Management of patients with inflammatory bowel disease: current and future treatments

Introduction

Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn’s disease (CD), relapsing and remitting diseases characterised by chronic gastrointestinal (GI) tract inflammation^[1]
. Several long-standing treatments are available to control symptoms and improve the quality of life (QoL) of affected patients^[1]
. Continued interest in more effective and locally targeted therapies has led to the development of biologic agents and other agents with unique mechanisms. This article will review currently available IBD treatments and future treatments undergoing evaluation.

Sources and selection criteria

Literature was retrieved using the key words ‘ulcerative colitis’, ‘Crohn’s disease’, or ‘inflammatory bowel disease’ in Pubmed/Medline. Medication treatment classes and specific agent names were also included as search terms (e.g. aminosalicylate, mesalazine, corticosteroid, prednisolone, budesonide, etc). Additional resources were identified through hand searches of bibliographies of current articles. In reviewing the literature, emphasis was placed on treatment guidelines, current systematic reviews and meta-analyses evaluating established IBD therapies when they were available, and primary literature reporting on the potential of treatments in development.

Inflammatory bowel disease

Of the two types of IBD, UC involves mucosal inflammation and is confined mainly to the rectum and colon with rare terminal ileum involvement. CD, in contrast, is a transmural inflammatory disease and can affect any part of the GI tract from the mouth to the anus.

Both UC and CD can affect any age group, but exhibit a bimodal age of onset with peak incidence of diagnosis in the second and third decades and a second peak between 60 and 80 years of age. Approximately 2.5 million–3 million people in Europe are affected by IBD^[1]
. The highest rates of IBD are reported in Scandinavia and the UK^[1]
. The incidence and prevalence of UC in the UK is estimated to be 13.9 cases per 100,000 person-years and 243.4 cases per 100,000 people, respectively^[1]
. The incidence and prevalence of CD in the UK is estimated to be 6.6–10.6 per 100,000 and 85–144.8 cases per 100,000 people, respectively^[1]
.

The aetiology of IBD has not been fully elucidated. It has been proposed that genetic susceptibility coupled with environmental factors trigger IBD. These factors are thought to stimulate sustained abnormal immune response resulting in disruption of the intestinal mucosa and underlying layers^[2]
. While it is not definitively known exactly which factors trigger IBD, data suggest genetics, smoking, antibiotics, oral contraceptives, appendectomy, and/or diet may play a role^[2]
.

Quality of life

IBD often manifests in young adulthood and the relapsing and remitting nature of the illnesses has been shown to affect patients’ perception, body image, and quality of life (QoL)^[3]
. This is especially the case in patients with active disease, who tend to report worse QoL compared with patients in remission^{[4]
,[5]
,[6]}
. Generally, patients with IBD report higher levels of psychiatric distress, anxiety, and somatosensory amplification, and perceive having lower social support compared with people without chronic illness^[7]
,[8]
.

Other factors that contribute to lower QoL include limitations on participation in social activities and the impact on relationships with friends, family members, and intimate partners^[9]
. In addition to reduced QoL, IBD is associated with decreased labour force participation^[10]
.

Symptoms and disease classification

Patients with IBD often complain of diarrhoea with or without rectal bleeding, abdominal tenderness or pain, and weight loss^{[11]
,[12]
,[13]
,[14]
,[15]}
. UC is more likely than CD to present with blood in the stool, rectal urgency or tenesmus (a continual or recurrent inclination to evacuate the bowels)^[16]
. UC affects the mucosal and submucosal layers of the colon with continuous lesions and no healthy tissue between areas of inflammation^[17]
,[18]
. Because of the lack of involvement of the deeper layers of the bowel wall, crypt abscesses rather than fistulas are common in UC^[17]
. Around 95% of patients with UC exhibit inflammation in the rectum and, in 25% of cases, inflammation is confined to the rectum^{[17]
,[18]
,[19]}
. Conversely, CD is a transmural disease leading to complications, such as fissures or fistulas, linear clefts, and strictures, which can lead to intestinal obstruction^{[12]
,[18]
,[20]}
. Intra-abdominal and peri-anal abscesses are other complications of CD^[21]
. CD exhibits areas of disease interspersed with healthy tissue, referred to as skip lesions. Lesions are confined to the ileum and caecum in 40% of patients, the small intestine in 30% of patients, and the colon in 25% of patients^[19]
.

Classification of disease severity

Disease extent, location and severity are necessary to determine the appropriate approach to treatment. In UC, disease extent and location are defined by a lesion’s proximal border. Proctitis involves inflammation confined to the rectum, distal disease extends to the splenic flexure, and extensive disease extends proximally beyond the descending colon and can encompass all or part of the colon, and potentially the terminal ileum^[11]
. In CD, while any portion of the GI tract may be affected, the ileum and colon are most frequently involved, which may make it difficult to distinguish CD from UC in some patients^[12]
.

