Perceived clinical utility of a test for predicting inadequate response to TNF inhibitor therapies in rheumatoid arthritis: results from a decision impact study

Dimitrios A. Pappas, Christine Brittle, James E. Mossell III, Johanna B. Withers, Jeraldine Lim-Harashima & Joel M. Kremer

Rheumatology International volume 41, pages585–593 (2021)


Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects about 1.3 million U.S. adults [1]. When RA is not adequately controlled, joint damage and chronic inflammation can lead to permanent disability and poor health outcomes, including shortened life expectancy. Often, multiple treatment cycles may be needed to find the appropriate therapeutic for an individual patient before adequate disease control is achieved. Such a “trial-and-error” approach increases overall costs while decreasing patient satisfaction [2].

The American College of Rheumatology (ACR) guidelines support the use of any targeted therapy, regardless of MOA, for the treatment of RA following inadequate response to a csDMARD [3]. Tumor necrosis factor inhibitor (TNFi) therapies are usually the first biologic tried after the failure of csDMARDs [4]. This prescribing behavior is reinforced by the current medical policies of insurers, which mostly cover TNFi therapies as the only first-tier treatment following csDMARD failure [5,6,7,8]. Despite being widely used, TNFi therapies are not always effective. Clinical studies show more than half of patients fail to achieve an ACR50 response (indicating a 50% improvement in disease activity) or meaningful clinical change [9, 10]. Precision medicine can alter this treatment paradigm to better meet the needs of individual patients, as has happened in other medicine fields, such as oncology [11,12,13].

In the absence of predictive markers to inform individual treatment decisions, rheumatologists have largely made drug selections based on insurance coverage or other drivers, such as habit and their familiarity with specific therapeutics. Precision medicine has the promise to change RA treatment using biomarkers to target drugs to patients based on their likely effectiveness [2, 14]. For example, knowing that the likelihood of non-response to a TNFi is high may lead to prescription of an alternative biologic.

Currently, when an initial TNFi therapy fails, patients may be placed on alternate TNFi therapy, a process known as TNFi cycling [15]. For a significant proportion of these patients, adequate disease control will not be achieved, thus leading to prolonged patient symptoms, loss of function, and frustration [15,16,17]. The European League Against Rheumatism (EULAR) acknowledges that a weakness in the current RA treatment paradigm is the absence of a method to stratify patients to the most appropriate treatment [16]. Thus, there is a need for a predictive test to identify which patients may be unlikely to have an adequate response to specific biologics.

Such a test (PrismRA) was made clinically available after this survey concluded and predicts inadequate response to TNFi therapies for RA patients with a positive predictive value of 89.7%, a specificity of 86.8%, and a sensitivity of 50%.

This decision-impact study was conducted to evaluate rheumatologists’ insights on the value and perceived clinical utility of a precision medicine test that predicts inadequate response to TNFi therapies for RA patients. Rheumatologists were asked to share their opinions about the inability to predict inadequate response to TNFi therapies, evaluate the characteristics of a test that would alleviate this issue, and investigate the possible clinical utility of such a test. A decision-impact study is important, because it is not known how rheumatologists would implement such a test. A large observational study of rheumatologists found that “physician preference was a significant determinant” of use of specific biologics, “independent of demographic and other clinical factors” [18]. Predictive tests of response may alter prescription patterns, and our study aimed to shed light on how such tests will be perceived by rheumatologists.

Materials and Methods: Data were collected via a cross-sectional survey of U.S. rheumatologists. A 32-item decision-impact survey was designed by HealthiVibe, a division of Corrona, LLC, a research and consulting company. The survey was conducted from May 28 to June 11, 2020 using the online survey platform SurveyGizmo. On average, the survey took 12 min to complete. The survey instrument was cognitively pretested with seven practicing rheumatologists using a think-aloud technique prior to being finalized, to ensure content and construct validity. The complete survey instrument is available electronically as supplemental information to this article (Supplement 1). The study was reviewed by the Sterling Institutional Review Board, and a letter of exemption as non-human subjects research was received. All respondents were asked to review an informed consent statement prior to participating. Respondents were advised that participation was voluntary and that they could withdraw at any time.

Results: Participants were informed about the predictive characteristics of the test and asked to indicate prescribing decisions based on four result scenarios. Overall, rheumatologists had a favorable view of the test: 80.2% agreed that it would improve medical decision-making, 92.3% said it would increase their confidence when making prescribing decisions, and 81.5% said it would be useful when considering TNFi therapies. Rheumatologists would be more likely to prescribe a TNFi therapy when the test reported that no signal of non-response was detected (79.8%) and less likely to prescribe a TNFi therapy when a signal of non-response was detected (11.3%–25.4%). Rheumatologists (84.7%) agreed that payers should provide coverage for such a test. This study shows that rheumatologists support the clinical need for a test to predict inadequate response to TNFi therapies. Test results were perceived to lead to changes in prescribing behaviors as results instill confidence in the ordering rheumatologist.

Conclusion: This study showed the need for predictive response tests in rheumatology and suggests that a test that predicts inadequate response to TNFi therapies has perceived clinical utility while providing meaningful new information for patient stratification in RA. Professional societies have long identified the need to tailor therapy approaches to individual patients [16] and to adopt a personalized, precision medicine approach in rheumatology. Pioneer specialties in precision medicine—oncology and hematology—have improved patient outcomes by adjusting therapy choice based on patient and tumor characteristics. The introduction of precision medicine would be welcomed by the rheumatology community, test results would lead to treatment changes, and patient care would improve by avoiding a medication class that would not result in meaningful change for those patients predicted to be inadequate responders.

View Full Paper