Clinical Review State of the Art Review

Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease

BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2505 (Published 19 June 2017) Cite this as: BMJ 2017;357:j2505
  1. Benjamin L Cohen, assistant professor of medicine1,
  2. David B Sachar, clinical professor of medicine1
  1. 1Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  1. Correspondence to: B L Cohen benjamin.cohen{at}mssm.edu

Abstract

The treatment of inflammatory bowel disease (IBD)—ulcerative colitis (UC) and Crohn’s disease (CD)—has evolved beyond surgery with the introduction of biologic agents, primarily antibodies against mediators of inflammation and cell attraction. Anti-tumor necrosis factor (TNF) agents have been the first line treatment for moderate to severe ulcerative colitis and Crohn’s disease for more than 15 years. During that time much has been learnt about how best to use these agents. This review will assess the evidence on how to optimize the use of anti-TNF agents; when and how to start treatment; how to monitor treatment and when to de-escalate it; and the potential adverse effects of these drugs. New and emerging treatments such as anti-attractants, anti-interleukins, and Janus kinase (JAK) inhibitors will also be discussed.

Introduction

Since the earliest descriptions of ulcerative colitis and Crohn’s disease, these inflammatory bowel diseases have grown to be among the most difficult to characterize, difficult to treat, and costly chronic gastrointestinal diseases in the developed world. Although the causes and treatment of inflammatory bowel disease (IBD) have long been studied, only with the advent of biologic drugs in the past two decades has the management of this disease been substantially reshaped. Estimates of treatment cost based on United States claims data from 2003 to 2004, before the introduction of many newer biologic therapies, showed a treatment burden of $6.3bn (£4.9bn; €5.6bn).1 This number is only likely to rise with the expense of newer treatments.

Anti-tumor necrosis factor (TNF) therapy was approved for use in Crohn’s disease in 1998 and for ulcerative colitis in 2005. Nearly 20 years later we are still gaining new insights about the optimal use of these drugs beyond what was shown in the initial pivotal trials. Clinical practice has evolved with respect to initiating therapy, managing loss of response, and even considering de-escalations of therapy. This review will assess the evidence about the optimal clinical use of anti-TNF biologics, and new and emerging treatments for IBD.

Epidemiology

Epidemiologic data regarding IBD vary across demographic and geographic boundaries. However, from 2000 to 2010, the incidence of Crohn’s disease and ulcerative colitis was estimated to be 10.7 and 12.2 cases per 100 000 person years, respectively, in the United States Olmstead County, Minnesota population based cohort.2 The steady increase in these diseases has resulted in a prevalence of 400-600 cases of IBD per 100 000 people in North America.2 It is currently estimated that IBD affects about four million patients worldwide.3

Genetic predisposition plays a key role in vulnerability to Crohn’s disease and, to a lesser degree, to ulcerative colitis. These genetic influences account in large part for higher incidences in certain ethnic groups and families.4 The number of genetic loci associated with different frequencies of IBD is approaching 200, yet in combination they seem to account for less than 15% of variance in Crohn’s disease and only 7.5% of variance in ulcerative colitis.5

Epidemiologic evidence indicates that environmental factors play a crucial role in the development of IBD. This is illustrated by the less than complete concordance for disease occurrence even in monozygotic twins, the rapidly increasing incidence of IBD over time, and the seismic shifts in incidence among populations of varying ethnicities as they migrate to different geographic areas.

Most environmental risk factors seem to operate in similar directions for Crohn’s disease and ulcerative colitis. However, the effects of smoking (protective against ulcerative colitis but worsens Crohn’s disease) and appendectomy (protective against ulcerative colitis but worsens Crohn’s disease) may be opposite between the two diseases, although even here the disease locations and the appendectomy indications may confuse the apparent distinctions.67

One fundamental question underlying all epidemiologic studies is whether IBD is one disease or two. We believe that ulcerative colitis and Crohn’s disease represent distinct entities more than a spectrum.8

Conventional treatments

For decades after the recognition of IBD, the only effective treatment was surgery. It was not until the middle of the 20th century that medical treatments for IBD began to appear in the form of aminosalicylates, adrenocorticotropic hormone (ACTH), and corticosteroids. In 1968 these drugs were supplemented by antimetabolites, and this was followed by the currently used biologic agents, primarily antibodies against several mediators of inflammation and cell attraction.9

Currently, an array of newer medical therapies are being rapidly developed, including Janus kinase (JAK) inhibitors, immune cell modulators, lymphocyte sequestration agents, anti-sense drugs, stem cells, granulocyte cell stimulating factors, mucosal barrier enhancers, and natural products.10

However, even today, it is not clear that any of these medical advances have reduced or will substantially reduce the pivotal role of surgery in managing IBD. Nonetheless, surgery is rarely if ever the initial treatment of choice in IBD, so it is essential to assess which drugs are the most effective and safe, and to deal with patients’ principal concerns.11

Despite the advent of biologic agents and new treatments for IBD, conventional drugs still have an important role in the first line management of both ulcerative colitis and Crohn’s disease. In the 40 years between the introduction of sulfasalazine and the first use of non-sulfa aminosalicylates, hundreds of studies have demonstrated the efficacy of these drugs in the induction and maintenance of remission in mild to moderate ulcerative colitis and to some extent for Crohn’s disease of the colon; both oral and rectal formulations have proved useful, individually and especially in combination.12

Similarly, since 1955 conventional corticosteroids (parenteral, oral, and rectal) and budesonide (oral and rectal) have become mainstays of the management of different presentations of IBD. Likewise, thiopurines (azathioprine and mercaptopurine) have become widely accepted as conventional treatment since 1970 and methotrexate (especially for Crohn’s disease) since 1990. Details of the applications of these treatments are beyond the scope of this review but can be found elsewhere.12

Sources and selection criteria

We used the terms “Crohn’s disease”, “ulcerative colitis”, “inflammatory bowel disease”, “Crohn’s disease treatment”, “ulcerative colitis treatment”, “inflammatory bowel disease treatment”, “anti-TNF”, “biologic therapy”, “infliximab”, “adalimumab”, “certolizumab”, “golimumab”, “biosimilar”, “anti-attractant”, “anti-integrin”, “vedolizumab”, “ozanimod”, “etrolizumab”, “anti-interleukin”, “ustekinumab”, “JAK inhibitor”, “tofacitinib”, “mongersen”, “future therapy”, “immunomodulator”, “thiopurine”, “azathioprine”, “6-MP”, “mercaptopurine”, “methotrexate”, “combination therapy”, “post-operative prophylaxis”, “de-escalation”, “antibody”, “immunogenicity”, “therapeutic drug monitoring”, “infliximab level”, “adalimumab level”, “safety”, “lymphoma”, “psoriasis”, “infection”, and “pregnancy” alone and in combination to search PubMed and Web of Science from the year 1998 to 30 November 2016. Landmark studies before that date were also included. In addition, we searched bibliographies of articles for relevant studies. Evidence was obtained from high quality randomized controlled trials (RCTs; placebo controlled, intention to treat, adjustment for covariables) and large systematic reviews and meta-analyses when available. Otherwise, data were obtained from high quality non-placebo controlled trials and uncontrolled cohort studies that mentioned the associated limitations to highlight areas in need of future research. Case reports and case series were excluded. Where relevant, we incorporated practice guidelines from the American College of Gastroenterology (ACG 2010, 2017), World Congress of Gastroenterology (2011), and European Crohn’s and Colitis Organization (ECCO 2016).131415161718