Severity of disease is often determined using a rating scale that incorporates a number of factors: subjective, patient-reported symptoms, such as number of bowel movements, presence or absence of blood in the stool, abdominal pain, cramping, or discomfort, and presence and severity of extraintestinal symptoms; laboratory findings such as haemoglobin or haematocrit, and erythrocyte sedimentation rate; and a patient’s or physician’s global assessment. Some indices also include an assessment of mucosal appearance on endoscopy.

For CD, the Crohn’s Disease Activity Index, Harvey Bradshaw Index and the Perianal Crohn’s Disease Activity Index are often used in clinical trials to determine disease severity and assess improvement^[22]
. Commonly used indices in UC include the Truelove and Witts Severity Index and the Sutherland Index, also known as the ulcerative colitis disease activity index^[23]
. Classification of disease severity is detailed in Table 1^{[24]
,[25]
,[26]}
.

Goals of therapy

In a patient with acute symptoms of IBD, the goal is to induce clinical remission of symptoms while improving QoL^[11]
,[12]
. Following attainment of remission, treatment is tailored to maintain remission. Additional goals of therapy include reducing long-term steroid use and, in the case of UC, mitigating long-term risk of colorectal cancer (CRC). Choice of therapy is based on disease severity and location as well as intestinal and extraintestinal manifestations. If induction therapy fails to control symptoms within a reasonable trial period, another therapeutic approach should be trialled until symptoms are controlled and maintenance therapy can be initiated.

In addition to clinical symptoms, mucosal healing may also be considered a goal of therapy in IBD. Mucosal healing is associated with an alteration in disease course and natural history for both CD and UC resulting in fewer hospitalisations, reduced need for surgery, and lower rates of disease complications^{[27]
,[28]
,[29]}
. While there is agreement that mucosal healing should be considered, consensus is lacking regarding the most effective means of measuring it, and the magnitude of healing required to alter disease course is uncertain^[22]
,[23]
.

Current treatment options

Pharmacological agents are the mainstay of therapy for the induction and maintenance of IBD remission, with surgical intervention as needed. The choice of pharmacological therapy is based on disease severity and location, an agent’s efficacy, and the desire to minimise adverse effects. Owing to the waxing and waning nature of IBD, long-term maintenance therapy is often required.

Aminosalicylates

Used for induction and maintenance of remission of mild to moderate IBD, aminosalicylates can be especially useful in UC, as they are more effective compared to when they are used in CD. Mesalazine, also known as 5-aminosalicylic acid (5-ASA), is the active component believed to confer topical anti-inflammatory effects within the GI tract via oral or rectal delivery to the site of action. Sulfasalazine is comprised of mesalazine linked to sulfapyridine by a diazo bond which, when administered orally, is broken by colonic bacteria leading to mesalazine delivery within the large intestine^[30]
,[31]
. The sulfapyridine component is associated with dose-related adverse effects, such as folate deficiency, nausea, vomiting, diarrhoea, headache, and arthralgia. Titrating the dose slowly can mitigate these adverse effects.

In addition, idiosyncratic reactions include hepatotoxicity, haemolytic anaemia, pancreatitis, pneumonitis, interstitial nephritis, and reduction in sperm count. Sulfasalazine is contraindicated in patients with sulfa allergy. To avoid exposure to sulfapyridine, and the associated adverse effects, mesalazine is available in formulations where it is bonded to an alternative inert carrier molecule, as with balsalazide, or to another mesalazine molecule, as with olsalazine. Topical administration via enemas and suppositories is also an option and is generally more effective than oral preparations for distal disease^[32]
,[33]
. Topical and oral preparations may be combined for added effectiveness. Oral mesalazine is available in a variety of oral formulations designed to affect a specific portion of the intestine. It is important to choose a mesalazine product that will be effective in the affected area of the GI tract. Mesalazine is generally well tolerated.

In a meta-analysis of 53 trials, fewer patients with UC treated with mesalazine formulations failed to enter clinical remission compared to placebo (71% versus 83%, relative risk (RR): 0.86; 95% CI: 0.82–0.89, number needed to treat (NNT): 7)^[34]
. Mesalazine formulations and sulfasalazine formulations performed similarly when compared, with 54% and 58% failing to enter clinical remission, respectively (RR: 0.9; 95% CI: 0.77–1.04)^[34]
. Mesalazine-related adverse effects were reported in 15% of patients compared with 29% of patients receiving sulfasalazine (RR: 0.48; 95% CI: 0.37–0.63)^[34]
.

An analysis of 12 trials evaluated the route of administration of mesalazine and reported on the efficacy of oral, topical, or combined oral and topical mesalazine therapy for UC^[35]
. Oral and topical mesalazine induced remission of active UC similarly (RR: 0.82; 95% CI: 0.52–1.28) and both had similar rates of adverse effects (RR: 0.61; 95% CI: 0.24–1.52). Oral mesalazine therapy resulted in failure to achieve clinical remission of active UC more often than combined oral and topical (rectal) mesalazine therapy (RR: 0.65; 95% CI: 0.47–0.91). Oral and combination mesalazine therapy resulted in similar rates of adverse effects (RR: 0.77; 95% CI: 0.55–1.09)^[35]
. When evaluating the effects of mesalazine in preventing relapse of UC, more patients receiving oral therapy experienced UC relapse compared with patients who received topical mesalazine (RR: 0.64; 95% CI: 0.43–0.95). However, there was no difference in the risk of UC relapse for patients who received oral vs. combined oral and topical mesalazine^[35]
.

