Patient Outcomes after Anti-TNF-α Drugs for Crohn's Disease

[David in Seattle]

Nazila Assasi; Gord Blackhouse; Feng Xie; John K Marshall; E Jan Irvine; Kathryn Gaebel; Diana Robertson; Kaitryn Campbell; Rob Hopkins; Ron Goeree
Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(2):163-175. © 2010 Expert Reviews Ltd.

Abstract and Introduction
Abstract

Crohn's disease (CD) is a chronic inflammatory bowel disease with a relatively high prevalence rate in North America. More than 50% of CD patients require surgery at some stage of their disease. Anti-TNF-α drugs are increasingly being used in patients with CD who have had an inadequate response to conventional therapy. Treatment with anti-TNF-α agents aims at improving symptom control and reducing the need for hospitalization and surgery. This review examines the clinical effectiveness of three anti-TNF-α agents (infliximab, adalimumab and etanercept) in moderate and severe CD. The review further considers the evidence for the harms and benefits associated with switching from one anti-TNF-α agent to another and strategies to optimize the timing of therapy.
Introduction

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract with unknown etiology.[1] CD is characterized by transmural inflammation that may affect any part of the gastrointestinal tract. Symptoms depend on the location, extent and severity of involvement, and can include abdominal pain, nausea, anorexia and weight loss. The presentation of CD is often subtle, leading to a delay in diagnosis. In Canada, CD affects approximately 233.7 per 100,000 people, with an incidence of 13.4 per 100,000 each year.[2]

As there is no cure for CD, patients often need continuous medication and long-term follow-up. Medical management of CD involves treatment of acute inflammatory symptoms followed by maintenance treatment to prolong remission and heal the gastrointestinal mucosa. The therapeutic approach is determined based on the severity of the symptoms and the degree of intestinal involvement. The most common treatments that are used for maintenance of remission are 5-aminosalicylic acid agents, immunomodulatory therapy and biologic therapy.[3] Antibiotics have been shown to be effective in the management of CD[4–6] but the role of probiotics remains unclear.[6,7] Surgical management may be necessary in poorly controlled or complex recurrent acute cases of CD.

Three biological treatments (etanercept, infliximab and adalimumab) are categorized as anti-TNF-α drugs.[8] Infliximab and adalimumab are increasingly being used in patients with CD who have an inadequate response to conventional therapy. In Canada, infliximab[9–12] and adalimumab[13] are approved for the treatment of CD; however, etanercept is not.

We conducted a systematic review to evaluate the comparative effectiveness of anti-TNF-α drugs in CD patients with inadequate response to conventional therapies. We also looked at the evidence for the optimal timing of anti-TNF-α, and the harms and benefits associated with switching from one anti-TNF-α to another.

Systematic Review of the Literature on the Effect of Anti-TNF-α Drugs in CD
Methods

Literature Search While the present report focuses on CD, this review was originally conducted as part of a health technology assessment (HTA) that included patients with ulcerative colitis.[14] As such, the original search strategy included this indication as a search term; however any documents retrieved relating to ulcerative colitis have been excluded from this review.

We searched for clinical trials, cohort studies and registries assessing infliximab or Remicade®, adalimumab or Humira®, or etanercept or Enbrel® for CD. Medline (1950–2008) and EMBASE (1988–2008) were searched through the Ovid interface. Parallel searches were run in PubMed (non-Medline records), Wiley's Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register and HTA Database) and Thomson's BIOSIS Previews. A search strategy was executed using controlled vocabulary and keywords focusing on the concepts of 'inflammatory bowel disease', 'Crohn's disease' or 'ulcerative colitis', and 'infliximab/Remicade', 'adalimumab/Humira', 'etanercept/Enbrel' or 'anti-tumor necrosis factor α drugs'. Retrieval was limited to humans and to the period January 1995–November 2008. No language restrictions were employed. A detailed search strategy is provided in APPENDIX 1 (www.expert-reviews.com/toc/erp/10/2).

Gray literature was identified by searching websites of HTA and related agencies and their associated databases, pharmaceutical manufacturers and clinical trial registers. Websites of professional associations were also searched for relevant evidence (including conference abstracts from 2006–2008, if available). Google and AlltheWeb search engines were used to search for additional web-based materials and information. These searches were supplemented by reviewing the bibliographies and abstracts of key papers and conference proceedings.

Study Selection Clinical trials (randomized and nonrandomized) of any duration, and observational studies primarily designed to evaluate clinical efficacy, effectiveness and adverse effects of infliximab, adalimumab or etanercept, were included in this review. Before–after trials and single-arm cohort studies were also included if they reported benefits and harms from switching from one anti-TNF-α drug to another. Studies with adult participants (aged ≥18 years) with CD (luminal and fistulizing) not responding to conventional treatment were included. Conventional therapies, anti-TNF-α drugs and surgical interventions were all considered as comparators. Studies were excluded if they had not finished recruiting, or if they had published only baseline characteristics.

Two reviewers independently screened titles and abstracts for relevance using a predefined checklist. Discrepancies between reviewers were discussed until consensus was reached. Full-text documents of any relevant titles or abstracts were retrieved and assessed for inclusion. Using explicit predetermined criteria, two reviewers made inclusion and exclusion decisions independently. Any discrepancies between reviewers were discussed until consensus was reached.

