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Tumour necrosis factor (TNF) is a cytokine playing a key role in the pathogenesis of Crohn’s disease (CD).1 Infliximab, a chimeric monoclonal antibody to TNF, is effective in inducing and maintaining response and remission in patients with moderate to severe CD.2, 3 However, infliximab is immunogenic and repeated administration can result in the development of antibodies to infliximab that lead to infusion reactions, loss of efficacy and delayed hypersensitivity reactions.4–6
Two anti-TNF agents which might be less immunogenic,7 namely adalimumab and certolizumab (a PEGylated humanized Fab′ fragment to TNF), have proven efficacy in the treatment of CD refractory to standard medical therapy with corticosteroids or immunomodulatory agents.8–13 Adalimumab is a recombinant human IgG1 human monoclonal antibody that binds with high affinity and specificity to human soluble TNF but not to lymphotoxin. In three placebo-controlled trials, adalimumab was effective for both induction and maintenance of clinical response and remission8–10 in moderate to severe CD.
Recently, two uncontrolled trials14, 15 and a 4-week randomized placebo-controlled trial named Gauging Adalimumab Efficacy in Infliximab Non-responders (GAIN)16 have demonstrated that adalimumab therapy was also effective in inducing remission in patients with active CD who had previously responded to infliximab and then lost response or became intolerant. Preliminary data from a retrospective study suggested that adalimumab may be an effective maintenance therapy for patients with CD who have experienced an attenuated response to infliximab.17 However, the long-term efficacy of adalimumab beyond 6 months in these patients is unknown.
We conducted a 52-week open-label trial to assess the long-term efficacy and safety of subcutaneous administration of adalimumab in CD patients who had an attenuated response to infliximab or had become intolerant to infliximab therapy.
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The development of an attenuated response or intolerance over time is a significant problem in CD patients treated with infliximab therapy. We found a rapid response to adalimumab therapy with first dose, as 16/24 (67%) of the patients were in clinical remission at week 4 compared with 8/24 (35%) at week 0. These findings are in agreement with the results of the GAIN study, a large phase III, double-bind, placebo-controlled trial, showing that approximately one of five patients (regardless of the placebo arm) treated with adalimumab benefit from the introduction of this anti-TNF agent.16 It should be noted that in our study, approximately one-third of the patients were in clinical remission defined as CDAI < 150 at week 0 because all patients who lost response or became intolerant were screened and treated with adalimumab, regardless of CDAI score. Only signs of disease activity (as judged by the treating physician) had to be present at screening. Nevertheless, the mean CRP concentration, which was 31.8 ± 40 mg/L at week 0 in this study, was higher to that reported (16.3 ± 24.5 mg/L) in a previous trial with similar design in which patients included had a baseline score ≥ 220,14 suggesting that most patients included in our study probably had active CD at time of screening.
More interestingly, 58% of the patients were still in clinical remission at the end of the study (primary pilot efficacy endpoint) compared with 35% of the patients at study entry. As all patients who were in clinical remission at study entry maintained remission at 1-year follow-up, we cannot conclude that these patients benefited from switching from infliximab to adalimumab. Thus, adalimumab may be effective in maintaining clinical remission in (at least) 20% of the patients who had secondary failure to infliximab therapy. The percentage of patients with prior intolerance to infliximab who were still in clinical remission at week 52 (83.3%) was higher to that in patients with prior response to infliximab who had quiescent CD defined as CDAI < 150 at week 52 (50%). These results indicate that switching from infliximab to adalimumab may be more efficacious for patients who became intolerant to infliximab than for those with prior loss of response to infliximab.
The percentage of subjects receiving concomitant azathioprine or mercaptopurine was similar at week 0 and in patients in clinical remission at week 52. Thus, the concomitant immunosuppressive therapy does not seem to influence the clinical efficacy of adalimumab in this population.
Clinical efficacy of adalimumab was accompanied by a decrease in plasma CRP concentrations at week 4, with an effect that persists at 1-year follow-up, reinforcing the potential benefit of adalimumab use in patients with CD who have secondary failure to infliximab therapy. Consistent with the results of the Crohn's trial of the fully Human antibody Adalimumab for Remission Maintenance (CHARM) trial,10 adalimumab also appears to be effective in treating fistulizing disease and obtaining steroid-free remission.
However, data regarding the efficacy of adalimumab in terms of clinical remission, steroid sparing and complete fistula closure should be interpreted with caution due to small sample size and the lack of placebo controls.
In the study by Papadakis et al.,17 patients were treated with adalimumab over a 6-month period. A longer duration of follow-up is likely required to assess the long-term efficacy of switching from infliximab to another anti-TNF agent in patients with loss of response or intolerance to this drug. Indeed, among the five patients who lost response to adalimumab therapy in our study, 4/5 (80%) had an attenuated response after a 6-month treatment period. These findings also highlight the need for a third-line treatment. As no other biologic agents as anti-TNF are currently available for the treatment of CD, patients who developed an attenuated response to both infliximab and adalimumab might benefit from switching to certolizumab. Additional investigations are required to address this issue.
Finally, none of the patients experienced intolerance to adalimumab that led to discontinuation of the drug, including six who previously experienced acute or delayed hypersensitivity reactions with infliximab. The safety profile was consistent with previous experience with this drug. Like in the GAIN trial,16 injection site reactions were the most common adverse events. None of the adverse events led to patient withdrawal. Moreover, no patients developed serious infections, malignancies, demyelinating disorders, drug-induced lupus, or died, but the power to detect these rare events was limited. Immunogenicity, i.e. occurrence of anti-adalimumab antibodies, was not evaluated in this study.
In conclusion, adalimumab therapy is well tolerated and appears to be effective in maintaining clinical remission in patients with luminal CD who had lost responsiveness or developed intolerance to infliximab. These preliminary data need to be confirmed in randomized, double-blind, placebo-controlled trials.