Anti-TNF agents

Since it was approved by the Food and Drug Administration in 1998 for use in Crohn’s disease and in 2005 for ulcerative colitis, infliximab (Remicade, Inflectra) has become a mainstay in the treatment of IBD.1920 In the past decade, three more injectable monoclonal anti-TNF antibodies have reached the marketplace for the treatment of IBD: adalimumab (Humira), certolizumab (Cimzia), and golimumab (Simponi). Their use has become so ubiquitous that most literature takes their administration for granted and mainly considers their relative merits and how each is best used when starting treatment, monitoring treatment, combining treatment, and withdrawing or changing treatment.

Starting anti-TNF treatment

Guidelines recommend that the initial treatment of ulcerative colitis should be with traditional agents like aminosalicylates, orally or rectally (or both), or with systemic or topical steroids for more serious attacks.13 Yet anti-TNF therapy, most often intravenous infliximab or subcutaneous adalimumab, is generally resorted to whenever these initial treatments do not achieve their goal.21 Indeed, with increasing recognition of ulcerative colitis as a progressive disease rather than a disorder with periodic flares,22 the threshold for introducing biologic drugs is steadily being lowered.23 Few head to head comparisons of different anti-TNFs exist in this situation, although experience suggests that infliximab is preferable for treating active disease.242526272829

However, there is less of a consensus on when to introduce biologic agents in patients with Crohn’s disease. ECCO guidelines from 2016 still recommend treatment with corticosteroids before starting anti-TNF agents (ECCO statements 5C, 5D, 5E, 5F).15 Not to oversimplify the question of whether to adopt a “step-up” (late introduction) or “top-down” approach,303132 many recent studies have tried to determine the optimal time to start treatment with a biologic agent in Crohn’s disease.33 Although some experts take a conservative approach regarding an early resort to biologic drugs,34 the consensus has swung strongly in favor of their introduction soon after diagnosis, especially in patients thought to have an unfavorable prognosis (ECCO statement 5G).15353637

Thus the challenge for clinicians is to identify those patients with an unfavorable prognosis who would benefit from early biologic therapy. Dozens of studies have looked at this question over the past 25 years and several factors have been proposed as indicators of a poor prognosis. Only a few such factors have been consistently noted—young onset, ileal location, early need for steroids, perianal disease, and high levels of inflammatory markers.3536383940 More recently, serologic markers have attracted attention as prospective indicators of a complicated disease course in both Crohn’s disease and ulcerative colitis.414243

Postoperative anti-TNF prophylaxis

Inhibition of the recurrence of Crohn’s disease after surgery is almost as important as preventing or retarding disease progression after diagnosis.44 Since a landmark report 10 years ago,45 which was soon corroborated,4647 anti-TNF prophylaxis has become a leading strategy to reduced the risk of postoperative recurrence after resectional surgery for Crohn’s disease.1648495051 Biologic agents were not the first agents proposed to suppress the recurrence of Crohn’s disease after surgery; the candidates have included aminosalicylates, thiopurines, antibiotics, and probiotics,52 but direct comparisons continue to find anti-TNF drugs the most effective.53

More recently, studies have focused on which of these agents is most effective,54 which concomitant drugs (if any) should be used,55 and the timing of their introduction.56 Regarding the choice of anti-TNF agent, the limited data available provide little evidence to prefer one over the other, at least with regard to safety or efficacy.54 Preliminary observations, however, suggest that combination with a thiopurine—as in primary therapy57—is also more effective in postoperative prophylaxis.55

Who should receive postoperative prophylaxis and when should they get it?

Three possible strategies have emerged:

  • Give it to everybody

  • Give it to patients at highest risk of recurrence only, but evaluate everybody at four to six months after surgery

  • Don’t give it to anybody until a colonoscopy (or other assessment) is performed at four to six months after surgery and then decide on the basis of the findings.

The strategy of treating all patients after surgery has not been generally advocated because of the risk of overtreatment, the risk of side effects, and the cost.58 An RCT of 63 patients that compared immediate postoperative treatment with azathioprine versus watchful waiting showed no significant difference in outcomes, but azathioprine is not an anti-TNF agent.59

The highly anticipated and widely cited POCER (Post-Operative Crohn’s Endoscopic Recurrence) study has provided some support for withholding postoperative anti-TNF prophylaxis until assessment at about six months after surgery.58 However, interpretation is complicated because all participants received postoperative metronidazole and “high-risk” patients also received a thiopurine, whereas those who were intolerant to thiopurine received adalimumab.

On the basis of the evidence to date a consensus seems to be emerging that rational decision making about postoperative prophylaxis depends on some degree of stratification for risk of recurrence.60 ECCO guidelines state that prophylactic treatment with thiopurines or anti-TNF therapy is recommended after ileocolonic resection in patients with at least one risk factor for recurrence (ECCO Statement 8G).16 Although there is no consensus on all the risk factors for early postoperative recurrence, it is generally agreed that previous surgery, extensive resection, penetrating disease, ileocolonic distribution, perianal involvement, young age at onset, and smoking all portend relatively poor prognosis.6162636465 Hence, patients in these risk strata may be the best candidates for early postoperative prophylaxis with anti-TNF drugs, with follow-up colonoscopy at four to six months. Advanced lesions at or close to the anastomosis at that point are considered an indication for escalated treatment.66

Starting anti-TNF drugs as combination therapy

Combination therapy of an anti-TNF agent with an antimetabolite (azathioprine, 6-mercaptopurine, or methotrexate) is thought to reduce the risk of immunogenicity to the anti-TNF agent and potentially to reduce disease activity. Two RCTs—SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease) and UC SUCCESS (Efficacy and Safety of Infliximab Monotherapy v Combination Therapy v AZA Monotherapy in Ulcerative Colitis) found that full dose azathioprine (2-2.5 mg/kg) combined with infliximab in patients naive to both drugs was superior to monotherapy with infliximab in achieving corticosteroid-free clinical remission in patients with Crohn’s disease (SONIC week 26: 56.8% v 44.4%; P=0.02) and ulcerative colitis (UC-SUCCESS week 16: 39.7% v 22.1%; P=0.017).5767 In both studies, patients on combination therapy also had higher rates of complete mucosal healing.5767 Hence, early combination therapy is becoming widely used in the management of IBD, although cost and safety concerns from both patients and physicians have prevented it from universally being used in all patients.6869

