An in-depth review of Janus kinase inhibitors, their risks & more
BARCELONA—Of the many advanced therapies available to rheumatologists for the treatment of their patients, Janus kinase (JAK) inhibitors are among the most interesting because they are administered orally and have a wide range of potential uses. However, they have also been associated with an increased risk of specific adverse events.
In the EULAR 2025 session, JAK It Out: New Perspectives on JAK Inhibitors, several speakers provided insights into these medications.
The Basics
The JAK-signal transducer and activator of transcription (STAT) pathway is central to immune dysregulation in many autoimmune diseases due to its role in transducing signals from an array of cytokines that regulate both innate and adaptive immunity.
In rheumatoid arthritis (RA), pro-inflammatory cytokines, such as interleukin (IL) 6, interferon-γ and GM-CSF, signal through JAKs, leading to STAT activation and transcription of genes that drive synovial inflammation, pannus formation and joint destruction. In other immune-mediated inflammatory diseases (IMIDs), such as systemic lupus erythematosus (SLE) and giant cell arteritis (GCA), aberrant activation of the JAK-STAT pathway leads to excessive production of pro-inflammatory cytokines, loss of immune tolerance and propagation of autoreactive lymphocytes.1
Conditions Treated with JAK Inhibitors
With this basis in mind, Andreas Kerschbaumer, MD, PhD, postdoctoral fellow, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, Calif., summarized the use of JAK inhibitors in a host of IMIDs.
JAK inhibitors—including tofacitinib, baricitinib, upadacitinib, filgotinib and others—have demonstrated significant efficacy in patients with RA, with multiple phase 3 clinical trials and meta-analyses showing superiority over placebo and, in some studies, over methotrexate and tumor necrosis factor (TNF) α inhibitors. In psoriatic arthritis, axial spondyloarthritis and inflammatory bowel disease, JAK inhibition has also demonstrated efficacy, with clinical trial data supporting their use for improving both the articular and extra-articular disease manifestations of these conditions.2
Dr. Kerschbaumer noted a recent phase 3study on the use of upadacitinib in GCA as particularly interesting. In this randomized, placebo-controlled trial, patients with new-onset or relapsing GCA were assigned to receive either 15 mg or 7.5 mg of upadacitinib daily with a 26-week glucocorticoid taper or placebo with a 52-week glucocorticoid taper. The study’s primary end point was sustained remission at week 52.
At week 52, the 15 mg dose of upadacitinib given daily demonstrated superior efficacy compared with placebo, with about 46% of patients achieving the end point in the upadacitinib arm compared to 29% in the placebo arm. The 7.5 mg dose of upadacitinib given daily did not demonstrate superiority over placebo.3 Based largely on the strength of this study, the U.S. Food & Drug Administration approved the dose of 15 mg of daily upadacitinib for the treatment of adults with GCA in April.4
Other Possibilities
Next, Dr. Kerschbaumer discussed the use of JAK inhibitors in other IMIDs. In SLE, JAK inhibitors have shown modest, but statistically significant, improvements in composite response indices, including the SLE Responder Index (i.e., SRI-4) and the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), particularly for musculoskeletal and mucocutaneous manifestations.
Emerging evidence also supports the use of JAK inhibitors in autoinflammatory diseases and difficult-to-treat conditions, such as adult-onset Still’s disease and systemic juvenile idiopathic arthritis. However, most of these data are from small case series or observational studies. Larger clinical trials are still needed.2
Research End Points
Throughout his talk, Dr. Kerschbaumer stressed a key point: Readers of clinical research articles should pay close attention to the primary end points used in each study because they inform what clinicians can and should take away from any one article.