In contrast with the findings in UC where aminosalicylates outperformed placebo for the induction of remission, an analysis of 20 studies evaluating aminosalicylates in the treatment of CD found that sulfasalazine performed statistically similarly to placebo (RR: 1.38; CI: 1.0–1.89)^[36]
. However, the reported CD remission rates indicated a positive trend toward aminosalicylates as the results differed numerically with 45% of patients receiving mesalazine (63/141) compared to 29% of patients receiving placebo (43/148) achieving CD remission^[36]
. The lack of statistical significance may be attributed to potential bias within the included studies, high drop-out rates of participants, possible selective reporting, and an overall low number of events. In addition, low-dose mesalazine (1–2g/day) was not superior to placebo for induction of remission (RR: 1.46; 95% CI: 0.89–2.40), nor was high-dose mesalazine (4g/day) (RR: 2.02; 95% CI: 0.75–5.45); however, this was based on the findings of one study, and so should be interpreted with caution^[36]
.

Corticosteroids

Potent anti-inflammatory agents, such as corticosteroids are used for the induction of remission of both UC and CD. Corticosteroids are generally reserved for mild to moderate disease that has failed aminosalicylate therapy, moderate to severe disease that necessitates rapid symptom management, or severe to fulminant disease with potential for surgical intervention. Short courses of prednisolone, hydrocortisone, or methylprednisolone are useful for induction of remission alone or in combination with other therapies. In a meta-analysis of five trials, systemic glucocorticosteroids induced UC remission more often than placebo (RR of no remission: 0.65; 95% CI: 0.45–0.93)^[37]
. Systemic glucocorticosteroids induced CD remission more often than placebo in two studies; however, the overall effect was not significant likely because of heterogeneity (RR: 0.46; 95% CI: 0.17–1.28). These systemically available corticosteroids are not effective maintenance therapies as they are ineffective in preventing relapse, and long-term use is associated with the development of diabetes, bone disease, and infection, among other adverse effects. Despite efforts to minimise chronic use, many patients become dependent upon the anti-inflammatory effects of corticosteroids, putting them at risk of developing serious adverse effects. Slowly tapering corticosteroid therapy and introducing corticosteroid-sparing agents may help reduce the reliance on these agents.

Budesonide is an orally administered corticosteroid that undergoes significant first pass metabolism resulting in low systemic bioavailability, with effects confined to the GI tract and limited systemic toxicity. Budesonide is available in two different formulations: the first is an enteric-coated controlled release capsule, marketed as Entocort or Budenofalk, indicated for the induction of remission of mild to moderate CD affecting the ileum and/or the ascending colon. The second formulation is budesonide multimatrix (MMX, Cortiment), which exerts its effects in the colon and is indicated for the induction of remission of mild to moderate UC when aminosalicylate therapy is not sufficient. In a meta-analysis of three studies and 900 subjects, budesonide-MMX® 9mg induced UC remission (combined clinical and endoscopic) more often than placebo at eight weeks, with remission achieved in 15% of budesonide-MMX® patients and 7% of placebo patients (RR: 2.25; 95% CI: 1.50–3.39)^[38]
.

Similarly, eight weeks of enteric-coated budesonide 9mg induced remission in 47% of patients with CD compared to 22% treated with placebo (RR: 1.93; 95% CI: 1.37–2.73; three studies, 379 patients)^[39]
. Overall, budesonide was better tolerated than conventional steroids with fewer adverse events compared to conventional steroids (RR: 0.64; 95% CI: 0.54–0.76). Additionally, budesonide, compared to conventional steroids, resulted in a lower risk of adrenal suppression (RR for abnormal ACTH test 0.65, 95% CI: 0.55–0.78)^[39]
.

Immunosuppressants

Immunosuppressive agents are reserved for patients with IBD who have failed treatment with mesalazine or are used for their corticosteroid-sparing effect in patients whose disease is dependent on chronic corticosteroids. The thiopurines, azathioprine and 6-mercaptopurine, are used for both UC and CD. Their full effects are delayed and may take six months to achieve, and so these agents are not useful for induction of remission. In a pooled analysis of six studies (489 participants), azathioprine maintained CD remission more often than placebo over a 6 to 18-month period (73% vs. 62%, RR of remission: 1.19; 95% CI: 1.05–1.34)^[40]
. In UC, azathioprine outperformed placebo as well, with 44% and 65% of patients failing to maintain remission, respectively (RR: 0.68, 95% CI: 0.54–0.86)^[41]
. The thiopurines are associated with serious adverse effects such as pancreatitis, allergic reaction, infection, and bone marrow suppression. These effects were more common in patients with CD treated with azathioprine or 6-mercaptopurine compared to placebo (RR: 1.29; 95% CI: 1.02–1.64), or when compared to mesalazine or sulfasalazine (RR: 9.37; 95% CI: 1.84–47.7)^[40]
.

