draft Guidelines for Juvenile Idiopathic Arthritis (JIA)
Debate: When Methotrexate Fails – The Use of JAK or TNF Inhibitors
Pharmacotherapy & Rheumatic Disease in Older Adults
Rheumatoid Disease Therapy and Immunological Complications
When Rheumatoid Arthritis Treatment Gets Difficult: 3 Cases Offer Potential Solutions

Debate: When Methotrexate Fails – The Use of JAK or TNF Inhibitors

An ACR Convergence 2020 Meeting Highlight with Vibeke Strand, MD, MACR, FACP, Michael E. Weinblatt, MD, and Elizabeth Wahl, MD


Under the 2015 ACR guideline for treating rheumatoid arthritis, TNF inhibitors are recommended before Janus kinase inhibitors (JAK inhibitors) when a patient fails to respond to conventional DMARD treatment. However, since then, data has accumulated that suggests JAK inhibitors may be more effective.

That was the topic of the Great Debate at ACR Convergence 2020. Here, the highlights of the arguments made by Vibeke Strand, MD, MACR, FACP, adjunct clinical professor of immunology at Stanford University School of Medicine, who took the side of using JAK inhibitors early, and Michael W. Weinblatt, MD, the John and Eileen Riedman professor of medicine at Harvard Medical School and Bruce and Joan Mickey Chair in Rheumatology at Brigham and Women's Hospital, who argued that TNF inhibitors should be first-line therapy when methotrexate fails in patients with rheumatoid arthritis. He cited the decades-long experience with TNF inhibitors, which he sees as no match for the JAK inhibitors' much shorter history.

Early Use of JAK Inhibitors

Early use of the JAK inhibitors has benefits, according to Dr. Strand. Among her arguments for this approach:

  • clinical responses: the three FDA-approved JAK inhibitors baricitinib (Olumiant), tofacitinib (Xeljanz), and upadacitinib (Rinvoq) have seemingly similar clinical responses
  • early onset of benefit
  • convenience of oral therapy

Clinicians can expect patients will be more responsive if the JAK inhibitors are given earlier in the disease process, she said. These patients are typically active, working inside or outside the home, and their expectations are high for the therapy.

They want to feel and function normally, said Dr. Strand, and with JAK inhibitors, "this is attainable." When patients are aware of the early improvement seen with JAK inhibitors, adherence to therapy is also increased, she has found.

Dr. Strand’s own study looking at tofacitinib in patients who failed methotrexate therapy showed significant improvement in VAS pain scale ratings relative to placebo at the first time point measure (as early as two weeks).

Among the many other studies cited by Dr. Strand was a Phase 3 RCT  comparing upadacitinib to placebo and to adalimumab in those with RA with inadequate response to methotrexate, with the JAK inhibitor resulting in greater improvement in signs and symptoms.

Remission is more likely with the JAK inhibitors and occurs earlier, she said. Clinically meaningful improvements in 55 to 75% of people occur at 3s months.

The Case for TNF inhibitors

Experience counts. That was the premise of Dr. Weinblatt's side of the debate, favoring TNF inhibitors first after methotrexate failure. He compared 22 years' worth of experience with TNF inhibitors and noted the 8 years that clinicians have been working with JAK inhibitors in the pain management space.

He pointed to head-to-head, long-term studies of approved TNF inhibitors with methotrexate. Among the reasons to utilize TNF inhibitors first, he said, are:

  • efficacy
  • clinical experience
  • toxicity (lack thereof)
  • cost

The efficacy of anti-TNF therapies, Dr. Weinblatt noted, has been proven for the five FDA approved therapies. These are etanercept (Enbrel), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi), and infliximab (Remicade). There have been placebo-controlled monotherapy studies, add-on studies on background methotrexate, comparative studies versus methotrexate, early remission and long-term studies as well as withdrawal and reduction studies.

He called the anti-TNF therapies a major advance in rheumatoid arthritis therapy.

As for flares that may occur when TNF inhibitors are withdrawn (a known consequence), he said that dose reduction has been shown to work, pointing to an older study published in The Lancet. "The bottom line is, when you stop anti-TNF therapy, there is a flare”– but lowering the dose helps.

Dr. Weinblatt acknowledged the safety concerns with TNF inhibitors, such as bacterial sepsis and opportunistic infections.

Costs are a concern as well, he said, citing a major savings with biosimilars compared to JAK inhibitors. In the US, JAK inhibitors can be $50,000-60,000 yearly, he said.

More monitoring is needed with JAK inhibitors, he added, noting toxicity questions centering on venous thromboembolism, reproductive issues, and colonic perforations, and infections such as herpes zoster). Tofacitinib was linked with a two-fold higher risk of developing zoster.

While JAK inhibitors work faster, he said, Dr. Weinblatt still favors trying TNF inhibitors first in those who have failed methotrexate. If no improvement occurs after 12 weeks, he said, then it's time to move on – ''perhaps to a JAK inhibitor." 

Who Won?

When both talks and rebuttals finished, participants voted on the winner. Elizabeth Wahl, MD, acting chief of rheumatology at VA Puget Sound Healthcare System, Seattle, the session moderator, tallied the results. While 69% thought Dr. Weinblatt won, 31% thought Dr. Strand did. "The majority are more comfortable using TNFs," Dr. Wahl shared.  

The consensus, at least from the ACR virtual meeting attendees, is that clinicians are not yet widely ready to use JAK inhibitors before TNF inhibitors in patients who have failed methotrexate, Dr. Wahl said.

However, on the comment board, one attendee, a rheumatologist based in Colorado, took a middle-ground approach, declaring the debate ''a draw." She noted that JAK inhibitors should be used in some patients, TNF inhibitors in others.

More on the potential of JAK inhibitors in PPM's Analgesics of the Future Review.


Disclosures: Dr. Strand is a biopharmaceutical consultant and reported financial relationships with several firms, including Amgen, Boehringer Ingelheim, GSK, Gilead and Merck. Dr. Weinblatt reported consultant work for Amgen, Lilly, Pfizer, Roche and others and stock options with Inmedix, Vorso and others.



Strand V, Kremer J, Wallensein G. Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDS. Arth Res Ther.  2015;17:Article number: 307.

Smolen JS, Nash P, Durez P, et. al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE):  randomized controlled trial. Lancet. 2013;381(9870:918-929.

Pawar A, Desai R, Gautam N, et. al. Risk of admission to hospital for serious infection after initiating tofacitinib versus biologic DMARDS in patients with rheumatoid arthritis: a multi-database cohort study. Lancet Rheumatol. 2020;2(2)E84-E98.


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