Quality-assessment & Data-extraction Strategy The methodological quality of all included clinical trials and observational studies was assessed using the Jadad[15] or Newcastle-Ottawa[16] scales. Relevant data were directly abstracted from the article into predefined data extraction forms. The data extraction was performed by one reviewer and verified by a second reviewer. Any discrepancies were discussed until consensus was reached.

Evaluated Outcomes The following outcomes were identified a priori: clinical response, defined as a decrease in the Crohn's Disease Activity Index (CDAI) of 70 points, or a decrease in CDAI of 70–100 points, and a 25% improvement from baseline (data on clinical response using other instruments and definitions were also collected, e.g., the Harvey-Bradshaw activity index),[17,18] clinical remission, defined as a CDAI score of no more than 150 points and a decrease by 50–100 points (data on clinical remission using other instruments and definitions were also collected, e.g., Truelove-Witts score and Seo index) and hospitalization, surgery, adverse events, serious adverse events and death.

Data Analysis When two or more comparable studies were identified, a pooled estimate of effect was obtained through meta-analysis to assess clinical effectiveness. Comparability of the studies was assessed by review of the population, interventions and outcome measures by clinical and epidemiologic participants in the project. Review Manager 5 was used to synthesize the data. Pooled estimates and their confidence intervals were calculated using both a fixed-effects model and a random-effects model. Relative risk (RR) was used to summarize effect sizes for all dichotomous outcome measures. Heterogeneity was investigated using χ2 test for homogeneity and Higgins I2.[19] The estimates obtained by both fixed- and random-effects methods were also compared to assess potential heterogeneity between studies. For the studies that were not comparable, a narrative synthesis of the studies is provided. Levels of significance for comparisons of anti-TNF a drugs with placebo were computed when not reported by the authors.
Results

A total of 2542 citations were identified through the systematic search. In total, 15 articles were identified from other sources. During the title and abstract review, 2103 citations were excluded based on irrelevance to the questions of interest. The full text of the remaining 454 articles was retrieved, and 407 articles that did not meet the eligibility criteria were excluded. This left 30 randomized controlled trial reports and 17 observational studies or single-arm trials that met all the inclusion criteria. From these, 13 randomized controlled trials (eight on infliximab,[20–27] four on adalimumab[28–31] and one on etanercept[32]) and five observational studies[33–37] pertained to treatment of patients with CD and were, therefore, included in the present review. Figure 1 shows the Quorum flowchart of the process used to identify and select studies for the review and the reasons for exclusion.

 

[David in Seattle]

The main characteristics, participants' eligibility criteria, methodological aspects of each study and the details of interventions examined are provided in APPENDIX 2 (www.expert-reviews.com/toc/erp/10/2). In general, participants in each study were adult patients with active CD, poorly controlled or failed on previous conventional treatment. Patient inclusion and exclusion criteria for individual studies varied. In the majority of full articles, predefined exclusion criteria were reported in detail. Most trials excluded patients with safety risks.

All but two of the randomized controlled trials[27,21] were placebo-controlled. One randomized controlled trial[27] was published as an abstract only. All included randomized controlled trials had a methodological quality score (Jadad scale) of 3 or more.
Clinical Outcomes

No head-to-head trials comparing the effectiveness of infliximab to adalimumab or to etanercept in CD were identified, nor were there any studies directly comparing anti-TNF-α drugs to conventional therapy in refractory CD. A combined immunosuppression therapy (including infliximab) was compared with conventional therapy in newly diagnosed patients in one randomized controlled trial.[21] In this open-label trial, induction therapy with three doses of infliximab 5mg/kg at weeks 0, 2 and 6 followed by maintenance therapy with azathioprine was shown to be superior to conventional treatment with a sequence of corticosteroids, azathioprine and infliximab in maintenance of remission up to 1 year.

Clinical Efficacy of Infliximab Table 1 summarizes the clinical and fistula response and remission rates after treatment with infliximab in the six included placebo-controlled trials, of which three studies[22–24] used short-term regimens of infliximab to induce disease remission, and three randomized controlled trials[20,25,26] evaluated the effectiveness of long-term infliximab in maintenance of remission.

Targan et al. reported a statistically significant difference in clinical response to induction therapy favoring single doses of 5, 10 and 20 mg/kg of infliximab compared with placebo.[22] However, induction therapy with a single dose of 5 mg/kg resulted in a higher clinical remission rate compared with placebo, only at weeks 2 and 4 after treatment. Lemann et al. included steroid-dependent CD patients.[23] In this study, three-dose induction therapy with infliximab 5 mg/kg was superior to placebo in induction of clinical remission at 12 weeks.

Significantly higher clinical response and remission rates to maintenance therapy were reported after maintenance therapy with doses of 5 mg/kg[20,25] and 10 mg/kg.[20,26] Pooled analysis of data from the A Crohn's disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen in Patients with Fistulizing Crohn's Disease (ACCENT) I and II trials, which compared infliximab 5 mg/kg with placebo[20,25] demonstrated a 2.75-times higher clinical response in patients on infliximab compared with those in the placebo group (Table 2). In the pooled analysis of data from the two randomized controlled trials comparing infliximab 10 mg/kg with placebo,[20,26] response and remission rates were significantly higher in the infliximab 10-mg/kg maintenance-therapy group than the placebo group (Table 2). There was no significant heterogeneity between the studies.