It is difficult to directly compare the relative risk of adverse events of the thiopurines compared with placebo or mesalazine owing to the sparsity of events, resulting in a low quality grade in the analysis. This was especially evident in the mesalazine comparison, which only included two trials resulting in a wide confidence interval and possibly a high point estimate of the risk of adverse events. Thiopurine S-methyltransferase (TPMT) is responsible for the metabolism of these medications. TPMT polymorphisms are common and affect the accumulation of toxic metabolites, which are associated with myelosuppression or hepatotoxicity^[42]
. TPMT activity should be assessed prior to initiating therapy^{[11]
,[12]
,[43]}
: dose adjustments of 30–70% should be considered for patients with intermediate activity and thiopurines should be avoided in patients with no, or low, TPMT activity^[44]
. Patients with IBD treated with a thiopurine who exhibit suboptimal efficacy may benefit from concomitant administration of allopurinol^[45]
. Allopurinol has been shown to increase the production of the active metabolite, 6-thioguanine, while reducing the concentration of the metabolite 6-methylmercaptopurine. However, the combination of a thiopurine and allopurinol may also increase the risk for leucopoenia and associated infection, and patients receiving this combination should be monitored for this risk. The combination of azathioprine with other therapies, specifically anti-tumour necrosis factor alpha (anti-TNFα) agents, has garnered interest for the potential to improve disease control and reduce immunogenicity with the anti-TNFα agents, but more information is needed about the safety of this combination.

Methotrexate is useful for CD maintenance therapy as an alternative to azathioprine. Intramuscular injections of 25mg/week of methotrexate performed better than placebo for the induction of remission of refractory CD^[46]
, and in addition, methotrexate provided better maintenance of remission with 15mg/week compared with placebo^[47]
. Methotrexate monotherapy following thiopurine discontinuation owing to adverse effect or lack of response in 174 patients with CD resulted in sustained benefits in 98 (86%), 50 (63%), 27 (47%), and 3 (20%) patients, at 6, 12, 24, and 60 months, respectively^[48]
.

Methotrexate use is associated with bone marrow suppression, pulmonary fibrosis, hepatotoxicity, nausea and vomiting, which are mitigated by folinic acid supplementation. Its teratogenic risk limits its use in women of childbearing potential.

Antibiotics

It is thought that intestinal bacteria play a role in the development of IBD, and antibiotics may be effective adjunctive therapies. In the treatment of active CD, a meta-analysis of ten trials with 1,160 patients showed a benefit in using antibiotics compared to placebo (RR of active CD not in remission: 0.85; 95% CI: 0.73–0.99; P =0.03)^[49]
. Ciprofloxacin and metronidazole, alone or in combination, were found to significantly reduce perianal fistula drainage compared to placebo (RR: 0.8; 95% CI: 0.66–0.98)^[49]
. Additionally, antibiotics are useful for patients who develop pouchitis following ileal-pouch anal anastomosis. In a systematic review of four randomised trials, ciprofloxacin was more effective at inducing remission of acute pouchitis than metronidazole, and rifaximin was not found to be more effective than placebo^[50]
. Long-term antibiotic use raises concerns of bacterial resistance and development of Clostridium difficile infection. Metronidazole may be associated with neuropathy and ciprofloxacin may increase the risk of tendon rupture, particularly in patients receiving high-dose systemic corticosteroids.

TNF blockers

These agents are monoclonal antibodies that bind the cytokine TNF-α and inhibit its inflammatory effects in the gut and are generally reserved for moderate to severe UC and CD that is refractory to anti-inflammatory and immune-modulating therapies^[51]
.

Infliximab, the first TNF blocker approved for long-term use in UC and CD, is a chimeric monoclonal antibody with both murine and human amino-acid sequences^[52]
,[53]
. The ACCENT 1 trial demonstrated infliximab’s efficacy in CD with 335 patients responding to initial infliximab infusion subsequently randomised to continue to receive either placebo or infliximab intermittent infusions every eight weeks^[52]
. Ongoing infliximab therapy significantly improved CD remission rates at week 30 compared to placebo (45% vs. 21%; P =0.002)^[52]
. The ACT 1 and 2 trials extended infliximab’s use to patients with UC^[53]
. Infliximab 5 mg/kg infusion induced clinical response at eight weeks in 69.4% of patients compared to 37.2% of patients receiving placebo in ACT 1 (P <0.001); and 64.5% vs. 29.3%, respectively, in ACT 2 (P <0.001)^[53]
. The effects were sustained at weeks 30 and 54, showing infliximab’s efficacy for both induction and maintenance of remission in UC.

