Loss of Response and Need for Adalimumab Dose Intensification in Crohn's Disease: A Systematic Review

Abstract

The objective of this study was to review loss of response and need for adalimumab dose intensification in adult and pediatric patients with Crohn's disease. Studies were identified through the electronic databases of MEDLINE and the annual meetings of Digestive Disease Week, of the United European Gastroenterology Week, and of the American College of Gastroenterology and the European Crohn's and Colitis Organization meetings. Studies evaluating loss of efficacy and/or need for dose intensification were included. Thirty-nine studies were included. The mean percentage of loss of response to adalimumab 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 adalimumab 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 adalimumab 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, concomitant corticosteroid use, no deep remission at week 12, low serum trough concentrations of adalimumab, previous infliximab non-response and being previously treated with an anti-tumor necrosis factor agent. Overall, around one fifth of adult patients require dose intensification and experience a loss of response after initiation of adalimumab therapy. Adalimumab dose escalation permits response to be regained in the majority of patients.

Positive relationship between infliximab and adalimumab trough levels at completion of induction therapy with clinical response rates, at a tertiary referral center

“…For ADL, dose intensifying can help to regain clinical response, avoiding the need to switch agents. A meta‐analysis from 2011 has shown that the mean percentage of patients who required dose intensification among primary responders to ADL was 37% and the annual risk was 24.8% per patient‐year 16. Thus, the combination of clinical, biochemical, and endoscopic evaluations and the increasing important role of TDM may help to address the difficulties of LOR to anti‐TNFα, develop strategies to induce and maintain long‐lasting clinical remission, and achieve mucosal healing.…”

Therapeutic Drug Monitoring in Inflammatory Bowel Disease

“…However, the risk is not distributed evenly, with roughly 2/3 of the patients developing LOR with the fi rst 12 months, and the rest losing response at a signifi cantly slower pace. For ADA, annual LOR incidence of 10%-24% has recently been reported [5,6].…”

Letter: infliximab and adalimumab in the management of Crohn's disease – are they really comparable?

“…4 Finally, in the adalimumab group, 16 patients dropped out before the scheduled 54 weeks for clinical worsening or loss of response (n = 8), in spite of which therapy was never intensified. 5,6 All these considerations prevent us to accept the conclusion that 'the efficacy of infliximab and adalimumab is comparable.' As the authors correctly state, 'future prospective double-blind studies in patients matched for clinical variables are required to further assess the efficacy and safety of different anti-TNFs in CD.'…”

“…2 In addition, the way biologics were used in this series contradict the assumption that this experience represents their 'real use' in Crohn's disease. [2][3][4][5][6][7] Firstly, cotreatment with immunosuppressors was given in just 16% of cases in the infliximab group. 2,6 Secondly, and surprisingly, only 77% of the infliximab-treated patients were able to complete the induction treatment, mainly due to severe adverse events in eight (18%) patients; this is not generally seen in clinical series.…”

“…3 This RIA has been extensively clinically validated in IBD and other diseases. [3][4][5][6] It has a higher sensitivity for anti-IFX Ab detection than bridging and capture ELISAs, and is capable of detecting all subtypes of anti-IFX Ab including monovalent IgG4 Ab, which predominate during long-term immunisations. 7 This subclass of Ab, although detectable in capture ELISA, are not detected in bridging ELISAs.…”