Anti-TNFα and anti-IL-12/23 antibody therapy as bridge to HSCT in IL10RA-deficient very-early-onset IBD: rationale for c.506T>C (p.Ile169Thr)

For IL10RA c.506T>C (p.Ile169Thr), a pathogenic missense variant that disrupts IL-10 receptor signaling and causes severe very-early-onset inflammatory bowel disease (VEOIBD), monoclonal antibody therapy with anti-TNFα agents (infliximab, adalimumab) and anti-IL-12/23 antibodies (ustekinumab) can provide critical disease control as a bridge to definitive curative allogeneic HSCT. While antibody therapy does not correct the underlying genetic defect, it targets the downstream inflammatory cascade driven by unopposed macrophage and T cell activation in the absence of functional IL-10 signaling.

IL-10 is a master anti-inflammatory cytokine; its receptor (IL-10RA/IL-10RB heterodimer) signals through JAK1/TYK2-STAT3 to suppress macrophage and dendritic cell proinflammatory cytokine production (TNFα, IL-1β, IL-6, IL-12, IL-23). Biallelic IL10RA loss-of-function variants cause severe colitis presenting in the first months of life, refractory to conventional immunosuppression. The p.Ile169Thr substitution affects the extracellular domain of IL-10RA, likely disrupting IL-10 ligand binding or receptor conformational signaling. Multiple case series have reported partial clinical response to infliximab (anti-TNFα) in IL10RA-deficient VEOIBD, with reduction in bloody diarrhea, fistulae, and inflammatory markers (Glocker et al., NEJM 2009; PMID:19890111; Kotlarz et al., Gastroenterology 2012; PMID:22902955). Ustekinumab (anti-IL-12/23 p40 subunit) has been used in refractory cases, targeting the Th1/Th17 axis that is overactivated when IL-10 suppression fails. However, long-term remission requires HSCT to replace the defective hematopoietic cells with donor-derived immune cells expressing functional IL-10RA.

Antibody therapy is palliative, not curative — it does not restore IL-10 signaling. Responses are often partial and wane over time, with frequent need for dose escalation or switching agents. Anti-TNFα therapy carries risks of serious infections (opportunistic infections, tuberculosis reactivation) particularly concerning in infants who are already immunocompromised by their primary immunodeficiency. Immunogenicity (anti-drug antibody formation) limits long-term efficacy of infliximab and adalimumab. The definitive treatment is allogeneic HSCT, which has shown high cure rates (~80-90% event-free survival) when performed early, but carries its own transplant-related mortality and morbidity. Antibody therapy data for IL10RA-VEOIBD come from small case series and case reports — no randomized controlled trials exist for this ultra-rare condition. The specific effect of the p.Ile169Thr variant on antibody therapy response has not been studied.