Two studies examined the effects of infliximab on fistula response and remission rates, one of which included only fistulizing CD patients.[24] Infliximab resulted in higher fistula response and remission as compared with placebo (Table 1).[24,25]

Clinical Efficacy of Adalimumab The effectiveness of adalimumab as induction therapy was compared with placebo in two randomized controlled trials (Table 2).[29,31] Both studies compared CD patients who underwent induction therapy with adalimumab 160 mg at baseline followed by 80 mg at week 2, with placebo users. In total, 2 weeks after the second injection, there were statistically significant differences between the two groups in terms of clinical response and remission rates. The pooled analysis of the results from the two studies confirmed that clinical response rates were at least 60% higher in the adalimumab 160-/80-mg induction-therapy group than the placebo users (Table 2).[29,31] The remission rate after adalimumab 160/80 mg was 2.94-times higher than when the patients received placebo (Table 2).

One of the induction therapy studies also used adalimumab 40-/20-mg and 80-/40-mg regimens for induction therapy.[29] Both regimens resulted in a statistically significant reduction of at least 70 points in the CDAI (70-point response) compared with placebo, over the 4 weeks of follow-up. Patients who received infliximab 80/40 mg also had a higher 100-point clinical reduction rate than the placebo group.

Two long-term studies used adalimumab for maintenance of remission in patients with CD (Table 3).[28,30] Colombel et al. reported significantly higher clinical response and remission rates in both adalimumab groups (40 mg weekly and 40 mg every other week) at weeks 26 and 56.[30] In the study by Sandborn et al., both adalimumab regimens were shown to be beneficial in maintenance of clinical remission.[28] However, a statistically significant difference in response rate was only found with the 40-mg/week regimen and with the lower defined threshold (70-point) for clinical response.

Pooled analysis of the data from two adalimumab maintenance-therapy studies,[28,30] using a fixed-effects model, showed both adalimumab regimens (40 mg every other week and 40 mg weekly) were superior to placebo in terms of 70- and 100-point response, as well as remission rates (Table 2). However, the summary estimates obtained using a random-effects model were no longer significant when the data were pooled for 70-point response rates (Table 4). This discrepancy between the two models, along with statistically significant χ2 test results and I2 values greater than 90% were suggestive of heterogeneity between the two studies. This heterogeneity partly could be a result of the limited number of the studies being included in the pooled analysis. In addition, Colombel et al. enrolled both anti-TNF-naive and anti-TNF-exposed patients, while Sandborn et al. enrolled only anti-TNF-naive patients. All of the participants in the CHARM trial received induction therapy with adalimumab 80/40 mg,[30] while the Clinical Assessment of Adalimumab Safety and Efficacy Studies as Induction Therapy in Crohn's Disease (CLASSIC) II trial[28] enrolled patients from the CLASSIC I trial,[29] in which participants could have been randomized to placebo or induction therapy with one of three adalimumab regimens (40/20, 80/40 or 160/80 mg). Primary outcomes of the two studies were also different (response to induction in CHARM and remission rate in CLASSIC II).

Induction therapy with adalimumab did not have any beneficial effects on fistula remission and response (Table 4). However, in the CHARM trial,[30] a significantly higher proportion of adalimumab users had fistula remission compared with the placebo group (Table 3).

Clinical Efficacy of Etanercept Only one randomized controlled trial comparing the effectiveness of etanercept to placebo in the treatment of CD was identified.[32] No significant differences in clinical response and remission rates were reported.

Benefits & Harms of Switching from One Anti-TNF-α Drug to Another There was no evidence assessing the effectiveness of infliximab in patients who lost response, or were intolerant, to adalimumab or etanercept.

Two randomized controlled trials[30,31] and four observational/uncontrolled studies[33–36] assessing the clinical effects of adalimumab following loss of response or intolerance to infliximab were identified.

In the Gauging Adalimumab Efficacy in Infliximab Nonresponders (GAIN) trial,[31] adult CD patients who had lost response or had been intolerant to infliximab were enrolled and assigned to receive either adalimumab, 160 mg at week 0 and 80 mg at week 2, or placebo at the same time points. Adalimumab showed a statistically significant superiority to placebo in terms of clinical remission and 70- and 100-point response rates.

In the Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) trial,[30] subgroups of patients who had been treated previously with infliximab or another anti-TNF drug had a lower remission rate than the patients naive to anti-TNF treatment, although this difference was not statistically significant. The remission rates were significantly greater than placebo in both subgroups at weeks 26 and 56.

Sandborn et al. used adalimumab to treat 17 patients who had lost response or developed intolerance to infliximab in an uncontrolled open-label trial.[34] The patients received adalimumab 80 mg at week 0 and 40 mg at week 2 and every other week thereafter for 12 weeks. At week 12, the rates of clinical remission and clinical response (100-point) were 29 and 59%, respectively. Complete fistula closure occurred in three out of nine patients who had draining fistulas at baseline (33%). In total, 56% of the patients with fistulising disease had a 50% or more decrease in the number of the draining fistulas.

In the study by Papadakis et al., 15 patients who had been treated with adalimumab following loss of response to infliximab were evaluated.[35] The patients received adalimumab 80 mg initially and 40 mg every 2 weeks after that. Of the 13 patients who completed the study, 54% had a complete response (Harvey–Bradshaw score ≤4 and withdrawal of corticosteroids), 31% had a partial response (≥50% reduction in Harvey–Bradshaw score and tapering of corticosteroids) and 15% failed to respond.

