Deciphering Novel Mechanistic and Pharmacokinetic Effects of Tofacitinib in Intestinal Inflammation: Expect the Unexpected.

Growing insights into underlying immunopathogenic mechanisms of inflammatory bowel diseases have led to the advent of targeted therapies, which selectively inhibit crucial mediators of the inflammatory process. Sustained activation of mucosal effector T cells and aberrant production of various proinflammatory mediators have been identified as main pathogenic mechanisms in the initiation and perpetuation of mucosal inflammation. A network of cytokines transduce messages via the Janus kinase (JAK) family of enzymes that are associated with the intracellular signal transducer and activation of transcription (STAT), conforming the JAK-STAT pathway, which is an attractive target to block various proinflammatory cytokines in immune cells.

Tofacitinib is the first representative of the class of JAK inhibitors that was approved for the treatment of patients with moderate-to-severe ulcerative colitis. It competitively binds to the adenosine triphosphate binding site in the catalytic cleft of the kinase, with a functional cellular specificity for JAK1 and JAK3 over JAK2. Tofacitinib interference with JAK-STAT signaling opens the possibility to block or modulate the activity of several cytokines and altered pathways simultaneously. However, its specific effector mechanisms remain poorly understood, indicating the need for further analyses. Furthermore, although well described for the systemic circulation, the pharmacokinetic profile of JAK inhibitors at the mucosal site of action remains to be elucidated during gut inflammation.

In the current issue of Cellular and Molecular Gastroenterology and Hepatology, Texler et al decipher cell-specific immunosuppressive effects of tofacitinib on innate and adaptive immunity and for the first time also elucidate its specific intestinal pharmacokinetic impact. They were able to show that tofacitinib distinctly suppressed Th1 and Th17 differentiation and effector function, while having a negligible effect on Th2 and Treg blood cells. Interestingly, tofacitinib-induced effects were not limited to T cells, but it was also able to inhibit M1 and promote regulatory M2 macrophage differentiation, which has been shown to be a relevant anti-inflammatory mechanism. These findings were complemented with studies performed on colonic organoids from patients with ulcerative colitis, where tofacitinib suppressed tumor necrosis factor–induced production of proinflammatory cytokines, rendering intestinal epithelial cells as an additional tofacitinib cellular target. For verification of these in vitro findings, further experiments were performed in the established experimental model of dextran sodium sulfate colitis, where tofacitinib application led to Th1 and Th17 mucosal cell reduction and amelioration of intestinal inflammation. The authors could not observe significant effects of tofacitinib on gut microbial alpha- or beta diversity composition, which might have been the result of the short treatment duration. Further studies in this regard are definitely warranted. Importantly, the authors shed light on the specific effects of intestinal inflammation on the pharmacokinetics of tofacitinib. Strikingly, serum concentrations strongly correlated with the severity of intestinal inflammation because of increased intestinal uptake. They additionally identified equilibrative nucleoside transporters, which are upregulated in activated immune cells, as promotors of cellular tofacitinib uptake.

The findings of the authors indicate that tofacitinib targets several different cell-types (T cells, monocytes, macrophages, intestinal epithelial cells) and pathways to suppress mucosal inflammation. This is in line with recent data, which implicated attenuated expression of proinflammatory cytokines and key Th2, Th9, Th17, and Treg cell-associated transcription factors in mucosal cells of patients with ulcerative colitis on tofacitinib application. Furthermore, decreased expression of both α4/β7 and α4/β1 integrin receptors on T cells from patients with ulcerative colitis after tofacitinib application was noted, resulting in significantly reduced homing capacity of human T cells in vivo in a humanized mouse model for inflammatory bowel diseases in dextran sodium sulfate–treated mice.

Remarkably, the described strong correlation between serum tofacitinib concentrations and colonic disease activity opens up a field of potential therapeutic interventions. The preferred uptake of tofacitinib into activated immune cells, which is facilitated by equilibrative nucleoside transporters, could potentially be pharmaceutically regulated by specific inhibitors, thus opening a novel field of therapeutic interventions. Increasing knowledge in this field is vital for the future use of not only tofacitinib, but all JAK inhibitors.

Altogether, the study by Texler et al adds important insights to the multifaceted mode of action and pharmacokinetic profile of tofacitinib. Only improved understanding in this field will enable effective use of available therapeutic options and identify predictors of response to allow personalized medicine in individual patients with inflammatory bowel diseases with higher response rates and lower levels of toxicity.