Safety of treatments for inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD)

Abstract

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn’s disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn’s disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.

Introduction

Several treatments are currently available for treating inflammatory bowel disease (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC). These treatments are primarily aminosalicylates [1], [2], [3], [4], [5], [6], [7], [8], [9], systemic corticosteroids [1], [2], [3], [4], [5], [6], [7], topical corticosteroids (budesonide; beclomethasone dipropionate, BDP) [10], [11], [12], and antibiotics (ciprofloxacin, metronidazole, rifaximin) [13], [14], [15]. Immunomodulators, including thiopurines (azathioprine, 6-mercaptopurine, 6-MP) [1], [16], [17], [18], [19], [20], methotrexate [21] and cyclosporine A (CsA) [22], [23], also show efficacy in IBD [1], [16], [17], [18], [19], [20], [21], [22], [23]. Since 1995 [24], a marked efficacy has also been shown for biologic therapies, including monoclonal antibodies against tumor necrosis factor-α (anti-TNFα) (infliximab, adalimumab, golimumab, infliximab biosimilars) [25], [26], [27], [28], [29], [30], [31], [32], [33] and, more recently, against integrins (vedolizumab, natalizumab) [1], [2], [34]. Combinations of these therapies are often used.

The European Crohn’s and Colitis Organization (ECCO) has published guidelines for the management of IBD [6], [7]. Nevertheless, national guidelines are also valuable because they take into consideration the local availability, feasibility and costs of both treatments and diagnostic approaches. National guidelines are also helpful because economic and legal issues differ between countries [35]. The Italian Society of Gastroenterology and the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) have already established Italian guidelines on the use of biologics in IBD [36]. However, guidelines on the safety of treatments for adult IBD patients are not yet available in Italy.

The IG-IBD therefore decided to prepare the present guidelines on the safety of IBD treatments available in Italy. The safety of the following treatments was considered: aminosalicylates, sulfasalazine, systemic and locally released corticosteroids, ciprofloxacin, metronidazole, rifaximin, thiopurines, methotrexate, CsA, TNFα antagonists, and vedolizumab.

For this purpose, 50 gastroenterologists, all belonging to IG-IBD and working at one of 28 IBD units at Italian Universities and Hospitals, agreed to participate in writing these national guidelines. The working group included two coordinators (from two institutes), 26 writers (from 20 institutes), and 22 discussants (from 20 institutes). Additionally, one expert in infectious diseases, one oncologist and one general practitioner were involved in drawing up the consensus and in making the online evaluations, for a multidisciplinary approach. Overall, 53 panelists discussed and approved the text and the statements. Statements elaboration was followed by consensus conferences in order to discuss the preliminary statements. Agreement (>85%) was reached after 5 online votes. Each statement was discussed by the 53 panelists, who met in Rimini (Italy) on November 11th, 2014, for a general consensus meeting (participants 43/53 panelists). Statements were further discussed and voted during 5 online voting procedures. Dates of these 5 sequential online voting procedures were: October 5th–30th, 2014 (participants 49/53 panelists); November 26th–December 12th, 2014 (participants: 52/53); April 12th–29th, 2015 (participants: 52/53); July 11th–28th, 2015 (participants: 51/53), September 11th–October 17th, 2015 (participants: 52/53). In order to formulate recommendations, each expert performed a literature search using the following key words: CD, UC, IBD, safety, treatments, aminosalicylates, sulfasalazine, systemic and low bioavailability corticosteroids, ciprofloxacin, metronidazole, rifaximin, thiopurines, azathioprine, 6-MP, methotrexate, CsA, TNFα-antagonists, infliximab, adalimumab, golimumab, infliximab-biosimilars, vedolizumab. For THE literature searches, PubMed, Embase and the Cochrane database were used, including articles published until September 2016. The Oxford methodology was used to establish levels of evidence (Table 1) [37].