The management of UC is complex, with various therapeutic options, such as corticosteroids, immunomodulators, biologics, and JAK inhibitors. This complexity stems from the inherent difficulty in predicting therapeutic responsiveness before initiating treatment. Our study focused on delineating factors that influence a favorable response to TOF in patients with UC. Immunohistological examination revealed that the presence of IL-17A-positive cells served as a predictive indicator of early failure of TOF during treatment for UC.
The current literature supports the concept that Th17 cells play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). The presence of Th17 cells in the intestinal lamina propria, along with the constitutive production of IL-17A in mice, has been documented [10]. In the context of pathogenesis, a detailed analysis of murine models of IBD revealed elevated levels of IL-23 [11] and IL-17A [12]. Notably, a recent study provided insights into the contribution of IL-23-dependent Th17 responses to the pathogenesis of colitis, especially in the later phase [13]. Consistent with these animal studies, a human study using tissue samples demonstrated upregulated levels of IL-17A in patients with UC [14]. Mucosal expression of mRNA IL-17A was 99.8 times higher in patients compared with controls, while the mRNA expression of IFN-gamma and IL-13 increased by factors of merely 12.4 and 6.7, respectively [15]. Moreover, serum IL-17A levels in treatment-naïve patients with UC not only reflect disease severity at disease onset but also predict the disease course over the ensuing 3 years [15].
JAK inhibitors, such as TOF, are increasingly being used to treat UC. The selectivity of the regulated pathways among JAK inhibitors may affect treatment outcomes. Detailed investigations using human cells have revealed that TOF inhibits JAK1, JAK2, JAK3 and, to a lesser extent, TYK2, whereas in vivo studies emphasize its preferential inhibition of the JAK1 and JAK3 functions [16]. Disruption of signals linked to JAK3- and JAK1-dependent cytokines include IL-2, IL-6, IFNs, IL-12, IL-4, IL-7, IL-15, and IL-21. Comprehensive pharmacological analysis also underscores that JAK inhibitors most potently inhibit the JAK1/TYK2-dependent pathway, with TOF emerging as the most potent inhibitor of JAK1/3-dependent cytokines among several JAK inhibitors [17]. However, studies investigating the immunosuppressive effects of TOF on JAK2/TYK2 dimer are limited. The IL-23 receptor complex, intricately associated with the JAK2/TYK2 pathway, predominantly facilitates STAT3 phosphorylation and, to a lesser extent, STAT1, STAT4, and STAT5 phosphorylation [18]. The pathological consequences of excessive IL-23 signalling are associated with its capacity to stimulate the production of inflammatory mediators linked to Th17 cells. These mediators include IL-17, IL-22, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNF-alpha among target populations, predominantly Th17 or IL-17-secreting TCRgd cells (Tgd17) [19]. This foundational verification suggests that TOF may not be able to exert optimal control over excessive Th17 cell responses stemming from aberrant IL-23 activation. In accordance with this concept, patients with an abundance of IL-17A-positive mononuclear cell infiltration exhibited a lack of positive response to TOF treatment in our investigation. Moreover, our results are supported by a previous study using a single-cell RNA sequence, in which high levels of IL17A-expressing T cells at baseline were significantly correlated with the failure to achieve a response to TOF treatment [9].
Given that advanced medications, including biologics and JAK inhibitors, are not universally effective, are associated with rare but serious side effects, and incur high costs, it is crucial to selectively administer treatments to patients with the highest likelihood of a favorable response. These considerations underscore the substantial demand for a reliable scale to predict the treatment response. Current indicators of a positive response include age, sex, body weight, smoking habits, disease duration, disease location, disease severity, and extraintestinal manifestations [20]. In addition to these physical factors, multiple studies have assessed the mucosal expression profiles in patients with UC to predict treatment responses. Gene-array analysis using pre-infliximab treatment of rectal mucosal biopsy samples from patients with active UC identified a panel of the top 5 DEGs that can indicate the responsiveness: osteoprotegerin (TNFRSF11B), stanniocalcin-1 (STC1), prostaglandin-endoperoxide synthase2 (COX2), IL13Ra2, and IL11. This analysis demonstrated the capability to distinguish responders from non-responders with 95% sensitivity and 85% specificity [21]. In another study, involving 67 patients with UC undergoing anti-TNF treatment, mucosal healing was associated with lower mucosal expression of TBX21 (a Th1-related transcription factor) and higher expression of RORC (a Th17-related transcription factor) before treatment [22]. However, it has been also shown that high mRNA expression of both mucosal IFN-gamma and IL-17A in biopsies obtained before treatment was linked to the response to anti-TNF induction therapy in patients with UC [23]. While our study demonstrated that the activation of the Th17 cell lineage contributes to resistance to TOF treatment, predictors of anti-TNF treatment may indicate the opposite.
Finally, recent studies have underscored the potential of histological examinations in predicting treatment responses among patients with UC. Gaujoux et al. reported that the altered abundance of plasma cells and inflammatory macrophages in the intestinal mucosa distinguished responders from non-responders to anti-TNF [24]. Tew et al. demonstrated that the mucosal expression of integrin E (ITGAE), examined by immunohistochemistry, can predict the treatment response to etrolizumab (a humanized monoclonal antibody that selectively binds the b7 subunit of both heterodimeric integrins a4b7 and aEb7) [25]. These findings suggest the potential existence of more refined histological predictors, such as the abundance of IL-17-positive mononuclear cells, to identify individuals who would well respond to treatment.
Our study had several limitations, the first of which was its small sample size, in addition to its retrospective, single-center design.
In conclusion, results of this study present evidence supporting the clinical applicability of an abundance of IL-17A-positive mononuclear cells in the colonic mucosa to predict responsiveness to TOF treatment. We hope that further studies will confirm our findings and our study contributes to the development of new methods for precise identification of suitable candidates for TOF treatment.