Some of the safety concerns regarding the use of thiopurines in IBD, whether alone or combined with a biologic agent, have recently prompted new interest in the benefits of methotrexate as the antimetabolite of choice.70

However, it is still unclear whether thiopurines and methotrexate are equally effective.7172 The COMMIT (Combination of Maintenance Methotrexate-Infliximab Trial) trial studied combination therapy of subcutaneous methotrexate (10 mg increased to 25 mg by week 5) with infliximab in naive patients (n=126) versus infliximab monotherapy for Crohn’s disease.73 Combination therapy was not superior to monotherapy for the primary endpoint of failure to achieve steroid-free clinical remission at week 14 or failure to maintain remission through to week 50.73 However, all patients in the trial had undergone a high dose steroid induction that may have obscured any benefit of methotrexate.7172 Patients randomized to the combination infliximab and methotrexate group showed a non-significant trend towards higher infliximab trough levels compared with those in the monotherapy group (6.35 μg/mL v 3.75 μg/mL; P=0.08).73

No high quality data are available on the use of methotrexate in combination therapy in ulcerative colitis, and it has not been found to be superior to placebo as monotherapy.7475 However, differences in trial design make it difficult to draw conclusions regarding the efficacy of thiopurines compared with methotrexate as the second agent in a patient newly starting anti-TNF therapy. Comparative effectiveness studies of oral and subcutaneous methotrexate are also lacking.7677

The benefits of combination therapy with an immunomodulator in patients who have not responded to an immunomodulator before they started an anti-TNF agent is less clear. A systematic review of 11 randomized clinical trials in patients with Crohn’s disease found that combination therapy with an immunomodulator was no more effective than anti-TNF monotherapy for inducing six month remission, inducing a response, or maintaining a response in patients previously exposed to immunomodulators.78 Subgroup analyses of individual anti-TNF agents showed a non-significant trend towards a benefit of combination therapy in achieving clinical remission at six months in patients treated with infliximab who had not previously been exposed to immunomodulators, but no such benefit was seen with adalimumab or certolizumab.78 Caution must be used in interpreting these data because many of the patients included in the adalimumab and certolizumab trials had already not responded to infliximab. Unfortunately, no direct comparative effectiveness trials are available.

The clinical efficacy of the available anti-TNF agents correlates highly with circulating drug levels.798081 Despite the ambiguity of the available data, combination therapy with immunomodulators and infliximab has been shown to have pharmacokinetic benefit even in previously exposed patients.82 However, data are mixed on the pharmacokinetic and immunogenic benefits of combination therapy with the three injectable anti-TNF agents. Subgroup analyses of the CHARM (Crohn’s trial of the fully human antibody adalimumab for remission maintenance) and the CLASSIC (clinical assessment of adalimumab safety and efficacy studied as an induction therapy in Crohn’s) trials found no significant differences in adalimumab trough levels on the basis of concomitant immunomodulator use, although combination therapy may have delayed the need for dose escalation.8384 Retrospective studies of adalimumab combination therapy are also inconclusive.8586 Immunogenicity data were not collected in the CHARM maintenance trial for adalimumab, but data from the pivotal certolizumab maintenance trial showed similar rates of antibody formation to infliximab when stratified for dosing schedules and immunomodulator use, suggesting that there should be a role for concomitant immune suppression with an injectable anti-TNF agent.7287

Ideally, early therapeutic drug monitoring (TDM) could be used to prevent loss of response rather than to reverse loss of response. Retrospective studies and analyses have identified week 14 infliximab drug concentrations as being predictive of a durable maintenance therapy response.888990 Low infliximab concentrations (<2.2 μg/mL) at week 14 of treatment have been shown to predict cessation of treatment owing to the development of anti-drug antibodies (ADAs) and loss of response.89 However, further prospective studies of proactive TDM in the induction and post-induction period are still needed.

Many unanswered questions remain about combination therapy. More prospective evidence is needed to establish the benefits of combination therapy with each of the available anti-TNF agents, the benefit of combination therapy in patients previously exposed to immunomodulators, and the lowest effective dose.

Despite these unanswered questions, the possible pharmacokinetic benefit of combination therapy with an anti-TNF agent and an immunomodulator makes it the preferred regimen for at least the first six to 12 months when starting treatment with an anti-TNF agent. It is advisable to begin the immunomodulator at the onset of anti-TNF therapy because immunogenicity may occur early in the treatment course.8591

Although most evidence supports thiopurines as the agent of choice in combination therapy with an anti-TNF agent,5767 combination therapy with methotrexate should be considered in certain patients. These include patients who are at high risk of complications with thiopurines, such as male patients under 35 years at risk of hepatosplenic T cell lymphoma,92 Epstein-Barr virus seronegative patients with IBD who are at risk of post-mononucleosis lymphoma,9394 and patients with a history of non-melanoma skin cancer.959697 Patients over 65 years who are being treated with an anti-TNF agent may be at increased risk of infection and lymphoma, so monotherapy might be preferable in these patients.9899

Assessing ongoing anti-TNF therapy

The rapid growth of early biologic drug treatment in IBD has been accompanied by the development of objective measures of its effectiveness. The Crohn’s disease activity index (CDAI)100 is rapidly becoming an outdated metric.101102103 The index’s complicated mix of objective and subjective indicators has proved to be a poor predictor of inflammatory markers, endoscopic findings, and clinical outcomes.104105

Today, there is a strong movement to substitute the index or other symptom based scores with objective biologic (C reactive protein (CRP) or calprotectin), radiologic, or endoscopic markers of active inflammation.106107108109110111 The aim of using such quantitative measures is to identify structural damage to the bowel,112 confirm mucosal healing,113114115 and select therapeutic targets.116 Potential objective markers of inflammation that are abnormal at the onset of treatment should be identified and monitored over time to assess response.117Table 1 shows the most commonly used markers and how they can be used to monitor treatment.118

Table 1

Applications for selected biomarkers.* Adapted, with permission, from Lewis118

View this table:

Stopping anti-TNF drugs

Once inflammation is controlled by anti-TNF agents, clinicians are often faced with the question of when it is safe to consider de-escalating or stopping treatment. Reasons for stopping treatment include patients’ concerns about side effects, costs, national regulations in some countries, and special situations such as pregnancy.119 The efficacy of combination therapy with a thiopurine and anti-TNF agent has not been proved beyond one year in Crohn’s disease.57 De-escalation of treatment comes in different forms, including stopping or reducing the dose of the anti-TNF agent for those on monotherapy or stopping or reducing the dose of the antimetabolite or anti-TNF agent for patients on combination therapy. However, as yet there are no guidelines for when or how to de-escalate anti-TNF agents.119120

