The clinical benefit of 5-aminosalicylates in Crohn’s disease is still under debate. A recent meta-analysis of mild to moderate Crohn’s disease showed that its benefit was close to that of placebo [1]. In addition, indications for the use of 5-aminosalicylates’ have been decreasing over time, even among patients with mild Crohn’s disease [2] with few symptoms and an absence of risk factors for a complicated evolution. In the postoperative setting, 5-aminosalicylates could be given to prevent recurrence since they demonstrated mildly but significantly better efficacy than placebo at a dosage of 4 g/day [3]. Concerning safety, these agents have a good tolerance profile, requiring kidney function surveillance twice a year.

In 2016 corticosteroids maintain a central role in the management of the first flare of Crohn’s disease, particularly in the early course, whatever the severity or extent of lesions. For decades, corticosteroids’ efficacy has been demonstrated in randomized controlled trials [4] and study population cohorts [5, 6]. Nonetheless, the two main limitations of steroid use in Crohn’s disease are its side effects and its lack of efficacy as a maintenance therapy. Importantly, steroids have no impact on mucosal healing of inflammatory endoscopic lesions. Budesonide represents an alternative to “conventional” corticosteroids, with a better safety profile due to its 90 % extraction by the liver. Because budesonide is delivered in the terminal ileum and right colon, it could be considered at a dosage of 9 mg/day in patients with Crohn’s disease with mild to moderate flares in these locations, providing clinical remission in nearly 50 % [7].

Thus, a short steroid course remains a pivotal treatment in patients with active disease. It should be followed by quick tapering (within 3 months) to limit exposure and avoid side effects. In the case of steroid-refractory Crohn’s disease, including dependence, failure, and intolerance, immunosuppressants and/or biologics should be considered.

For more than 30 years, thiopurines (azathioprine and 6-mercaptopurine) have been considered as the referential maintenance therapy in refractory Crohn’s disease, providing sustained, steroid-free remission [8–11]. However, because most patients who previously responded to thiopurines relapse with time after drug withdrawal, these agents are considered as having only a suspensive action [12, 13]. To modify the course of Crohn’s disease and limit thiopurine exposure, it was expected that an early treatment with thiopurines could be beneficial. This strategy was explored in two recent randomized control trials. Unfortunately, no clinical benefit of early treatment with thiopurines was observed in the first 3 years compared with controls who received a placebo in a Spanish trial [15] or a conventional step-up approach in a French one [14]. Moreover, one-third of the patients randomized in the control arm in the French study did not require any immunosuppressants during the study period. This suggests that giving thiopurine to patients with early Crohn’s disease with several poor prognostic factors – age at diagnosis <40 years, active luminal disease requiring steroids, perianal lesions at diagnosis – may lead to overtreatment in many patients. Indeed, beyond the risk of opportunistic infection [16] or hematologic and liver toxicities, a neoplastic risk related to thiopurines is now well established; an increased risk of lymphoma [17] and nonmelanoma skin cancer were observed in the large, prospective CESAME cohort [18]. Thus, the trend of early azathioprine administration is declining because biologics have better efficacy than thiopurines [19] and an equivalent safety profile. At the moment, azathioprine is started after a first flare in the case of noncomplicated steroid-refractory disease [2] and, more often, in combination with an anti-TNF agent (cf. Sect. 19.2.1.3).

Methotrexate is the other conventional immunosuppressant that can be used in Crohn’s disease. Its efficacy is established by two randomized controlled trials and confirmed by further meta-analysis and seems comparable to that of thiopurines [20–23]. The parenteral route is preferred, with weekly 25-mg methotrexate injections followed by maintenance at a lower dose. Despite more rapid action than thiopurines and no increased risk of induced malignancy, methotrexate is usually limited to patients with previous azathioprine failure or intolerance and is associated with anti-TNF agents, as in inflammatory rheumatisms [24].

Available since 1998, anti-TNF agents have dramatically changed the management of Crohn’s disease. Two drugs that have shown efficacy as induction and maintenance treatments are available: infliximab [25, 26] and adalimumab [27, 28]. Usual indications for anti-TNF agents are refractory and severe luminal Crohn’s disease after failure or intolerance of systemic steroids, including budesonide, and conventional immunosuppressants. In addition, the efficacy of infliximab has been demonstrated in fistulizing disease, particularly for anoperineal lesions [29]. Beyond their well-known clinical benefit, anti-TNF agents also allow patients to be weaned from steroids, provide mucosal healing, and may prevent bowel damage that leads to strictures and/or fistulas and surgical resections.

