TNFBs are contraindicated if the CD patient has an abscess, intestinal stricture, a flare of colitis in association with an enteric infection with Clostridium difficile or cytomegalovirus, severe congestive cardiac failure (NYHA III or IV), uncontrolled HIV disease, endemic mycosis, multiple sclerosis, or evidence of tuberculosis (TB) (positive interferon-gamma assay and/or chest X-ray prior to a four weeks course of isoniazid). TNFBs should also be used with caution and balanced consideration in CD persons with neurological disease, chronic liver disease, a history of malignancy (especially lymphoma), and in the woman who is pregnant or plans to begin parenthood (see below).

Because the peak prevalence of inflammatory bowel disease (IBD) is between approximately 20 years to 40 years of age, for the couple where one or both partners have CD or UC, the issues of pregnancy, lactation and contraception are important. These issues need to be discussed proactively and in detail with the patient and their sexual partner.

The American Food and Drug Administration (FDA) classifies IFX and ADA as pregnancy class B agents. So, IFX and ADA may be used during the first two trimesters of pregnancy if clinically indicated, and absolutely necessary[36-38]. There is no detailed published data on the safety of CER in pregnancy. Because clinically significant levels of IFX have been described in the serum of a baby 6 wk after delivery[39], it is recommended for the pregnant IBD mother to stop IFX in the third trimester of her pregnancy. There is no transfer of IFX to mother’s breast milk, so the IFX may be restarted shortly after the child has been delivered.

Recommendations have been made for the regular scheduled monitoring of persons on TNFB[40]. When the diagnosis of IBD is initially established, the patient's vaccination status should be reviewed. Unfortunately, the assessment of the IBD patient for vaccine-preventable diseases is not well considered by many healthcare providers[41]. If the vaccination program is not current, then it must be updated before the use of TNFBs. Ideally, vaccinations should be updated before the use of immunosuppressants such as AZA or MTX, or GCS.

Under no circumstance should the patient on TNFB be given live vaccines. To stress, these include vaccines for measles-mumps-rubella, varicella (oral), yellow fever vaccine, or oral polio vaccine. The injectable (non-oral) vaccines for polio and for typhoid are considered to be safe. Live vaccines may be given safely three weeks before or three months after stopping AZA or metronidazole (MTZ), or given at any time to persons on GCS, as long as the dose is below prednisone 20 mg/d. There are no guidelines for the ideal time to vaccinate before or after the use of higher doses of GCS.

In the IBD patient who is hepatitis B virus (HBV) positive (regardless of negative hepatitis B surface antigen, and regardless of elevated or normal liver enzyme test), the HBV must be treated before starting TNFB (Table 4).

The regular travel precautions are taken for malaria. As with all travellers, ciprofloxacin and/or metronidazole should be available to the traveler, in the event that they develop symptoms suggestive of traveller’s diarrhea. It is useful if the traveler has a typed copy of their medical records, a copy of their consultant physicians’ most recent letter, documentation for custom officials of their prescribed medications, purchase of traveller’s insurance without exclusion for pre-existing conditions (i.e., IBD), contact names and numbers of physicians in foreign countries with IBD experience, and contact numbers for care-givers at home. IBD patients with an ileostomy should be aware of the importance of their not becoming dehydrated.

There are several situations when TNFB should not be used, or used after full consideration of the consequences and patient awareness and patient awareness and consent.

Narrowing of bowel and TNFB use: (1) Inflammatory-yes (no pre-stenotic dilation); and (2) Fibrostenotic-no.

Latent infection: (1) TB; (2) HBV; (3) HIV; and (4) Live vaccines within last 3 mo.

Active infection: Perianal or intra-abdominal abscess must be drained.

Present malignancy or disorder: Present/previous malignancy (other than non-melanoma skin cancer) or lymphoprolifer-ative disorder.

Cautious use in children: Because of 48 cases of malignancy, 88% (almost 9 out of 10) of which were while the patient was on both TNFB plus immunomodulators, and half developed lymphoma.

General considerations: There are several goals of therapy in CD (Table 5). It is important to consider a number of factors pertaining to the clinical trials which have been used in meta-analyses to provide therapeutic recommendations for the use of TNFBs for induction and maintenance of CD. What proportion of CD patients will have an initial non-response to IFX (primary non-response), a continued response or remission, and a secondary non-response? The definition of response and remission may vary between studies, the time of assessment of these outcomes may vary, and most studies exclude the primary non-responders at 2 wk. Also, the placebo response rates vary widely, and therefore so too does the therapeutic gain [therapeutic gain (TG); therapeutic minus placebo response]. Some patients may have a short or a long duration of CD before IFX for example was initiated used, and some trial participants were previously or concurrently on GCS, AZA, or MTX, and the dose and duration of use of GCS, AZA and MTX may have varied widely.

About a quarter of persons treated with TNFB will be primary non-responders, i.e., will not respond to an initial dose of TNFB. Because primary non-responders are often excluded from analysis, the response and remission rates in the intention-to-treat group are much lower than the per-protocol group[44]. Patients and physicians must be made aware that some of the published rates of TNFB response (about 2/3 of TNFB users) and remission (about 1/3) are in those persons who responded initially, and do not include the percentages based on all users (i.e., intention-to-treat). The overall desired outcome of TNFB therapy is prolonged steroid-free remission, mucosal healing, good quality of life, and normalization of laboratory markers of inflammation [e.g., C-reactive protein (CRP), erythrocyte sedimentation rate], an acceptably low risk/benefit ratio, and acceptable cost to ensure widespread availability.

There are different ways in which a response to therapy may be defined, and these definitions vary from study to study. In clinical trials of CD, the CD activity index (CDAI) is often used as one of the outcome measures. The CDAI is based on the patient’s symptoms, the presence of an abdominal mass, anemia (reduced hematocrit), weight loss, and use of an anti-diarrheal agent. CD is arbitrarily said to be “active” if the CDAI is above 150 points. Clinical response in CD may be a decrease in CDAI of ≥ 70 points, or a decrease in CDAI of 70 to 100 points plus a 25% improvement from baseline[45]. Clinical remission might be variably defined as a CDAI of < 150, or CDAI < 150 plus a decrease by 50 to 100 points from baseline. Because of these variations in definition, the results from one study cannot be directly compared with another study. Comparing the placebo responses gives only a very rough approximation of the comparison of the population of patients examined in two studies, because of the very large heterogeneity of CD sufferers. The only totally valid method of comparison of one TNFB to another is a head-to-head randomized controlled trial (RCT). Note that there are no head-to-head comparisons of IFX, ADA, CER. Taking the largest trials into account, and considering all of these previously mentioned cautionary points, it is suggested that there are numerically similar post-induction success rates of clinical remission and fistula closure for IFX, ADA and CER.

Specific considerations: Induction of remission, and primary non-response: Patient selection characteristics and the time in the course of the patients’ disease will influence outcomes with TNFB therapy, so there may be large variations in the placebo response in one study vs another, and therefore gain achieved with TNFB (Table 6)[46-50]. Careful consideration must be given as when to start TNFB therapy: When to start TNFB depends upon consideration of (1) clinical characteristics (steroid-refractory and steroid-dependent); (2) previous response to treatment; (3) complications and comorbidity; (4) cost/availability; and (5) patient preference and IFX. The 2 wk induction response rates for IFX ranges from 52% to 73% (Table 7). However, the therapeutic gain for single dose IFX for induction of response and remission in CD varies with the time of assessment and dose, and is quite modest, for example, only a 10% to 22% remission rate at week 12. Quoting from the CADTH review[51], “a total of 47 citations reporting 20 RCTs and 17 observational and uncontrolled studies were included. All the RCTs had a parallel group design. Four studies were open-label, single-arm trials. Of the remaining 13 cohort studies, seven studies used a prospective design, and the remaining six studies used a retrospective design. Five cohort studies and one RCT were published as abstracts only. The remaining studies had at least one full peer-reviewed publication. IFX was used as the treatment for patients with CD in eight RCTs (total number of participants 1091; range: 36-335) and 10 observational and uncontrolled studies (total number of participants 1402; range: 12-614), and for patients with UC in six RCTs (total number of participants 1477; range: 299-499) and five observational and uncontrolled studies (total number of participants 157; range: 15-36). One cohort study (10 participants) reported the use of ADA in UC. One RCT of 43 participants evaluated the effects of ENT in patients with CD. Of six which included placebo-controlled trials assessing the effectiveness of IFX in the treatment of CD, three studies used short-term regimens of IFX to induce disease remission, and three RCTs evaluated the effectiveness of long-term IFX in maintenance of remission”[51].