Stopping or reducing the dose of antimetabolite drugs

When considering the de-escalation of treatment in patient’s on combined anti-TNF and thiopurine therapy, many physicians choose to stop thiopurine. A systematic review in 2015 identified eight studies (six on Crohn’s disease, one on ulcerative colitis, and one on both) that examined stopping thiopurine in patients on combination therapy with an anti-TNF agent.119 Of these, the IMID (infliximab maintenance/immunosuppressives discontinuation) trial is the only RCT in adults that compared stopping thiopurines with continuing these drugs in 80 patients on stable combination therapy with infliximab for at least six months.122 No significant difference was found in the composite primary endpoint of requiring an infliximab dose escalation or needing to stop infliximab (60% v 55%; P=0.65). However, patients in the group who discontinued thiopurine therapy had significantly higher CRP and lower infliximab trough concentrations at most time points from week 8 to the end of the study compared with those patients who stayed on combination therapy.122

Retrospective studies have confirmed the IMID trial’s findings, reporting similar relapse rates between patients with Crohn’s disease on stable combination therapy who continued or discontinued thiopurine.119123124125126127 One retrospective multicenter study from France looked at the effect of withdrawing thiopurine after at least six months of combination therapy with infliximab in 82 patients with ulcerative colitis.128 When time on combination therapy was compared with time on infliximab monotherapy, significantly fewer clinical relapses and longer time to relapse were seen on combination therapy, although no significant difference was seen for failure of infliximab treatment (defined as drug withdrawal) or colectomy. The only factor that protected against clinical relapse was combination therapy for at least nine months (hazard ratio 0.38, 95% confidence interval 0.21 to 0.69).128

The dosing of azathioprine in the SONIC and UC SUCCESS trials was based on weight (2.5 mg/kg), with the goal of reaching optimal 6-thioguanine (6-TGN) levels, which were previously established as greater than 235 pmol/8×108 erythrocytes for a clinical response in Crohn’s disease.5767129 However, lower 6-TGN goal values may be adequate for preventing immunogenicity to anti-TNF therapy in patients undergoing combined immunosuppression. A cross sectional analysis of patients on combination therapy showed that a 6-TGN cut-off point of 125 pmol/8×108 erythrocytes predicted higher levels of infliximab and were significantly less likely to be associated with the formation of antibodies to infliximab.130 Therefore, reducing the dose of thiopurine is an alternative strategy that may minimize potential adverse events while helping to maintain optimal anti-TNF therapy. A single center retrospective study of 73 patients assessed optimal maintenance dosing of methotrexate in combination therapy with anti-TNF therapy.131 It found that a methotrexate dose greater than 12.5 mg (oral or subcutaneous) was more likely to maintain clinical remission than a lower dose.131 Pharmacokinetic data were not available for analysis.

Overall, the data suggest that stopping the antimetabolite in patients on stable combination therapy with an anti-TNF agent is probably safe for patients in confirmed clinical and endoscopic remission after at least six months of combined therapy. Patients should be risk stratified for possible relapse by predictive factors such as raised CRP at the time of withdrawal,124 age less than 16 years at diagnosis,126 low anti-TNF trough levels at discontinuation,124 duration of combination therapy less than six months,126 and methotrexate used as the antimetabolite in Crohn’s disease.119126 Biomarkers and anti-TNF drug levels should be monitored closely in these patients.

Stopping or reducing the dose of anti-TNF drugs

The 2016 ECCO guidelines do not specifically cover stopping or reducing the dose of anti-TNF therapy but state that thiopurines may be an option as monotherapy in selected patients who have achieved sustained remission on combination therapy for Crohn’s disease (statement 6F, EL3).15 No recommendation can be made for the duration of therapy in ulcerative colitis, and the prolonged use of anti-TNF therapy may be necessary (ECCO statement 12L).17

Most studies on the discontinuation of anti-TNF therapy are single center retrospective cohort studies, which are inherently limited by their design. A recent systematic review and meta-analysis identified 27 studies (14 on Crohn’s disease, two on ulcerative colitis, 11 on both) reporting on the risk of relapse after discontinuation of anti-TNF drugs (adalimumab or infliximab).120 Twelve months after discontinuation, 36% of patients with Crohn’s disease (95% confidence interval 29% to 43%; I2=73%; 706 patients) and 28% of patients with UC (6% to 51%; I2=93%; 201 patients) had relapsed. In patients with Crohn’s disease, the risk of relapse at 12 months decreased to 26% (15% to 37%; I2=0%; 57 patients) when the analysis was restricted to patients in whom clinical and endoscopic remission was confirmed before discontinuation. The rate of medium term relapse (13-24 months) was 43% (31% to 55%; I2=75%; 297 patients) in Crohn’s disease and 36% (31% to 50%; I2=35%; 65 patients) in ulcerative colitis. The rate of long term relapse (≥25 months) was 49% (31% to 68%; I2=88%; 228 patients) in Crohn’s disease but was not calculated for ulcerative colitis. Although antimetabolite agents were widely used after discontinuation of anti-TNF drugs in these studies, comparisons between those on or off antimetabolite therapy could not be made. Study heterogeneity and lack of patient level data also limited the ability to assess the impact of factors such as presence of perianal disease, degree of mucosal healing, specific anti-TNF agent used, and other previously published risk factors for flare after anti-TNF withdrawal (young age,132 smoking,133 raised CRP133134135 and calprotectin,134135136 anemia,134 and adequate anti-TNF drug concentrations134137).120138

The study of the discontinuation of infliximab in patients with Crohn’s disease who are in stable remission on combined therapy with immunosuppressors (STORI) represents the best designed study of de-escalating anti-TNF therapy to date. STORI is a prospective multicenter cohort study in France and Belgium designed to see whether combination therapy could be safely de-escalated by stopping the anti-TNF agent after at least one year of combined therapy with an antimetabolite agent (azathioprine, mercaptopurine, or methotrexate).134 All 115 patients were in steroid-free clinical remission for at least six months before discontinuation of infliximab. The one year relapse rate for the cohort was 43.9% (standard deviation 5.0%) after discontinuation of infliximab. However, the authors identified six risk factors for relapse in multivariate analysis: male sex, absence of surgical resection, leukocyte count greater than 6.0×109/L, hemoglobin 145 g/L or less, CRP 5.0 mg/L or more, and fecal calprotectin 300 μg/g or more. Patients with two or fewer risk factors had only a 15% risk of relapse within one year. Similarly, a large international multicenter retrospective study of the relapse rate after discontinuation of anti-TNF therapy in patients in deep remission found a 19% per patient year relapse for both Crohn’s disease and ulcerative colitis.139

Follow-up of the STORI patients showed that increases in CRP and fecal calprotectin preceded clinical relapse by four months.135 A subsequent study also showed that increases in fecal calprotectin preceded clinical relapse by a median of 94 days in patients with IBD who stopped anti-TNF therapy after confirmed clinical, endoscopic, and biomarker remission.140 These findings suggest that close monitoring of biomarkers such as calprotectin may help prevent relapse in those who de-escalate treatment.