Infliximab is administered as an intravenous infusion of 5mg/kg at weeks 0, 2, 6 and every 8 weeks thereafter. One of the most common adverse effects of infliximab is a flu-like infusion reaction^[54]
, which can be prevented or lessened by the premedication of an antihistamine and paracetamol, with or without a corticosteroid. Additional adverse reactions that occur more rarely include new onset or worsening congestive heart failure, reactivation of infections, and rare lymphomas. Prior to infliximab use, patients must undergo screening for tuberculosis and hepatitis B, counselling regarding the risk of lymphoma, as well as being considered for hepatitis C and HIV screening^[54]
.

Several other TNF blockers have been approved for the treatment of CD and UC since infliximab^{[55]
,[56]
,[57]
,[58]}
. Adalimumab, certolizumab, and golimumab are fully humanised monoclonal antibodies with data available for the treatment of IBD, and may be helpful especially for patients who cannot tolerate, or have become resistant to, infliximab. They are administered subcutaneously and provide a more convenient option for patients as they circumvent the need for an infusion centre or intravenous access. In the UK, adalimumab is indicated for the treatment of both UC and CD, and golimumab is indicated for the treatment of UC. Currently, golimumab is not approved for the treatment of IBD in the UK. The humanised monoclonal antibodies have similar risks for worsening of heart failure, reactivation of infections and malignancy. In addition to the TNF blockers mentioned, biosimilar agents may provide alternative and potentially cost-saving options. Data are increasingly becoming available regarding efficacy and safety of biologic agents specifically for the treatment of IBD^[59]
.

Leucocyte adhesion inhibitors

Inflammation caused by leucocyte migration to the parenchymal tissue in the gut is dependent upon adhesion molecules^[60]
,[61]
. Natalizumab (Tysabri; Biogen) is a humanized monoclonal antibody that inhibits the adhesion of alpha-4-beta-7 integrin to receptors on the endothelial cells of the gut, thus preventing inflammation^[62]
. Natalizumab also binds alpha-4-beta-1 integrin, which is expressed in the skin, bone marrow, and brain. This non-selectivity imparts the risk of life-threatening Progressive Multifocal Leukoencephalopathy (PML). Given the risk of PML, natalizumab is limited to CD patients whose disease is refractory to all other therapies.

Vedolizumab, a humanised monoclonal antibody that inhibits leucocyte adhesion, is more selective for alpha-4-beta-7 integrin and is therefore more specific to the GI tract than natalizumab^[60]
. Currently, there have not been any reported cases of PML with vedolizumab. Vedolizumab is administered as an intravenous infusion for use in UC and CD based on the results of the three GEMINI trials^[63]
. GEMINI 1 showed vedolizumab to be superior to placebo for the induction and maintenance of remission in patients with UC who had failed previous therapy, including TNF blockers. At six weeks, more patients receiving vedolizumab achieved clinical response compared to placebo (47.1% vs. 25.5%; P <0.001). Patients who responded to treatment continued receiving vedolizumab or placebo for a total of 52 weeks at which point vedolizumab achieved response more often than placebo (41.8% for every eight-week infusion vs. 44.8% for every four-week infusion vs. 15.9% for placebo; P <0.001). GEMINI 2 was a similar study evaluating vedolizumab in patients with CD who had failed therapy with a TNF blocker^[64]
. Although a significantly greater number of patients achieved clinical remission (CD Activity Index (CDAI) score <150) after the six-week induction phase with vedolizumab compared to placebo (14.5% vs. 6.8%; P =0.02), the magnitude of reduction of the CDAI score was not significantly different between the groups, with 31.4% of patients treated with vedolizumab and 25.7% of patients receiving placebo achieving a 100-point reduction in CDAI (P =0.23). As in GEMINI 1, patients achieving a clinical response in the induction phase were randomised to a maintenance phase where a greater number of patients achieved clinical remission at 52 weeks when treated with vedolizumab infusion every eight weeks (39%) and every four weeks (36.4%) compared to placebo (21.6%; P <0.001)^[64]
.

Therapeutic drug monitoring

Patients who are treated with biologic agents may experience a loss of sustained response to therapy over time, resulting in symptom flares^[65]
. The mechanisms behind this loss of response is unclear, but is thought to be primarily because of the gradual development of antibodies to the agent being used. To reduce these symptomatic flares, clinicians may empirically adjust therapy by reducing the dosing interval, increasing the total dose, or switching to a different therapy^[66]
. Another option is TDM of serum trough concentrations^[67]
. Post-hoc analysis of the ACCENT 1 trial sought to establish a connection between patient response to infliximab, serum C-reactive protein (CRP) concentration as a general marker of inflammation, and infliximab serum concentrations^[68]
. In ACCENT 1, serum concentrations of CRP and infliximab were measured in 291 patients treated for CD at week 14 of therapy. Patients receiving 5mg/kg of infliximab who had a sustained clinical response at week 54 were those with a serum infliximab trough concentration of at least 3.5µg/ml and a reduction in CRP of at least 60% from baseline.