For the treatment of fistulizing CD, reporting on 776 patients in 10 studies, after open-label induction, maintenance trials showed a mean difference of 16% (95%CI: 8%-25%, P < 0.001)[3]. Thus, only 11% had induction of remission as compared to placebo, and only 8% maintained their remission for about half a year.

The TG is the treatment response minus placebo response. The TG for significant response at weeks 4, 12, 24, and 30 and 54, a response will be seen in 50% and 37%, 30, 52, and 54 is 48%, 29%, 28%, 23%, 18%, and 22% with TG for remission of 16% and 13%.

In IFX primary non-responders, there is no proven benefit in using ADA. Of those who do respond initially at 2 wk, then after 4 wk of IFX about two-thirds respond (CDAI > 70 point reduction), and about one-third are in remission (CDAI < 150 points)[52]. At 24 wk, 57% will still show a response, but will not be in remission [IFX = placebo (PL), P = 0.31][52,53]. At 30 wk and 54 wk, 39% and 28% were in remission[54].

The two major studies evaluating ADA in CD need to be evaluated separately due to heterogeneity in terms of whether the CD patients were naive to TNFB[51]. Similar to IFX, about 30% of persons with CD given ADA will be primary non-responders. Of those who do respond initially at week 1, about 52% will have responded at 4 wk and 21% will be in remission. The secondary non-response rate to ADA is 23%-48% at 24-26 wk and 23%-59% at 56 wk. The TG (active agent-placebo response) at weeks 4, 26, and 56 was 14%, 23%-25% and 23%-24% (Table 8)[54-56].

The Community Economic Development Assistance Corporation recommends ADA for patients with moderate to severely active CD who are “refractory to or who experience contraindication to an adequate course of 5-ASA and corticosteroids and other immunosuppressive therapy”[42]. It is not defined how long the patient must have been on conventional therapies before declaring that they have continuing symptoms, or how minor these continuing symptoms may be before considering adding TNFB therapy. It is not clear whether patient preference represents a “contraindication” to an adequate course of conventional therapy.

The mean percentage of loss of response to ADA among primary responders was 18.2% and the annual risk was 20.3% per patient-year. The mean percentage of patients who required dose intensification among primary responders to ADA was 37% and the annual risk was 24.8% per patient-year. When considering initial responders and patients with primary non-response, the mean percentage of patients who needed an ADA dose escalation was 21.4% and the annual risk was 24.4% per patient-year. Pooled analysis showed that dose escalation permitted response to be regained in 71.4% and remission in 39.9% of patients. Predictors for loss of response or dose escalation were male gender, current/former smoker status, family history of inflammatory bowel disease, isolated colonic disease, extra-intestinal manifestations, 80/40 mg induction therapy, longer disease duration, greater baseline Crohn's Disease Activity Index (Table 9), concomitant corticosteroid use, no deep remission at week 12, low serum trough concentrations of ADA, previous IFX non-response and being previously treated with an anti-tumor necrosis factor agent.

The Precise 2 trial with CER in CD over 26 wk showed clear superiority to placebo in terms of clinical response and remission[57].

There have been five systematic reviews and meta-analyses published on the efficacy of TNFB in inducing remission of active luminal CD[3,58-61], as well as Cochrane review of the efficacy of natalizumab in the same clinical setting[62]. The most recent meta-analyses on the therapeutic management of IBD have appeared in the “Red Journal” (Table 10)[61]. Funnel plot asymmetry was considered regarding evidence of publication bias and small study effects, and Cochran Q values for heterogeneity. The criteria for inclusion of studies was stringent, using rigorous and conservative methodologies and these data should be used to better guide and care for patients suffering from CD and UC.

In summary, in persons with active luminal CD who have failed treatment with first and second-line agents or who are corticosteroid dependent, for induction of remission of active luminal CD, “IFX, natalizumab, and ADA appear to have the most evidence for their use, although the latter two therapies performed only moderately in this setting”[61].

The clinical definition of primary non-response is lack of improvement of clinical signs and symptoms with induction therapy. Definitions and time-frames for the assessment of response and non-response have varied amongst clinical trials for different biological agents; in the original “Targan” study of IFX in refractory CD, response was defined as a 70-point reduction in the CDAI after 4 wk[52].

To a shift in the dominant mechanism of inflammation (loss of the pharmacodynamic effect), increasing symptoms or signs not related to IBD activity (for example, irritable bowel syndrome, concomitant infection, bacterial overgrowth, and so on), or failure to wean off corticosteroids. Loss of response can also imply.

A “relative” term for patients who have shorter durations of response (for example, less than 4 wk for IFX, 1 wk for ADA, or 2 wk for certolizumab) or require dose escalation, which may become economically impractical.

In the Accent I study of IFX, which assessed the maintenance benefits of IFX, the initial response was defined as a 70-point reduction in the CDAI at 2 wk[54]. Most clinicians will consider lack of response after two consecutive infusions of IFX of at least 5 mg/kg body weight and will assess treatment failure at 4 wk[50].

Recent data suggest that patients who initially respond may, more gradually, accrue remissions over time[55].

All three currently approved anti-TNFα biological agents are administered differently and have different pharmacokinetics and dosing intervals, and a reasonable assessment of lack of response to IFX would be after 2 wk, and to ADA and certolizumab pegol would be made after completion of induction therapy at 4 wk and 6 wk.

In approximate terms, 70% of IFX-treated CD patients show a response after 2 wk of treatment. In these primary responders, the secondary non-response rate (i.e., those who initially respond, but then lose their response) is 40%-50% at 24-30 wk, and 60%-63% at 52-54 wk. At one year, about 30% of the initial responders will still be responding, and about 20% will be in remission.

About 30% of persons given TNFB therapy do not initially respond (primary non-response). The explanation of this is unknown, but it may be speculated that this may be done to the use of too low a dose of IFX (the serum through concentration of TNFB generally correlates with CD response), or the inflammatory process may be independent of TNFα. Of the initial primary non-response responders, about 70% respond and 35% go into remission. Including all persons with active CD, and taking into consideration the initial non-responders, out of 100 CD patients with active disease treated with TNFBs, approximately (100 × 70% = 70, 70 × 70% = 49) will respond and (70 × 30% = 21) will go into remission. These figures are lower than historically reported clinical response and remission rate with conventional (i.e., standard-of-care) management with GCS or, AZA/MTX, however it must be stressed again that because of large differences in study populations and study designs, the clinician must be very caution about accepting comparisons in anything other than direct head-to-lead studies.

There are numerous possible reasons for lack of response (Table 11)[63].

Secondary failures to IFX may be as common as 48% in the first year of anti-TNF therapy, and 66% in the second year[69]. In secondary IFX non-responders, switching to ADA results in a response in 59%-83%, and remission in 29%-50%[70-72].

Secondary non-responders may respond to an increase in IFX dose, or a decrease in dosing interval, or both[73]. In secondary non-responders to IFX, 80%-90% responded to treatment intensification with IFX[54,74]. After two and a half years after an initial response to IFX, about half (54%) of patients require dose intensification[51,75]. Other studies have confirmed the use of dose escalation[76,77]. Dose acceleration helps maintain response: for luminal disease, 90%[74], for fistulising disease, 60%[78]. At 40 wk, 65% were still responding after the last dose intensification over 52 wk[72,73]. The therapeutic gain for IFX maintenance of remission was low, ranging from 14% to 33% at one year (Table 14).

