Frequency of Prescription Claims for Drugs that May Interact with Janus Kinase Inhibitors Among Patients with Rheumatoid Arthritis in the US

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent joint pain and damage leading to functional impairment [1]. Among patients living with RA, polypharmacy is relatively common [2]. The concomitant exposure to multiple drugs may result in drug–drug interactions (DDIs) in which the efficacy and/or safety of one or more of the drugs are altered. The potential for DDIs is a clinical concern because they may be associated with increased morbidity, hospitalization, prolonged hospital stays, or worsened outcomes [3].

The development of biologic disease-modifying antirheumatic drugs (bDMARDs) and small molecule agents, also referred to as targeted synthetic DMARDs (tsDMARDs), has been a pivotal progression in the therapeutics for rheumatic diseases, such as RA. In contrast to conventional synthetic DMARDs (csDMARDs), bDMARDs and tsDMARDs are directed against specific targets in the immune cells and pathways important to RA pathogenesis. The bDMARDs can be classified by their mechanism of action as (1) anti-cytokines or cytokine receptor antagonists (i.e., tumor necrosis factor [TNF] α-, interleukin [IL]-6-, IL-1 inhibitors) and (2) cell function blockers (B- and T- cell modulators); whereas tsDMARDs target intracellular signaling pathways (i.e., Janus kinase [JAK] inhibitors), and have been successfully developed and implemented as RA therapies [4, 5]. Furthermore, bDMARDs have been formulated for the parenteral route (subcutaneous injections or intravenous infusions), while the JAK inhibitors are administered orally. In the US, the JAK inhibitors available as treatment options for patients with RA include baricitinib, tofacitinib, and upadacitinib [6].

These JAK inhibitors have demonstrated safety and efficacy in randomized controlled trials [7‐10]. The safety profiles of JAK inhibitors are generally similar to bDMARDs, with the exception of an increased incidence of herpes zoster infection (with highest rates reported in Japan and Korea) and warnings for increased risk of thromboembolism [7, 9‐11].

Baricitinib, tofacitinib, and upadacitinib have unique pharmacokinetic profiles, and subsequently, drug interaction profiles. While the JAK inhibitors are metabolized through the cytochrome P450 (CYP) system, primarily via the CYP3A4 metabolizing enzyme, the extent of metabolism by this and other enzymes varies by agent, as does the extent of renal excretion [7, 9, 10]. Concomitant administration of baricitinib and a strong organic anion transporter (OAT3) inhibitor, such as probenecid, may increase the serum concentration of baricitinib and thus a dose reduction of baricitinib is recommended [9]. Tofacitinib labeling advises dose adjustment with concomitant strong CYP3A4 inhibitors (e.g., ketoconazole) or when moderate CYP3A4 inhibitors are used in combination with strong CYP2C19 inhibitors (e.g., fluconazole) [10]. Upadacitinib labeling recommends using concomitant strong CYP3A4 inhibitors with caution; no specific dosing recommendations are included [7].

To our knowledge, there are no studies assessing the relative frequency of prescription claims for drugs that may interact with JAK inhibitors in the US population of adult RA patients. Because of the rapidly changing treatment options for RA, information on the relative use of drugs with DDI potential may be informative in the shared decision making between the health care provider and patient.

The objective of this retrospective, cross-sectional study was to describe the frequency of prescription claims for drugs that may interact and require adjustment in therapy with JAK inhibitors, without documentation of concomitant administration, among adult patients with RA in a large, administrative US claims database.

This analysis investigated the frequency of prescription claims for drugs that have DDI potential when co-administered with JAK inhibitors. Among the JAK inhibitors currently indicated for RA in the US, there is great variability in the number of potentially interacting drugs by metabolic pathway, with the highest number associated with strong CYP3A4 inhibition (described in the product labeling for tofacitinib and upadacitinib) and the lowest number associated with strong OAT3 inhibition (described in the product labeling for baricitinib). In this large US claims database, we observed that up to 10% of RA patients had claims for drugs with DDI potential. These results confirm that DDIs are a risk for RA patients and, subsequently, there is a need to recognize and manage DDIs to minimize the risk of therapeutic failure or of adverse drug effects [13].

The recognition and management of DDIs is difficult. Prescribers may not identify potential DDIs without the assistance of reference materials [14]. Additionally, drugs identified with potential DDI are often prescribed by primary care providers; whereas DMARDs, such as JAK inhibitors, are more likely prescribed by rheumatologists [15]. Thus, DDIs may be missed at the point of prescribing.

There are limitations to this analysis. First, there are inherent limitations when working with an administrative claims database. Namely, the claims reflect prescription of a drug, but not necessarily subsequent consumption. Second, the database does not provide information on over-the-counter drugs, supplements, or foods that may affect DDIs. Some interacting drugs, such as antibiotics and antifungals, may be used for a short duration, and temporary interruptions or dose adjustments may be employed to address potential DDIs. The co-administration of JAK inhibitors and the drugs in this analysis could not be evaluated because of the limited number of JAK inhibitor prescription claims during the study period; this is a potential analysis for future study. Clinical outcomes were not evaluated, so we are unable to determine if RA patients encountered any adverse clinical outcomes with the administration of drugs with DDI potential.

To our knowledge, no other administrative claims database analysis has investigated the use of drugs that have the potential to cause DDIs among RA patients in a real-world setting. With commonly used administrative claims database methodologies, this analysis provides a new perspective on the treatment experience for a large, representative sample of RA patients in the US.

In this analysis, up to 10% of patients with RA may be prescribed a drug with the potential to cause a DDI with a JAK inhibitor. As treatment options and polypharmacy management expand, rheumatologists should consider potential DDIs and adjust treatment according to the respective drug-label recommendations. Many of the potentially interacting drugs observed in this real-word analysis may be used acutely (e.g., antifungals), which may require a temporary treatment interruption or dose adjustment of the chronic RA therapy. This study highlights the need to consider the potential for DDIs for RA patients in the clinical setting.