Adalimumab Therapy in Pediatric Crohn Disease: A 2-Year Follow-Up Comparing “Top-Down” and “Step-Up” Strategies

Abstract

Objectives: European Crohn’s Colitis Organization (ECCO) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend the early use of anti-tumor necrosis factor (TNF) biologicals in pediatric Crohn disease (CD) patients with positive predictors for poor outcome. The objective of the present study was to compare early “Top-Down” use of adalimumab (ADA) immunomodulator/biologics-naive patients to conventional “Step-Up” management. Methods: One hundred and twenty consecutive patients with a confirmed diagnosis of CD and treated with ADA between 2008 and 2019 were included and allocated to the ADA-Top Down (n = 59) or ADA-Step Up group (n = 61). The primary endpoint was prolonged steroid-/enteral nutrition-free clinical remission at 24 months, defined by a weighted Pediatric Crohn’s Disease Activity Index (wPCDAI) < 12.5. Clinical and biological data were collected at 12 and 24 months. Results: At start of ADA, disease activity was comparable between the ADA-Top Down group and the ADA-Step Up group (wPCDAI = 31 ± 16 vs 31.3 ± 15.2, respectively, P = 0.84). At 24 months, the remission rate was significantly higher in the ADA-Top Down group (73% vs 51%, P < 0.01). After propensity score, the Top-Down strategy is still more effective than the Step-Up strategy in maintaining remission at 24 months [hazard ratio (HR) = 0.36, 95% CI (0.15–0.87), P = 0.02]. Patients in the ADA-Top Down group were mainly on monotherapy compared to patients in the ADA-Step Up group (53/55 vs 28/55 respectively, P < 0.001). Serum levels of ADA were higher in the ADA-Top Down group than in the ADA-Step Up group (12.8 ± 4.3 vs 10.4 ± 3.9 µg/mL, respectively, P < 0.01). There were no serious adverse events. Conclusions: Early use of ADA appears to be more effective in maintaining relapse-free remission at 2 years, while using it as monotherapy. These findings further favor the recommendation of early anti-TNF use in high-risk CD patients.

Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies

“…In addition, Jongsma and colleagues found that the probability of continued clinical remission at week 52 with monotherapy of azathioprine was higher in children who received infliximab as first-line therapy to induce remission [ 50 ]. Comparable results were shown for adalimumab [ 72 ]. In Crohn’s disease, early and effective use of TNF-α blockers also prevented the development of disease complications, for example, strictures or penetrating ulcerations and disease progression [ 28 ].…”

Reversing the Inflammatory Process—25 Years of Tumor Necrosis Factor-α Inhibitors

“…In addition, the probability of continued clinical remission at week 52 with azathioprine monotherapy was higher in children who received infliximab as a first-line remission-inducing therapy. Comparable results were shown for adalimumab [47].…”

“…Therapy with TNF-α inhibitors can thus be used to break the vicious cycle of chronic inflammation early and effectively [46,47], since TNF-α blockade weakens several inflammatory networks and promotes anti-inflammatory processes [13,14,[29][30][31][32]48]. Consequently, the blockade of TNF-α has a systemic effect and is not restricted to a specific inflammatory disease, which is why the development of further organic manifestations can be prevented and chronic comorbidities can be treated efficiently [6,10,11,[49][50][51].…”

The Management of Postoperative Recurrence in Crohn’s Disease

“…Among patients without endoscopic recurrence, top-down reduced risk of these outcomes (clinical recurrence HR 0.59, p = 0.025; bowel damage progression HR 0.73, p < 0.001) [ 73 ]. Another study compared top-down vs. step-up ADA strategies in 120 pediatric patients over 24 months [ 113 ]. At the endline, remission was higher in the top-down group (73% vs. 51%, p < 0.01).…”

“…A propensity analysis found top-down to be more effective in maintaining remission (HR = 0.36, 95% CI 0.15–0.87, p = 0.02). Top-down mainly used monotherapy vs. combination in step-up ( p < 0.001) [ 113 ]. Previous results may be indirectly confirmed by a retrospective Scottish study, which found 5-year surgery risks fell from 20.4% to 13.0% ( p < 0.001), while biologic use rose from 5.7% to 44.9% ( p < 0.001) from 2000–2004 to 2014–2017 [ 114 ].…”