Case-Based Review

Rheumatoid Arthritis: Therapeutic Strategies After Inadequate Response to Initial TNF Inhibitor Therapy



From the University of Iowa Hospitals and Clinics, Iowa City, IA.


  • Objective: To discuss the variability in response to tumor necrosis factor inhibitors (TNFis) observed in patients with rheumatoid arthritis (RA) and discuss therapeutic options for patients who do not respond to initial TNFi therapy.
  • Methods: Review of the literature.
  • Results: Optimal treatment of RA aims at achieving and then maintaining remission or low disease activity. In a patient with an inadequate response to initial biologic therapy, several therapeutic options exist. Current evidence supports TNFi dose escalation for only infliximab; optimization of concurrent conventional synthetic disease-modifying antirheumatic drug (csDMARD) or switching to a different csDMARD are other options. Cycling (switching to an alternative TNFi) and swapping (switching to a therapy with a different mode of action) strategies are other alternate approaches supported by many observational studies. While no head-to-head trials exist directly comparing the 2 strategies, data suggest superiority of the swapping strategy over the cycling approach. Also, several studies have shown that switching to a drug with a different mechanism of action is associated with higher treatment persistence and lower health care costs than TNFi cycling.
  • Conclusion: Physicians have a growing list of treatment options to help their patients with RA achieve disease remission. The choice of best treatment for a given patient needs to be individualized, keeping in mind other factors, including comorbidities.

Keywords: biologics; rheumatoid arthritis; swapping strategy; cycling strategy; TNF inhibitors.

Following the discovery of tumor necrosis factor (TNF) as a proinflammatory cytokine 30 years ago, the use of TNF antagonists has revolutionized the treatment of rheumatoid arthritis (RA). Although TNF inhibitors (TNFIs) are frequently used as a first-line biologic disease-modifying antirheumatic drug (bDMARD), they are not uniformly efficacious in achieving remission in all patients with RA. This article highlights the reasons for such variability in observed response and discusses therapeutic options for patients who do not respond to TNFi therapy.

Case Presentation

A 60-year-old woman is evaluated in the clinic for complaints of pain in her hands, morning stiffness lasting 2 hours, and swelling in her wrists, all of which have been ongoing for 3 months. Physical exam reveals evidence of active inflammation, with synovitis in her second, third, and fourth metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints bilaterally, swelling over both wrists, and a weak grip. Inflammatory markers are elevated, and rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) are both positive at high titer. Radiographs reveal evidence of small erosions at the third and fourth MCPs and PIPs bilaterally and periarticular osteopenia. The patient is diagnosed with seropositive, erosive RA based on history, physical exam, laboratory studies, and imaging. She is started on 20 mg of prednisone for acute treatment of her symptoms along with methotrexate, and, initially, her symptoms are well controlled. A few months after starting treatment, she develops voluminous diarrhea that necessitates cessation of methotrexate. Leflunomide also causes similar symptoms. The combination of sulfasalazine and hydroxychloroquine does not adequately control her symptoms, and ongoing use of low-dose glucocorticoids is required to improve functionality in all joints. Using the treat-to-target (T2T) strategy, adalimumab is initiated. However, she continues to report persistent swelling and pain and still requests oral glucocorticoids to help decrease inflammation. The 28-joint Disease Activity Score (DAS28) is 4.8, suggestive of moderate disease activity.

Why are TNFi agents sometimes ineffective?

The introduction of monoclonal antibodies and fusion proteins to block TNF and other cytokines was a remarkable development in the treatment of RA that revolutionized patient care. Despite the efficacy of TNFis, clinical response to these agents is not universal and only some patients achieve complete remission. In targeting the eventual goal of remission or low disease activity in patients with RA, the concept of “TNF failure” becomes extremely relevant. These inadequate responses to anti-TNF therapy may be due to primary failures, or complete lack of clinical response after initiation of the bDMARD, and secondary failures, or the loss of initially achieved clinical response to therapy. Other reasons for discontinuation of a given TNFi include partial disease control and intolerance to the medication (possible injection-site or infusion reactions). Keystone and Kavanaugh1 divided causes of failure of TNF agents into 2 broad categories: perceptual (related to natural variations in disease course like hormonal variation and physical and emotional stress) and pathophysiological failures (genetic variations, high body mass index, concomitant cigarette use).

Another important consideration in patients treated with a TNFi is the consequent formation of anti-drug antibodies (ADAs). TNFi agents are immunogenic and normally elicit an immune response. The appearance of such ADAs may reduce the bioavailability of free drug, resulting in a decreased clinical response,2 or may lead to serious adverse effects.


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