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Recent advances in the management of perianal fistulizing Crohn's disease: lessons for the clinic.

ABSTRACT: INTRODUCTION:Managing fistulizing perianal disease is among the most challenging aspects of treating patients with Crohn's disease. Perianal fistulas are indicative of poor long-term prognosis. They are commonly associated with significant morbidities and can have detrimental effects on quality of life. While durable fistula closure is ideal, it is uncommon. In optimal circumstances, reported long-term fistula healing rates are only slightly higher than 50% and recurrence is common. Achieving these results requires a combined medical and surgical approach, highlighting the importance of a highly skilled and collaborative multidisciplinary team. In recent years, advances in imaging, biologic therapies and surgical techniques have lent to growing enthusiasm amongst treatment teams, however the most advantageous approach is yet to be determined. Areas covered: Here we review current management approaches, incorporating recent guidelines and novel therapies. Additionally, we discuss recently published and ongoing studies that will likely impact practice in the coming years. Expert opinion: Investing in concerted collaborative multi-institutional efforts will be necessary to better define optimal timing and dosing of medical therapy, as well as to identify ideal timing and approach of surgical interventions. Standardizing outcome measures can facilitate these efforts. Clearly, experienced multidisciplinary teams will be paramount in this process.

SUBMITTER: Lopez N

PROVIDER: S-EPMC6545251 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Project description:To evaluate the imaging course of Crohn's disease (CD) patients with perianal fistulas on long-term maintenance anti-tumor necrosis factor (TNF)-α therapy and identify predictors of deep remission.All patients with perianal CD treated with anti-TNF-α therapy at our tertiary care center were evaluated by magnetic resonance imaging (MRI) and clinical assessment. Two MR examinations were performed: at initiation of anti-TNF-α treatment and then at least 2 years after. Clinical assessment (remission, response and non-response) was based on Present's criteria. Rectoscopic patterns, MRI Van Assche score, and MRI fistula activity signs (T2 signal and contrast enhancement) were collected for the two MR examinations. Fistula healing was defined as the absence of T2 hyperintensity and contrast enhancement on MRI. Deep remission was defined as the association of both clinical remission, absence of anal canal ulcers and healing on MRI. Characteristics and imaging patterns of patients with and without deep remission were compared by univariate and multivariate analyses.Forty-nine consecutive patients (31 females and 18 males) were included. They ranged in age from 14-70 years (mean, 33 years). MRI and clinical assessment were performed after a mean period of exposure to anti-TNF-α therapy of 40 ± 3.7 mo. Clinical remission, response and non-response were observed in 53.1%, 20.4%, and 26.5% of patients, respectively. Deep remission was observed in 32.7% of patients. Among the 26 patients in clinical remission, 10 had persisting inflammation of fistulas on MRI (T2 hyperintensity, n = 7; contrast enhancement, n = 10). Univariate analysis showed that deep remission was associated with the absence of rectal involvement and the absence of switch of anti-TNF-α treatment or surgery requirement. Multivariate analysis demonstrated that only the absence of rectal involvement (OR = 4.6; 95%CI: 1.03-20.5) was associated with deep remission.Deep remission is achieved in approximately one third of patients on maintenance anti-TNF-α therapy. Absence of rectal involvement is predictive of deep remission.

Project description:Background and aimsPerianal fistula represents one of the most disabling manifestations of Crohn's disease (CD) due to complete destruction of the affected mucosa, which is replaced by granulation tissue and associated with changes in tissue organization. To date, the molecular mechanisms underlying perianal fistula formation are not well defined. Here, we dissected the tissue changes in the fistula area and addressed whether a dysregulation of extracellular matrix (ECM) homeostasis can support fistula formation.MethodsSurgical specimens from perianal fistula tissue and the surrounding region of fistulizing CD were analyzed histologically and by RNA sequencing. Genes significantly modulated were validated by real-time polymerase chain reaction, Western blot, and immunofluorescence assays. The effect of the protein product of TNF-stimulated gene-6 (TSG-6) on cell morphology, phenotype, and ECM organization was investigated with endogenous lentivirus-induced overexpression of TSG-6 in Caco-2 cells and with exogenous addition of recombinant human TSG-6 protein to primary fibroblasts from region surrounding fistula. Proliferative and migratory assays were performed.ResultsA markedly different organization of ECM was found across fistula and surrounding fistula regions with an increased expression of integrins and matrix metalloproteinases and hyaluronan (HA) staining in the fistula, associated with increased newly synthesized collagen fibers and mechanosensitive proteins. Among dysregulated genes associated with ECM, TNFAI6 (gene encoding for TSG-6) was as significantly upregulated in the fistula compared with area surrounding fistula, where it promoted the pathological formation of complexes between heavy chains from inter-alpha-inhibitor and HA responsible for the formation of a crosslinked ECM. There was a positive correlation between TNFAI6 expression and expression of mechanosensitive genes in fistula tissue. The overexpression of TSG-6 in Caco-2 cells promoted migration, epithelial-mesenchymal transition, transcription factor SNAI1, and HA synthase (HAs) levels, while in fibroblasts, isolated from the area surrounding the fistula, it promoted an activated phenotype. Moreover, the enrichment of an HA scaffold with recombinant human TSG-6 protein promoted collagen release and increase of SNAI1, ITGA4, ITGA42B, and PTK2B genes, the latter being involved in the transduction of responses to mechanical stimuli.ConclusionsBy mediating changes in the ECM organization, TSG-6 triggers the epithelial-mesenchymal transition transcription factor SNAI1 through the activation of mechanosensitive proteins. These data point to regulators of ECM as new potential targets for the treatment of CD perianal fistula.

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Recent advances in the management of perianal fistulizing Crohn's disease: lessons for the clinic.

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