Key evidence. Anti-TNF therapy has been extensively studied in double-blind RCTs in adults, which have been assessed in a number of SRs with or without meta-analyses.^126–128 In most of the studies assessing its use to induce remission, patients had previously received other treatments, including corticosteroids and immunosuppressants, and analyses according to type of prior treatment were not performed. For induction therapy, a meta-analysis including 10 trials found that anti-TNF therapy alone or with concomitant therapies was significantly more effective than placebo for the outcome of failure to achieve symptomatic remission (RR, 0.87; 95 % CI, 0.80–0.94; P = .0004). Results were significant for infliximab and adalimumab, but not certolizumab pegol.¹²⁶ For maintenance therapy, meta-analysis of 5 RCTs showed that anti-TNF therapy significantly reduced the risk of relapse in patients with CD in clinical remission compared to placebo (RR, 0.71; 95% CI, 0.65–0.76; P < .00001).¹²⁶ Results were significant for infliximab and certolizumab pegol, but not adalimumab. In another meta-analysis, all 3 anti-TNFs were significantly more effective than placebo for both induction and maintenance of remission.¹²⁹

In the SR&MA, there were no significant differences in the incidence of adverse events with anti-TNF used for induction (RR, 0.99; 95% CI, 0.90–1.08) or maintenance of remission (RR, 0.93; 95% CI, 0.84–1.03) compared with placebo.¹²⁶

The quality of evidence was rated as high with no concerns for risk of bias, inconsistency, indirectness, or imprecision.

Discussion: There is high-quality evidence for the efficacy of anti-TNF therapy for patients who have failed corticosteroids, or immunosuppressant therapies. These subgroups are not clearly differentiated in most trials, and most of the RCTs included both populations. Adalimumab and infliximab have demonstrated efficacy in adults in RCTs and in children in trials with open-label induction and randomized dose-ranging maintenance therapy. Results from studies assessing certolizumab for induction of remission did not demonstrate significant benefit, but benefit was demonstrated for maintenance of remission.¹²⁶ However, there were no controlled trials in pediatric patients, and generally maintenance therapy is continued with the agent used for induction, making certolizumab less appropriate.

In pediatric patients, anti-TNF induction therapy has been reported only in open-label trials.^130–133 For maintenance, 1 double-blind RCT¹³² and 2 open-label RCTs (REACH-1¹³¹ and a French trial¹³³) were found. None of these trials was placebo-controlled, but rather compared different doses, different dosing intervals, or scheduled vs on-demand therapy. The majority of patients were receiving concomitant immunosuppressant therapy. The 1 double-blind RCT (IMAgINE-1) assessed adalimumab dose-ranging maintenance therapy after open-label weight-adjusted induction therapy, and reported a remission rate of 33.5% at week 26, with no significant difference between high- and low-dose adalimumab.¹³² In the open-label RCT (REACH) of infliximab every 8 weeks vs every 12 weeks after open-label induction, the clinical remission rate was 56% after 1 year.¹³¹

Impaired growth, particularly if defined by the most sensitive parameter of reduced height velocity, has historically been a frequent complication of pediatric CD developing before puberty. Risk factors include prolonged disease before diagnosis and the inter-related factors of chronically, uncontrolled, intestinal inflammation, under-nutrition, and chronic corticosteroid use.^6,69 Anti-TNF therapies have been associated with improved growth in IMAgINE-2,^134,135 REACH-1,¹³¹ the French trial,¹³³ the RISK study,¹³⁶ and a prospective cohort study.¹³⁷

Anti-TNFs are generally well tolerated; however, increased risk of infections and reactivation of tuberculosis have been reported in adults.^79,138,139 In pediatric patients, upper respiratory tract infections and nasopharyngitis were frequent, being reported in about 37%–43% of children in open-label extension trials.^134,140 During almost 5 years of follow-up of 100 pediatric patients who entered the IMAgINE-2, open-label, extension study, the incidence of opportunistic infections was 5.7% (2.2/100 patient-years), with all but 1 being considered non-serious adverse events.¹³⁴ Only one opportunistic infection was reported in the open-label extension of the REACH trial (n = 60, up to 3-year follow-up), also considered non-serious.¹⁴⁰ In adults, the risks of lymphoma were highest in those exposed to combination therapy, but were also elevated in patients exposed to anti-TNF monotherapy compared to no exposure (adjusted HR, 2.41; 95% CI, 1.60‒3.64; P < .001).⁷⁹

Based on the efficacy demonstrated in RCTs in adults and children, the consensus group strongly recommended anti-TNF therapy for patients with moderate to severe CD who have failed corticosteroid or immunosuppressant therapy.

