Sulfasalazine and the mesalamine conjugates have had mixed results in the trials designed to determine if they are effective in treating active Crohn’s disease [5, 6]. A meta-analysis of placebo-controlled trials of active Crohn’s disease over 16 weeks found a statistically significant but clinically insignificant improvement in Crohn’s Disease Activity Index (CDAI) [7, 8]. Their role as maintenance therapy has not been supported by the literature [5, 9, 10]. Overall, the mesalamine agents have a role limited to patients with mild Crohn’s disease, and their efficacy should be proven with periodic objective assessments of disease activity (endoscopic and/or radiographic).

Corticosteroids have a deservingly bad reputation in Crohn’s disease; although they might temporarily alleviate some of the signs and symptoms, they do not change the disease course, and their long-term side effects can be catastrophic. Budesonide, which is available as a controlled-ileal release capsule targeting the small intestine and right colon, has been shown comparable to prednisolone in inducing clinical remission (53 % vs. 66 %) with far fewer side effects [11]. The maintenance benefits of budesonide have yet to be proven; a systematic review of budesonide use as a maintenance therapy did not demonstrate efficacy beyond 3 months following the induction of remission [12].

The thiopurine agents (azathioprine and 6-mercaptopurine) are slow-acting agents; induction of remission typically requires the use of a fast-acting corticosteroid or biological agent. Treatment with thiopurine therapy has demonstrated effectiveness in the discontinuation or reduction of steroid use, although often with up to a 3-month delay in response [13]. Further studies assessing the withdrawal of thiopurine therapies leading to clinical relapse provide proof of concept for the beneficial effects of thiopurine therapy in the long-term maintenance of disease control [14–17]. However, thiopurine monotherapy has been tempered by the lack of improved outcomes as an induction therapy in the early diagnosis of Crohn’s disease, as well as the associated rare risks of lymphoproliferative disorders, myeloid disorders, and nonmelanoma skin cancers [18–22].

Methotrexate also requires a faster-acting agent to induce remission in Crohn’s disease (such as corticosteroids or biologics). The administration of injectable methotrexate (25 mg once weekly) when compared to placebo resulted in clinical remission (defined by a score ≤150 CDAI) at the end of a 16-week trial in 39.4 % of patients receiving methotrexate compared to 19.1 % on placebo [23]. In a maintenance study arm, among those patients achieving clinical remission after 16–24 weeks of therapy, those randomized to receive 15 mg of intramuscular methotrexate compared to placebo maintained remission at 40 weeks of therapy (65 % randomized to methotrexate compared to 39 % with placebo) [24]. Therefore, methotrexate use has demonstrated effectiveness for the induction and maintenance of clinical remission in an era prior to the initiation of biologic therapies.

The advent of biologic therapies has revolutionized treatment strategies and endpoints in clinical trial design with demonstrated effectiveness in the induction and maintenance of clinical disease activity. In addition, biologic therapy use has introduced the concept of early aggressive medical therapy in those with a short duration of disease and prognostic factors associated with the development of disease complications. A meta-analysis of ten studies demonstrated that, when compared to placebo, anti-TNF therapies resulted in an increased likelihood of induction of remission (RR: 1.66, 95 % CI: 1.17–2.36) as well as maintenance of remission (RR: 1.78, 95 % CI: 1.51–2.09) [25]. Furthermore, recent studies have extended the results of steroid-free remission to 4 years of therapy with decreases in the rates of hospitalization and surgery among those receiving scheduled therapy [26–30]. With a safety profile that does not include the development of malignancy and an increased risk of serious infection of 0.64 per 100 patient-years (compared to conventional Crohn’s disease therapies), biologic therapies have been advocated as the initial therapy in individuals with poor prognostic factors [31–33].

The anti-integrin antibodies are also proven effective in the induction and maintenance of remission in patients with Crohn’s disease. Early enthusiasm over natalizumab, used mostly in multiple sclerosis as it targets adhesion molecules in the central nervous system as well as the gut, quickly vanished when reports appeared of disabling or fatal progressive multifocal leukoencephalopathy. Subsequent investigations identified this as a complication of infection by the John Cunningham (JC) virus. Current treatment paradigms require first a blood test for antibodies to the virus; if these are not present, natalizumab monotherapy can be instituted, but should be discontinued if the patient subsequently tests “positive” for the JC virus on annual or semiannual testing. Natalizumab’s long-term efficacy in Crohn’s disease patients, including those who were nonresponders to infliximab, keeps this alive as a backup option in these patients.

Vedolizumab’s emergence into the field in mid-2014 has supplanted natalizumab; this anti-integrin antibody targets only the gut; there have not been any PML infections seen nor expected. The excellent safety profile of this agent is tempered only by its short time on the market, as well as a slower onset of action than the anti-TNF biologics.

Given the success rates achieved with biologic therapies, the state of the art in Crohn’s disease therapy comes in the optimization and prolongation of biologic therapy responses [34, 35]. With the demonstration of antibody formation to biologic therapies and decreased immunogenicity with concomitant immunosuppressive therapy, approaches to combined immunosuppression have been introduced. An open-label 2-year trial randomizing 133 patients to early combined immunosuppression with azathioprine and infliximab (utilizing an episodic dosing schedule) compared to a conventional approach of corticosteroids followed in sequence by azathioprine and infliximab demonstrated rates of corticosteroid-free remission in 60 % in the early combined immunosuppression arm compared to 35.9 % in the conventional therapy arm at 26 weeks [36]. The subsequent SONIC trial randomized 508 patients with moderate-severe Crohn’s disease to infliximab monotherapy, azathioprine monotherapy, or combined immunosuppression. With a primary outcome of corticosteroid-free remission at 26 weeks, the endpoint was met in 56.8 % randomized to combination therapy, 44.4 % receiving infliximab alone, and 30 % receiving azathioprine alone. Furthermore, mucosal healing occurred in 43.9 % in the combination therapy group, 30.1 % in the infliximab monotherapy arm, and 16.5 % receiving azathioprine [37].

The increased use and recognition of biologic therapies has led to increasing evidence with respect to the optimal use and monitoring of drug therapy. Factors associated with improved treatment responses have included early initiation of biologic therapy, maintenance biologic therapy as opposed to episodic dosing schedules, the use of concomitant immunosuppression, and the use of premedication to suppress antibody responses to biologic therapies [37–40]. In addition, increased monitoring of drug levels has led to preliminary work resulting in predictive values of clinical response [41–43]. Future works will continue to include therapy optimization algorithms in addition to incorporation of novel therapeutic agents and objective disease monitoring [44–52].

Targeting sustained clinical and endoscopic remission aims to interrupt the naturally progressive and destructive disease course that culminates in the development of intestinal failure and associated disease complications. The choice of initial therapy should incorporate the individual profile in order to make more potent compounds available to high-risk patients. Surgery remains an indication in complex Crohn’s disease and although not curative, when used restrictively is effective in providing prolonged disease control [1, 53, 54]. Future studies will continue to guide the optimization of drug therapies in order to create personalized algorithms with respect to disease activity and therapy monitoring while maintaining a focus on altering the natural history of the disease.