Cancer Risk in IBD Patients Treated with JAK Inhibitors: Reassuring Evidence from Trials and Real-World Data

Abstract

The advent of Janus kinase (JAK) inhibitors, including tofacitinib, filgotinib, and upadacitinib, has significantly widened the therapeutic options for patients with inflammatory bowel disease (IBD). These agents offer the advantage of oral administration and have demonstrated efficacy in inducing and maintaining remission. However, concerns regarding their safety have emerged, particularly concerning cardiovascular and infectious complications, which appear more pronounced in patients with pre-existing risk factors such as older age, smoking, or comorbidities. While these risks are better understood, the potential association between JAK inhibitors and malignancies remains a subject of ongoing investigation. Current data from randomised controlled trials, pooled and integrated analyses, and real-world studies provide conflicting evidence regarding cancer risk. Notably, studies in patients with rheumatologic diseases treated with JAK inhibitors have contributed additional insights into long-term safety outcomes. Despite the uncertainty surrounding malignancy risks, it is likely that predisposing factors, including older age, smoking history, and long-standing IBD with chronic inflammation, play a more substantial role in cancer development than JAK inhibitor therapy alone. This paper reviews safety data from clinical trials, meta-analyses, and observational studies, focusing on cancer risk in patients treated with JAK inhibitors for IBD. We also review evidence from rheumatology studies, highlighting the need for individualised risk assessment and close monitoring to optimise the safety profile of these medications in clinical practice.

Keywords: JAK inhibitors; cancer; filgotinib; inflammatory bowel disease; malignancies; tofacitinib; upadacitinib.

Figure 1

JAK-signal transduction pathway and its role in cellular signalling and immune regulation. (A) The schematic representation shows the JAK–STAT signalling cascade: (1) Cytokine binding induces receptor dimerisation, activating JAKs. (2) JAKs phosphorylate the receptor and recruit STAT proteins. (3) Phosphorylated STATs dimerise and translocate to the nucleus. (4) STATs bind DNA promoters, initiating gene transcription. (B) Different JAK pairings and their downstream effects, highlighting specific immune and inflammatory processes such as antiviral immunity, antibody production, Th17 differentiation, hematopoiesis, and bone metabolism. This pathway is a key target for therapies addressing inflammatory and autoimmune diseases.

Figure 2

Molecular structure of tofacitinib, filgotinib, and upadacitinib.

Figure 3

Long-term tofacitinib safety. The results from three integrated analyses, based on data from three phase 2 and phase 3 induction studies, a phase 3 maintenance study, a long-term extension study, an open-label, and a phase 3b/4 study. NMSC: non-melanoma skin cancer; IR: incidence rate; CI: confidence interval; TNFi: tumour necrosis factor inhibitors. REFERENCES: milestone 1: [38]; milestone 2: [39]; milestone 3: [40].