 

[David in Seattle]

Hinojosa et al. reported the short-term results of a 52-week prospective cohort study in which patients with active CD, nonresponsive or intolerant to infliximab, were treated with adalimumab, 160 mg at first visit and 80 mg at week 2.[36] At week 4, 83% of 36 patients with luminal disease had a 70-point clinical response, and 42% were in clinical remission. Of 22 patients with fistulizing disease, 41% had a 50% or more reduction in the number of draining fistulas. Complete closure of all draining fistulas was reported in 23% of the patients.

In the single-arm trial by Peyrin-Biroulet et al., 24 patients who had lost response or become intolerant to infliximab were treated with adalimumab 80 mg at week 0 and 40 mg at week 2 and every other week thereafter.[33] At baseline, 33% of the patients were in clinical remission. This proportion was higher at week 26 (67%) and week 52 (58%; p = 0.04). Of the 18 patients with prior loss of response to infliximab, 15% achieved a clinical remission through week 52. The corresponding rate in the six patients with prior intolerance to infliximab was 83.3%. Two out of three patients with open fistulas at baseline experienced complete fistula closure within 1 month. Adalimumab was well-tolerated in the infliximab-failure participants of the aforementioned studies.

Optimal Timing of Anti-TNF-α Treatment (Early vs Later in the Course of Disease)

One randomized controlled trial and one comparative observational study compared early use of infliximab for CD versus administration of this drug in later stages of the disease. The relationship between disease duration and clinical effect of adalimumab treatment was addressed in one article.

D'Haens et al. compared a combined immunosuppression treatment (including infliximab) with the conventional treatment of CD in an open-label trial.[21] In this study, newly diagnosed patients were assigned to receive infliximab 5 mg/kg at weeks 0, 2 and 6 with concomitant azathioprine (n = 67) or conventional treatment with corticosteroids followed by azathioprine and then by infliximab (n = 66). At week 26, the proportion of patients without corticosteroids and without surgery was greater in the combined immunosuppression group (60%) than the conventional-treatment group (35.9%; p = 0.006). At week 52, the corresponding rates were 61.5 and 42.2%, respectively, for early combined immunosuppression and conventional-treatment groups. After week 52, there was no statistically significant difference between groups in terms of clinical remission. In this trial, patients in the early immunosuppression group achieved remission more quickly than the patients on conventional treatment, in which infliximab was administered only if the patients were not responsive to corticosteroids and azathioprine (p = 0.018).

Matsumoto et al. compared the effects of infliximab in patients who were treated with infliximab within 12 months of diagnosis versus patients who were treated in later stages of their disease.[37] In the short term, a significantly higher remission rate was observed in the early-administration group (76%) than the late-administration group (37%; p < 0.001). Of the patients in the early administration group, 78% achieved a 70-point response compared with 47% in the late-administration group (p = 0.002).

In a post hoc analysis of the CHARM trial presented by Schreiber et al.,[38] the clinical remission rates were compared between subgroups of adalimumab-treated patients with disease duration of less than 2 years, between 2 and 5 years and 5 years or longer. A significantly higher proportion of the patients with disease duration of more than 2 years achieved clinical remission than the patients with longer disease duration. An adjusted logistic regression model found disease duration had a significant effect on clinical remission (RR: 0.96; 95% CI: 0.94–0.99; p = 0.002).

Hospitalizations

The proportion of patients who required hospitalization was reported in three infliximab trials[22,39,40] and one adalimumab trial.[41]

In the trial by Targan et al., only one hospitalization in the placebo group was reported.[22] In the ACCENT I trial,[39,42] the overall rate of hospitalization was 33% in the episodic treatment group compared with 20 and 19% in the patients on scheduled maintenance treatment with infliximab 5 and 10 mg/kg, respectively. CD-related hospitalizations were greater in the episodic group (38%) than in both the infliximab 5-mg/kg group (23%; p = 0.047) and the infliximab 10-mg/kg group (24%; p = 0.023). The number and duration of hospitalizations were significantly lower in the combined infliximab group than in the episodic-treatment group (p = 0.018).

In the ACCENT II trial, initial responders in the infliximab 5-mg/kg maintenance-therapy group had significantly lower hospitalization rates than the initial responders in the placebo group (11 vs 33%, respectively; p < 0.05).[40] The corresponding rates in all of the randomized patients (responders and nonresponders) were 14 and 31% for the infliximab and placebo groups, respectively (p < 0.01). There was a statistically significant reduction in the mean number of days in hospital in the infliximab group (0.5) compared with the placebo group (2.5; p < 0.05).

In the CHARM trial, the rates of hospitalization were significantly lower in the group receiving adalimumab every other week (14.4%) and the weekly adalimumab group (5.6%) than the placebo group (24.8%; p < 0.02 for each adalimumab group vs placebo).[41] Based on the results of this study, over 12 months, maintenance therapy with adalimumab every other week and adalimumab every week reduced the CD-related admission rates to 9.7 and 2.8%, respectively, compared with 13.4% in placebo-treated patients (p = 0.12 for adalimumab every other week vs placebo, and p < 0.01 for adalimumab every week vs placebo).