Only 2 members of the consensus group reported no conflict of interest regarding anti-TNF therapies. Two separate votes were conducted for statement 17, one for these 2 members, and another for the consensus group as a whole, in both cases the vote was unanimously “strongly agree.”

Key evidence. The efficacy of anti-TNF therapy in adults with CD is described under Statements 17 and 18. The majority of RCTs were conducted in patients who had received previous non-biologic therapies. These data were extrapolated to the use of these agents as first-line treatments, and therefore downgraded in assessment of quality to very-low-quality evidence.

Additional support for the early use of anti-TNF therapy comes from open-label, prospective trials using combined anti-TNF and immunosuppressive therapy in newly diagnosed, treatment naïve patients.^119,141 In these studies, “top-down” treatment was associated with significantly higher rates of symptomatic remission at earlier time points compared to not using early anti-TNF therapy. Post-hoc analyses of several other adult RCTs have suggested that rates of deep remission (clinical remission plus mucosal healing) may be highest in patients with early CD (<18–24 months duration) with anti–TNF-containing regimens.^142,143

Discussion: Some evidence has demonstrated the benefits of using early anti-TNF therapy in adults who are treatment naïve^119,141 and those who are naïve to anti-TNF and immunosuppressant therapy.^119,142

Secondary analysis of data from the RISK observational study using propensity scores compared the early introduction of anti-TNF therapy, immunosuppressant therapy, and no immunotherapy, within 3 months of diagnosis in pediatric patients in a real-world clinical setting.¹³⁶ Early anti-TNF therapy was superior to early treatment with an immunosuppressant (85.3% vs 60.3%; RR, 1.41; 95% CI, 1.14–1.75; P = .0017), or no early immunotherapy (54.4%; RR, 1.57; 95% CI, 1.23–1.99; P = .0002) in achieving corticosteroid-free remission at 1 year after diagnosis. In addition, the mean height z-scores increased compared with baseline only in the early anti-TNF group.

The consensus group suggested the use of anti-TNF agents as a first-line treatment based on the demonstrated efficacy as induction therapy, and supportive data suggesting benefits in newly diagnosed patients. This was a conditional suggestion because of the same concerns discussed under Statements 17 and 18.

The group discussed that early anti-TNF may be warranted in pediatric patients with extensive disease or deep colonic ulcerations, or in those in whom corticosteroids could be expected to provide no benefit or could have the potential to exacerbate underlying conditions, such as complex perianal disease, severe bone disease, mental health disorders, or linear growth delay. The group also emphasized that there is an urgent need for better predictors of chronically active, severe inflammatory disease, and disease that will result in progressive intestinal damage that would necessitate intestinal resection.

Key evidence. Evidence of a treatment benefit for infliximab in combination with a thiopurine comes from the prospective randomized SONIC trial in adults, which demonstrated higher rates of clinical remission and endoscopic healing at week 26 with combination vs infliximab monotherapy (57% vs 44%; P = .02).¹¹⁸ In an SR&MA, this yielded an RR of failure to achieve remission with combination vs infliximab monotherapy of 0.78 (95% CI, 0.62–0.97).¹⁴⁴

An SR&MA of cohort data from RCTs of anti-TNF therapy (adalimumab, certolizumab, or infliximab), found no significant differences in the rates of clinical remission with the combination of an anti-TNF plus an immunosuppressant (thiopurine or methotrexate) compared to an anti-TNF alone for induction (OR, 1.28; 95% CI, 0.77–2.16) or maintenance therapy (OR, 1.02; 95% CI, 0.80–1.31).¹⁴⁵ There were no significant differences in rates of clinical remission between monotherapy and combination therapy for maintenance treatment when the 3 anti-TNF agents were pooled, or when they were analyzed separately.

