The use of Adalimumab in the Management of Refractory Crohn's Disease
The use of Adalimumab in the Management of Refractory Crohn's Disease
Background: Adalimumab is a humanized monoclonal antibody targeting tumour necrosis factor-α. Recent clinical trials have demonstrated its efficacy in Crohn's disease; however, experience in clinical practice remains limited.
Aim: To investigate the efficacy and safety of adalimumab in the clinical setting.
Methods: The clinical outcomes of patients with medically refractory Crohn's disease treated with adalimumab in the Western General Hospital Edinburgh, over a 3-year period (2003-2006), were studied.
Results: Twenty-two (14 females; age at therapy: 32.6 years) patients were treated using an 80/40 mg induction regimen followed by fortnightly 40 mg treatment. All had proven refractory/intolerant to corticosteroids and immunosuppression. Twenty patients had had previous infliximab infusions - of these eight (36%), six (27%), three (14%) had previous infusion reactions, no response and lost response to infliximab, respectively. Over a period of 1.0 years (IQR: 0.62-2.5), Kaplan-Meier analyses showed that 68% (seven nonresponders) were in clinical remission and 67% (five surgery - discounting oral CD) avoided further surgery for active disease. 59% required dose escalation to 40 mg weekly (0.55 years; IQR: 0.22-1.4). Three (50%) primary nonresponders to infliximab achieved remission. Two patients developed serious infective complications and one patient developed lung cancer.
Conclusions: Adalimumab is efficacious in refractory Crohn's disease, with benefit observed in infliximab primary nonresponders. However, many patients require escalation of dosing regimen.
Monoclonal antibodies targeting antitumour necrosis factor (TNF) are highly effective therapies in Crohn's disease (CD) and to a lesser extent in ulcerative colitis (UC). Use of infliximab, a chimaeric monoclonal anti-TNF antibody is established in the current management of inflammatory bowel disease (IBD). Recent controlled trials have demonstrated the efficacy and safety of adalimumab (Humira; Abbot Laboratories, Abbott Park, IL, USA), a fully humanized subcutaneous delivered monoclonal antibody (immunoglobulin G1) in CD. The CLASSIC-I (CLinical assessment of Adalimumab Safety and efficacy Studied as an Induction therapy in Crohn's disease) showed significantly improved remission rates at week 4 using 160 mg/80 mg induction regimen (36% vs. 12%; P = 0.001) in moderate-to-severe CD patients naive to anti-TNF therapy. The CHARM (Crohn's trial of the fully Humanised Antibody Adalimumab for Remission Maintenance) trial demonstrated superior remission rates in patients maintained on 40 mg weekly and fortnightly compared with placebo (remission rates of 36%, 41%, and 12%, respectively; P < 0.001 at week 56). This conclusion was also supported by the recently published CLASSIC-II study, with remission rates of 79% (40 mg fortnightly), 83% (40 mg weekly) compared to 44% in the placebo group (P < 0.05) at week 56. In the group of patients who had lost response or were intolerant to infliximab, the GAIN (Gauging Adalimumab efficacy in Infliximab Nonresponders) induction study showed that 21% of patients could achieve clinical remission at week 4 (by using the higher dosage induction regimen of 160/80 mg).
The development of adalimumab and other alternative anti-TNF treatments, such as certolizumab pegol has undoubtedly increased the therapeutic armamentarium in IBD, in particular, in the difficult group of patients who have demonstrated loss of efficacy and intolerance in conjunction with infliximab use. Nevertheless, several issues including safety considerations have made the extrapolation of the recent data for the management of IBD in the direct clinical setting difficult. For example, the CLASSIC and CHARM studies included a wide spectrum of patients with CD, whereas at present, it remains likely that the anti-TNF therapies would be targeted and licensed in the use in patients with medically refractory/aggressive disease [refractory to corticosteroids, surgery and immunosuppression such as mercaptopurine (6-mercaptopurine)/azathioprine and methotrexate]. It remains pertinent that patients with stomas are also excluded from the clinical trials. In addition, studies on maintenance therapy data have been limited by the fact that no data beyond 12 months have been presented. Further problems to be taken into account in evaluation of the clinical trials include the definite short-term complications associated with biological therapy, and also the uncertainties of long-term complications. Recent open-labelled data on adalimumab have provided useful insights into the areas discussed.