In the Accent I Study[54], dose escalation was needed for persons who initially responded but then worsened at some time during the 54 wk study in 49% of persons on episodic treatment, 30% on 5 mg/kg IFX scheduled treatment, and 26% on 10 mg/kg scheduled treatments (secondary, non-response). Response was re-established with higher doses in 90% of the 5 mg/kg and 80% of the 10 mg/kg scheduled treatment groups treated with higher doses. Most of the cross-overs to higher doses occurred at week 14. In a 40 wk study, 83% of secondary IFX non-responders did respond after the first intensification of IFX, and 65% of patients were still responding after the last intensification dose.

Patients who lost their response to IFX were switched to ADA, and then continued with it for 52 wk. Secondary non-response to ADA was seen in 25%, and therefore, patients required a dose escalation[72]. These response rates are even higher in persons treated with ADA for the first time (i.e., IFX- and ADA-naive CD patients). Two RCTs and four observational and uncontrolled studies assessed the clinical effects of ADA after a loss of response or intolerance to IFX[51]. Re-induction therapy with ADA has a 60% clinical response[79]. Similarly, the Precise II study[57] showed a benefit of reinduction in clinical response and remission of CD with CER in those patients who had received IFX in the past .

Long-term maintenance with IFX 3 mg/kg maintains mucosal integrity and avoids CD recurrence one year after surgery[80]. Another study evaluated endoscopic recurrence of CD post-operatively and found the rates to be lower with IFX at one year vs placebo (9.1% vs 85%)[81]. However, clinical remission was not significant (80% IFX vs 53.8% placebo, P = 0.38). A recent review of the literature also shows that there is statistical benefit with IFX use within 4 wk of surgery on mucosal healing. But this effect was not statistically significant in reduction of CDAI.

There are two RCTs[55,56] and four observational and uncontrolled studies[70-72,82,83] assessing the clinical effects of ADA after a loss of response or intolerance to IFX. Blinded clinical trials show that ADA is effective first-line therapy for TNFB-naive CD patients, and is an option for IFX-refractory or-intolerant persons[84]. In the Gain study[55], secondary non-responders to IFX responded better when switched to ADA than when switched to placebo (IFX→ADA vs IFX→PL). In an uncontrolled open-label study, the switch from IFX to ADA (IFX→ADA) was associated at week 12 with a 59% clinical response and 29% remission rate[70]. A 50% or greater decrease in the number of draining fistulas was seen in 56%, while 33% had complete absence of fistula. In a second study[82], switching from IFX to ADA (IFX→ADA) gave a partial response in 31% and a complete response in 54%. In a single-arm study[72], 50% of IFX→ADA had a clinical remission at week 52. Four weeks after switching to ADA, 83% had a clinical response and 42% were in remission[72].

In the Crohn's trial of the fully human antibody adalimumab for remission maintenance (CHARM) study[56], there was no statistically significant response to ADA in IFX non-responders (IFX→ADA) or in those who were IFX-naive. When switching from IFX to ADA[56], the response at 26 and 56 wk in the TNFB-naive patients was 47% and 42%, compared to 32% and 31% in the non-responder group. Overall the ADA treated group did better than the placebo group. The ADA group had a higher rate of staying free of steroids for > 90 d and achieved clinical remission at week 26 (19% for 40 mg every other weeks vs 15% for 40 mg every week vs 3% for placebo, P < 0.001). The therapeutic gain of ADA for maintenance of remission ranged from only 25% to 39% (Table 15).

The proportion of ADA-treated patients who required dose escalation and the results of treatment were reported in two RCTs and one small before-after study[51]. In secondary non-responders to ADA, 76% responded to dose escalation and 45% went into remission[55,72,85].

There is no data available to assess the effectiveness of using IFX for secondary non-responders of ADA. In the CHARM study[55], 46% of the persons randomized to receive ADA were secondary non-responders. Of those who received dose escalation of ADA, 76% had a no-point response rate and 45% went into clinical remission. In the Classic II study[55] (following from the Classic I study), only 5% of patients who completed the 56 wk of treatment needed dose escalation.

In CD patients who responded to CER induction therapy (Precise 2), and then relapsed during continuous or interrupted maintenance therapy, recapture therapy with CER was provided. The response rates at week 4 were 63%-65%, and 55%-59% at 1 year (Precise 4)[86]. Using Certolizumab pegol maintenance therapy for persons with CD, there was clinically meaningful improvement with the Inflammatory Bowel Disease Questionnaire score (60% vs 40%, P < 0.001), Short Form 36-Hem Health Survey (SF-36) physical (51% vs 34%, P < 0.001) and mental component summary responses (44% vs 32%, P = 0.016), and the proportion of persons living a normal life (21.4% vs 12.4%, P = 0.019), (57% vs 35%, P = 0.001). The therapeutic gain of CER for maintenance of remission was at 28% at week 26 (Table 16), similar to the 24 wk and 30 wk result for IFX and ADA. The therapeutic gain of CER varied little between weeks 2 and 12, and with doses of CER 100 mg, 200 mg and 400 mg (Table 17).

In the Precise 2 trial, the 26 wk therapeutic gain in response rates of therapeutic gain with CER were lower in those who had first failed IFX, than in those starting CER and never previously having been on IFX (19% vs 29%)[87]. This was also the case with IFX in the Precise 2 study: the response in the IFX-naive group was 69%, compared with 44% (P < 0.001) in the non-naive group. Thus, there may be benefit switching from IFX to ADA in the IFX-failure patient. In patients who were treated with IFX and experienced secondary failure, and then were treated with open-label CER, 62% enjoyed a response and 39% remission rate at week 6[88]. When extended to 26 wk, the response and remission rates were 40% and 37%, respectively. CER also improved work productivity during the induction and maintenance components of the Precise study[89].

Also from the Precise 2 study, 58 CD patients with draining fistulas (mostly perianal fistula) who responded initially to CER were continued on CER or placebo[90]. At week 26, 36% on CER had fistula obscure compared with 17% receiving placebo (TG, 19%). Using the definition of ≥ 50% closure at two consecutive post-baseline visits ≥ 3 wk apart, there was only a trend for achieving this end point (54% vs 43%, P = 0.069).

The maintenance response rate was inversely related to the duration of the patient’s history of CD: maintenance of response to CER was present in 90% of patients with a CD diagnosis less than one year, compared with 57% continued response in those with a CD diagnosis ≥ 5 years[91]. Corresponding remission rates were 68% vs 44%. This suggests that there may be improved efficacy of TNFB maintenance therapy when initiated “early” as compared “late” in the history of the patient’s disease[92].

The results of the most recent vigorous meta-analysis of biological therapies in preventing relapse of disease activity in quiescent luminal CD is shown in Table 18. These authors suggest that the most marked effect of biological therapies was in preventing relapse of luminal CD once remission had been achieved, with a NNT of only 4. This benefit was observes for both IFX and certolizumab, but not for adalimumab[61].

About a third of patients treated with anti-TNFα therapy, who meet the criteria for an initial clinical response, eventually lose response, with the magnitude depending on the duration of follow-up on maintenance therapy. Loss of response, also referred to as secondary non-response, is defined as recurrence of disease activity during maintenance therapy after achieving an appropriate induction response. In maintenance trials with IFX and ADA, significant percentages of patients required increased doses (IFX) and or decreased treatment intervals (adalimumab) in order to restore response after interval symptoms developed between dosing[54,56,78,93]. Even after scheduled maintenance therapy and dose adjustments, substantial numbers of patients will still have a poor response[44]. Of the initial responders, 65% need dose escalation, which appears to be successful in approximately 70%, and the probability for dose escalation throughout time is approximately 80% at 120 wk[94].