Surgery

Two infliximab trials[25,39] and one adalimumab trial[41] reported the proportion of patients who needed surgery.

In the ACCENT I trial, analysis of data from all enrolled patients (including responders and nonresponders) showed a significantly higher rate of CD-related surgery in the episodic-treatment group (7.4%) than in the combined scheduled-treatment strategy group (2.8%; p = 0.01).[39,42]

In the ACCENT II trial, the mean number of surgeries for each 100 patients was significantly lower in the infliximab maintenance-therapy group (65 per 100 patients) than the placebo group (126 per 100 patients; p < 0.05).[25] Similar results were shown for the mean number of surgeries in all randomized patients (60 vs 118 in the infliximab and placebo groups, respectively; p < 0.01). The mean number of major surgeries in the infliximab group was reduced by more than 80% (two and 11 per 100 patients, in all patients and initial responders, respectively) compared with the placebo group (13 and 11 per 100 patients, in all patients and initial responders, respectively; p < 0.05).

In the CHARM trial, the 12-month risk of major surgeries was significantly lower in the patients who received adalimumab-maintenance treatment (0.6%) than the placebo group (3.8 %; p = 0.0005).[41]

 

[David in Seattle]

Death

Three infliximab randomized controlled trials[20,23,25] and three adalimumab trials[28,29,31] reported mortality as a drug safety outcome. However, in all but one of the trials no deaths occurred during the course of the study. In the ACCENT I trial, three deaths were reported in the infliximab 5-mg/kg scheduled maintenance-therapy group (n = 193); two were due to sepsis and one as a result of myocardial infarction.[20]

Safety

Five infliximab placebo-controlled trials,[20,22,23,25,26] four adalimumab trials[28–31] and one etanercept trial[32] reported adverse events. For the studies that included more than one anti-TNF-α therapy arm, the rates for each arm were summed and considered as a single rate for that adverse event. If more than one study reported the same adverse event, a weighted average of the rates was calculated. There was limited reporting of adverse events in the available randomized controlled trials. In the five infliximab trials, a significantly higher rate of nausea was reported among infliximab patients compared with those on placebo (14.7% versus 6.8%; p = 0.031). Patients on active treatment in the four adalimumab trials reported significantly higher rates of pharyngitis (10.0 vs 6.3%; p = 0.047), injection site infection (4.9 vs 1.1%; p = 0.005), arthralgia (10.4 vs 6.1%; p = 0.014), urinary tract infection (5.0 vs 1.5%; p = 0.017) and injection site reaction (21.6 vs 12.1%; p = 0.003). No significant differences in adverse events were reported in the etanercept trial. No data on the incidence of malignancy were reported.

Expert Commentary

This article updates the previously published evidence of the clinical effectiveness of anti-TNF-α drugs in CD; however, it differs from previous reviews in several respects. First, it was not limited to randomized controlled trials but considered data using other study design methodology. Second, the potential sources for data retrieval were broader and included publications from professional associations and conference proceedings. Third, the present systematic review went beyond the efficacy of anti-TNF-α drugs and considered other relevant clinical issues, including optimal timing of anti-TNF-α treatment and the harms and benefits of switching from one anti-TNF-α drug to another. Owing to the lack of head-to-head trials comparing the effectiveness of anti-TNF-α drugs in CD patients, our review is mostly focused on the results of placebo-controlled trials.

Certulizumab pegol, a newer anti-TNF-α agent that was not approved for the treatment of CD at the time of study initiation, is not included in our review. This drug has shown superiority to placebo in treatment of refractory CD in two randomized controlled trials.[43,44]

The findings of the present systematic review indicate that infliximab is an effective treatment for the induction and maintenance of clinical response and remission in patients with luminal or fistulizing CD[20,22–26] who are resistant or refractory to conventional therapy. Infliximab also reduces the need for surgical resection and hospitalization in CD[25,42] and fistulizing CD.[40] Adalimumab has been shown to be an effective option for inducing and maintaining clinical remission in patients with CD who have a secondary nonresponse to infliximab (lost response or became intolerant) or those who are naive to anti-TNF-α drugs.[28–31] In short-term follow-up studies, no significant difference was observed between adalimumab users and placebo-treated patients in terms of fistula improvement or fistula remission rates.[29,31] However, in the CHARM study, a significantly higher rate of fistula remission was reported when adalimumab was used as maintenance therapy.[30]

Our review also demonstrates that CD patients with secondary nonresponse to infliximab could benefit from adalimumab therapy.[30,31,34–36] Other published evidence that did not meet the inclusion criteria for the current review is available, indicating the effectiveness of adalimumab in primary nonresponders to infliximab.[45,46] There are no data to suggest that the sequence of anti-TNF-α agents in patients who do not respond to an initial anti-TNF-α drug makes a difference.

