What information is available regarding the safety of Janus kinase (JAK) inhibitors in patients with rheumatoid arthritis?

Rheumatoid arthritis
The treatment landscape for patients with rheumatoid arthritis (RA) has expanded immensely over the last few decades. Although methotrexate (MTX), a conventional synthetic agent, remains the first-line disease-modifying antirheumatic drug (DMARD) for many patients, additional or alternative treatments are often necessary.^1,2 Disease-modifying treatment options for RA include:

• Conventional synthetic DMARDs (hydroxychloroquine, MTX, leflunomide, sulfasalazine)
• Biologic DMARDs:
  • Tumor necrosis factor (TNF) inhibitors (etanercept, adalimumab, infliximab, golimumab, certolizumab pegol)
  • A T cell costimulatory inhibitor (abatacept)
  • Interleukin (IL)-6 receptor inhibitors (tocilizumab, sarilumab)
  • An anti-CD20 antibody (rituximab)
• Targeted synthetic DMARDs:
  • Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, upadacitinib)

JAK inhibitors
JAK inhibitors are synthetic, small molecule drugs that inhibit the activity and response of Janus kinases and their signaling pathways.^3-6 JAK inhibitors are useful in treating conditions that result from overactive JAK signaling and are indicated for a variety of autoimmune conditions, including RA. Although there are numerous JAK inhibitors available for a variety of uses, tofacitinib, baricitinib, and upadacitinib are Food and Drug Administration (FDA)-approved JAK inhibitors for RA. The American College of Rheumatology 2021 guidelines for RA recommend JAK inhibitors as a treatment option in patients who fail to reach therapeutic goals with MTX monotherapy.¹ However, they do note that safety concerns with the JAK inhibitors require further investigation, and guideline recommendations may require adjustment when further, peer-reviewed, safety information becomes available.

FDA safety communication
In 2021, the FDA communicated the increased risk of cardiovascular-related events, cancer, thromboembolism, and death with the use of JAK inhibitors.⁷ This communication updated a 2019 drug safety update warning of blood clots and death in patients taking tofacitinib.⁸ The FDA required boxed warnings for all 3 JAK inhibitors approved for RA; however, the warnings were not required for JAK inhibitors used in other conditions. The warnings encouraged healthcare professionals to consider patient-specific risks including cardiovascular risk factors and malignancy when prescribing JAK inhibitors for RA. They also recommended JAK inhibitor use only in patients who had failed therapy with a TNF inhibitor. Patients taking tofacitinib, upadacitinib, or baricitinib were encouraged to inform their healthcare provider if they were a current or former smoker, had heart problems, or had a history of heart attack, stroke, or thromboembolism.

Key tofacitinib safety literature in RA
The FDA safety warnings with JAK inhibitors originated from interim analyses and preliminary reports from the ORAL surveillance study, a phase 4 post-marketing safety study of tofacitinib compared with a TNF inhibitor in patients with RA.^9,10

The ORAL surveillance study was required by the FDA when tofacitinib initially received approval in 2012.^9,10 The study was initiated in 2014 and completed mid-2020. Individuals enrolled in the open-label, noninferiority study were at least 50 years of age with 1 or more cardiovascular risk factors.¹⁰ The trial had coprimary endpoints of adjudicated major adverse cardiovascular events (MACE [death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke]) and cancer (excluding nonmelanoma skin cancer).

A total of 4362 patients were randomized to tofacitinib (5 or 10 mg twice daily) or a TNF inhibitor (adalimumab or etanercept).¹⁰ The mean treatment duration was 41.1 months in the tofacitinib 5 mg group, 38.5 months in the tofacitinib 10 mg group, and 40.2 months in the TNF inhibitor group. Notably, the tofacitinib 10 mg group was discontinued in early 2019 due to more frequent pulmonary embolism occurrence and higher mortality, and patients treated with this dose were reduced to 5 mg twice daily.

Overall, patients receiving tofacitinib 5 or 10 mg twice daily had higher MACE than those receiving a TNF inhibitor (3.4% vs 2.5%; hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.91 to 1.94) at a median follow-up of 4 years; noninferiority was not demonstrated due to the upper boundary of the 95% CI exceeding 1.8. Cancers were also more common for patients receiving tofacitinib compared with a TNF inhibitor (4.2% vs 2.9%; HR, 1.48; 95% CI, 1.04 to 2.09). The cumulative probability of cancer over 5.5 years was 6.1% with tofacitinib and 3.8% with a TNF inhibitor.

