Anti-TNF-alpha antibody therapy as a bridge in IL10RA-deficient very early onset IBD: infliximab for p.Tyr167Ter

For IL10RA c.501T>G (p.Tyr167Ter), a pathogenic nonsense variant that abolishes IL-10 receptor alpha chain expression and causes very early onset inflammatory bowel disease (VEO-IBD) presenting in the first year of life, anti-TNF-alpha monoclonal antibodies (infliximab, adalimumab) serve as the primary pharmacological bridge therapy to control intestinal inflammation before definitive treatment with allogeneic HSCT. IL10RA deficiency disrupts anti-inflammatory IL-10 signaling in macrophages and dendritic cells, leading to uncontrolled TNF-alpha and IL-1beta-driven colitis. Anti-TNF antibodies directly neutralize this downstream effector cytokine. While antibody therapy does not address the root genetic cause, it is essential for disease stabilization, nutritional optimization, and surgical avoidance prior to transplant.

Glocker et al. (2009, PMID: 19890111, NEJM) first identified IL10/IL10R deficiency as a monogenic cause of VEO-IBD, establishing that loss of IL-10 signaling leads to severe infantile colitis unresponsive to conventional immunosuppression. Clinical case series have reported partial response to infliximab (chimeric anti-TNF IgG1) in IL10RA-deficient patients, with reduction in bloody diarrhea and inflammatory markers, though responses are often incomplete and temporary compared to typical pediatric IBD. Kotlarz et al. (2012, PMID: 23000145) reported that HSCT is the only curative approach, with successful immune reconstitution and IBD resolution in transplanted patients. Anti-TNF therapy has been used in >50 reported IL10RA-deficient patients as a pre-transplant bridge, with variable efficacy. For p.Tyr167Ter, the complete absence of IL10RA surface expression (confirmed by flow cytometry) predicts absent STAT3 phosphorylation in response to IL-10, complete loss of anti-inflammatory feedback, and typically severe refractory colitis requiring early HSCT.

Anti-TNF antibodies provide symptomatic relief but do not cure IL10RA deficiency — they address one downstream effector (TNF-alpha) while the broader IL-10 signaling defect persists. Many IL10RA-deficient patients are partially or completely refractory to anti-TNF therapy, likely because inflammation is driven by multiple cytokines beyond TNF. Infliximab carries risks of serious infection (particularly relevant in immunodeficient infants), infusion reactions, and anti-drug antibody formation leading to loss of response. The definitive treatment remains allogeneic HSCT, which has significant transplant-related mortality (estimated 10-20% in VEO-IBD cohorts) and graft-versus-host disease risk. For p.Tyr167Ter, the very early presentation (typically first weeks to months of life) means that anti-TNF therapy must be initiated in young infants, raising pharmacokinetic and safety concerns in this age group. Gene therapy for IL10RA deficiency (ex vivo HSPC correction) is theoretically possible but has not been developed, partly because HSCT outcomes are generally favorable when performed early.