Effectiveness and safety of tofacitinib in rheumatoid arthritis: a cohort study

New strategies have been developed to treat rheumatoid arthritis (RA) by inhibiting Janus kinase (JAK) pathways. The first JAK inhibitor approved for the treatment of RA in the United States (November 2012) was tofacitinib. This drug is an oral small molecule and recommended by both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) as an alternative to biologic drugs when a patient remains with moderate or high disease activity after a first-line disease-modifying antirheumatic drug (DMARD), usually methotrexate, in patients with established RA [1, 2].

Indirect comparisons have suggested that patients with RA in whom DMARD treatment fails experience similar efficacy in response to tumor necrosis factor inhibitors (TNFi), abatacept, tocilizumab, or tofacitinib (monotherapy or in combination with methotrexate). However, caution must be taken when interpreting that result because indirect comparisons are potentially biased [3]. Researchers studying a cohort derived from U.S. administrative databases (2012–2014) reported that patients using tofacitinib, etanercept, adalimumab, and abatacept had similar persistence and adherence at the end of the first year of therapy [4]. In terms of drug safety, it is well known that RA therapies can exacerbate the risk for herpes virus, and evidence from phase III and long-term extension of randomized controlled trials (RCTs) suggests that patients treated with tofacitinib have a higher incidence of herpes virus infection than those treated with placebo or adalimumab [5]. Another systematic review demonstrated that RCTs might not be sensitive enough to compare the risk of adverse events with tofacitinib [6], whereas researchers in one cohort study reported a higher risk for herpes virus infection with tofacitinib than with abatacept, TNFi, and other RA biologics [7]. Thus, the long-term safety of tofacitinib remains mostly uncertain.

More real-world evidence generated during routine clinical practice and obtained outside the context of RCTs is needed [8]. RCTs are typically planned to assess efficacy outcomes and are underpowered for detecting adverse events. Also, follow-up duration in RCTs is short, and long-term extension studies are potentially affected by healthy user bias. Evidence on new drug therapies is required throughout the entire product life cycle, therefore there has been increased interest in comparative effectiveness research on interventions to inform regulatory bodies for health care decision-making and to support optimization of practitioners’ strategies for the management of RA [9].

To provide direct comparative evidence for tofacitinib’s effectiveness and to expand the safety literature as well, we performed a study using real-world population data of tofacitinib, DMARDs, TNFi, and non-TNF biologics for patients with RA. ACR and EULAR recommend tofacitinib after a trial of methotrexate [1, 2]; thus, we studied patients with RA who had been or were exposed to methotrexate.

In this retrospective cohort study, we used data from the MarketScan® Commercial Claims and Encounters database and the MarketScan Medicare Supplemental and Coordination of Benefits database (Truven Health Analytics, Ann Arbor, MI, USA) for the period between January 1, 2010, and December 31, 2014. These databases contain claims data for millions of privately insured individuals and their dependents, with many different health plans from large employers, indemnity plans, and health maintenance organizations as well as Medicare-covered patients. These databases include inpatient and outpatient visits, emergency room visits, and outpatient prescription drug information and have been widely used for diverse studies, including RA [10, 11].

We studied adult individuals with RA (at least 18 years old) who were previously treated with methotrexate (oral or subcutaneous) and newly dispensed other DMARDs, biologics, and tofacitinib between January 1, 2011, and December 30, 2014 (see below for complete list of drugs). Patients could be currently using methotrexate. The date of the first medication claim, either an outpatient prescription or a procedure claim (in-office drug administration), was defined as the cohort entry. We selected individuals with no use of these medications any time before cohort entry (minimum 12 months), although previous use of DMARDs was allowed for individuals in the biologic and tofacitinib groups. Patients with RA were identified as individuals with at least one inpatient or two outpatient claims (30 to 365 days apart) with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), code for RA (714.0x or 714.3x). Patients were excluded if they had another diagnosis before cohort entry for which relevant biologics are also approved: ankylosing spondylitis (ICD-9-CM code 720.0x), chronic lymphocytic leukemia (204.1 x), Crohn’s disease (555.xx), juvenile idiopathic arthritis (714.3x), non-Hodgkin’s lymphoma (200.xx, 202.xx), plaque psoriasis (696.1x), psoriatic arthritis (696.0x), or ulcerative colitis (556.xx) [12‐14]. We also restricted our analysis to individuals with 12 continuous months of medical and pharmacy coverage prior to cohort entry and for the duration of follow-up.

A total of 21,832 patients with RA previously exposed to methotrexate met the inclusion criteria. The therapy at cohort entry included TNFi with or without DMARDs (61.2%), DMARDs alone (24.7%), non-TNF biologics with or without DMARDs (13.3%), and tofacitinib with or without DMARDs (0.8%). Baseline characteristics were similar across groups (Table 2).

In this retrospective cohort study of patients previously treated with methotrexate, we evaluated the effectiveness and risk of serious infection of tofacitinib compared with DMARDs, TNFi, and non-TNF biologics. Effectiveness at 1 year of follow-up, estimated by a claims-based algorithm, was noted in 15% of tofacitinib users, 11% of DMARD users, and around 19% of TNFi and non-TNF biologic users. The adjusted analysis showed that patients using tofacitinib were as likely as non-TNF biologic users to show effectiveness. The algorithm measures effectiveness on the basis of changes of the initial therapy that can capture both lack of or low effectiveness as well as drug intolerance and side effects. Therefore, it may be expected that our results show lower “success” rates than RCTs. In addition of course, our “real-world” data reflect a different population from the relatively narrow and homogeneous range of subjects enrolled in RCTs, which also will result in different “success” rates as compared with RCTs.