When the 5 mg and 10 mg dose groups were analyzed separately, the risk of MACE was not significantly increased with the 5 mg group (HR, 1.24; 95% CI, 0.81 to 1.91) while the 10 mg group maintained a significantly greater risk for MACE than a TNF inhibitor (HR, 1.43; 95% CI, 0.94 to 2.18).¹⁰ The cancer risk did not appear to be dose dependent with a HR of 1.47 (95% CI, 1.00 to 2.18) in the 5 mg group and 1.48 (95% CI, 1.00 to 2.19) in the 10 mg group.

Although the overall incidence of adverse events (AEs) was similar among treatment groups, several AEs of special interest were higher among patients treated with tofacitinib and are summarized in Table 1.¹⁰

Multiple posthoc analyses of the ORAL surveillance trial have been published.^11-14 Kristensen et al evaluated risk according to age and smoking status finding that patients 65 years of age or older and those who had any history of smoking were at high risk for malignancy, MACE, myocardial infarction, venous thromboembolism (VTE), or death with tofacitinib compared with TNF inhibitors.¹⁴ Patients less than 65 years of age and those who had never smoked did not have increased risk of these events with tofacitinib use.

Real-world tofacitinib safety data
The Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) trial was an observational cohort study conducted with insurance claims data in US patients.^15,16 The investigators identified patients with RA who had initiated treatment with either tofacitinib or a TNF inhibitor (infliximab, adalimumab, certolizumab pegol, etanercept, and golimumab), and developed 2 cohorts, one with all RA patients from routine care and a second cohort limited to inclusion and exclusion criteria of the ORAL surveillance trial. The risk of malignancy with tofacitinib was not increased in the real-world population (HR, 1.01; 95% CI, 0.83 to 1.22) or in the cohort similar to the ORAL Surveillance population (HR, 1.17; 95% CI, 0.85 to 1.62).¹⁵ The authors concluded that although their cohort study did not identify an increased risk of malignancy, the possibility of increased risk with longer treatment periods should not be ruled out. Similarly, the STAR-RA trial did not detect a significant difference between tofacitinib and TNF inhibitors in cardiovascular outcomes in the real-world population (HR 1.01; 95% CI, 0.83 to 1.23) or the older cohort with cardiovascular risk (HR 1.24; 95% CI, 0.90 to 1.94).¹⁶

Baricitinib and upadacitinib safety in RA
The safety data for the other JAK inhibitors are more limited at this time with little comparative literature. A retrospective analysis evaluating the risk of malignancy, infection, or MACE with tofacitinib (n=192), baricitinib (n=104), or a TNF inhibitor (n=203) was conducted in Japanese patients treated between 2013 and 2020.¹⁷ The median length of observation was 1.3 years. The incidence rate (IR) of serious infection per 100 patient-years was highest with tofacitinib (IR, 8.68), followed by baricitinib (IR, 7.09), and TNF inhibitors (IR, 4.07). The hazard ratio did not indicate significant differences between the JAK inhibitors and TNF inhibitors (HR, 0.782; 95% CI, 0.412 to 1.485) or between the 2 JAK inhibitors (HR, 0.750; 95% CI, 0.302 to 1.862). Herpes zoster infections were also highest with tofacitinib (IR, 13.37), followed by baricitinib (IR, 11.63), and lowest with TNF inhibitors (IR, 1.47). Only 2 cases of MACE occurred (both in patients treated with tofacitinib), and no further analysis was provided. The malignancy rate with JAK inhibitors was higher than those treated with a TNF inhibitor (1.61 vs 0.94; HR, 0.381; 95% CI, 0.094 to 1.546), but this was not statistically significant. The malignancy rate was similar between baricitinib and tofacitinib (HR, 0.541; 95% CI, 0.113 to 2.597). This analysis is limited by its retrospective nature, and no firm conclusions regarding the relative safety of JAK inhibitors can be drawn.

Other safety literature for baricitinib has been conflicting. A recent real-world data study conducted in the US, Europe, and Japan found a significantly increased incidence rate ratio (IRR) with baricitinib compared with a TNF inhibitor for VTE (1.51; 95% CI, 1.10 to 2.08).¹⁸ Incidence rate ratios for MACE and serious infection were also numerically increased (1.54; 95% CI, 0.93 to 2.54 and 1.36; 95% CI, 0.86 to 2.13), but the difference was not statistically significant. An evaluation of treatment-emergent AEs from 9 baricitinib RA clinical trials identified 3770 patients with 14,744 patient-years of exposure.¹⁹ The incidence rates per 100 patient-years were 2.6, 3.0, and 0.5 for serious infections, herpes zoster, and MACE, respectively. The authors noted no new safety signals and considered the results to be in line with previous safety reports.

There is more limited information for upadacitinib.²⁰ A recent analysis of the 5 pivotal RA trials did not find any significant difference in MACE, malignancy, or VTE compared with adalimumab or methotrexate. However, patients receiving upadacitinib did have increased risk of herpes zoster and creatine phosphokinase elevation than those treated with adalimumab.

