Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

Abstract

Ulcerative colitis (UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor (anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve (primary non-response) or lose response after a period of improvement (secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters that may predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular (immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.

Efficacy of Tumor Necrosis Factor Antagonist Treatment in Patients With Refractory Ulcerative Proctitis

“…[19] Previous studies have identified several clinical or biological factors influencing response to anti-TNF in UC, such as severity of the disease, younger age, duration of colitis or extensive colitis. [20] In our study, we found that extraintestinal manifestations, ongoing topical steroids and 5-ASA at baseline were significantly associated with the absence of clinical remission in patients with refractory UP. Another recent study also identified extraintestinal manifestation as a risk factors for colectomy in patients with UC on thiopurine treatment.…”

Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy

“…While antibodies against IFX are associated with loss of response [3], they are not suitable to predict response in IFX-naive patients. Recently, in addition to routine laboratory indicators and immune markers [4] much research activity focused on the measurement of gene expression values in colon biopsy samples and peripheral blood to predict the individual response to IFX in IFXnaive IBD patients. However, study designs including methods used to determine gene expression and patient populations to be enrolled were quite heterogeneous.…”

“Miniguts” from plucked human hair meet Crohn’s disease

“…To date, the immunological as well as genetic factors involved in a therapy re-fractory course of IBD are poorly understood and the relevance of reduced therapeutic response for the strength of the models phenotype still has to be determined. Finally, we were able to reproduce differentiation efficiency of previous publications [69,82] using the diseased cell lines. There were no observable differences in the organoids generated by treatment with the two different mid-/hindgut formation media and patient-derived organoids compared to control organoids from healthy donors, indicating that gut development is not obviously altered within the patient-derived organoids [69].…”