Adherence was an important component in our effectiveness algorithms: less than half of patients in the TNFi and non-TNF biologic groups and only one-third in the tofacitinib and DMARD groups continued their initial therapy. This criterion does not distinguish between actual noncompliance with the treatment and intolerance or adverse events. Switching/addition was another important factor contributing to overall algorithm failure, particularly in the TNFi group. Note that patients using tofacitinib did not increase their initial dose, given that there is only one Food and Drug Administration-approved dose. The adjusted comparisons of the final algorithm result suggested greater effectiveness for TNFi or non-TNF biologics than for DMARDs, and we were unable to establish differences for tofacitinib and DMARDs. In effect, tofacitinib appeared as effective as biologics on the basis of most criteria. Researchers in another cohort study using pharmacy claims reported a similar proportion of persistence and adherence (measured by proportion of days covered) at the first year of therapy among patients using tofacitinib, etanercept, adalimumab, and abatacept. A greater proportion of patients using etanercept and adalimumab switched to tofacitinib or another biologic. Finally, dose increase happened in 5% of patients using tofacitinib [4].

Our study shows that the unadjusted incidence of hospitalizations for infection was 3.6 per 100 patient-years for tofacitinib, compared with 2.2 and 2.5 per 100 patient-years in individuals using TNFi and non-TNF biologics, respectively. Higher rates were observed in each of these groups in the cohort containing only patients covered by Medicare (aged > 65 years). Recent cohort studies showed different point estimates for DMARDs and biologic agents [24‐26], which may be explained by the difference in the definition of serious infections, by differences in patients’ profiles regarding other risk factors for infections, or perhaps by chance alone. Our adjusted comparisons did not demonstrate that tofacitinib users had an increased risk of serious (hospitalized) infections compared with those treated with non-TNF biologics. One recent study using Medicare and MarketScan databases showed that patients using tofacitinib had a higher risk for herpes virus infection than those using biologic drugs [7]. Although the aim of our study was not to directly compare infection risk of tofacitinib patients with that of those treated with anti-TNF drugs only, we performed this comparison and did not find a significant difference. Factors that were associated with higher risk of infection in our study were current use of methotrexate, use of oral glucocorticoid before cohort entry, and previous use of biologics.

In our sample, after a first treatment with methotrexate, tofacitinib was not commonly prescribed. Although the ACR and EULAR guidelines recommend the use of tofacitinib after failure of therapy with DMARDs in patients with established RA, others argue that the JAK inhibitors (owing to the uncertainty about long-term safety and cost-effectiveness) should be used only after insufficient response to initial biologic treatment [27]. The dearth of evidence from observational studies to date was in part the motivation for our work in this analysis to inform the comparative effectiveness and safety of tofacitinib. Our additional analysis of tofacitinib after failure of a first biologic therapy for patients with RA showed similar safety in terms of serious (hospitalized) infection.

Our study has potential limitations. First, we obtained a small sample of tofacitinib users, which was expected for a novel therapy. The patients were not clinically confirmed, but we did use a validated RA definition; our patients were all previously exposed to the cornerstone RA therapy (methotrexate); and we excluded patients with other indications for various RA drug exposures (e.g., cancer, other rheumatic diseases). Still, although MarketScan databases collect data on a large population, it lacks data on important clinical variables and reasons for changing the initial therapy. As a result, we indirectly measured therapy effectiveness using an algorithm based on registers of drug prescriptions or drug administration. This algorithm is composed of criteria related to actionable interventions used by physicians. Although the algorithm has previously been validated for anti-TNF and DMARD therapy in RA, it seemed reasonable to apply the same set of criteria to measure the response to non-TNF biologics and tofacitinib as we did in our study. In addition, herpes zoster (which usually does not require hospitalization) is potentially an important infectious outcome but not one we focused on in this analysis.

All observational studies are at risk of “channeling”; that is, persons are not allocated drugs randomly, and the characteristics of certain people who tend to receive certain drugs may become confounders (e.g., RA disease duration and prior biologic use, which have been shown to be confounders of infection risk [28]) if those are also associated with the outcome of interest. So, for example, it may be that people assigned to tofacitinib were more or less likely (because of their past response to drugs in terms of effectiveness or infection) to have the outcome of interest. We aimed to overcome this potential issue by studying only those patients with RA with previous methotrexate exposure, and we also controlled for proxies of disease severity (e.g., past drugs and rheumatology visits).

We note that in the dataset that we used, patients’ follow-up could have happened because of a loss or change in their health insurance. Medicare completely captures patients’ claims, and the analysis restricted to those patients showed similar risk for infections, despite the lower precision.

As a final point that should be taken into account when interpreting and comparing our results, in our analyses, patients using biologics or tofacitinib could also be taking one or more DMARDs, including MTX. However, most of these combinations would be with drugs such as hydroxychloroquine, which itself tends not to increase infection risk.

In summary, in this report of a large population-based cohort study, we present novel data on real-world use of tofacitinib in patients with RA previously treated with methotrexate. Our study estimated similar (relatively low) effectiveness rates at 1 year of follow-up for patients starting tofacitinib after therapy with methotrexate, as opposed to initiators of non-TNF biologics. Our comparisons of tofacitinib versus non-TNF biologics, though not definitive, did not clearly demonstrate differences with respect to hospitalized infections.