Some of the most commonly used end points in SLE clinical trials are the SLE Disease Activity Index 2000 (SLEDAI-2K), BICLA and SRI-4. SLEDAI-2K is notable for its simplicity, but has limitations, such as not capturing partial improvements or all organ manifestations. BICLA and SRI-4 are more sensitive to change and are frequently used as primary end points in clinical trials of new therapies, including those evaluating the effects of JAK inhibitors.5
Treatment Risks
The elephant in the room for any discussion of JAK inhibitors is the ORAL Surveillance study, which raised concerns about risks of major adverse cardiovascular events and cancer.6
This study was conducted in patients aged 50 and older with moderate to severe RA, one or more cardiac risk factors and an inadequate response to methotrexate. Patients were divided into one of three treatment groups to receive either 5 mg of tofacitinib given twice daily plus methotrexate, 10 mg of tofacitinib given twice daily plus methotrexate or a TNF-α inhibitor plus methotrexate. (Note: After a drug safety monitoring review, the 10 mg dose of tofacitinib given twice daily was lowered to 5 mg given twice daily.) The study demonstrated that the risks of major adverse cardiovascular events and cancers were higher for the patients who received tofacitinib than for those who received a TNF-α inhibitor.6
Malignancy
Kim Lauper, MD, PhD, consultant, Division of Rheumatology, Geneva University Hospitals and Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Switzerland, addressed the risk of malignancy with JAK inhibitors. Interestingly, she discussed how JAK inhibitors can be combined with immunotherapy in cancer treatment to modulate the tumor microenvironment and immune response. However, this approach requires careful consideration of their dual immunosuppressive and immunomodulatory effects.
In cancer, the JAK-STAT pathway is often dysregulated, contributing to tumor growth, immune evasion and resistance to immune checkpoint inhibitors. JAK inhibitors can suppress tumor-promoting inflammation and cytokine signaling, potentially reducing tumor progression and overcoming resistance to immunotherapies, such as PD-1/PD-L1 inhibitors.7 Dr. Lauper noted that much work has been—and will be—done to further explore the potential relationship between JAK inhibitors and incident malignancy.
Dr. Lauper helped author a 2024 article discussing key considerations for the initiation of targeted therapies in patients with inflammatory arthritis and a history of cancer. In the article, they note that these deliberations require careful, individualized risk-benefit analysis, with particular caution paid to JAK inhibitors and abatacept due to limited safety data in this population.8
Infection
David Liew, MBBS, FRACP, lead for the Medicines Optimization Service, Austin Hospital, Melbourne, Australia delivered the session’s final talk, which dealt with JAK inhibitors and infection risk. He left the audience with specific items to think about when selecting a biologic or conventional synthetic disease-modifying antirheumatic drug (DMARD):
- Refrain from avoiding treatments due to fear of infection if doing so will increase disease activity and glucocorticoid use—both of which are associated with increased risk of infection;
- Consider if the patient has a specific history or elevated risk of herpes zoster and/or tuberculosis;
- Be mindful of the increased risk of infection in older adults treated with JAK inhibitors; and
- Make sure vaccinations are provided to patients before starting treatment.
Jason Liebowitz, MD, FACR, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
References
- Tanaka Y, Luo Y, O’Shea JJ, et al. Janus kinase-targeting therapies in rheumatology: A mechanisms-based approach. Nat Rev Rheumatol. 2022 Mar;18(3):133–145.
- Konzett V, Smolen JS, Nash P, et al. Efficacy of Janus kinase inhibitors in immune-mediated inflammatory diseases a systematic literature review informing the 2024 update of an international consensus statement. Ann Rheum Dis. 2025 May;84(5):680–696.
- Blockmans D, Penn SK, Setty AR, et al. A phase 3 trial of upadacitinib for giant cell arteritis. N Engl J Med. 2025 May 29;392(20):2013–2024.
- Rinvoq (upadacitinib) receives U.S. FDA approval for giant cell arteritis (GCA) [news release]. AbbVie Inc. 2025 Apr 29.
- Banjari M, Touma Z, Gladman DD. Improving measures of disease activity in systemic lupus erythematosus. Expert Rev Clin Immunol. 2023 Feb;19(2):193–202.
- Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022 Jan 27;386(4):316–326.
- Wei XH, Liu YY. Potential applications of JAK inhibitors, clinically approved drugs against autoimmune diseases, in cancer therapy. Front Pharmacol. 2024 Jan 3;14:1326281.
- Sebbag E, Lauper K, Molina-Collada J, et al. 2024 EULAR points to consider on the initiation of targeted therapies in patients with inflammatory arthritis and a history of cancer. Ann Rheum Dis. 2024 Dec 20:ard-2024-225982.
