expert roundtables

Non–Tumor Necrosis Factor Biologic Therapies in Rheumatoid Arthritis: The Expanding Evidence Base

by Leonard H. Calabrese, DO; Jeffrey R. Curtis, MD, MS, MPH; and Jonathan Kay, MD


Methotrexate (MTX) and anti–tumor necrosis factor (anti-TNF) agents are therapeutic mainstays in the treatment of rheumatoid arthritis (RA). However, for some patients who only receive a partial response to their anti-TNF agent, emerging data suggest that switching to a therapy that has a different mechanism of action (MOA) may have an upside and is unlikely to result in worsening disease activity.


How do maturing data and emerging findings shape the understanding of the utility of non-TNF biologic therapies, such as anti–IL-6 agents?

Jeffrey R. Curtis, MD, MS, MPH

Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine
Co-Director, UAB Pharmacoepidemiology and Pharmacoeconomics Research (PEER) Unit
Division of Clinical Immunology and Rheumatology
University of Alabama at Birmingham
Birmingham, AL

“In patients with an inadequate response to anti-TNF therapy, switching to an agent with a different MOA may be more effective than switching to a different agent within the same drug class.” 

Jeffrey R. Curtis, MD, MS, MPH

In patients with an inadequate response to anti-TNF therapy, switching to an agent with a different MOA may be more effective than switching to a different agent within the same drug class. Some data support this concept, even though the magnitude of the benefit may be small to moderate. Despite this, the most common thing that rheumatologists do after a patient fails a first anti-TNF agent is use a second anti-TNF agent. The reasons for this pattern are not completely understood, but they may be due to physician preference and/or insurance company requirements.

Another issue is determining how to treat patients who have a partial response on an anti-TNF agent but have not achieved low disease activity or remission. For these individuals, a critically important question is: What will happen with the switch to a new medication? Or, more precisely, what are the chances that they will lose ground by switching? This comes up frequently in the hearts and minds of patients who feel that their anti-TNF agent helped some, but who wish it worked better. They are worried that a new agent might take them backward, recalling their experience with RA prior to being on biologic therapy. They often prefer not to gamble with their disease and may decide to stay with their current therapy because it is helping to some degree, even though it is not entirely effective.

This question was addressed in an analysis of the MONARCH trial that evaluated switching from adalimumab to sarilumab in patients who had partially responded to adalimumab. Notably, only 6% of those who switched therapies experienced worsening disease activity, while 57% experienced improvement in disease activity. These data can be used to offset patient fears that switching to a new MOA might entail losing their partial response, showing them that there may be an upside to the switch and that they do not need to smolder along as partial responders to their prior anti-TNF therapy.

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

I think that it is perfectly acceptable to use any of these biologic disease-modifying antirheumatic drugs or targeted synthetic disease-modifying antirheumatic drugs in patients who are MTX failures.”

Leonard H. Calabrese, DO

We have been very fortunate for the past 20 years to have had anti-TNF biologics, which have raised the bar for the effectiveness of our overall regimens for RA. Rheumatologists have extensive experience using these agents; we have a database of more than 3 million people who have been exposed to these agents worldwide and across many indications, giving us confidence in their use.

Over the past decade, newer therapies from different classes have become available, including anti–interleukin-6 (anti–IL-6) agents, anti–T-cell agents, and anti–B-cell agents, and now the Janus kinase inhibitors. The guidelines have ultimately been liberalized, and I think that it is perfectly acceptable to use any of these biologic disease-modifying antirheumatic drugs or targeted synthetic disease-modifying antirheumatic drugs in patients who are MTX failures.

The following question arises: Why must a patient experience failure on MTX before using these newer agents? The answer involves a complicated matrix that relates not only to efficacy but also to the cost-benefit analysis, as well as our limited ability to predict which patients will benefit individually from these therapies. We do not currently have biomarkers that tell us which agent to use after MTX. While some of the newer therapies are more effective than MTX, the use of MTX initially, barring contraindication, is strongly endorsed by contemporary guidelines. Regarding comparative effectiveness of the newer therapies, all are very effective. Further, the numbers needed to treat are not radically different across these agents.

