Janus kinase inhibitors: efficacy and safety.

PURPOSE OF REVIEW: Janus kinase inhibitors (JAKi) have been available for the treatment of rheumatoid arthritis (RA) since 2012 and are indicated for patients with active disease despite csDMARD therapy. Efficacy and safety, as demonstrated in the clinical trials, was similar to biologics. A recent post marketing trial suggested safety concerns with the JAKi, which will be reviewed. RECENT FINDINGS: A post marketing Food and Drug Administration (FDA) mandated open-label randomized clinical trial of tofacitinib 5 and 10 mg twice daily (b.i.d.) compared with adalimumab and etanercept was conducted in RA patients on background methotrexate who were at a high risk for cardiovascular disease. This was a noninferiority study evaluating the incidence of major adverse cardiovascular events (MACE) and malignancy with the therapies. Noninferiority for both doses of tofacitinib was not achieved with a numerical increase in MACEs and malignancy with tofacitinib compared to the TNF inhibitors. A dose-dependent increase in venous thromboembolism (VTE) risk with tofacitinib was observed. The findings from this study resulted in the FDA and European Medicines Agency (EMA) restriction of use for all Jaki to RA patients who had failed TNF inhibitors. SUMMARY: JAK inhibitors are effective treatments for RA. Issues have been raised regarding safety in patients with an increase in cardiovascular risk and VTE risk resulting in the need for risk stratification.

Role of Janus Kinase inhibitors in rheumatoid arthritis treatment.

PURPOSE OF REVIEW: To review recently published articles on use of Janus Kinase inhibitors (Jaki) in the clinic for rheumatoid arthritis (RA). RECENT FINDINGS: Several Jaki have been approved for RA patients failing csDMARDS. Over the last 2 years, EULAR and ACR have published updated recommendations for the pharmacologic management of RA providing guidance on the utilization of Jaki after csDMARD failure. Clinical trials have been published addressing the efficacy of Jaki monotherapy as patients often choose monotherapy because of a desire to avoid multiple therapies and aggravating adverse events with csDMARDs. Previous clinical trials have compared the efficacy and safety of Jaki to adalimumab, and a trial comparing abatacept to upadacitinib has recently been published. An increased risk of venous thromboembolism (VTE) has been suggested with Jaki and additional information has recently become available with conflicting results. SUMMARY: Jaki are now standard therapy for RA patients failing csDMARDs and are being utilized frequently as an alternative to biologics in patients without risk factors for VTE. Jaki monotherapy has been demonstrated to be effective, although combination therapy has been demonstrated to be superior in clinical and radiographic outcomes. Preliminary data suggests that cycling through Jaki in patients with incomplete response to initial Jaki treatment may be an appropriate strategy.

JAK Inhibitors: What Is New?

PURPOSE OF THE REVIEW: Three Janus kinase (JAK) inhibitors are approved for rheumatoid arthritis (RA) with a fourth awaiting approval. Multiple clinical trial results with these molecules have recently been reported. These were the first small molecule oral targeted synthetic DMARDs (tsDMARDs) to be approved for RA. RECENT FINDINGS: Preclinical studies have suggested differential affinity for JAK isoform inhibition but it is not presently clear that there is any difference in efficacy in the clinic with these therapies. Preliminary data has suggested that filgotinib may have a modestly different safety profile but lacking direct comparisons, this will be difficult to confirm. Long-term safety studies have suggested similar safety signals to biologics although a possible signal for VTE/PE risk has been noted with tofacitinib and baricitinib. Having an oral small molecule such as the JAK inhibitors with similar or better efficacy than biologics has been a major advance in RA treatment.

Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis.

OBJECTIVE: Research has examined the association of folate-dependent gene polymorphisms with methotrexate (MTX) toxicity in racially homogenous patients with rheumatoid arthritis (RA). We examined the influence of MTX transporter gene polymorphisms on MTX toxicity in 2 racial groups of patients with RA. METHODS: Using a retrospective cross-validation approach, the association of polymorphisms in 6 genes in the MTX cellular pathway with MTX toxicity was examined in training and validation cohorts. The genes analyzed were ATP-binding cassette transporter B1 (ABCB1), C1 (ABCC1), C2 (ABCC2), folylpolyglutamyl synthase (FPGS), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TYMS). Both cohorts included Caucasian Americans and African Americans. Statistical analyses consisted of Fisher exact tests, multivariable logistic regression models, and survival analyses. RESULTS: Four of 25 variants displayed significant associations with MTX toxicity in the training cohort. The intronic single-nucleotide polymorphism (SNP) ABCC2 IVS 23+56 T --> C was associated with alopecia in Caucasians (p = 0.035). ABCB1 1236 C --> T was associated with overall toxicity (p = 0.013); ABCC2 1249 G --> A with gastrointestinal toxicity (p = 0.009); and ABCC2 1058 G --> A with hepatotoxicity (p = 0.04) in African Americans. These 4 SNP and the MTHFR 677 C --> T variant were assessed in the validation cohort. Of these, only the MTHFR 677 C --> T SNP was associated with alopecia, and only in African Americans (p = 0.032). The ABCC2 IVS 23+56 T --> C genotype influenced toxicity-related time to discontinuation or dose decrease in the Caucasian validation cohort (p < 0.0001). CONCLUSION: In addition to SNP in folate-dependent genes, MTX transporter gene SNP may be important markers of MTX toxicity in RA. Such pharmacogenetic associations are race-specific.