Predicting Lowest Effective Dose For Biologics in Rheumatoid Arthritis Treatment

synovial joint human finger
synovial joint human finger
Study finds weak evidence for using biomarkers as a guide to tapering or discontinuing biologic therapy in patients with rheumatoid arthritis.

A review of past studies that attempted to predict successful discontinuation or dose reductions of biologic agents used to treat rheumatoid arthritis (RA) concluded that there is little evidence to support the utility of biomarkers to guide clinical care for optimal treatment. Researchers from The Netherlands conducted the review, led by Lieke Tweehuysen, MD, from the department of rheumatology at Sint Maartenskliniek in Nijmegen, The Netherlands.

The investigators acknowledged that if a biomarker could be used to accurately predict successful discontinuation or dose reduction of a biologic used to treat RA, then it could help reduce the risk of adverse effects of overtreatment, including serious infections, and medication costs. “The ability to accurately predict the success of dose reduction or discontinuation of a biologic agent is likely to constitute a major improvement over the current trial-and-error, disease activity-guided tapering,” they wrote in a study published in the February issue of Arthritis & Rheumatology.

What Dr Tweehuysen and colleagues found was that among the 16 studies that qualified for review based on the study selection criteria, only 3 biomarkers could be identified as having predictive value for dose reduction or discontinuation of a biologic agent for treating RA. The original pool of 16 studies examined 52 biomarkers (17 studied multiple times) for predictive value in dose reduction. Meanwhile, the same pool of studies evaluated 64 biomarkers for discontinuation of biologic treatment (33 studied multiple times).

High-Yield Data Summary

  • Further research is required to validate the prognostic value of biomarkers that can be used to guide treatment decisions on biologic agents for rheumatoid arthritis.

Adalimumab trough level, Sharp/van der Heijde erosion score, and shorter symptom duration at the start of biologic treatment — the 3 biomarkers the researchers identified as predictors — were only investigated in 2 studies, which they said indicated a lack of consistent predictors. Just 2 of the biomarkers (Sharp/van der Heijde erosion score and shorter symptom duration at the start of biologic treatment) had a statistically significant association, albeit a weak one, the investigators affirmed.

“Therefore, the clinical relevance of these identified predictors could be questioned,” wrote Dr Tweehuysen and colleagues, adding that “our findings regarding the predictive value of the third biomarker (adalimumab trough level) could be questioned considering extensive multiple testing in one study and disputed results in another.”

Summary & Clinical Applicability

The investigators closed their analysis by advising current groups studying predictive markers for tapering of biologic treatment on how to increase the quality of their studies. For example, before they can be considered predictors, the 3 biomarkers they identified in their review need to be replicated in other cohorts using a predefined tapering protocol.

“We would recommend that the various research groups validate the prognostic value of potential predictors and report the predictive value of all their investigated biomarkers with the appropriate association measures.”

Study Limitations

  • The studies in this review all used a disease activity measure to define outcomes, but the threshold for failure and time point of assessment differed among the studies. To achieve comparable information, the use of a standardized outcome is required.
  • Most of the studies reviewed (11 of 16) were considered of low quality based on incomplete reporting.
  • Reporting bias and multiple testing mean that positive findings should be cautiously interpreted. The researchers noted that negative results found for potential biomarkers were not mentioned by all studies they reviewed. 


Dr van den Hoogen has received personal fees from Biogen, Celltrion, Janssen, and Sandoz (less than $10,000 each).

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Tweehuysen L, van den Ende CH, Beeren FMM, 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. doi:10.1002/art.39946

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