From the Figure 1, it is apparent that approximately 10% (56%/5 years.) of patients treated with TNFB lose their response each year. If patients who are doing well on IFX + AZA, and the IFX is stopped, 39% relapse within one year[95]. Persons who are likely to relapse when IFX is stopped are those with objective signs of continued inflammatory activity (↑CRP, Crohn's disease endoscopic index of severity ≥ 2) or low IFX though level. Fortunately, almost all (> 95%) of those who recurred when IFX was stopped respond to IFX retreatment. Presumably a greater proportion relapse as this interval is followed out beyond one year; it is unknown if those longer term relapsers will continue to have such a favorable response to retreatment with the originally successful TNFB.

How is this loss of response to TNFB managed? A useful suggested clinical approach to loss of response to TNFB therapy has been published (Figure 2). First determine if the patients symptoms might be due to something other than active CA. For example, exclude enteric infection (including Clostridium difficile) or small intestinal bacterial overgrowth, bile salt wastage, or adverse reaction to other drugs. What are the options if the CD is active[96]? The initially chosen TNFB is increased in dose, decreased in dosing interval, or both! If there is no response, switch to another TNFB[96].

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Figure 2 Suggested clinical approach to loss of response to anti-tumor necrosis factor-α therapy. CRP: C-reactive protein; TNF: Tumor necrosis factor.

Suggested clinical approach to loss of response to TNFB (Figure 2), to quote the approach suggested by Yanai et al[63]: (1) Confirm that intestinal inflammation is the cause of the “loss of response”; (2) Measure IFX levels at 4 wk after an infusion (therapeutic ≥ 12 μg/mL); (3) Measure antibodies to IFX (ATI) measurements not available for ADA or CER. The Mayo Clinic group has demonstrated the utility of combining IFX levels and determination of ATI in the clinical management of patients who lose response to IFX[97]; (4) “Patients who lose response to a first agent are more likely to lose response to a second and, similarly, those with toxicity to a first agent are more likely to develop toxicity from a second anti-TNFα agent. This diminishing outcome may, in part, be due to a class effect”; (5) “Patients who lose response to IFX associated with anti-IFX antibodies respond well to switching to adalimumab or certolizumab pegol”; (6) “In the majority of patients, response can be restored by dose and interval adjustments”[44,94]; (7) “Switching between biologics is an important strategy for patients who lose response because of immunogenicity followed by rapid drug clearance or when a significant alternative pathogenic role is suspected. Switching can be within class or with an alternative class”; and (8) “Efficacy of successive agents is decreased compared with the primary agent”.

In this situation where there has developed secondary failure, 75% to 78% regain a durable response after dose intensification[73,98,99]. It is recognized that over time after a surgical resection “cure”, most CD patients recur endoscopically, and fewer recur symptomatically. In the study by Regueiro et al[81], the endoscopic recurrence rate of 85% was reduced to 9% with continued IFX treatment.

How long to treat with TNFB? Five observational studies have shown the response to IFX or ADA ranges from 73% to 100% at year one, 65% to 90% at year two, 61% to 68% at year three, and 52% to 58% at year five[102-105]. RCT data is not available yet for more than one year. Clear evidence based guidelines have not been developed as to when to stop TNF therapy, but reasonable empirical suggestions would be with loss of response or severe adverse effects to TNFB. Perhaps after one year TNFB treatment, when the patient is in clinical remission, there are no signs of active inflammation, and perhaps when mucosal healing is achieved, stopping TNFB therapy may be considered and discussed with the patient.

There are no head-to-head trials of one TNFB against another. There is heterogeneity in the CD patients recruited for the clinical studies, but interestingly the therapeutic gain for remission at weeks 26 to 30 were close to 18% to 23% (Table 19). It is unfortunate that these rates are so low.

Patient-reported outcome (PRO) instruments are used to provide information about health-related quality of life. The minimal clinically important difference (MCID) and minimal important difference (MID). PRO score changes have been determined from two TNFB clinical trials[106]. The MCID is the smallest difference in a PRO score that is associated with a clinically relevant difference or change[1,107]. The MID is the smallest difference in a PRO score that a patient can perceive as beneficial and would require a change in their treatment. The MCID and MID units are meaningful measures to assess alterations in PRO scores, rather than changes which albeit are statistically significant, are not necessarily useful in a practical sense.

When considering possible advantages of different TNFB, for example, ADA vs IFX, ADA has greater ease of administration (subcutaneous, self-administered vs infusion facility), no infusion reactions, higher remission rates among secondary non-responders to IFX[72,108], possibly reduced need for dose escalation over time [fewer secondary failures[109], higher later rates of response and remission (maintenance), lower cost [$ incremental cost-utility ratios (ICUR) per quality-adjusted life-year (QALY)][51], and lower risk of developing neutralizing antibodies. Again it must be stressed that there is no head-to-head direct data to allow for a definitive statement to be made about any comparison, including cost and patient preference. These conclusions are based on observations.

In contrast, the possible advantages of IFX vs ADA include no injection site reactions or infections, fewer numbers of individual adverse effects, higher early rates (induction) of response and remission, and high rate of fistula improvement or remission with both short- and long-term therapy. IFX also gave higher initial response and remission rates as compared to ADA. Comparatively, the use of ADA led to lower relapse rates, indicating that patients retained longer benefit from ADA vs IFX[51].

Most guidelines suggest that TNFB therapy be started when immunosuppression alone has failed. The used of TNFB plus immunosuppression is known as concomitant immunosuppression (CI). To understand the subtle aspects of the question about CI use with TNFBs in CD, we need to reflect upon several important studies.

Scheduled maintenance IFX treatment is more effective than episodic treatment (Accent I)[74]; Scheduled maintenance therapy is superior to episodic treatment in terms of the use of steroids or the use of hospitalization and surgery[44]. IFX induction plus azathioprine/6-mercaptopurine (6-MP) is more effective than azathioprine/6-MP alone in AZA-naive patients who are steroid-dependent (GETAID)[53]. Early treatment with IFX in combination with an antimetabolite is more effective than conventional therapy (step-up top-down)[110]. IFX plus azathioprine is significantly better for inducing steroid-free remission and mucosal healing than azathioprine alone in azathioprine-naive patients [study of biologic and immunomodulator naive patients in Crohn’s disease (SONIC)][102]. In initial IFX responders, the maintenance of response falls from 83% at 30 wk, to 64% at 54 wk, and to 45% at 108 wk[111].

Scheduled maintenance IFX is more effective than episodic treatment[74]. The standard of care is to use TNFB on a regular and scheduled basis. The benefit of scheduled vs episodic use of IFX is related to there being lower levels of antibodies to IFX (ATI), fewer infusion reactions, and fewer hospitalizations and major surgery[54,112,113]. IFX induction plus AZA/6-MP is more effective than AZA/6-MP alone in AZA-naive patients who are steroid-dependent[53]. Early treatment with IFX in combination with an immunosuppressant is more effective than conventional therapy[110]. IFX plus AZA is significantly better for inducing steroid-free remission and mucosal healing, than is AZA alone in AZA-naive patients[114].

There is no additional benefit of adding MTX in the steroid-treated CD patient who is also on IFX[115]. It remains unknown if the continuation of MTX might be useful if the person were just on MTX + TNFB, rather than just being on GCS.

Most current guidelines recommend that AZA/MTX must have been used and be considered to have failed before TNFBs are introduced what should be. The duration of previous use of this immunosuppression and should AZA be continued TNFB once has been started is not known. Some data suggested that continuation of AZA after the introduction of IFX offers no additional benefit beyond 6 mo of combined therapy, as long as the TNFB is used on the basis of a regular schedule, rather than being given episodically. The authors of one trial suggested that “continuation of immunosuppression for more than 6 mo offers no clear benefit over scheduled IFX monotherapy”[116]. IFX monotherapy is superior to IFX plus immunosuppressive therapy after CD induction with IFX. In one study, four times more relapses occur with AZA maintenance after IFX induction, as compared with IFX induction and placebo maintenance[53]. In a second study, maintenance of remission of CD was no different when AZA plus IFX were given for maintenance, vs IFX alone[117].