Dose reduction guided by therapeutic drug monitoring is an alternative strategy to complete discontinuation of anti-TNF drugs. Patients on stable maintenance therapy may have different drug requirements from those in the middle of a flare who are at risk of rapid drug clearance owing to factors such as high CRP and low albumin concentrations. The Trough level Adapted InfliXImab Treatment (TAXIT) trial was an RCT that compared targeted infliximab dosing in patients with Crohn’s disease and ulcerative colitis to a trough level of 3-7 μg/mL, with dosing based on symptoms.141 At study entry 72 of 263 patients had infliximab trough concentrations greater than 7 μg/mL and required dose reductions. The dose reductions in patients with high trough levels contributed to a 28% cost saving and did not result in decreased remission rates or increased CRP.141

Resuming anti-TNF therapy

It is reassuring that re-initiation of infliximab after relapse in the STORI trial was safe and effective, with 88% of patients in remission and 98% showing a clinical response by the third dose of infliximab after the drug holiday.134 Although resumption of anti-TNF seems to be effective, it is unclear how it should be restarted. Infliximab re-induction regimens vary greatly (dose at weeks 0, 2, 6 v weeks 0, 4, 8 v weeks 0, 8) and specific strategies have not been compared. However, patients restarting infliximab after a drug holiday have been shown to be at higher risk of infusion reactions (odds ratio 24.9; P<0.001).142

Predictors of response after re-initiation of infliximab include having stopped while in remission and using antimetabolite combination therapy at restart.143 The systematic use of steroid premedication has not been shown to be beneficial during infliximab re-induction.143 The presence of antibodies after the first re-induction dose of infliximab correlates negatively (hazard ratio 0.14; P=0.021) with response to therapy.143 Antibodies to infliximab at the time of discontinuation usually dissipate over the next 12 months.143144 If antibody status at discontinuation was unknown, it is not clinically useful to check this before treatment is restarted. However, antibody checks between the first and second re-induction doses can identify patients at risk of infusion reactions and treatment failure.143

Because the decision to maintain therapy or de-escalate is highly individual, patients on anti-TNF drugs should review their therapeutic plan yearly with their physician and a comprehensive risk-benefit discussion should take place. Patients in “deep remission”—defined as the absence of clinical symptoms, of raised biomarkers, and of endoscopic and radiologic disease activity—are probably the best candidates for de-escalation.

Non-response to anti-TNF therapy

About a third of patients will be primary non-responders to anti-TNF induction,14145 and half of patients who do respond may experience loss of response within a few years.146147 When patients lose response to anti-TNF therapy, it is common practice to attempt salvage therapy by empirically escalating the dose, switching to another anti-TNF agent, or changing treatment to a different mechanism of action altogether.148 The GAIN (Gauging Adalimumab efficacy in Infliximab Nonresponders) study and the WELCOME (26 week open label trial evaluating the clinical benefit and tolerability of certolizumab pegol induction and maintenance in patients with Crohn’s disease and previous loss of response or intolerance to infliximab) study established the efficacy of empiric within class switching after loss of response to infliximab in Crohn’s disease, but short term remission rates were less than 40%.149150 Infliximab levels and antibody status were unknown, suggesting that dose optimization rather than switching may have yielded greater efficacy.148

TDM has been proposed as a way to make more rational treatment decisions because empiric dose escalation or drug switching without knowing drug or antibody levels can be misguided, expensive, and wasteful of available treatment options.148 Anti-TNF drug level measurements are mostly unaffected by the assay used to measure them.151 However, the assessment of ADAs is more complex to interpret and may vary with different assays. Standardized reporting is lacking and most studies report the presence of ADA as a binary variable (positive or negative).151152

The interpretation of drug and antibody levels must take into account the technical limitations of the assays because there are clinical implications to how the patient’s response to anti-TNF agents is classified in a TDM based strategy.151 For example, false negative ADA results may occur if low titer ADAs have been cleared or if a drug sensitive assay is used.91151153154 Also, high anti-TNF drug levels may mask the detection of ADAs. In these cases, low serum anti-TNF trough levels may predict later development of ADAs.8990151155 In addition, transient ADAs that have few clinical implications have been described in IBD.8991153154156 In contrast to transient ADAs, persistent ADAs tend to be present in higher titers and to appear earlier in the course of treatment.8991151153154156 Repeat measurements of ADAs over time should help distinguish between transient ADAs and clinically significant persistent ADAs.151 Finally, relapse of disease symptoms may lag behind the appearance of ADAs.91

Figure 1 describes an algorithm for how to use TDM in managing the failure of anti-TNF therapy according to the presence of ADAs and therapeutic drug levels.151 Patients with both undetectable ADAs and sub-therapeutic anti-TNF drug levels have insufficient drug bioavailability owing to non-immune pharmacokinetic problems and may benefit from anti-TNF dose escalation. Patients with detectable ADAs and undetectable anti-TNF are defined as having immunogenicity and may need to switch to a different anti-TNF agent.151

Figure1

Fig 1 Algorithm for managing the failure of anti-TNF therapy. ADA=anti-drug antibody; IM=immunomodulator; MOA=mechanism of action; TNF=tumor necrosis factor

Alternatively, if these patients are on anti-TNF monotherapy, the addition of an immunomodulator may be able to restore the response by reversing antibody formation and increasing drug levels.79157158159 For example, in one study, 11 of 23 patients did not respond to adalimumab despite dose escalation. They had confirmed antibodies on repeat measurements, and they underwent sero-reversal after the addition of a thiopurine or methotrexate, which resulted in a clinical response and normalization of biomarkers.157

In unresponsive patients with therapeutic anti-TNF drug levels and undetectable ADAs, the inflammation may not be TNF mediated; hence, the patient may need to switch to a drug with an alternative mechanism of action.151 Patients with therapeutic anti-TNF drug levels in the presence of detectable ADAs may have either transient ADAs or a false positive ADA test.151 Repeat measurements should be performed over time to determine whether ADA levels are persistent.151

Observational studies have supported the use of TDM to guide management in secondary loss of response to anti-TNF agents.89160161162 An RCT from Denmark compared algorithm based TDM to empiric dose escalation (shortened interval to every four weeks) for secondary loss of response to anti-TNF agents.163 It found that TDM based management of infliximab administration resulted in greater than 50% cost savings and had no negative clinical impact. Interestingly, relapse as a result of immunogenicity was reported in only 20% of the patients who had secondary loss of response. Very few patients had sub-therapeutic infliximab drug levels. Most infliximab “failures” were caused by an alternative inflammatory pathway or non-inflammatory causes of symptoms such as strictures, bile salt diarrhea, or irritable bowel syndrome. However, the study was small and important deviations from the TDM algorithm occurred.151 Larger studies are needed to compare algorithm based TDM with other dose escalation strategies.163