In the SONIC trial, the incidence of adverse events was generally similar in the combination and monotherapy groups, and there were no significant differences in the RR of serious infection.^118,144 Evidence on rare, but important adverse events was very low quality. Observational data suggest a higher risk of lymphoma⁷⁹ and activation of tuberculosis¹³⁸ in patients exposed to combination vs anti-TNF monotherapy.

One open-label, pediatric RCT randomized patients after 10 weeks of combination induction therapy to maintenance with either 54 weeks of combination therapy or 26 weeks of combination therapy, followed by 26 weeks of anti-TNF monotherapy.¹⁴⁶ At the end of the 10-week open induction phase, 65.5% of patients were in clinical remission. At the end of the 54-week maintenance phase, there was no significant benefit of combination therapy with <5% of patients in either group experiencing a loss of response. The incidence of serious adverse events was 9%, of which the most common was primary Epstein-Barr virus infection.

The evidence was downgraded to low due to serious inconsistency and serious imprecision.

Discussion: In the REACH pediatric study of infliximab, all patients were required to be administered immunosuppressants, and 10-week remission rates were 59%. However, there was no monotherapy comparison group.¹³¹ One RCT in adults (downgraded to low-quality evidence for indirectness [extrapolated to pediatric] and imprecision [low number of events]) suggested a potential efficacy benefit with combination therapy over anti-TNF monotherapy. However, administration of infliximab monotherapy in the SONIC study was strictly according to standard protocol (precisely 5 mg/kg every 8 weeks) without any attention to optimizing drug exposure via therapeutic drug monitoring. There is also an important benefit of concomitant immunomodulators in prolonging clearance of infliximab and reducing rates of anti-infliximab antibody development, as demonstrated in SONIC and in pediatric cohort studies.^137,147 Avoiding secondary loss of response related to anti-drug antibody development is extremely important in young patients, given the long lives ahead, during which treatment will be needed. The modest increment in efficacy of combination therapy might be overcome via individualized dosing regimens of infliximab monotherapy to avoid low or absent trough titers to help avoid development of anti-drug antibodies.

The consensus group recognized the improved durability of infliximab response with combination therapy, but suggested against selection of thiopurines as the concomitant drug for males based on safety concerns, as described in Statements 12 and 13. Specifically, the risk of the extremely rare but almost uniformly fatal HSTCL, is attributable to thiopurine use, both alone and in combination with anti-TNF. The highest risk has been reported among males aged <35 years receiving combination thiopurine and anti-TNF therapy.¹⁴⁸ Post-marketing surveillance of infliximab continues to identify at least 2 occurrences worldwide annually and always in patients receiving anti-TNF in combination with a thiopurine. Two such occurrences were reported in the DEVELOP pediatric IBD registry.⁹¹

In adults, the risk of other lymphomas (usually Epstein-Barr virus–driven), which is age-related and of lesser concern for pediatric patients, was increased in patients exposed to combination thiopurine plus anti-TNF therapy compared to no exposure, thiopurine monotherapy, or anti-TNF monotherapy.⁷⁹ In the open-label, RCT in 84 pediatric patients, there were 4 occurrences of primary EBV infection, 1 of herpes simplex virus, and 1 of chickenpox infection, throughout the study.¹⁴⁶

The group concluded that the benefits of thiopurine in combination with infliximab did not outweigh the risk of HSTCL in males. However, the consensus group did not make a recommendation regarding the use of combination therapy for females. The risk of HSTCL, although lower in females, remains elevated compared to no exposure, therefore, some participants argued that the risks outweighed the benefits, while others disagreed and noted that combination therapy with thiopurines remains a potentially useful strategy for some patients.