In the study by Van Assche et al[116], at 6 mo in person on IFX in whom AZA had been withdrawn (IFX plus AZA D/C vs IFX + AZA), the CRP levels were higher, and IFX levels were significantly lower. Perhaps if the patients had been followed for longer than 6 mo, the AZA discontinuation group might have begun to experience more recurrences. The RAND appropriateness methodology, through a modified Delphi panel approach based on expert interpretation of the available literature, has been used with a “globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease”[118]. Using a total of 134 clinical scenarios, concomitant use of immunomodulatory was generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. However, CI were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (> 26 years)”. In the GETAID study, the IFX + AZA (CI) gave a significant therapeutic gain of clinical remission off steroids, as compared with AZA alone, of 37% and 28% at weeks 12 and 24 respectively. But the benefit was lost at week 18 (Table 20).

Several important aspects to consider when attempting to answer the question of the benefit of using CI with IFX are the duration of follow up, whether the patient is naive to the immunosuppressants or the TNFB, whether the activity of the disease is high as suggested by an elevated surrogate marker such as CRP or mucosal lesions, what is using an endpoint of immunogeneity (such as antibody to TNFB or a disease activity index or QoL score), and whether the question is focused on the CD patient in whom you are trying to achieve induction or maintenance of remission. CI is clearly beneficial when added to IFX regimens which are episodic[112,119], but the controversy about CI comes from studies using regularly scheduled TNFB, the method which is new to the standard of care.

In the SONIC study, CD patients who were naive to both immunosuppression and to TNFB, the rate of clinical remission at week 26 was higher in those given IFX + AZA as compared with IFX alone or AZA alone (57%, 44%, and 31%, respectively)[120]. In a subgroup of patients who initially had both an elevated CRP and mucosal lesions at baseline, the IFX plus AZA + IFX alone values were even higher (69% and 57%, respectively). Since the difference between IFX + AZA was statistically greater than IFX alone, the data may be interpreted to indicate that CI is advisable, at least in the relatively short period of 26 wk, for steroid-free remission. However, the benefit of CI appears to fades after 6 mo to 12 mo[116,121].

In the infliximab maintenance immunosuppression discontinuation study (Van Assche), in CD patients who had been on AZA/MTX before starting IFX, stopping the immunosuppression at 6 mo did not have an adverse effect at 2 years to shorten the interval between IFX infusions, or the time to stopping IFX dosing. The prevalence of antibodies to IFX were similarly low in each group, and CI with IFX + AZA had no different effect in terms of mucosal healing.

The same message comes from the 2-year long COMMIT trial of steroid-requiring CD patients on IFX or IFX + MTX (Feagan 2010): CI does not provide a medium term (2-year) advantage. On the other hand, CI may increase the risk of adverse effects such as non-Hodgkin’s lymphoma in adults[122], hepatosplenic lymphomas in children[123], as well as other concerns in children[124]. As well, CI did not benefit the medium term risk of surgery[125]. These individual studies suggest that in many CD patients, CI is “bridge” therapy for 6 mo while the full effect of TNFB is being achieved.

In an observational serial observation of 88 CD patients in remission and on IFX, half had their CI with AZA stopped. The IFX failure free status was 85% at 12 mo, and 41% at 24 mo and 32 mo[126]. This failure rate of IFX maintenance may have been due to the withdrawal of CI with AZA. Failure of CI on AZA-withdrawal was more likely to occur if the initial duration of IFX-AZA therapy was less than 27 mo, if the CRP was greater than 5 mg/L or the platelet count higher than 298 109/L. Until further data becomes available, we can be encouraged by “expert opinion” from the BRIDGE group analysis[118], suggesting that bridging CI may not be necessary such as in young males especially with limited disease, or some case scenarios including uncomplicated CD.

CI[127]treatment also reduces antibody to IFX (ATI) formation [24% vs 63%, on CI vs not on CI, P = 0.007; 43% vs 75%, P < 0.01]. Former researchers have proposed a time-structural treatment algorithm for moderate CD. This may of course need to be altered in future if “top down” (IFX→AZA→GCS) approaches to CD are shown to be beneficial.

The major role of CI may be in the patient who is on episodic IFX: in these persons, the incidence of ATI was 0% on CI vs 60%, not on CI, P = 0.018[128]. Comparatively, CI had no relationship on ATIs with scheduled IFX infusions. Combined immunomodulator with TNFB provides small therapeutic gain for 24 wk. Then, it is likely that CI can be abandoned without any detrimental effect of clinical response, and possibly a lower risk of adverse events. In fair balance for the issue of AZA discontinuation in the TNFB-treated patient, the “jury is still out”, or as the Scots would say, the case is “not prove”. Clearly, more data is needed.

In summary of Combination therapy: (1) In AZA and TNFB naive persons, with ↑ CRP or mucosal lesions on colonoscopy, remission and one year mucosal healing response to combination therapy (SONIC) A AZA = TNFB; (2) Unknown what to do after one year: for IFX alone after successful induction, maintenance for 54 wk gave a therapeutic gain of (28%-14%) 14% and 24% (38%-14%) for 5 mg/kg and 10 mg/kg IFX (Accent I). It is unknown what is best to do after one year treatment with IFX; (3) In post hoc analysis of combination therapy of immunomodulators plus IFX/ADA/certolizumab pegol (CZP) vs monotherapy with TNFB, there is no benefit in terms of induction synergy; (4) Because of study design, it is not possible to comment whether MTX plus TNFB is superior to TNFB alone; and (5) Not possible yet to predict which patient can be induced with TNFB and maintained on AZA (TNFB as a “bridge”).

At 2 wk and 4 wk after a single dose of IFX (5 mg/kg), the therapeutic gain (TG; IFX response minus the PL response) for clinical response was 56% and 64%, respectively (Table 7), and then fell to 36% at 12 wk[52]. The TG for remission was 36% and 46%, respectively, for weeks 2 and 4. When IFX (5 mg/kg) is given 2, 6 and every 8 wk until week 48[54] or 54[69,82], the week 54 TG for response ranged from 22%[54] to 30%[69,82], and for remission, the TG was 14% for IFX 5 mg/kg and 24% for 10 mg/kg. IFX doses of 10 mg/kg or 20 mg/kg did not give higher therapeutic gains in terms of response.

Thus, after excluding the approximately 30% initial IFX primary non-responders, about the two-thirds will respond and about one-third will go into remission at 4 wk (therapeutic gain). With continued 8-weekly IFX infusion for approximately one year, the TG for response is about one in four, and for remission one in eight. These represent relatively small gains which are not necessarily higher than reported historical figures for conventional therapy induction or maintenance therapy in CD. In children with CD, Kaplan-Meier analysis has shown that the cumulative probability of losing response to IFX after 1 year, 3 years and 5 years is 13%, 40% and 50%[131]. In adults with CD who chose to stop their IFX after achieving remission, 50% relapsed within 477 d after IFX discontinuation[132].

For the currently recommended dose of ADA of 160 mg at weeks 0 and 80 mg at week 2, TGs for response range from 15% to 19% at week 2, and 13% to 25% at week 4 (Sandborn et al[93]). The corresponding TGs for remission at 2 wk and 4 wk range from 10% and 14%-24%. The TGs for response at 56 wk range from 7%-25% when ADA is given as 40 mg q every other week, to 15%-33% when ADA is given as 40 mg q weekly[55,56,85,127,133]. The corresponding values for TG for remission at 56 wk range from a low of 4% to a high of 39%[55,56,85,127,133]. The values for the initial TGs in response and remission for induction therapy are numerically slightly lower for ADA; it is slightly higher for ADA for maintenance of response and remission. After two years of maintenance therapy with ADA every other week, 42% were in remission compared to 38% on placebo[134], and 50% with weekly ADA. This study also showed an improvement in IBD QoL questionnaires, suggesting clinical response. There is insufficient evidence at this time to recommend one type of ADA therapy over another.

In addition to therapeutic gains in terms of response and remission rates, other important clinical outcomes include improvements in quality of life, hospitalization and surgery. In patients with RA, combinations of TNFB with low-dose MTX are generally more efficacious than either drug used alone[135], the mechanism of anti-inflammatory properties of this combination is not totally clarified and it is not known if TNFB plus MTX have a synergistic mechanism[136], especially in CD.

