Janus kinase inhibitors (JAKi) are new advanced therapies for the treatment of a variety of autoimmune diseases, including Crohn’s disease (CD) and ulcerative colitis (UC). Unlike biologics, JAKi is a small molecule that can be absorbed directly through the intestine and taken orally. JAKi blocks the effects of the JAK/STAT family, which are vital for intracellular signaling for several important inflammatory cytokines. The JAK/STAT pathway is also key in lipid metabolism. Tofacitinib, approved for UC, is non-selective, inhibiting JAK1, JAK2, and JAK3; upadacitinib, approved for both CD and UC, is a selective inhibitor of JAK 1.
The efficacy of tofacitinib was evaluated in two pivotal clinical induction trials (OCTAVE 1 and 2), which demonstrated superiority over placebo for induction and maintenance of remission. The efficacy of upadacitinib was evaluated in two pivotal trials for UC (U-ACHIEVE and U-ACCOMPLISH), which also demonstrated the superiority of upadacitinib over placebo for induction and maintenance of remission. Likewise, In CD, the U-EXCEL trial demonstrated the superiority of upadacitinib induction therapy compared to placebo; the superiority of upadacitinib over placebo for maintenance of remission was confirmed in the U-ENDURE maintenance study. Response to treatment can be rapid with JAKi, with improvement in stool frequency and rectal bleeding occurring in as little as a few days.
The most common and clinically important adverse effects associated with JAKi include serious infection (two per 100 patient-year), non-melanoma skin cancer (one per 100 patient-year), hyperlipidemia (20-25% increase in LDL from baseline), and possibly lymphoma. A phase 4 study was conducted in patients with rheumatoid arthritis 50 years of age or over with at least one risk factor for cardiovascular disease to assess the safety of anti-TNF, low dose tofacitinib, or high dose tofacitinib. All patients were on concurrent methotrexate therapy. A higher incidence of major cardiovascular events (MACE)(2.5 versus 3.4%), thromboembolic events (VTE)(0.8 vs. 0.9 per 100 patient-years), and malignancy overall (2.9 versus 4.2%) was observed in patients treated with tofacitinib compared to anti-TNF. Based on the results of this study, the Food and Drug Administration recommended using JAKi only after the failure of an anti-TNF.
However, it is not clear that patients with IBD, who are generally younger and with less comorbid conditions including preexisting cardiovascular disease, have similar risks of MACE, VTE, and malignancy. The evidence supporting a lower risk in patients with IBD comes from the open label extension and real-world studies of tofacitinib for UC and upadacitinib for UC and CD which do not demonstrate an increased risk of these adverse events. Additionally, it was notable in the phase 4 study above, that patients under 65 years of age, no smoking history, and no prior VTE were not at increased risk for adverse effects if treated with tofacitinib.
At DDW, two abstracts were presented, which provide reassuring real-world data on the safety of JAKi in patients with IBD. First, Patel et al. presented the results of a retrospective analysis of the TriNetX database between 2015 and 2023. Episodes of composite MACE (myocardial infarction, ischemic stroke, percutaneous coronary intervention(PCI), or coronary artery bypass surgery (CABG)) were compared between various therapeutic classes, adjusting for confounding variables. Anti-TNF agents were associated with a 40% reduction in PCI/CABG and a 20% reduction in composite MACE, and anti-integrins were associated with a 24% reduction in composite MACE. Importantly, JAKi were not associated with any specific MACE or the composite outcome. Qapaja et al. evaluated the risk of cancer in patients with IBD treated with small molecules, including JAKi, compared to patients treated without small molecules or with biologic therapy using the same database. The investigators were unable to verify an increased risk of cancer up to four years after initiating small molecule therapy. Additionally, an increased risk of cancer was not demonstrated in a subset of older adults with IBD.
Overall, these abstracts provide reassuring data regarding the safety of JAKi in the treatment of patients with IBD. Because these therapies have an increased rate of adverse effects compared to the newer biologic therapies, I tend to reserve them for patients who have experienced failure or intolerance of one advanced therapy and for patients with more severe symptoms and inflammatory burden and/or with concurrent extraintestinal manifestations. Despite the reassuring signal of no increased risk of cancer in older patients, I still use these drugs with caution in older adults, particularly in those with a history of MACE, VTE, and/or solid organ malignancy.
Dr. Cross has disclosed financial ties with Abbvie,, BMS, Fresenius Kabi, Fzata, Janssen, Magellan Health, Option Care, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, Sebela, and Takeda
Illustration by Jennifer Bogartz