Regarding loss of response, ECCO guidelines state: “Confirmed loss of response to anti-TNF agent should be first managed by dose optimization [EL3]. Dose increase or interval shortening are equivalent strategies [EL4]. If dose optimization is ineffective, switching to a different anti-TNF agent is recommended [EL2]. Where available, measurement of serum anti-TNF trough levels and anti-drug antibodies could be used to guide optimization strategy [EL4].”15

The usefulness of TDM in patients with primary non-response to anti-TNF therapy is unclear, because data from this population are lacking and drug clearance may be different during induction in the face of high inflammatory burden.151 Non-response or incomplete response in these situations is of particular interest in severe ulcerative colitis. The Active Ulcerative Colitis Trials (ACT 1 and ACT 2) found an eight week response rate of 64-69% after induction with infliximab 5 mg/kg and a colectomy rate of 10% at one year.164165 However, infliximab rescue therapy may be even less efficacious in hospital inpatients with more severe, steroid refractory disease, with 90 day colectomy rates reported as 29-60%.155166167168A cohort study of 115 patients found that standard three dose infliximab induction was associated with lower rates of clinical response (70% v 41%; P=0.004), clinical remission (41% v 17%; P=0.015), and endoscopic remission (26% v 4%; P=0.046) in patients with severe ulcerative colitis than in those with only moderately severe disease.155 Similarly, patients with severe ulcerative colitis who did not respond to infliximab induction had significantly more fecal loss of drug,169and lower day 14 trough levels170compared with infliximab responders. This observation suggests that rapid infliximab clearance is responsible for the lack of response.

The concept of rapid infliximab clearance in severe ulcerative colitis has led to the belief that escalated infliximab induction dosing may be needed.171 A 2015 survey of the International Organization of IBD (IOIBD) members showed that fewer than 25% of these experts used standard infliximab induction dosing in patients with severe ulcerative colitis.172 Among respondents who preferred accelerated dosing schedules, 39% started induction with a 10 mg/kg dose and 42% started with a 5 mg/kg dose and then gave higher or more frequent (or both) subsequent doses as needed.172

Evidence favoring accelerated dosing is limited to one retrospective study showing that patients with severe ulcerative colitis who received accelerated 5 mg/kg induction doses (median total induction time 24.5 days), based on clinical need or raised biomarkers, had lower short term colectomy rates with no difference in long term colectomy rates.173 However, data from CYSIF (study comparing ciclosporin with infliximab in steroid refractory severe acute ulcerative colitis) showed an 85.7% response at day 7 using initial 5 mg/kg dosing.174

Prospective studies of accelerated infliximab dosing protocols using both 5 mg/kg and 10 mg/kg are needed. Irrespective of initial dose, patients with severe ulcerative colitis should be monitored closely in hospital; if the response plateaus or if symptoms or biomarkers worsen, early additional doses of infliximab should be considered if colectomy is not preferred.

Concerns about anti-TNF agents

A comprehensive review of non-infectious, non-malignant adverse effects of anti-TNF agents can be found elsewhere.175 Individual cases of rare adverse reactions are reported for almost all drugs, and the main safety concerns about anti-TNF agents fall into the following main categories: skin lesions, immune reactions, peri-operative complications, infections, cancers, and adverse effects on fertility and pregnancy.

Skin lesions

It is an irony of modern medicine that drugs intended to treat certain conditions occasionally cause those same conditions: dopamine antagonists used to treat movement disorders occasionally cause movement disorders, and aminosalicylates used to treat colitis occasionally provoke colitis. Similarly, anti-TNF agents, among the most effective treatments for psoriasis, occasionally cause psoriasis.176177178179 The particular hallmarks of anti-TNF induced psoriasis, more common in women than in men, is a distribution on palms, soles, and the scalp (fig 2).180

Figure2

Fig 2 Anti-tumor necrosis factor induced palmar psoriasis. Image borrowed from Mark Lebwohl

A recent multicenter study of 7415 patients in Spain, treated for IBD with anti-TNF drugs, noted an incidence of psoriasis of 0.5% per patient year.181 A substantial proportion (40%) of patients were transferred to another anti-TNF agent without recurrence, but most (60%) experienced the same reaction. Fortunately, standard treatments for psoriasis, usually topical steroids, controlled the disease and allowed continuation of anti-TNF therapy in most cases. Recent data confirm the ability to continue treatment despite skin lesions and also showed no difference in infliximab trough levels between affected and unaffected patients.180 Other skin lesions mistakenly described as having been “induced” by anti-TNF therapy may or may not have had any connection with the drug.182

Immune reactions

All biologic agents tend to be immunogenic and anti-TNF drugs are no exception. The development of antibodies to anti-TNF agents is the most common reason for loss of response to this treatment,183 and it occurs to some extent in almost 60% of patients with IBD within three years.184 Most, although not all, studies show an inhibition of antibody formation and an increase of active drug levels with the concomitant use of thiopurines1479185 or methotrexate,73 although clinical benefits are not universally demonstrable, especially if the previous antimetabolite therapy had been unsuccessful.78

A more acute problem than secondary loss of response caused by anti-drug antibodies, however, is the induction of infusion or injection reactions. In diseases other than IBD, it is not always clear that hypersensitivity reactions to anti-TNF agents are correlated with anti-drug antibodies.186 Indeed, the incidence and implications of antibodies to anti-TNF agents in various other diseases may not be applicable to each other or to IBD.187 Nonetheless, it is generally accepted that in patients with IBD, severe acute reactions to infliximab infusions, which occur in about 5% of patients, are attributable to anti-infliximab IgG antibodies.188189

More common (up to 20% of patients) but less serious are the local injection site reactions that occur with the three anti-TNF agents that are administered subcutaneously—namely, adalimumab, certolizumab pegol, and golimumab. These reactions are generally traumatic and not immunologic in nature.175

The clearest association with anti-drug antibodies seems to be with delayed or so called serum sickness-like reactions. These reactions, probably caused by type III immune complex hypersensitivity mechanisms, usually appear five to seven days after drug administration and in most cases lead to discontinuation of the implicated agent.190 More rarely, long term autoimmune diseases, such as drug induced lupus erythematosus, vasculitis, polyarthritis, and others, have been induced by anti-TNF agents.175

Malignancy and infection

Because TNF stands for tumor necrosis factor it might be reasonable to think that an anti-TNF agent might allow tumors to grow. Fortunately, there is little if any evidence that anti-TNF drugs increase the risk of cancer,191192 except possibly non-melanoma and melanoma skin cancers (ECCO statement 6K).15193194 However, most of the increased risk of skin cancer and lymphomas sometimes attributed to anti-TNF therapy may result from these agents being combined with thiopurines.195196 In addition, a history of cancer does not seem to be a contraindication to the use of anti-TNFs.197 However, annual skin examination is recommended for patients exposed to thiopurines or anti-TNF agents.18