Key evidence. An open-label, RCT (DIAMOND), in adults who were immunosuppressant- and biologic-naïve found no difference in 26-week clinical remission rates between the combination of adalimumab plus azathioprine (68.1%) and adalimumab monotherapy (71.8%; P = .63). The rate of endoscopic improvement was significantly higher with combination therapy at 6 months but not 12 months.¹⁴⁹ Similarly, post-hoc analyses of cohort data from RCTs in adults did not show a significant benefit with combination adalimumab and immunosuppressant therapy (thiopurine or methotrexate) over adalimumab alone for induction (OR, 0.88; 95% CI, 0.60–1.27) or maintenance of remission (OR, 0.88; 95% CI, 0.58–1.35).¹⁴⁵

Additional very low quality of evidence data in pediatric patients also reported no benefit with the combination of adalimumab plus an immunosuppressant. In a post-hoc analysis of the IMAgINE-1 RCT, there was no difference in remission rates between those who received concomitant immunosuppressants and those who did not (35.9% vs 29.6%).^132,150

The evidence was downgraded to very low due to serious risk of bias and very serious imprecision.

Discussion: There were very few data to suggest a benefit of adding a thiopurine when starting adalimumab therapy. In the DIAMOND trial, the primary end point was negative, but there was evidence of more rapid mucosal healing in the combination group.¹⁴⁹

Although not statistically significant, there were trends toward higher adalimumab trough levels and lower rates of anti-adalimumab antibodies in the combination group compared to the monotherapy group. Although overall there were not significant differences in the rates of adverse events or study discontinuations between the combination and monotherapy groups, withdrawals specifically for side effects were significantly more frequent in the combination group.

For the same reasons as described in Statement 20 for infliximab/thiopurine combination therapy regarding safety concerns and less evidence of benefit, the consensus group suggested against the combination in males and did not make a recommendation regarding the use of combination therapy in females.

Key evidence. SRs have found few studies assessing the efficacy of concomitant methotrexate.^129,145 One RCT, the COMMIT study, compared the efficacy of combination therapy with infliximab plus methotrexate to infliximab alone, and found no difference in rates of symptomatic remission between the 2 treatment groups (HR, 1.16; 95% CI, 0.62–2.17; P = .63).¹⁵¹ A very, small, open, pilot study reported an early benefit of combination therapy that was not sustained.¹⁵²

The open-label, RCT in pediatric patients, described under Statement 20, included patients on either azathioprine or methotrexate in the combination treatment group, but did not specify the proportion receiving each drug. Overall combination therapy with infliximab plus an immunosuppressant was not associated with a benefit over infliximab alone in preventing loss of response over the 1-year follow-up.¹⁴⁶ Similarly, in the RCT assessing adalimumab in pediatric patients (IMAgINE-1), >60% of patients received immunosuppressants; however, the proportion receiving methotrexate was not reported, and a post-hoc analysis did not demonstrate a difference in remission rates between those who received concomitant immunosuppressants and those who did not.^132,150 All pediatric patients in the REACH study received concomitant immunosuppressants, but only 10% specifically received methotrexate.¹³¹

The quality of evidence was downgraded to very low due to serious risk of bias and very serious imprecision.

Discussion: Although the double-blind, placebo-controlled RCT failed to show a benefit with combination anti-TNF and methotrexate therapy, the evidence was assessed as very low quality.¹⁵¹ The trial demonstrated that combination infliximab plus methotrexate was associated with a lower likelihood of developing antibodies to infliximab (4% vs 20%; P = .01), and there was a trend to higher median serum trough infliximab concentrations (6.35 μg/mL vs 3.75 μg/mL; P = .08). However, there was no significant clinical benefit. Of note, there were very high success rates among the patients in this trial, potentially due to the use of systemic corticosteroids to induce remission in all patients. The high success rate in both arms of the trial may have resulted in a lack of power to demonstrate clinical benefit of concomitant methotrexate.¹⁵¹

The most frequent adverse event with methotrexate therapy is nausea (up to 25% of patients), however, there is a risk of rare, but serious adverse events, including hepatotoxicity, bone marrow suppression, hypersensitivity pneumonitis, gastrointestinal toxicity, teratogenicity, and infections.¹⁵³ In contrast to thiopurines (see Statement 20), methotrexate has not been associated with an increased incidence of lymphoma, however, historic rates of use in CD are low.¹⁵³

Although a vote was conducted, both insufficient evidence and lack of consensus prevented the group from making a recommendation regarding combining infliximab or adalimumab with methotrexate to maintain a durable clinical remission in all patients or males alone. However, if a clinician judges a patient to require the combination of an anti-TNF and an immunosuppressant, the consensus group suggested that methotrexate should be used over thiopurines in males. This was a conditional suggestion, as, despite the lower risk of lymphoma, there are other safety concerns in addition to a lack of evidence demonstrating the efficacy of combination therapy with methotrexate in CD.