Hospitalization: In Canada, about 20% of persons with CD have IBD-associated hospitalizations per year[2]. The proportion of patients who needed hospitalization for IBD were reported in three IFX trials and one ADA trial. Two IFX trials and one ADA trial reported the patients who needed surgery[51]. Overall, CD patients who received IFX maintenance therapy had an approximately 50% reduction in the rate and duration of hospitalization[74,129]. Lower hospitalization rates were also seen with ADA[93]. Infusing IFX on a scheduled vs an episodic basis reduces the rate of all-cause hospitalization, as well as IBD-related hospitalization. For example, in Accent I[74,137], the rate of IBD-related hospitalization was 28% in the episodic treatment group vs 23% in the IFX 5 mg/kg group (P = 0.047) and 24% in the 10 mg/kg group (P = 0.023). Furthermore, the number and duration of hospitalizations were lower in the scheduled vs episodic group (P = 0.018). In Accent II[129], the hospitalization rates were lower with IFX than placebo (14% vs 31%, P < 0.01), and 11% vs 33% in the initial IFX responders vs placebo (P < 0.05). Also, the mean duration of days in hospital was less with IFX vs placebo (0.5 d vs 2.5 d, P < 0.05).

In a population based study from the University of Manitoba of health care resource use among IFX users, hospitalizations were higher in the IFX cohort until 18-24 mo after the first IFX prescription, at which point the rate of hospitalization in the IFX group fell to the level of the CD patients treated with AZA or GCS[138]. The likelihood of surgery was similar in IFX and GCS, which was higher than in AZA; even at 3 years post-closing. Overall physician visits were similar between IFX, GCS and AZA. Interestingly, ADA reduced hospitalization rates at 12 mo from 14% with placebo vs 10% and 3% with maintenance ADA given every other week and every week (P = 0.12 and P < 0.01, respectively)[115]. Hospitalizations account for more than 50% of the direct costs of CD[115]. Thus, in responders, TNFB reduced the rate of hospitalization, and this reduction in hospital days carries a major economic impact, which has to be countered against the high cost of maintenance TNFB requiring long-term use of drug, and the cost of management of adverse effects.

CD-related surgery was more likely in the episodic vs the scheduled treatment groups (9% vs 3%, P = 0.01)[74], and the mean number of surgeries was higher (118 vs 60, P < 0.01). As compared with the placebo group, the mean number of surgeries in the IFX group was 13 vs 2 per 100 in all patients, and from 11 to 11 per 100 in the IFX initial responders[78]. With ADA maintenance, the 12-mo risk of major surgeries was 0.6% vs 3.8% in the placebo group (P = 0.0005)[115]. Data to date shows that TNFB reduce serious health utilization in persons with IBD.

There are many differences between CD and UC (Table 26). Only for purposes of comparison, a very brief overview is provided on IFX use in persons with UC, bearing in mind that these are separate and distinct conditions. About 20% of UC patients on 5-ASA maintenance therapy will have an acute attack each year, and about 10% of those with more severe symptoms will require hospitalization, usually for intravenous (IV) steroid therapy, cyclosporine or TNFB therapy; or surgery. About a third of these will not respond to IV steroids, and may be candidates for colectomy, cyclosporine or IFX.

In the Accent I and 2 studies, approximately half as many of those in the combined IFX group than placebo-treated UC patients required surgery (74% vs 8%), and the number of hospitalizations were also lower (18/102 patients vs 9/102 patients, P < 0.01)[74,115,129]. The colectomy rate in the placebo group is also approximately twice as high as in the IFX group: at 90 d, 67% vs 29% (P = 0.017)[141], and at 2 years, 76% vs 46% (P < 0.05)[142]. When IV GCS fail in patients with severe UC admitted to hospital for IFX[143], colectomy rates were as follows: in hospital colectomy, 24%; later colectomy, 14%; no colectomy, 62%. It is not clear how many will eventually require colectomy, whether they will need to be maintained long-term on IFX, or if they should simply be maintained on AZA or 5-ASA.

Primary non-response has been noted in 22% of UC patients treated with IFX[126]. IFX dose optimization was required in 45%, and colectomy was required in 19%. In a single-centre, prospective out-patient cohort of UC patients, response to induction therapy with IFX was 96% and 80% for ADA[144]. For maintenance therapy response to IFX and ADA, the rates were 78% and 70%. None of these differences was statistically significant.

Recent meta-analysis has considered the efficacy and safety of biological therapies in inducing remission in moderately to severely active UC (Table 27)[61].

The summary points are as follows: (1) No data on the efficacy and safety of biological therapies vs placebo in preventing relapse of disease activity in quiescent UC; (2) “IFX was highly effective in inducing remission in patients with moderate to severely active UC who had failed therapy with first and second-line agents, and who had also failed to respond to a course of high-dose corticosteroids, with a NNT of only 4[61]”; (3) IFX for rescue therapy in severe UC, with a therapeutic gain of (71%-33%) 38% (NNT, 3); (4) IFX will induce and maintain clinical remission and mucosal healing in treatment–refractory, moderate/severe UC; (5)Unknown if IFX plus AZA is superior to monotherapy with AZA or IFX; (6) Before starting IFX in UC, discuss options of AZA, cyclosporine A (Cy A), and pan proctocolectomy with ileoanal pouch procedure; (7) Unknown comparison of Cy A vs TNFB for rescue therapy; (8) Short term: young age, absent pANCA (in CD, presence of pANCA, ASCA, or pANCA + ASCA had no predictive valve); and (9) Long-term (predictors for no colectomy): short term clinical response to CRP < 5 mg/L, no previous treatment with IV steroids or Cy A.

There are a number of potential advantages in achieving mucosal healing in CD (Table 28). In both CD and UC, the rates of mucosal healing range widely depending upon the therapeutic agent and the duration of treatment (Table 29).

In clinical trials, there has been no uniform standard for defining mucosal healing (MH), no agreed-upon optimal time for assessing MH. It is not surprising then that the ranges of MH are very wide.

The clinical trials of agents used to treat IBD have used a variety of clinical scores heavily based on symptoms (CDAI), measures of QoL, appearance of the mucosa on diagnostic imaging, endoscopic appearance, or histopathology. Some patients with CD treated with TNFB achieved MH and the question was raised whether MH by itself, independent of patient’s symptoms or QoL, was an important outcome variable. MH would be an important outcome if it were to be shown that it was associated with reduced risk of recurrence (i.e., greater likelihood of maintenance of remission), reduced risk of extraintestinal complications, reduced risk of medical treatment-associated complications, long-term risk of hospitalization, surgery or development of colorectal cancer. The risk of development of stricture or fistula in CD increases over time[46,145], so maintaining mucosal healing may decrease these problems. However, there is no evidence to answer the above asked questions.

It seems self-evident that MH should become an outcome objective of therapy in IBD. However, this needs to be proven. Because the prevalence of MH may decline over time, and the number of the week of study repeating MH varied widely, it is not possible to assert which class of drug has the highest rate of MH (Table 29), nor is it plausible to compare IFX with ADA or CER. In an open-label study of ADA in which there was a “placebo” (3 doses of ADA for induction), the therapeutic gain in the 12 wk complete mucosal healing (CMH) was 14% in the intention-to-treat analysis (ITT) and 15% in the per-protocol analysis, with 52 wk ITT CMH of 24% (Table 30).

This question may also be considered as “step-up”vs“start high”. When considering a comparison in outcomes from a management approach starting early with biological therapy in the patients’ lifelong CD course, vs the standard of care of step-up therapy, we must reflect the strength of the evidence supporting each of the components of the traditional approach in CD of using 5-ASA products, antibodies, GCS, and the immune suppressants AZA and MTX. The excellent systematic reviews and meta-analyses in the “Red Journal”[61] are very helpful in this regard, and will be reviewed briefly here to demonstrate the potential limitations of the currently accepted standard of care.