Similarly, an increased risk of infection is a potential concern with anti-TNF therapy. A recent systematic review suggested a small increased incidence of infections for ulcerative colitis (relative risk 1.2, 1.0 to 1.3) associated with infliximab and adalimumab, but no increased risk for Crohn’s disease.191198 Vaccination guidelines are offered in the 2017 ACG clinical guidelines on preventive care in IBD.18

The association of anti-TNF therapy with postoperative complications and infections is controversial. The literature comprises mostly single center retrospective studies with conflicting results. Meta-analyses have shown an association between anti-TNF therapy and postoperative infections in Crohn’s disease,199200201 but not ulcerative colitis.199200202203 A single center study associated detectable anti-TNF drug levels at the time of surgery with increased postoperative morbidity and infection.121 More recently, a multicenter French cohort study found no association between anti-TNF therapy and postoperative infection in ileocecal resections.204 The multicenter PUCCINI (Prospective Cohort of Ulcerative Colitis and Crohn’s Disease Patients Undergoing Surgery to Identify Risk Factors for Post-Operative INfection) trial funded by the Crohn’s and Colitis Foundation is near completion in the US.

Pregnancy and fertility

Given the predilection of IBD for young people, it is no surprise that hundreds of publications have been devoted to outcomes of pregnancies in women with these diseases, with respect to both the natural course of the disease and the effects of treatment.205206 Although the full results of the PIANO study (Multicenter National Prospective Study of Pregnancy and Neonatal Outcomes in Women with Inflammatory Bowel Disease) have not yet been published,207 available data suggest a reasonable degree of safety for the use of thiopurines and biologic agents before, during, and after pregnancy. A review in 1216 concluded that “Aside from methotrexate, immunomodulators and biologics may be used during pregnancy to achieve and maintain disease control. Based on available safety data, there is no increased risk of congenital anomalies among infants exposed to these medications.”208

Anti-attractants

Leukocyte attraction inhibitors were first used more than 20 years ago with the idea of using natalizumab, an inhibitor of α4 integrin, for the treatment of multiple sclerosis. Within five years, this agent (Tysabri) was being studied in Crohn’s disease, and by January 2008 the FDA approved it for this indication. However, because the inhibition of α4 integrins extended to the central nervous system, allowing a few cases of progressive multifocal leukoencephalopathy to occur in patients receiving the drug, there was keen interest in developing a more gut selective anti-integrin antibody. This goal was achieved in 2008 with the introduction of α4β7 integrin selective vedolizumab (Entyvio) for the treatment of Crohn’s disease.209210 Although nasopharyngitis and arthritis have been reported as side effects of vedolizumab,211212 extensive clinical experience over the past eight years has amply validated the safety and effectiveness of vedolizumab for the induction and maintenance of remission in patients with Crohn’s disease and ulcerative colitis.213214215216217218 Progressive multifocal leukoencephalopathy has not been reported with vedolizumab and JC virus does not need to be checked before starting treatment.219

Whenever a new agent shows efficacy and safety, the question arises whether to use it as the primary biologic treatment, to reserve it for rescue when anti-TNF therapy is ineffective, or to introduce it for maintenance of remission induced by another drug that is too toxic to use long term (for example, steroids, ciclosporin).

With respect to primary therapy with vedolizumab, a recent cohort study of 212 patients has confirmed its efficacy in both Crohn’s disease and ulcerative colitis, albeit with maximal benefit not achieved until about 14 weeks.220 As with most drugs, it seems to be more effective in patients who have never taken anti-TNF agents than in those in whom these drugs have not been effective. Similarly, another large randomized controlled multicenter study of about 400 patients indicated that six to 10 weeks of treatment may be needed before patients manifest clinical benefit, and once again that the effect is significantly greater in patients naive to anti-TNF agents than in those in whom treatment has been unsuccesful.221

Because vedolizumab is currently being used less often as primary treatment for IBD than as a “rescue” treatment after anti-TNF agents stop working, it is particularly important to investigate how well this drug performs in patients for whom anti-TNF treatment has been unsuccessful. A recent French prospective cohort study focused exclusively on patients with IBD who had initially not responded to anti-TNF therapy. Of the 294 patients enrolled (173 with Crohn’s disease and 121 with ulcerative colitis), 280 patients completed a full induction regimen. In both diseases, the clinical remission rate at week 6 was about 30% and the steroid-free remission rate was about 20%.222 The efficacy was modest, but still clinically important given the highly refractory profile of this cohort of patients who had previously not responded to anti-TNF therapy.

The more selective action of vedolizumab on the gut, in contrast to anti-TNF agents, is an advantage in terms of potential side effects, but this selectivity may limit its usefulness in the treatment of extra-intestinal manifestations.

Although rigorous pharmacoeconomic analyses have not yet confirmed the drug industry’s claims about the incremental cost effectiveness ratio of vedolizumab treatment in all scenarios,223 a systematic review has suggested that vedolizumab “provides a clinically meaningful improvement in HRQL [health related quality of life] in UC [ulcerative colitis] patients receiving maintenance therapy.”224

It is noteworthy that the concept, suggested above, of using vedolizumab to take over for long term maintenance after steroids or ciclosporin have induced remission, is in fact under active investigation.225

Moreover, we should not ignore the possibility of using vedolizumab or other anti-integrins in combination with infliximab or other anti-TNF agents. Although this practice has not entered mainstream use, a few observations suggest that it may be a viable therapeutic option.226227

Meanwhile, other anti-adhesion agents are under development. The most advanced is etrolizumab, which by targeting β7 integrins inhibits both α4,β7 integrin and αE,β7 integrin.228

Emerging treatments

Biosimilars

On 15 March 2016, the FDA approved the first biosimilar drug for use in the US, Xarxio, Sandor’s version of filgrastim, formerly available only from the parent company, Novartis, as the leukocyte stimulating agent, Neupogen. Just 11 days later, the FDA approved a second biosimilar, Inflectra, a form of infliximab, previously introduced as Remicade and marketed by Janssen, part of Johnson & Johnson. Inflectra (inflizimab-dyyb) is manufactured by Celltrion, located in Incheon, Republic of Korea, and co-marketed by Pfizer. This agent and two other infliximab biosimilars, Remsima and Flixabi, are also poised on the verge of marketing around the world.