Post-hoc analyses of Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) produced similar results with an association between week 14 infliximab trough concentration of 5.1µg/ml and a clinical response at weeks 30 and 54 in patients treated for UC^[69]
. Limitations to the post-hoc analyses were the inability to quantify the presence of anti-infliximab antibodies due to the lack of reliable assay methods at the time of study completion, and small sample sizes.

Given the promising results of the post-hoc analyses, the Trough Level Adapted Infliximab Therapy (TAXIT) trial was designed to further evaluate whether adjusting infliximab dosing based on target infliximab trough concentrations would improve outcomes in patients with CD and UC^[70]
. TAXIT was a prospective, randomised trial with optimised infliximab dosing to achieve trough levels of 3–7µg/ml in patients treated for either CD or UC. After an initial dose optimisation period, patients were randomised to receive either traditional infliximab dose adjustments based on clinical symptoms and CRP levels, or continuous dose adjustments to achieve target infliximab serum trough levels.

For both CD and UC patients, the primary endpoint of clinical remission after one year of dose adjustments did not differ between the two groups. In contrast, the secondary endpoint of clinical relapse requiring rescue therapy did differ significantly between the two groups, with the clinically dose-adjusted group exhibiting a greater need for rescue therapy. An evaluation of endoscopic outcomes showed that patients with mucosal healing had significantly higher infliximab trough levels than those without mucosal healing (median 5.2 vs. 2.8µg/ml; P =0.009).

There have been several explanations put forward to explain the results of the TAXIT trial^[71]
. One explanation is that the large proportion of patients in remission (87.5%) after the dose optimisation phase may have affected the results, given that continued dose adjustment is unlikely to be necessary in these patients. Also, the patients enrolled in the study had been treated with infliximab for a median of 4.6 years prior to enrolment, whereas previous studies have shown that patients typically experience suboptimal infliximab levels within the first year of therapy.

TDM of adalimumab has been evaluated in both CD and UC. A total of 23 patients with CD who were naive to biologic therapy were given adalimumab to induce and maintain remission^[72]
. Serum trough levels of adalimumab were higher in patients who had maintained remission compared to those who experienced a relapse of their disease at 48 weeks (remission 10.1µg/ml, mild symptoms 7.4µg/ml, moderate to severe symptoms 4.5µg/ml). Patients who had anti-adalimumab antibodies present tended to have lower trough levels. In another trial, 43 patients with UC who had failed therapy with infliximab were initiated on adalimumab^[73]
. Serum trough concentrations of adalimumab were evaluated at weeks two and four of treatment, and short-term mucosal healing was evaluated by endoscopy between weeks 8 and 14. Patients with short-term mucosal healing had higher adalimumab trough concentrations at week four compared to patients who did not have mucosal healing (10.6µg/ml vs. 7.4µg/ml, respectively).

There are several scenarios in which TDM may be clinically useful, such as maximizing induction regimens or managing a patient with a loss of response to biologic therapy; however, more research is needed to clearly define its utility, establish a therapeutic range, and prospectively validate TDM as a viable monitoring approach when compared to conventional symptom-based strategies^[65]
. In addition, TDM should be employed in conjunction with anti-drug antibodies to provide a more complete assessment of a patient’s loss of efficacy.

Future agents

Although significant progress has been made in the treatment of IBD, current options achieve remission in only a portion of patients affected. Research continues to unveil novel mechanisms of action and new approaches using approved therapies. The section below is a summary of these strategies, which are anticipated to become available in the next three to five years. This is not intended to be an exhaustive review of future treatments, and we refer the reader to in-depth reviews elsewhere^[74]
,[75]
. Also see Table 2 for a summary of potential future agents.

Inhibitors of RNA and intracellular cytokine pathways

Antisense oligonucleotides (ASOs)

ASOs are single-stranded nucleotides that target specific messenger RNA (mRNA) or DNA sequences. Two classes of ASOs have been described based upon their mechanism of action: RNase H-dependent ASOs that induce mRNA degradation, and steric-blocker ASOs that physically inhibit the translation process. Unmodified ASOs have a relatively short half-life in vivo and are quickly metabolised by intracellular exonucleases and endonucleases. Additionally, these degradation products of ASOs can be cytotoxic and exert antiproliferative effects; therefore, biochemical modifications have been developed to address these issues^[76]
.

Alicaforsen (Atlantic Healthcare) targets intercellular adhesion molecule-1 (ICAM-1), a protein found on the surface of leucocytes and vascular epithelial cells and which is up-regulated in inflamed tissue in IBD. Alicaforsen was initially developed as a promising intravenous therapy for CD; however, in subsequent phase III trials, alicaforsen was not superior to placebo for induction of remission in CD. It has been hypothesized that the drug concentration following IV administration was not sufficient, and future drug development has been directed at topical administration for distal UC and pouchitis.

