Tumor necrosis factor inhibitors (TNFi), such as adalimumab and etanercept, are widely used for treating rheumatoid arthritis (RA) by reducing the disease activity.1 However, there are uncertainties regarding flare prediction after TNFi tapering in stable RA cases.2 A post-hoc analysis from the Optimizing Treatment with TNFi in RA (OPTTIRA) trial, presented at the European League Against Rheumatism (EULAR) Congress 2018, investigated the association between psychological state and disease flare.2,3
Previous findings from the OPTTIRA trial have demonstrated that reducing TNFi doses by one-third appears to have no impact on disease flares, thus practical in RA patients in sustained remission and low disease activity states.2 Disease activity of RA is measured by DAS28, whereas DAS stands for ‘disease activity score’ and 28 refers to the 28 joints examined.4
OPTTIRA enrolled 97 RA patients with low disease activity (DAS28 score 2.6-3.2) or remission (DAS28 score <2.6) who were taking standard TNFi doses (either etanercept or adalimumab) and receiving one or more DMARDs (69% of patients were on methotrexate).2,3 Multivariate Cox analysis of the intention-to-treat population showed no evidence that 33% tapering reduced time to flare (adjusted HR=0.87; 95% CI: 0.22-3.88; p=0.835).2
The secondary outcomes of the study included changes in Health Assessment Questionnaire (HAQ), EuroQol 5-dimension scale (EQ5D-3L), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and Functional Assessment of Chronic Illness Therapy FACIT-F), assessed at 0, 3, 6, and 12 months.2 A post-hoc analysis, presented at the EULAR Congress 2018, found that mental health, fatigue, and functional status were associated with increased risk of disease flare in RA patients following TNFi tapering.3,5
Disability (SF-36 physical component score), fatigue (FACIT-F) and mental health (SF-36 mental health [MH] subscale) predicted flare in unadjusted model.5 However, after adjusting for age, gender, treatment arm, DAS28, and body mass index (BMI), only SF-36 MH remained a statistically significant predictor of flare (adjusted HR per 10 units=0.74; 95% CI: 0.60-0.93; p=0.01).5 Of note, higher baseline DAS28 was also associated with flare (adjusted HR=1.96; 95% CI: 1.18-3.24; p=0.01).5
DAS28 as a biomarker for flare prediction has been investigated in other studies.6 However, this may be the first study demonstrating the association between mental health status and success in drug tapering.3
“[Depression] is an independent predictor for flare in patients with active disease and is negatively associated with remission,” the researchers wrote. “To date, there are no studies directly addressing the role of depression, anxiety, or low mood in predicting flares in patients tapering their biological therapy.”3
Depression (as assessed in SF-36 MH subscale) may affect patients’ perception and interpretation of their symptoms, and is associated with poor health behaviour like reduced treatment adherence.5 Moreover, patients with mental illness are more prone to the nocebo effect, a phenomenon where patients’ concerns and expectation about the therapeutic intervention negatively influence adherence and treatment response.5 This may account for the unsuccessful drug tapering and increased risk of flare in patients with poor mental health.5
“Baseline DAS28 and mental health predict flare events in patients [with low disease activity] who taper their [TNFi],” the researchers wrote. “Other psychological and functional states, measured by patient-reported outcome, do predict flare events, although the effect size is small and does not persist when adjusting for known predictors.”3
The study is not without its limitations, particularly due to the relatively small sample size and short duration of study.5 Yet, the study still gives an indication that mental health and function status should be considered in TNFi tapering decision in order to optimize the chance of success.5
1. Ma X, Xu S. TNF inhibitor for rheumatoid arthritis. Biomed Rep. 2013;1(2):133-184.
2. Ibrahim F, Lorente-Cánovas B, Doré CJ, et al. Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis—a proof of principle and exploratory trial: is dose tapering practical in good responders? Rheumatology. 2017;56:2004-2014.
3. RA: Psychological State Predicts Disease Flare Following TNF Tapering. Rheumatology Advisor. 2018 (Accessed June 26, 2018, at https://www.rheumatologyadvisor.com/eular-2018-coverage/function-psychological-state-predicts-disease-flare-following-tnf-tapering-in-ra/article/773334/).
4. The DAS28 score. National Rheumatoid Arthritis Society. 2018 (Accessed June 26, 2018, at https://www.nras.org.uk/the-das28-score).
5. Bechman K, Sin FE, Ibrahim F, et al. Mental health, fatigue and function are associated with increased risk of disease flare following TNF inhibitor tapering in patients with rheumatoid arthritis: an exploratory analysis of data from the Optimizing TNF Tapering in RA (OPTTIRA) trial. RMD Open. 2018;4(1):e000676.
6. Tweehuysen L, van den Ende CH, Beeren FM, et al. Little Evidence for Usefulness of Biomarkers for Predicting Successful Dose Reduction or Discontinuation of a Biologic Agent in Rheumatoid Arthritis: A Systematic Review. Arthritis Rheumatol. 2017;69(2):301-308.