Benefit of anti-TNF agents is inversely correlated with the duration of Crohn’s disease; that is, it is better for early lesions, before bowel destruction [30]. This explains the current trend toward earlier and longer treatment with anti-TNF agents. In practice, these drugs could be considered early in the case of an extended and severe first attack of Crohn’s disease, mainly when associated with complicated anoperineal lesions. In the case of a steroid-refractory course, anti-TNF agents are more effective than conventional immunosuppressants; this point has been demonstrated only with infliximab over azathioprine. In addition, the combination therapy associating an anti-TNF agent with an immunosuppressant – so-called combotherapy – is the most effective strategy, as shown in the SONIC trial [19]. At the moment, the long-term safety and duration of such combotherapy and how to manage therapeutic deescalation in patients in remission are pending issues.

Concerning anti-TNF tolerance, most side effects are shared by both infliximab and adalimumab. Neoplastic risk related to anti-TNF agents has been scrutinized and was suggested only for melanoma (odds ratio, 1.88) [31]. Infection risk, mainly concerning opportunistic infections, is increased by anti-TNF agents per se, but also by age and associated steroids and immunosuppressants [32]. Importantly, cases of tuberculosis developed while taking anti-TNF agents have become the exception since the implementation of systematic screening before starting treatment. Other common anti-TNF agent side effects are the occurrence of immunologic paradoxical manifestations involving the skin (psoriasis-like and/or eczema-like) or the joints.

Nearly 20 % of patients with Crohn’s disease are diagnosed with a form complicated by obstruction, intra-abdominal abscess, or fistula [33], leading to early surgery, especially when the complications occur in within the short terminal ilium. Despite advances in medical treatment, the vast majority of patients with Crohn’s disease will require surgery during their lifetime because of complications or treatment failure. Nowadays, laparoscopy has become the standard surgical approach in Crohn’s disease, even for complicated forms [34]. Last, the combination of intestinal resections and medical therapies, such as biologics that have a low impact on surgical outcomes, is more frequent.

In the absence of a demonstrated benefit to start conventional immunosuppressants early, two major approaches could be discussed with regard to Crohn’s disease.

In 2016, the initial therapeutic strategy for Crohn’s disease is usually a quick step-up approach taking into account disease severity and the patient’s prognostic factors. The best established factors associated with a poor disease course are young age at diagnosis, stenosing and penetrating phenotyp, anoperineal and/or rectal location, upper and extensive gastrointestinal tract involvement, and severe endoscopic lesions.

To summarize, a therapeutic algorithm [35] has been proposed for managing Crohn’s disease at diagnosis (Fig. 19.1): steroids alone in mild disease or associated with immunosuppressants in moderate disease without a poor prognosis and without complications; early anti-TNF agents with or without immunosuppressants in severe disease and in moderate forms with poor prognostic factors and/or extensive intestinal involvement and/or perianal lesions.

In the case of a loss of response to an anti-TNF agent, two primary therapeutic options should be considered before surgery or new therapeutic agents are administered: optimizing the drug (reducing the dosing interval or increasing the dose) or switching to another anti-TNF agent – both ideally according to pharmacokinetics.

Vedolizumab has now become an alternative to anti-TNF agents in Crohn’s disease. This intravenously administered humanized monoclonal antibody specifically targets the α4β7 integrin and selectively blocks gut lymphocyte trafficking. It can be use as induction and maintenance therapy after anti-TNF failure [36].

Following the development of the therapeutic armamentarium for Crohn’s disease, new therapeutic goals emerged during the past decade. Mucosal healing and the prevention of bowel damage are desirable and achievable. Because there is a poor correlation between clinical symptoms and objective inflammation in Crohn’s disease [37], closely monitoring a patient using biomarkers (fecal calprotectin– and protein C–reactive dosages, anti-TNF pharmacokinetics), endoscopy [38], and magnetic resonance imaging [39] identify early therapeutic changes if inflammation is not controlled.