Benefits and Risks of Combining Anti-tumor Necrosis Factor with Immunomodulator Therapy in Pediatric Inflammatory Bowel Disease

Abstract

Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy.

Vitamin D deficiency in patients with intestinal malabsorption syndromes – think in and outside the gut

“…compared patients with inactive Crohn's disease to control subjects, they found elevated levels of tumor necrosis factor (TNF)‐α in the colonic mucosa of patients . This finding is in keeping with the success of infliximab (IFX) anti‐TNF‐α therapy for patients with refractory Crohn's disease . When Simoneau et al .…”

“…Although there is a body of strong evidence suggesting that inflammation causes the metabolic conversion of 25(OH)D to 1,25(OH) 2 D in the inflamed intestine of patients, thereby reducing the serum level of 25(OH)D, well‐designed clinical studies are still needed to conclusively establish the biological significance of the local production of 1,25(OH) 2 D in relationship to GI diseases. Also, it will be important to investigate whether, in addition to TNF‐α, other inflammatory cytokines also regulate the local conversion of 25(OH)D to 1,25(OH) 2 D in the inflamed GI system of patients and, if so, how significant this is to the development of disease or disease activity. The outcomes of such studies may perhaps lead to the identification of new biomarkers for hypovitaminosis D associated with GI syndromes and also novel drug targets.…”

Use of Biologics in Pouchitis

“…Thus, the adverse event profile of mono anti-TNF therapy or combination therapy with an immunosuppressant such as azathioprine/6-mercaptopuirne seems to be similar to the profile described for Crohn’s disease or ulcerative colitis. 67 All studies listed in table 2 and 3 do not state any specific pouch related side effect, which could be attributable to potential differences in the pathophysiology of pouchitis compared to Crohn’s disease or ulcerative colitis.…”

Management of Crohn’s Disease

“…32 These benefits need to be balanced against the side effects and long-term risks of immunosuppressant therapy. 33 For detailed management of azathioprine see Fell et al 13a Methotrexate Paediatric retrospective cohort studies report 50%-80% effectiveness of methotrexate (MTX) in children who failed to respond or were intolerant to thiopurine therapy in maintaining remission. 34 35 MTX (15 mg/m 2 one time per week, maximum: 25 mg subcutaneously) in conjunction with folate supplementation is an alternative option as primary maintenance therapy or following thiopurine failure or intolerance.…”