A meta-analysis of four phase II studies confirmed the efficacy of alicaforsen in active UC, particularly in patients with distal disease (up to 40cm from anal sphincter) and with moderate-to-severe disease. Mesalazine was used as an active comparator and similar improvement in disease activity was seen early; however, the activity of mesalazine was diminished beyond week 30 and alicaforsen became significantly more efficacious^[77]
. A phase III clinical trial of alicaforsen for pouchitis began in early 2016, and a phase III trial in active distal UC is expected to begin soon^[78]
.

Increased gut inflammation in CD is characterised by abnormal decreases in activity of immunosuppressive cytokine transforming growth factor (TGF)-β1 and mediated by SMAD7, an intracellular protein that ultimately prevents TGF-β1 signalling. Mongersen is a phosphorylated ASO which binds human SMAD7 mRNA and facilitates RNase H-mediated degradation. Mongersen is formulated as a tablet with a pH-dependent coating that delivers active drug to the terminal ileum and right colon. In a double-blind, placebo-controlled phase II trial, the effectiveness of mongersen (10, 40, and 160mg per day) in active CD was evaluated after two weeks. Mongersen was well tolerated with significant improvements in the percent of participants reaching clinical remission in both the 40mg (55%) and 160mg (65%) mongersen groups compared with placebo (10%; P<0.001)^[79]
. Additionally, results of a double-blind, multicentre study of mongersen 160 mg daily for four, eight, or 12 weeks in both TNF-naïve and TNF-experienced patients with active CD have been reported. A total of 63 patients were enrolled with mean CDAI of 294 and mean duration of CD of 11.6 years. The highest clinical response (67%) and clinical remission (48%) rates were observed in the 12-week treatment arm. Likewise, the greatest improvement from baseline CDAI was observed in subjects receiving mongersen for 12 weeks, with a mean reduction in CDAI of 133 points^[80]
.

Janus Kinase (JAK) inhibitors

The JAK proteins are a family of tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2 [TYK2]) that play a central role in signal transduction pathways for multiple cytokines, including proinflammatory cytokines involved in IBD pathogenesis.

Tofacitinib is an oral inhibitor of JAK1 and JAK3 with some activity against JAK2. Two identical phase III double-blind, placebo-controlled studies (OCTAVE Induction 1 and 2) evaluated the safety and efficacy of tofacitinib 10 mg twice daily for moderate to severe UC. Overall, a significantly greater proportion of participants in the tofacitinib group were in remission at eight weeks compared with placebo (18.5% vs. 8.2%; 95% CI: 4.3–16.3) in OCTAVE Induction 1 and in OCTAVE Induction 2 (16.6% vs. 3.6%; 95% CI: 8.1–17.9), respectively^[81]
. Results from a placebo-controlled study evaluating tofacitinib 10 mg and 5 mg twice daily as maintenance therapy in moderate to severe UC (OCTAVE Sustain) is expected by the end of 2016^[82]
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Biologics

In addition to the specific classes and agents discussed below, considerable research is underway to optimise available biologic therapies with activity in IBD. For example, optimisation of TNF-α antagonists via TDM, as discussed previously, has important implications on the clinical utility of biologics in the future.

Interleukin-12 (IL-12) and interleukin-23 (IL-23) antagonists

IL-12 and IL-23 serve as gatekeepers to a pro-inflammatory pathway involving immune activation of T-helper and natural killer cells. Activation of this pro-inflammatory pathway is thought to increase immune cell differentiation, proliferation, and activation; ultimately increasing TNF, interferon-gamma, IL-17 and other pro-inflammatory cytokines, which lead to mucosal inflammation and ulceration along the GI tract.

Ustekinumab was recently approved by the US Food and Drug Adminstration and European Medicines Agency for patients with moderate-to-severe active CD who have failed, lost response to, or were intolerant to, conventional therapies (i.e. immunomodulators or corticosteroids) or a TNF-É‘ antagonist. These approvals were granted based upon three large phase III studies in over 1,700 patients. In the two induction studies (CD-1 and CD-2) using ustekinumab 6mg/kg, significant differences between placebo and ustekinumab were noted in pooled results for both clinical remission (12.9% vs. 29.7%, respectively; P <0.001) and clinical response (25.7% vs. 46.9%, respectively; P <0.001) at eight weeks. Patients receiving ustekinumab classified as responders in the two induction studies were randomised to placebo or ustekinumab 90mg every eight weeks. At week 44 of the maintenance trial a greater proportion of patients receiving ustekinumab achieved clinical remission (53% vs. 36%; P <0.01) or clinical response (59% vs. 44%; P <0.05) compared to placebo, respectively. Additionally, a higher proportion of patients receiving ustekinumab were in clinical remission and were corticosteroid-free at week 44 compared to placebo (P -value not reported)^[83]
.