Key evidence. One RCT (TAXIT) evaluated the efficacy of regular therapeutic drug monitoring (TDM) in adults with IBD, who were stable on infliximab maintenance therapy, and had their dose proactively optimized before study entry to achieve an infliximab trough concentration between 3–7 μg/mL.¹⁵⁴ Among CD patients, there was no significant difference in clinical remission rates between those who were randomized to dosing guided by TDM and those randomized to standard clinically-based dosing (62.6% vs 54.9%; P = .353). Relapse rates were significantly lower in patients who received TDM-based dosing compared to those who received clinically based dosing (17% vs 7%; P = .018); however, this was in the combined IBD population.

The majority of data related to TDM come from observational studies, which have been assessed in SR&MAs of studies in adults using infliximab^155,156 or adalimumab.¹⁵⁷ These analyses showed that antibodies to anti-TNFs were associated with greater likelihood of loss of response,^156,157 and higher serum anti-TNF levels were associated with a greater probability of clinical remission and mucosal healing.^155,157 However, these studies do not assess whether using TDM proactively will have an impact on patient outcomes, as opposed to reactive TDM when patients are symptomatic.

In the IMAgINE-1 study in pediatric patients, higher trough levels were associated with greater rates of remission, but there was no correlation between antibodies to anti-TNF therapy and remission/response (n = 6 patients with antibodies).¹⁵⁸ In a retrospective case series of pediatric patients with IBD, those with very low infliximab drug levels had high rates of infliximab antibodies, non-response, or loss of response.¹⁵⁹

The quality of evidence was downgraded to very low due to serious risk of bias and very serious imprecision.

Discussion: Evidence suggests that regimen intensification (increasing the dose or shortening the dosing interval) may help increase remission rates. In TAXIT, dose optimization before randomization resulted in significant improvements in remission rates (88% vs 65%; P = .02) and median C-reactive protein concentrations (3.2 mg/L vs 4.3 mg/L; P < .001) compared to before dose escalation.¹⁵⁴ Two SRs of case series have shown response rates of about 54%–90%, and remission rates of about 31%–40% among patients who underwent dose intensification.^160,161 In addition, among pediatric patients losing response in the REACH trial, planned dose intensification resulted in 75% of patients (n = 24/32) regaining response.¹³¹

Observational data suggest that antibodies to anti-TNFs are associated with greater likelihood of loss of response, and higher serum anti-TNF levels are associated with a greater likelihood of maintained remission. However, the only RCT that prospectively assessed the impact of proactive TDM to guide dosing during infliximab maintenance therapy demonstrated no significant benefit in its primary outcome of higher clinical remission rate at 1 year.¹⁵⁴ In a small, single-blind RCT, treatment of secondary anti-TNF failure using an algorithm based on combined drug serum levels and antibody measurements significantly reduced average treatment costs per patient compared with routine dose escalation.¹⁶² The TDM-guided approach did not have a negative effect on clinical efficacy, and was cost-effective during longer-term follow-up.¹⁶³

Based on the evidence that regimen intensification can improve outcomes, the consensus group suggested this strategy before considering a change in therapy. The statement was a conditional suggestion because of uncertainties of TDM, not uncertainty pertaining to the value of dose intensification.

Key evidence. Evidence for the potential benefits of mucosal healing and the rates of mucosal healing with anti-TNF therapy were discussed under Statement 16.

Discussion: The discussion around the utility of assessing for mucosal healing was discussed under Statement 16.

In the context of anti-TNF therapy, the consensus group did not make a recommendation regarding endoscopic assessment of mucosal healing among patients in clinical remission. Data concerning endoscopic healing achieved with other agents, including alternate pathway biologic therapies, are very sparse. In addition, the degree of mucosal healing warranting a change in therapy has not been defined, nor has the ideal duration of therapy before assessing for endoscopic healing.