The current findings also suggest that anti-TNF-α treatment administered earlier in the disease course improves the remission rate.[21,37,38] Adalimumab-treated patients who had a shorter disease duration were found to have higher response and remission rates.[38] Remission was achieved more quickly in CD patients treated with infliximab at an earlier stage of disease than in patients who first received conventional treatment with corticosteroids and immunosuppressants.[21] The preliminary results of a more recent trial (the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease [SONIC] study, which was presented as a conference abstract after the literature search update for this review ended) showed that CD patients with a poor prognosis could benefit from treatment with combined infliximab and immunosuppressants.[47] This multicenter randomized controlled trial enrolled 508 anti-TNF and immunomodulator-naive CD patients and randomized them to infliximab, azathioprine or infliximab plus azathioprine. At week 26, combined infliximab and azathioprine was significantly superior to both infliximab monotherapy (p = 0.022) and azathioprine monotherapy (p = 0.009) in terms of steroid-free remission rate. In another randomized controlled trial reported by Feagan et al. (Combination Of Maintenance Methotrexate–Infliximab Trial [COMMIT]), which was not included in our review, researchers found no statistically significant difference between the groups of CD patients treated with infliximab alone and infliximab plus concomitant methotrexate.[48] However, patients in both arms of this trial received concomitant corticosteroid induction, which may have maximized response rates.

There is limited evidence evaluating maintenance using immunosuppressants after induction treatment with anti-TNF-α drugs. We found one study in which patients received infliximab plus azathioprine followed by maintenance therapy with azathioprine alone.[27] The 12-month follow-up results showed that azathioprine maintenance does not maintain response and remission.

The results of our review are consistent with the results of the previously published systematic reviews on the clinical effectiveness of anti-TNF-α drugs in CD. The systematic review published by the Cochrane Collaboration evaluated the effects of anti-TNF-α drugs in maintenance of remission in CD patients.[49] The results of this review, which included three infliximab[20,25,26] and two adalimumab randomized controlled trials,[28,30] showed that both infliximab and adalimumab were effective in maintenance of remission. This review also concluded that infliximab was effective in maintenance of fistula closure after induction therapy. Similar results were achieved in the Drug Class Review by Oregon Health and Science University.[8] This review included six infliximab trials,[22,24–26,42,50] one adalimumab[29] and one etanercept trial.[32] The meta-analysis of randomized controlled trials evaluating the effectiveness and safety of anti-TNF agents (including anti-TNF-α drugs), performed by Peyrin-Biroulet et al., showed that infliximab and adalimumab were effective and safe in the treatment of refractory CD.[51] There are a number of systematic reviews and meta-analyses that have included fewer studies, mainly owing to the limited number of completed relevant randomized controlled trials at the time of review,[52,53] or they provided a single-effect measure for a group of anti-TNF drugs.[54,55] Additional narrative reviews exist that discuss and compare different strategies of anti-TNF-α use based on different levels of evidence that did not meet the inclusion criteria of our review.[56–59]

Five-year View

The development of biologic therapies has changed the management of moderate and severe CD. In CD patients who fail conventional treatments, anti-TNF-α drugs, including infliximab and adalimumab, have shown substantial benefit in terms of induction and maintenance of remission, mucosal healing and reduction of surgeries and hospitalizations. However, the limited number of long-term randomized controlled trials, assessing both the effectiveness and safety of anti-TNF-α drugs, underscores the need for head-to-head trials comparing anti-TNF-α drugs to one another and with other novel biologics to assist clinicians in their decision making.[60,61]

Recent evidence suggests that combining anti-TNF-α drugs and immunosuppressants can lead to a higher sustained remission rate over 6 months compared with infliximab monotherapy.[47] However, the long-term benefits versus the harm of combined treatments remain to be proven. In addition, there is a paucity of evidence on the effectiveness of continuing concomitant immunosuppressives in patients who have started biologic therapy and failed the immunosuppressive treatment. Additional studies are needed to examine the necccessity and the optimal time for withdrawal of biologic therapy in patients in stable remission.

The available evidence also suggests that the use of anti-TNF-α drugs may be associated with an increased risk of infections or certain malignancies. Future studies can address whether there is a direct relationship between anti-TNF drugs and malignancy or serious infections, and in which patients anti-TNF-α drugs should be administered as a first-line treatment or together with immunosuppressives to optimize patient outcomes.

 

[David in Seattle]