The formal FDA approval of Inflectra, which includes Crohn’s disease and ulcerative colitis among its indications, was granted in part on the basis of clinical trials carried out in patients with rheumatoid arthritis and ankylosing spondylitis. The rationale behind extending approval to patients with IBD as well as those with plaque psoriasis and psoriatic arthritis, is a concept known as extrapolation, which posits that the biosimilar is sufficiently similar to the reference product using current assays that are highly sensitive and manufacturing process controls that are at least as good as that of the reference products. This ensures that the biosimilar will exert the same clinical effect across all diseases. The validity of this rationale for extrapolation has recently been explored in several thoughtful commentaries.229230231232233 Moreover, early clinical experience suggests that the biosimilar is effective in the real world treatment of IBD.234

Another concern about biosimilars, besides extrapolation to other indications, is whether the immunogenicity of the original drug (the originator) will interfere with a switch from the originator to the biosimilar in the same patient. The most recent studies of this question suggest that switching from the originator to the biosimilar is safe and effective in children and adults with IBD and other diseases.235236 Similarly, existing assays seem to be capable of monitoring biosimilar drug levels.237

The main incentive for the development of biosimilars, as with generics, is economic; the potential savings are considerable.238 But, as the development of biosimilars is still in its infancy, gastroenterologists worldwide are just beginning to understand its implications.239

Anti-interleukins

Certain interleukins are key molecular mediators of inflammation and are prime targets of treatments for IBD. New inhibitors of interleukin 23 (IL-23; eg, risankizumab) and IL-12/IL-23 (eg, briakinumab) are currently under development.240 However, one IL-12/IL-23 inhibitor, ustekinumab, which is used in the management of psoriasis and psoriatic arthritis,241 was FDA approved for the treatment of Crohn’s disease in September 2016.242

Response and remission rates on ustekinumab were significantly superior to placebo in phase II and phase III studies, in patients who had not responded to anti-TNF agents and anti-TNF naive patients.243244 Safety data from the Crohn’s disease clinical trials and the psoriasis literature are also promising, suggesting that ustekinumab may have a place as a first line therapy for Crohn’s disease alongside anti-TNF agents.245 However, it is still early days, and much has to be learnt about the real world application of ustekinumab with regard to optimal dosing, treatment of specific phenotypes (eg, patients with perianal disease), and long term safety before it can be routinely recommended ahead of anti-TNF therapy.

JAK inhibitors

About 200 small molecule kinase inhibitors have attracted the interest of the drug industry as potential anti-inflammatory and anti-tumor agents. Among these, about a dozen are JAK inhibitors. Some JAK inhibitors have been tested for the treatment of hematologic diseases like polycythemia vera and myelofibrosis. Three have shown considerable promise in the management of rheumatoid arthritis and have attracted attention for the treatment of IBD.

Tofacitinib, a broad-spectrum inhibitor of JAK1, JAK2, and JAK3, is furthest along in the developmental pipeline. Early results as a treatment for ulcerative colitis look promising, including evidence of mucosal healing.246247248249 The results in Crohn’s disease have not been as robust, perhaps because of reliance on CDAI for outcome measurement and a high placebo response, but the data for maintenance of remission still seem positive.250251

Another JAK1 inhibitor, filgotinib, has been reported to be superior to placebo in inducing remission in patients with moderate to severe Crohn’s disease.252253 The third JAK inhibitor being actively tested in IBD is ABT-494. This drug was shown to be effective in rheumatoid arthritis refractory to anti-TNF agents and methotrexate, and it is about to undergo studies in Crohn’s disease.

Perhaps the most important characteristics of these JAK inhibitors is that they are given orally instead of parenterally and instead of being monoclonal antibodies are small molecules and thus relatively non-immunogenic.

Other emerging oral treatments

Two other emerging treatments are also orally administered. One is an inhibitory agonist of the sphingosine-1-phosphate receptor 1 (S1P1R), ozanimod. It blocks the egress of lymphocytes from secondary lymphoid organs, thus inhibiting recruitment of immune activating cells to sites of inflammation. This agent is a small molecule fusion protein that is not immunogenic, unlike monoclonal antibodies. Early studies suggest some efficacy as induction and maintenance treatment for ulcerative colitis.254

The second emerging oral treatment is an anti-sense inhibitor of SMAD7, mongersen. This oligonucleotide interferes with the translation of SMAD7, a molecule that inhibits the expression of transforming growth factor β (TGF-β). Consequently, administration of mongersen results in an increase in TGF-β1 concentrations, which in turn downregulates inflammatory cytokine production and thus could theoretically ameliorate IBD. A recently reported clinical trial of mongersen in Crohn’s disease showed that the drug produced more clinical benefit than placebo.255 This study has been widely criticized for a paucity of objective evidence of mucosal healing or abatement of inflammation,256257 so the therapeutic role of this agent has yet to be established.

Guidelines

Practice guidelines are available from the American College of Gastroenterology (ACG 2010, 2017), World Congress of Gastroenterology (2011), and European Crohn’s and Colitis Organisation (2016).131415161718 All guidelines are of high quality, and we have cited recommendations from these guidelines on medical management of Crohn’s disease and ulcerative colitis using biologic agents where applicable.

Conclusions

Many anti-TNF agents, anti-attractants, anti-interleukins, and newer oral agents are already in use or on the horizon for the treatment of IBD. Yet the exact positioning and ideal application of even the currently available drugs have not been definitively established. Nearly 20 years since anti-TNF biologics were first approved for treatment of Crohn’s disease, we are still learning how best to use them in clinical scenarios such as postoperative prevention, pregnancy, loss of response, development of immunogenicity, and treatment de-escalation. The challenges for the future are to determine the optimal timing, dosing, monitoring, convenience, adjustments, sequencing, and drug combinations to produce the most effective, durable, and safest outcomes for patients. High quality studies for these scenarios are needed beyond what has been learnt in the pivotal clinical trials.

Questions for future research

  • Does the preoperative response to anti-tumor necrosis factor (TNF) therapy predict its effectiveness for postoperative prophylaxis?

  • Are the dose regimens and combination therapies used for primary therapy appropriate for postoperative prophylaxis?

  • Will anti-attractants like vedolizumab, apparently quite effective for maintenance of medically induced remissions, prove as or more useful than anti-TNF agents for maintenance of surgically induced remission?

  • Will early therapeutic drug monitoring of anti-TNF agents in the induction period prevent loss of response and immunogenicity and improve long term outcomes such as mucosal healing and reduced need for surgery?

  • Will accelerated anti-TNF induction protocols yield increased response and remission in severe ulcerative colitis and Crohn’s disease?

How patients were involved in the creation of this article

A patient with inflammatory bowel disease (MD) was asked to review the paper and his feedback was incorporated into the final manuscript. Specific suggestions included adding more supporting data in the de-escalation of therapy section and incorporating patient preferences into the discussion.

Footnotes

  • Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

  • Contributors: BLC and DBS contributed equally to the literature review, writing, and reviewing of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work. BLC has done consultancy work for Celltrion; he has served on advisory boards for Abbvie and Janssen; and he has performed expert witness work for Allergan. The authors have no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; externally peer reviewed.

References

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