Background: Adalimumab is a humanized monoclonal antibody targeting tumour necrosis factor-α. Recent clinical trials have demonstrated its efficacy in Crohn's disease; however, experience in clinical practice remains limited.
Aim: To investigate the efficacy and safety of adalimumab in the clinical setting.
Methods: The clinical outcomes of patients with medically refractory Crohn's disease treated with adalimumab in the Western General Hospital Edinburgh, over a 3-year period (2003-2006), were studied.
Results: Twenty-two (14 females; age at therapy: 32.6 years) patients were treated using an 80/40 mg induction regimen followed by fortnightly 40 mg treatment. All had proven refractory/intolerant to corticosteroids and immunosuppression. Twenty patients had had previous infliximab infusions - of these eight (36%), six (27%), three (14%) had previous infusion reactions, no response and lost response to infliximab, respectively. Over a period of 1.0 years (IQR: 0.62-2.5), Kaplan-Meier analyses showed that 68% (seven nonresponders) were in clinical remission and 67% (five surgery - discounting oral CD) avoided further surgery for active disease. 59% required dose escalation to 40 mg weekly (0.55 years; IQR: 0.22-1.4). Three (50%) primary nonresponders to infliximab achieved remission. Two patients developed serious infective complications and one patient developed lung cancer.
Conclusions: Adalimumab is efficacious in refractory Crohn's disease, with benefit observed in infliximab primary nonresponders. However, many patients require escalation of dosing regimen.
Monoclonal antibodies targeting antitumour necrosis factor (TNF) are highly effective therapies in Crohn's disease (CD) and to a lesser extent in ulcerative colitis (UC). Use of infliximab, a chimaeric monoclonal anti-TNF antibody is established in the current management of inflammatory bowel disease (IBD). Recent controlled trials have demonstrated the efficacy and safety of adalimumab (Humira; Abbot Laboratories, Abbott Park, IL, USA), a fully humanized subcutaneous delivered monoclonal antibody (immunoglobulin G1) in CD. The CLASSIC-I (CLinical assessment of Adalimumab Safety and efficacy Studied as an Induction therapy in Crohn's disease) showed significantly improved remission rates at week 4 using 160 mg/80 mg induction regimen (36% vs. 12%; P = 0.001) in moderate-to-severe CD patients naive to anti-TNF therapy. The CHARM (Crohn's trial of the fully Humanised Antibody Adalimumab for Remission Maintenance) trial demonstrated superior remission rates in patients maintained on 40 mg weekly and fortnightly compared with placebo (remission rates of 36%, 41%, and 12%, respectively; P < 0.001 at week 56). This conclusion was also supported by the recently published CLASSIC-II study, with remission rates of 79% (40 mg fortnightly), 83% (40 mg weekly) compared to 44% in the placebo group (P < 0.05) at week 56. In the group of patients who had lost response or were intolerant to infliximab, the GAIN (Gauging Adalimumab efficacy in Infliximab Nonresponders) induction study showed that 21% of patients could achieve clinical remission at week 4 (by using the higher dosage induction regimen of 160/80 mg).
The development of adalimumab and other alternative anti-TNF treatments, such as certolizumab pegol has undoubtedly increased the therapeutic armamentarium in IBD, in particular, in the difficult group of patients who have demonstrated loss of efficacy and intolerance in conjunction with infliximab use. Nevertheless, several issues including safety considerations have made the extrapolation of the recent data for the management of IBD in the direct clinical setting difficult. For example, the CLASSIC and CHARM studies included a wide spectrum of patients with CD, whereas at present, it remains likely that the anti-TNF therapies would be targeted and licensed in the use in patients with medically refractory/aggressive disease [refractory to corticosteroids, surgery and immunosuppression such as mercaptopurine (6-mercaptopurine)/azathioprine and methotrexate]. It remains pertinent that patients with stomas are also excluded from the clinical trials. In addition, studies on maintenance therapy data have been limited by the fact that no data beyond 12 months have been presented. Further problems to be taken into account in evaluation of the clinical trials include the definite short-term complications associated with biological therapy, and also the uncertainties of long-term complications. Recent open-labelled data on adalimumab have provided useful insights into the areas discussed.