Briakinumab, another IL-12/23 antibody, had a favourable safety profile but further development was halted because of failure to meet the primary end point of clinical remission at week six. The authors attributed this to carryover effects of patients randomised to placebo in the maintenance phase who had received briakinumab during the induction phase^[84]
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Lymphocyte trafficking vs. leucocyte adhesion inhibitors

Ozanimod is an oral sphingosine-1-phosphate (S1P) subtype 1 (S1P1) and subtype 5 (S1P5) receptor modulator under investigation for induction and maintenance treatment of moderate to severe active IBD. Modulation of S1P receptors is thought to interfere with the signalling of lymphocytes to exit lymph nodes. Ultimately, this results in peripheral sequestration of lymphocytes and reduces the availability of circulating lymphocytes to areas of inflammation. Preliminary results from a small phase II study in active UC (TOUCHSTONE) revealed promising results^[85]
. A large phase III study with an estimated enrolment of 900 patients is currently recruiting for UC and a phase II study is ongoing for CD^[86]
,[87]
.

Humanised monoclonal antibodies (i.e. natalizumab and vedolizumab) that bind to integrins have demonstrated efficacy for both UC and CD, as discussed previously under Leucocyte adhesion inhibitors. Etrolizumab is a subcutaneously administered humanised monoclonal antibody that selectively binds the b7 subunit for the a4b7 and aEb7 integrin heterodimers. Antagonism of lymphocyte migration from the mucosal vasculature to areas of active inflammation is a therapeutic approach for IBD. Phase II results demonstrated a 20% difference in response between etrolizumab and placebo at week ten (P <0.01). Phase III clinical trials evaluating etrolizumab in UC are ongoing and phase III clinical trials in CD are planned^[88]
,[89]
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Therapies which modify the gut microbiome

Several clinical trials have assessed the effect of modulating the microbiota in patients with IBD. These trials have provided evidence in favour of the role gut microbiota play in IBD. However, the complex nature of IBD makes it difficult to assess the effect of individual microorganisms, or communities, on the different phenotypes and ‘phases’ of IBD, such as active disease and maintenance of remission.

Faecal microbiota transplant

Patients with active IBD appear to have reduced bacterial diversity within the intestinal lumen, which FMT is effective in improving^[90]
. FMT involves delivery of gut micro-organisms directly to the gastrointestinal tract during endoscopy, or orally via nasogastric or lyophilised capsules. The process has demonstrated therapeutic potential for recurrent or refractory C. difficile infections with cure rates of approximately 90%. Because of the role that intestinal microbiota are thought to play in the pathogenesis of IBD, FMT has been used for the management of IBD with some positive outcomes reported, primarily in small case series or non-randomised trials. In a systematic review, results from 17 articles involving 41 patients (27 with UC, 12 with CD, and 2 unclassified IBD) were summarised. Overall, the results appeared promising with 76.0% reporting cessation of medications and symptom reduction, and 62.5% reporting disease remission^[91]
. However, while results from FMT studies have been encouraging, larger randomised studies are necessary to evaluate the full benefits and risks associated with this procedure. A recent systematic review of adverse events associated with FMT for a variety of indications (n=1089) revealed 9.2% of patients experienced a serious adverse event with death (3.5%) and infection (2.5%) being the most commonly reported^[92]
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Probiotics

In the last decade, probiotics have increasingly been investigated for a variety of medical conditions, including IBD. Probiotics are any live microorganisms that may confer a health benefit on the host when administered in adequate amounts. Probiotics may have multiple interactions on the host, including competitive inhibition of other microorganisms, effects on the mucosal barrier, and immune modulation through interaction with antigen-presenting cells in the GI tract^[93]
.

Multiple reports have documented changes in the gut microbiota in IBD, with the most consistently reported changes being a reduction in Firmicutes, specifically Faecalibacterium prausnitzii, and an increase in Bacteroidetes phylum members. This imbalance is thought to promote a shift in several pathogenic variants leading to chronic inflammation in patients with IBD.

One of the largest (n=327) and most influential trials of probiotics for IBD was the use of Escherichia coli Nissle 1917 for maintenance of remission in UC. The trial was a double-blind, double-dummy comparison of the probiotic vs. mesalazine. Patients in both treatment groups had equivalent rates of relapse; thus, E. coli Nissle is accepted as an effective alternative to mesalazine treatment for maintenance of remission in UC^[94]
. VSL#3, a multi-strain probiotic, has also been shown in placebo-controlled clinical trials to improve disease activity scores, but the impact of this improvement compared to available treatments is unknown. Unfortunately, there is no clinically significant role for the use of probiotics in CD as yet.

When surgery for UC is required, the procedure of choice is restorative proctocolectomy with ileal-pouch anal anastomosis. Pouchitis, or inflammation of the surgically formed ileal-pouch, occurs in about 50% of patients, and antibiotics are generally considered the first-line therapy. However, when compared with placebo, the multi-strain probiotic VSL#3 significantly reduced acute pouchitis and improved quality of life in patients with ileal pouch anal anastomosis^[95]
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Conclusion

IBD is a common disorder with profound effects on morbidity and a patient’s QoL. Despite advancements in the last decade, a substantial number of patients are not fully responsive to treatment or lose efficacy over time. Recent approvals and novel therapies in development offer alternatives to existing therapies for IBD with the hope that in the near future more patients can attain disease remission.