Discussion
Based on the final publication of the ORAL surveillance study, tofacitinib should be used with caution in older patients with cardiovascular risk factors. Importantly, these results must be applied only to patients at least 50 years of age with 1 or more cardiovascular risk factors, as younger, healthy patients were not included in this study. It is also important to consider that this risk is relative to the risk of TNF inhibitors. The risk of malignancy or cardiovascular events in younger, healthy patients appears to be low but requires further investigation.

Whether the safety concerns noted with tofacitinib are truly applicable to the other JAK inhibitors approved for RA, baricitinib and upadacitinib, remains questionable. Although there are differences in selectivity amongst the agents, with tofacitinib considered to be the least selective and upadacitinib the most selective, it remains unclear how this may affect the safety profiles of the agents.^21,22

In conclusion, rheumatologists and other healthcare professionals must remain vigilant of the safety concerns with JAK inhibitors; however, it appears that these agents can be used safely in many patients with RA.

References

1. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924-939. doi:10.1002/acr.24596
2. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update [published correction appears in Ann Rheum Dis. 2023 Mar;82(3):e76]. Ann Rheum Dis. 2023;82(1):3-18. doi:10.1136/ard-2022-223356
3. Clinical Pharmacology. Elsevier; 2023. Accessed April 14, 2023. https://www.clinicalkey.com/pharmacology/?kbmRecipientKyCd=K52318174&keyCode=16n14255
4. Xeljanz/Xeljanz XR. Package insert. U.S. Pharmaceuticals. 2022.
5. Olumiant. Package insert. Eli Lilly and Company. 2023.
6. Rinvoq. Package insert. AbbVie, Inc. 2022.
7. FDA requires warning about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. FDA web site. Updated December 2021. Accessed April 12, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death
8. FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). FDA web site. February 2019. Accessed April 12, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-xr
9. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis. Updated August 17, 2021. Accessed April 12, 2023. https://clinicaltrials.gov/ct2/show/NCT02092467
10. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927
11. Curtis JR, Yamaoka K, Chen YH, et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2023;82(3):331-343. doi:10.1136/ard-2022-222543
12. Charles-Schoeman C, Buch MH, Dougados M, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis. 2023;82(1):119-129. doi:10.1136/ard-2022-222259
13. Balanescu AR, Citera G, Pascual-Ramos V, et al. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2022;81(11):1491-1503. doi:10.1136/ard-2022-222405
14. Kristensen LE, Danese S, Yndestad A, et al. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance [published online ahead of print, 2023 Mar 17]. Ann Rheum Dis. 2023;ard-2022-223715. doi:10.1136/ard-2022-223715
15. Khosrow-Khavar F, Desai RJ, Lee H, Lee SB, Kim SC. Tofacitinib and risk of malignancy: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Arthritis Rheumatol. 2022;74(10):1648-1659. doi:10.1002/art.42250
16. Khosrow-Khavar F, Kim SC, Lee H, Lee SB, Desai RJ. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann Rheum Dis. 2022;81(6):798-804. doi:10.1136/annrheumdis-2021-221915
17. Uchida T, Iwamoto N, Fukui S, et al. Comparison of risks of cancer, infection, and MACEs associated with JAK inhibitor and TNF inhibitor treatment: a multicenter cohort study [published online ahead of print, 2023 Feb 16]. Rheumatology (Oxford). 2023;kead079. doi:10.1093/rheumatology/kead079
18. Salinas CA, Louder A, Polinski J, et al. Evaluation of VTE, MACE, and serious infections Among Patients with RA treated with baricitinib compared to TNFi: A multi-database study of patients in routine care using disease registries and claims databases. Rheumatol Ther. 2023;10(1):201-223. doi:10.1007/s40744-022-00505-1
19. Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81(3):335-343. doi:10.1136/annrheumdis-2021-221276
20. Cohen SB, van Vollenhoven RF, Winthrop KL, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme [published correction appears in Ann Rheum Dis. 2021 May;80(5):e83]. Ann Rheum Dis. 2021;80(3):304-311. doi:10.1136/annrheumdis-2020-218510
21. Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM. A comprehensive overview of globally approved JAK inhibitors. Pharmaceutics. 2022;14(5):1001. Published 2022 May 6. doi:10.3390/pharmaceutics14051001
22. Liu C, Kieltyka J, Fleischmann R, Gadina M, O’Shea JJ. A decade of JAK inhibitors: what have we learned and what may be the future? Arthritis Rheumatol. 2021;73(12):2166-2178. doi:10.1002/art.41906

Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2023

The information presented is current as of April 12, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.