Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis

TNF in the liver: targeting a central player in inflammation

“…In addition, NAFLD/ NASH is associated with intestinal dysbiosis, probably resulting from intake of an inconvenient diet, which leads to a dysfunction of the epithelial barrier in the gut, associated with increased permeability and translocation of bacteria and bacterial products into the portal blood. Bacterial products such as LPS that function as pathogen-associated molecular patterns (PAMPs) also activate TLRs, thereby amplifying the inflammatory response in the High expression levels of TNF in innate-like CD4 + T cells from PSC patients [113], Moderate effectiveness of anti-TNF therapies in PSC/IBD patients [114,115] liver, characterized by increased production of cytokines such as TNF, IL-1, and IL-17A as well as the chemokines CCL2 and CCL5 that further recruit inflammatory monocytes into the liver [53,56,57]. Moreover, changes in BA metabolism, associated with enhanced systemic levels of potentially cytotoxic BA, have been identified in NASH patients (reviewed in [58]).…”

“…Hence, Th17 cells expressing IL-17, IL-23, and other cytokines as well as T cells and innate lymphocytes expressing IFNγ and TNF have been associated with disease pathology of PSC. Several small cohort studies in PSC and PSC/IBD patients analysed the impact of anti-TNF therapies, which seemed to be only moderately effective [ 113 , 114 ]. It was concluded that the heterogeneity of the phenotype in PSC possibly makes it difficult to draw clear conclusions from studies involving only a small number of patients [ 113 ].…”

EASL Clinical Practice Guidelines on sclerosing cholangitis

“…The effect of anti-TNF in IBD with concomitant PSC has been studied in small or retrospective studies where biologics have been used for the IBD indication. 181,182 Treatment was shown to be moderately effective for gut inflammation and no concerning safety signals were found. The side effects of anti-TNF treatment in PSC-IBD are reported to be similar to those in IBD alone, and no exacerbation of PSC symptoms or specific liver-related side effects have been noted.…”

“…181 In a retrospective analysis of 141 people with PSC and IBD, anti-TNF agents (infliximab and adalimumab) were moderately effective in reducing ALP with a possible positive signal for adalimumab warranting further investigations. 182 Other IBD drugs targeting the immunology of the gut-liver axis (e.g. other integrin blockers such as etrolizumab, MAd-CAM and VAP-1 inhibitors, ustekinumab, and tofacitinib) are also attractive candidates for clinical testing in PSC and for some of these agents clinical studies have already been initiated.…”

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

“…Currently, an ongoing international multicenter retrospective study initiated by the International PSC Study Group (IPSCSG) is investigating the effect on ALP and PSC-related clinical events of anti-TNF-a therapy used for IBD in PSC patients. Preliminary reports from the assessment do not suggest an efficacy on the hepatobiliary disease in PSC from anti-TNF therapy [168].…”