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

“We have an expanding clinical armamentarium, with demonstrated efficacy of these newer medications in comparison with adalimumab.” 

Jonathan Kay, MD

Clinical trial data have established the utility of non-TNF biologic therapies. The FUNCTION trial showed that the anti–IL-6 receptor monoclonal antibody tocilizumab, alone or in combination with MTX, was superior to MTX plus placebo for the treatment of patients with early RA. As alluded to by Dr Curtis, sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical function of patients with RA who were unable to continue MTX treatment in the MONARCH trial. Further, studies evaluating the Janus kinase inhibitors used in combination with MTX have shown that tofacitinib is noninferior and that baricitinib and upadacitinib are superior to adalimumab plus MTX. Thus, we have an expanding clinical armamentarium, with demonstrated efficacy of these newer medications in comparison with adalimumab. This prompts strong consideration of their use to treat patients who respond inadequately to anti-TNF agents.

Fatigue is another important end point that has been included in clinical trials. When fatigue is due to RA, most agents that reduce disease activity by interfering with inflammatory cytokine activity also improve fatigue. This is important because patients value the absence of fatigue as a major determinant of their quality of life.


Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847.

Burmester GR, Rigby WF, van Vollenhoven RF, et al. Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial. Ann Rheum Dis. 2017;76(7):1279-1284.

Curtis J, Aletaha D, Burmester G, et al. Low probability of clinical worsening following switching biologic DMARD in patients with RA and partial response to adalimumab [abstract 1387]. Arthritis Rheumatol. 2019;71(suppl 10). Accessed March 13, 2020.

Strand V, Msihid J, Kimura T, Boyapati A, St John G, Wei W. High baseline serum IL-6 predicts increased sarilumab treatment response for patient reported symptoms and health-related quality of life among rheumatoid arthritis patients with inadequate response to methotrexate [abstract 1378]. Arthritis Rheumatol. 2019;71(suppl 10). Accessed March 13, 2020.

Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662.

van Vollenhoven RF, Fleischmann R, Cohen S, et al; ORAL Standard Investigators. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis [published correction appears in N Engl J Med. 2013;369(3):293]. N Engl J Med. 2012;367(6):508-519.

More in Rheumatoid Arthritis


Rheumatoid Arthritis

Clinically Meaningful Improvement in Patient-Reported Outcomes With Interleukin-6 Inhibition

Clinical Study Insights by Daniel E. Furst, MD

Clinical Study Title:Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour n...READ MORE


Rheumatoid Arthritis

Recommended Treatment of Patients With Rheumatoid Arthritis and Comorbidities Such as Liver Impairment, Chronic Kidney Disease, or Interstitial Lung Disease

Patient Care Perspectives by James O’Dell, MD, MACR, MACP

All of the anti–rheumatoid arthritis (RA) agents may be associated with hepatic effects. Methotrexate (MTX), in particular, is contraindicated in p...READ MORE


Rheumatoid Arthritis

Appropriate Use of Biologics in Rheumatoid Arthritis Based on Recent Guidelines

Expert Roundtables by Jonathan S. Hausmann, MD, James O’Dell, MD, MACR, MACP, Alvin F. Wells, MD, PhD

Earlier use of biologics is a point of contention in the field of rheumatology, but there is no discord on the overarching goal of achieving rapid ...READ MORE

More In Rheumatology

Systemic Lupus Erythematosus

Can Research On Drug Induced Lupus Erythematosus Shed Light On Autoimmunity?

Clinical Topic Updates by George C. Tsokos, MD

Systemic Lupus Erythematosus

Genetic Susceptibility To Common And Severe Manifestations Of Systemic Lupus Erythematosus

Clinical Topic Updates by Joan T. Merrill, MD

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus: Outcomes With B Cell Inhibition In The Real World Setting

Patient Care Perspectives by Bevra H. Hahn, MD