5-aminosalicylates therapy: In contrast to the supportive data in UC for the use of 5-ASA to induce remission and to prevent relapse, the data for CD is poor (Table 31)[61]. Thus, for the usually accepted ITT analyses, neither SASP nor 5-ASA can any longer be recommended in persons with CD to induce or maintain remission.

Antibiotic therapy: There is diversity in the design of antibiotic studies in IBD, including which antibiotic, as well as dose and duration of therapy. The antibiotics often used in clinical practice for this indication were metronidazole, cipro’, and rifaximin (not yet available in Canada). While taking into account these events, it may surprise some readers that antibiotics are superior to placebo for the induction and maintenance of remission in CD, as well as induction of remission UC (Table 32)[146].

Glucocorticosteroid therapy: Standard GCS remains the standard for inducing remission in moderate-to-severe UC, but must never be used for maintenance of disease because of its lack of efficacy and its high adverse effects risk profile. While the trials of GCS in active CD individually showed efficacy because of heterogeneity between studies (I² = 88%, P = 0.004) and the small size of the studies. When the risk difference was used as the summary statistic, the treatment effect became significant, with NNT = 3 (95%CI: 2-11)[61]. Furthermore, systematic review and meta-analysis showed that standard GCS were superior to the locally acting budesonide in achieving remission in active CD (RR = 0.82; 95%CI: 0.68-0.98); oral budesonide itself was superior to placebo for CD remission (RR = 0.73; 95%CI: 0.63-0.84). Oral budesonide used for up to one year delays the time to recurrence of active CD.

Adverse effects of GCS therapy in the setting of treating active CD could not be determined in the studies of Ghosh et al[34] and Summers et al Standard GCS-related adverse effects were more frequent than with budesonide (RR = 1.64; 95%CI: 1.34-2.00). Thus, GCS and budesonide will continue to be used for short term treatment of active CD, and the choice between standard GCS vs budesonide must be made on the trade-off of efficacy, adverse effects and cost.

Immunosuppressive therapy: The meta-analysis of the use of Immunosuppressants in CD was disappointing; example (Table 33), the relative risk of not being in remission for active CD was not different from placebo. However, if OR was used rather than RRs as the summary statistic, then the result was significant, using a random effects model (OR = 0.42; 95%CI: 0.2-0.89). While some clinicians would accept significant ORs of AZA/6-MP/MTX vs placebo as reason to use immunosuppression to induce remission of active disease, the onset of biological benefit takes 2-3 mo. While many gastroenterologists use AZA/6-MP/MTX to prevent relapse in CD, this is likely based on the evidence of individual trials or previous meta-analysis. Surprising to some, while immunosuppressant therapy in UC was not significantly superior to placebo to induce remission, azathioprine was efficacious to prevent relapse (Table 33).

In summary then of the standard step-up approach to the care of patients with CD, in the treatment of active disease to achieve remission, the step using 5-ASA/SASP should be removed; the antibiotic and GCS/budesonide steps remain, and the AZA/6-MP/MTX step is rather shaky and quite slow.

In the end, we may believe that early use of biologics is too aggressive a step, which needs to be shored up by more data, but we need to acknowledge that the standard step-up approach is not as good as we used to accept.

The presence of two mutant nucleotide-binding oligomerization domain-containing protein 2 (NOD2) alleles may be quite specific for future complicated disease. Although the sensitivity is poor and the area under the sROC curve is poor, the high degree of specificity may be sufficient to recommend testing for double mutations if we can identify therapies that can truly change the outcomes for this high-risk stratum of patients. Testing for double mutations would likely miss many patients with aggressive disease. However, the presence of double mutations, particularly mutations in P.Leu1007fsX1008, does identify a high risk stratum of reagent-grade patients that should be identified and analyzed as a distinct subgroup in clinical trials. If prospective trials can show a change in outcomes in these patients, this would be a strong justification for targeted top-down therapy in this group of high-risk patients to prevent stricturing or fistulising complications.

The other major finding of this meta-analysis is the lack of prognostic value of the presence of one mutant allele for predicting CD behaviour. Although we specifically studied NOD2 mutations, recent genome-wide association studies have identified numerous other genes that contribute to the susceptibility of developing CD. It is likely that the level at which genetics contributes to phenotypic disease expression is complex and multiple risk alleles contribute to complex interactions. Further studies addressing disease behaviour will likely require large-scale, multicenter trials to obtain sufficient clinical data to accurately ascertain the cumulative risk from clinical, genetic, and environmental factors. Once additional predictive factors are identified and validated, we will be better able to study targeted therapies in high-risk patients.

In a prospective extension of a patient cohort study of 133 newly-diagnosed CD patients recruited from 18 European Centres, half of the patients were initially treated with as “top-down”, and the other half as step up[147]. In the 46 persons who had endoscopically proven mucosal healing at two years, ileocolonoscopies were continued at year three and four. The results can be interpreted as being either for or against mucosal healing as an important therapeutic outcome: complete mucosal healing at year two was associated with a greater proportion of steroid-free clinical remissions (71% vs 27%, respectively; P = 0.036). While MH may be associated with later steroid-free remission, it is not clear if this correlates with fewer adverse effects, or better outcomes such as QoL, hospitalizations or surgery. There are studies in which the support for the benefit of MH is positive, or negative (Table 34). The case remains “unproven” about the long-term importance of mucosal healing rather than symptom relief as the major end point of treatment of CD.

In accordance with recommendations from current guidelines, the TNFBs are usually initiated in the CD patient who has failed the “step up” approach of sequential use of GCS, ASA/MTX. Initial clinical trials of TNFB were designed to take this conventional sequence into account, and to use TNFB as “add-on” therapy. The terms “step-up, step-down”“top-down” and “fast forward” all related to the concept of whether CD patients will do better in the long-term if using TNFBs earlier vs relatively later after the diagnosis of CD, in an attempt to possibly alter the course of the disease and to thereby improve patient outcomes.

Is the response to TNFBs greater when used early in the history of the person’s CD? Is there benefit of starting recently diagnosed CD patients on IFX or IFX+AZA immediately, i.e., “top down”vs the “step-up” of GCS→AZA/MTX→TNFB? In the open label trial of D’Haens et al[110], newly diagnosed CD patients were treated either with AZA + IFX, or conventional therapy with GCS, followed by AZA, and then followed by IFX (GCS→AZA→IFX). With the early use of AZA + IFX with GCS (top-down), at week 26 and 52 the proportion who were steroid-free and who had not undergone IBD-related surgery was 60% and 62%, respectively. In the step up group, the corresponding figures were lower at 36% (P = 0.006) and 42%, respectively. Although the top down group achieved remission faster than did the GCS-AZA-IFX group (P = 0.018), at 53 wk a similar percent of patients in each group were in remission (Table 35).

What then is the influence of confounders such as CD duration, or being TNFB- or AZA/MTX naives? In a post-hoc analysis of the use of ADA in the Charm study[57], after adjustment for potential confounders, disease duration had an effect on clinical remission (RR: 0.96, 95%CI: 0.94, P = 0.002). In the Sonic study (REMICADE), patients with CD who had not previously received treatment with anti-TNFBs or immunomodulators (anti-TNF naive as well as anti-AZA/MTX naive) were randomized to IFX, AZA, or IFX + AZA. At 26 wk, the steroid-free remission rate was higher with IFX monotherapy (P = 0.022) or AZA monotherapy (P = 0.009) groups (Table 36).

When IFX was used within one year of the diagnosis of CD, 78% of the early treatment group responded and 76% were in remission, as compared to 47% and 37% (P < 0.001 and P = 0.002, respectively)[51]. This suggests that earlier use of TNFB may be better when looked from the perspective of this relatively short term follow-up. But of course, those persons started earlier on TNFBs might possibly have more total adverse events (AEs), because of their potentially longer duration of total exposure to drug.

Clearly, current guidelines must be respected. More data is necessary, but it looks promising that the early use of TNFBs (or AZA) may provide outcome advantages. If this possibility becomes evidence based, then guidelines and clinical practice will need to change appropriately.