References

1. Friedman S, Blumberg RS. Inflammatory bowel disease. In: Harrison's Online. Kasper DL, Braunwald E, Fauci AS et al. (Eds). McGraw-Hill Health Professions Division, NY, USA (2008).
2. Bernstein CN, Wajda A, Svenson LW et al. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am. J. Gastroenterol. 101(7), 1559–1568 (2006).
3. Wong JLH. Inflammatory bowel disease. In: Clinic Handbook: Gastroenterology. Taylor & Francis, Abington, UK (2002).
4. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of antibiotic therapy for active ulcerative colitis. Dig. Dis. Sci. 52(11), 2920–2925 (2007).
5. Feller M, Huwiler K, Schoepfer A, Shang A, Furrer H, Egger M. Long-term antibiotic treatment for Crohn's disease: systematic review and meta-analysis of placebo-controlled trials. Clin. Infect. Dis. 50(4), 473–480 (2010).
6. Doherty GA, Bennett GC, Cheifetz AS, Moss AC. Meta-analysis: targeting the intestinal microbiota in prophylaxis for post-operative Crohn's disease. Aliment. Pharmacol. Ther. (2010) (In Press).
7. Rahimi R, Nikfar S, Rahimi F et al. A meta-analysis on the efficacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohn's disease. Dig. Dis. Sci. 53(9), 2524–2531 (2008).
8. Gartlehner G, Hansen RA, Thieda P et al. Drug Class Review on Targeted Immune Modulators: Final Report. Oregon Health & Science University, OR, USA (2007).
9. Remicade. In: Notices of Compliance. Health Canada, Canada (2001).
10. Remicade [expansion of indication for Crohn's disease]. In: Notices of Compliance. Health Canada, Canada (2004).
11. Remicade [new indication – treatment of fistulizing Crohn's disease, in adult patients, who have not responded despite a full and adequate course of therapy with conventional treatment]. In: Notices of Compliance. Health Canada, Canada (2005).
12. Remicade [reduction of signs and symptoms and induction and maintenance of clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy]. In: Notices of Compliance. Health Canada, Canada (2006).
13. Humira [new indication: reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy, including corticosteroid and/or immunosuppressants]. In: Notices of Compliance. Health Canada, Canada (2007).
14. Assasi N, Blackhouse G, Xie F et al. Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical – and Cost–Effectiveness Analyses. Canadian Agency for Drug and Technologies in Health, ON, Canada (2009).
15. Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin. Trials 17(1), 1–12 (1996).
16. Wells GA, Shea B, O'Connell D et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-analyses. Ottawa Health Research Institute, ON, Canada (2008).
17. Sands BE, Abreu MT, Ferry GD et al. Design issues and outcomes in IBD clinical trials. Inflamm. Bowel Dis. 11(Suppl. 1),S22–S28 (2005).
18. Sandborn WJ, Feagan BG, Hanauer SB et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology 122(2), 512–530 (2002).
19. Principles of meta-analysis. Cochrane handbook for systematic reviews of interventions 5.0.0. In: The Cochrane Library. Higgins JPT, Green S (Eds). John Wiley & Sons Ltd, NJ, USA (2008)
20. Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359(9317), 1541–1549 (2002).
21. D'Haens G, Baert F, van AG et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 371(9613), 660–667 (2008).
• Evidence that shows infliximab administered earlier in Crohn's disease (CD) can improve remission rate.
22. Targan SR, Hanauer SB, Van Deventer SJ et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N. Engl. J. Med. 337(15), 1029–1035 (1997).
• Induction trial of infliximab in CD.
23. Lemann M, Mary JY, Duclos B et al. Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial. Gastroenterology 130(4), 1054–1061 (2006).
24. Present DH, Rutgeerts P, Targan S et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med. 340(18), 1398–1405 (1999).
• Induction trial of infliximab in fistulizing CD.
25. Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N. Engl. J. Med. 350(9), 876–885 (2004).
• Maintenance trial of infliximab in fistulizing CD.
26. Rutgeerts P, D'Haens G, Targan S et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 117(4), 761–769 (1999).
• Maintenace trial of infliximab in CD.
27. Mantzaris GJ, Ployzou P, Karagiannidis A et al. A prospective, randomized trial of infliximab (IFX) and azathioprine (AZA) for the induction and maintenance of remission of steroid-dependent Crohn's disease (CD). Gastroenterology 126(4 Suppl. 2),A54 (2004).
28. Sandborn WJ, Hanauer SB, Rutgeerts P et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut 56(9), 1232–1239 (2007).
• Maintenance trial of adalimumab for CD.
29. Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 130(2), 323–333 (2006).
• Induction trial of adalimumab for CD.
30. Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 132(1), 52–65 (2007).
• Maintenance trial of adalimumab for CD.

 

[David in Seattle]

31. Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann. Intern. Med. 146(12), 829–838 (2007).
• Maintenance trial of adalimumab in CD patients with a loss of response to infliximab.
32. Sandborn WJ, Hanauer SB, Katz S et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121(5), 1088–1094 (2001).
• Only randomized controlled trial of etanercept for CD.
33. Peyrin-Biroulet L, Laclotte C, Bigard MA. Adalimumab maintenance therapy for Crohn's disease with intolerance or lost response to infliximab: an open-label study. Aliment. Pharmacol. Ther. 25(6), 675–680 (2007).
34. Sandborn WJ, Hanauer S, Loftus EV Jr et al. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn's disease. Am. J. Gastroenterol. 99(10), 1984–1989 (2004).
35. Papadakis KA, Shaye OA, Vasiliauskas EA et al. Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab. Am. J. Gastroenterol. 100(1), 75–79 (2005).
36. Hinojosa J, Gomollon F, Garcia S et al. Efficacy and safety of short-term adalimumab treatment in patients with active Crohn's disease who lost response or showed intolerance to infliximab: a prospective, open-label, multicentre trial. Aliment. Pharmacol. Ther. 25(4), 409–418 (2007).
37. Matsumoto T, Iida M, Motoya S et al. Therapeutic efficacy of infliximab on patients with short duration of Crohn's disease: a Japanese multicenter survey. Dis.Colon Rectum 51(6), 916–923 (2008).
38. Schreiber S, Reinisch W, Colombel JF et al. Early Crohn's disease shows high levels of remission to therapy with adalimumab: sub-analysis of charm. Gastroenterology 132(4 Suppl. 2),A-147 (2007).
39. Rutgeerts P, Feagan BG, Lichtenstein GR et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology 126(2), 402–413 (2004).
40. Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology 128(4), 862–869 (2005).
41. Feagan BG, Panaccione R, Sandborn WJ et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn's disease: results from the CHARM study. Gastroenterology 135(5), 1493–1499 (2008).
42. Colombel Jf, Rutgeerts P, Yan S et al. Infliximab maintenance treatment results in lower hospitalization rate in Crohn's disease patients. Gastroenterology 122(4 Suppl. 1),A613 (2002).
43. Sandborn WJ, Feagan BG, Stoinov S et al. Certolizumab pegol for the treatment of Crohn's disease. N. Engl. J. Med. 357(3), 228–238 (2007).
44. Schreiber S, Khaliq-Kareemi M, Lawrance IC et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N. Engl. J. Med. 357(3), 239–250 (2007).
45. Lofberg R, Louis E, Reinisch W, Kron M, Camez A, Pollack P. Adalimumab effectiveness in TNF-αntagonist-naive patients and in infliximab nonresponders with Crohn's disease: results from the CARE study. Am. J. Gastroenterol. 103(Suppl.), 1069 (2008).
46. Loftus E Jr, Feagan B, Colombel JF et al. Adalimumab treatment significantly reduces hospitalization risk for TNF-αntagonist-naive patients with Crohn's disease. Am J Gastroenterol. 103(Suppl.), (2008).
47. Sandborn W, Rutgeerts P, Reinisch W et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn's disease naive to immunomodulators and biologic therapy. Am. J. Gastroenterol. 103, 1117 (2008).
• Evidence that demonstrates a combination of infliximab and immunosuppressants is superior to both infliximab monotherapy and immunosuppressant monotherapy in maintenance of remission in anti-TNF and immunosuppressant-naive CD patients.
48. Feagan B, McDonald JW, Panaccione R et al. A randomized trial of methotrexate in combination with infliximab for the treatment of crohn's disease. Gastroenterology 135(1), 294–295 (2008).
49. Behm BW, Bickston SJ. Tumor necrosis factor-α antibody for maintenance of remission in Crohn's disease. Cochrane Database Syst. Rev.(1),CD006893 (2008).
50. D'Haens G, van DS, Van HR et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial. Gastroenterology 116(5), 1029–1034 (1999).
51. Peyrin-Biroulet L, Deltenre P, de SN, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin. Gastroenterol. Hepatol. 6(6), 644–653 (2008).
52. Clark W, Raftery J, Song F et al. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn's disease. Health Technol. Assess. (Winch. Eng.) 7(3), 1–67 (2003).
53. Bebb JR, Scott BB. Systematic review: how effective are the usual treatments for Crohn's disease? Aliment. Pharmacol. Ther. 20(2), 151–159 (2004).
54. Rahimi R, Nikfar S, Abdollahi M. Do anti-tumor necrosis factors induce response and remission in patients with acute refractory Crohn's disease? A systematic meta-analysis of controlled clinical trials. Biomed. Pharmacother. 61(1), 75–80 (2007).
55. Tine F, Rossi F, Sferrazza A et al. Meta-analysis: remission and response from control arms of randomized trials of biological therapies for active luminal Crohn's disease. Aliment. Pharmacol. Ther. 27(12), 1210–1223 (2008).
56. Sandborn WJ. Current directions in IBD therapy: what goals are feasible with biological modifiers? Gastroenterology 135(5), 1442–1447 (2008).
57. Yun L, Hanauer S. Selecting appropriate anti-TNF agents in inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 3(3), 235–248 (2009).
58. Hanauer SB. Positioning biologic agents in the treatment of Crohn's disease. Inflamm. Bowel Dis. 15(10), 1570–1582 (2009).
59. Krygier DS, Ko HH, Bressler B. How to manage difficult Crohn's disease: optimum delivery of anti-TNFs. Expert Rev. Gastroenterol. Hepatol. 3(4), 407–415 (2009).
60. Peyrin-Biroulet L, Desreumaux P, Sandborn WJ, Colombel JF. Crohn's disease: beyond antagonists of tumour necrosis factor. Lancet 372(9632), 67–81 (2008).
61. Bosani M, Ardizzone S, Porro GB. Biologic targeting in the treatment of inflammatory bowel diseases. Biologics 3, 77–97 (2009).

Papers of special note have been highlighted as:
• of interest
•• of considerable interest

 

[D Bergy]

Of course a person can just use Turmeric or Curcummin in larger doses as it has the same anti-TNF affect, without the side effects of the drugs.

It should be used with Coconut Oil or taken with a meal with fat in it, to help absorption. Turmeric is difficult to absorb.

Dan

 

[David in Seattle]

Dan - What doses do you take? You're taking LDN as well?

Do you find your current regimen completely eliminates your symptoms?

 

[D Bergy]

I only take 500 mg of Turmeric and Ginger. Ginger is somewhat similar in properties. I do not need it for treating inflammation now. I just take it for the other benefits, which are many.

When I was flared I took 1000 mg of each three times a day. I was in a pretty bad flare at that time. It made it better, but did not completely resolve the flare.

I look at Turmeric as a supportive treatment, but not a treatment in itself. It helps with symptoms, but I prefer getting closer to the source of the problem.

I do not have any symptoms that I can discern, other than some loose stool on occasion. This is pretty much caused if I eat dairy products or a few other things that do not sit well with me.

If I do get loose stool that is not present for any good reason, I simply take a couple of doses of Miracle Mineral Solution. It always brings things back to normal quickly.

I guess I do not give it much opportunity to increase in severity. I am pretty proactive if I get any hint of a problem.

Dan