In some CD patients who develop secondary non-response to TNFB, this may be due to the development of neutralizing antibodies, what proportion of patients on IFX or ADA develop antibodies to IFX (ATIs), or antibodies to ADA [antibodies to adalimumab (ATAs)]? In patients given scheduled IFX 5 mg/kg, 10%-16% develop ATI, whereas ATA occur in 0.04%-2.60%. Infusion reactions with IFX are more common if there are ATI (36%-50% with, and 21%-24% without ATI). Concurrent immunosuppressant (CI) therapy reduces ATI (63%-75% with concurrent AZA/MTX, vs 24%-43% with no concurrent AZA/MTX). This beneficial effect of concurrent immunosuppressant on the rate of development of ATI or ATA is most pronounced with episodic rather than with the scheduled use of IFN. This is because the development of ATIs is greater with episodic than with scheduled infusion of 5 mg/kg or 10 mg/kg IFX: 30%, 10%, and 7%, respectively (P < 0.001)[113]; 39% episodic vs 16% scheduled (P = 0.036)[128].

The presence of ATI/ATA is of clinical importance. In fact, there is a negative correlation between the concentration of ATIs and the duration of response to IFX (P < 0.001)[112]. Furthermore, the median ATI concentration was 15-fold higher in those with loss of response to IFX than in those who maintained response (P < 0.0001)[148].

The development of ATAs is uncommon: in ClassicI, the rate of ATA formation at week 4 was 0.04%[149]. In Classic II, 2.6% showed ATA[55]. The presence of ATA is also clinically important: there is a significant relationship between the presence of ATAs and non-response to ADA (OR = 12.7, 95%CI: 1.7-92.6, P = 0.05)[83].

Protection against the development of ATIs may be achieved with intravenous hydrocortisone premedication given immediately before each IFX infusion, with lower median levels of ATI[150]. However, in this study, even though ATIs were lower, the use of hydrocortisone did not affect the rate of infusion reactions or increase clinical response. As noted previously, the major role of concurrent immunosuppression with maintenance TNFB may be when TNFB is not given in the recommended scheduled manner. Therefore, due to higher rate of ATI with episodic treatment, it is not a recommended route of therapy.

When considering the safety of TNFB, it is important to consider whether the TNFB was given with immunosuppressants or steroids, and for how long therapy was undertaken. In one study, steroid use in persons on IFX were the only independent risk factor for infections [or 2.69 (95%CI: 1.18-6.12, P = 0.018)][151]. The overall rate of AEs in IFX-treated patients is about 13%[77,111,151,152], which is not statistically significantly different from the 19% AE rate quoted for non-IFX treated patients [OR = 1.33 (95%CI: 0.56-3.00, P = 0.45)][151].

In a case-controlled family practice, population-based retrospective study of 15 471 IBD patients followed for an average of 6.4 years, AZA did not increase the risk for solid organ cancer development (OR = 1.04, 95%CI: 0.89-1.21), but the risk of lymphoma was enhanced 3.22-fold[153]. If myelosuppression occurs with AZA in naive CD patients, it does so in the first 6 wk of AZA therapy[154].

AE data has been collected from 10 TNFB randomized controlled trials in IBD [(five IFX[45,52-54,69], four ADA[55,56,85,93] and one with etanercept[31]). More AEs (serious AEs, pharyngitis, urinary tract infection, injection site reaction or infection)] were reported with ADA vs placebo than IFX vs placebo (Table 37). From four ADA placebo-controlled trials[54-56,93], there was no difference between ADA and placebo in the percentage of persons with overall AEs (77% vs 80%, P = 0.145). AEs that were more common in the ADA than the placebo group were pharyngitis (10% vs 6%, P = 0.047), injection site infection (4.9% vs 1.1%, P = 0.005), injection site reaction (22% vs 12%, P = 0.003), arthralgia (10.4% vs 6.1%, P = 0.014) and urinary tract infection (5.0% vs 1.5%, P = 0.017) (Table 37). Curiously, ADA had significantly fewer serious AEs than did placebo (6% vs 10%, P < 0.001), and the placebo group from one study had numerically more AEs than another placebo group (11% vs 18%, P = 0.065).

The medium-term safety of TNFB has been reviewed: In 21 studies enrolling 5356 CD patients, TNFBs did not increase the risk of serious infection malignancy or death[3]. However, as cautioned by these authors, “definitive conclusions cannot be drawn because of methodological limitations (safety analyses satisfied by concomitant therapy were not performed in the individual studies”. Fortunately, not all trials reported death as an outcome. In ACCENT I[54], with IFX 5 mg/kg, two patients unfortunately died from sepsis and one from a myocardial infection.

The most common AEs with CER were upper respiratory tract infection (20%), urinary tract infection (7%) and arthralgia (6%)[155]. From five IFX placebo-controlled trials[52-54,78,156], there was no difference between IFX and placebo in the percentage of persons with overall AEs (93% vs 95%, P = 0.355). The absolute serious AE was 7% higher in IFX vs the placebo groups (24% vs 17%, P = 0.019), and only sinusitis was reported more frequently in UC given IFX vs placebo (9% vs 5%, P = 0.04). Concomitant immunosuppression with maintenance IFX does not significantly extend the duration of clinical response[111]. Nausea was the only AE which was more frequent in IFX than placebo (15% vs 7%, P < 0.031), with a higher trend for pharyngitis (18.9% vs 2.8%, P = 0.056). Importantly, the increased role of infections in CD or in CD patients on IFX may be from their concomitant use of GCS[129,151].

Life-threatening side effects occur in 2%-5% of persons on IFX, with twice the rate of sepsis, myelotoxicity or risk of lymphoma as those on thiopurines[157]. However, IFX has been used by approximately one million persons worldwide. As a class, the main complications of TNFBs are infections, lymphoproliferative disorders and malignancy[158]. As well, neurological, dermatological, autoimmune and cardiac complications commonly occur with these agents (Table 37). Deaths have been reported in persons using TNFB. The risk of sepsis, malignancies and myelosuppression is higher if AZA/MTX is given with TNFB. For example[159], the risk of opportunistic infections is increased with TNFB (OR = 4.4), and is increased much more if two or more immunosuppressants and used (OR = 12.9).

It is recommended that the complete blood count (CBC) be performed at 1 wk, 2 wk, 3 wk, 4 wk, 6 wk and 8 wk after starting AZA therapy, and then to continue a monthly CBC thereafter. During the first 8 wk of AZA therapy, the risk of leucopenia (white blood cell, < 1.0 × 10⁹/L), neutropenia (platelet-neutrophil complexes, < 1.0 × 10⁹/L), and thrombocytopenia (platelet count, < 20 × 10⁹/L) were 0.3%, 1.0% and 0.2%, respectively[154]. For treatment intervals of greater than 26 wk, these hematological risks were 0.2%, 1.1% and 0.1%.

IBD patients, including those on GCS and AZA/MTX, have an increased risk of TB (RR = 2.36, 95%CI: 1.17-4.74). TB reactivation is an accepted risk of TNFBs, with the RR for reactivation 2-20 times that of the general population[160,161]. In high-risk areas, IBD patients who are scheduled to be placed on TNFBs must be screened for histoplasmosis and coccidiomycosis[162].

Some authors suggest that CD itself, in the absence of the use of AZA/MTX/TNFB, does not have an increased risk for the development of lymphoma[163]. Others would argue that CD itself does carry a small increased risk. However, these drugs used to treat CD certainly are associated with as much as a 4-fold increased risk of the development of lymphoma[157]. And yet, in the Treat registry of IBD patients, the incidence of malignancies was 0.53 per 100 patient years in the IFX group and 0.49 in the non-IFX group[164]. A small number of adolescents with CD on IFX and thiopurines have been reported as developing hepatosplenic T-cell lymphoma[165]. This consensus is that the concurrent use of both AZA/MTX plus TNFB should not be used in non-adults.