Patients with deficiency of the x-linked inhibitor of apopotosis (XIAP) may present with inflammatory bowel disease (IBD) and predisposition to hemophagocytic lymphohistiocytosis (HLH). Predominant inactivation of the wildtype x-chromosome has been identified as cause of symptomatic x-linked conditions in females. Inflammation-induced reprogramming of Xiap−/− Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R) in mice.
A girl presented with very early onset IBD, dermatitis, two episodes of immune dysregulation (5/8 HLH criteria) with spontaneous remission, flares of autoinflammation with fever and elevated markers of inflammation. Infliximab, adalimumab and anakinra only resulted in limited short time effect on IBD and stool-frequency up to 10 times per day, still requiring frequent hospitalization. The introduction of the humanized monoclonal interleukin-6 (IL-6) antibody tocilizumab resulted in absence of fever, resolution of dermatitis, decrease of stool-frequency to 3 times per day, normal activity level, and substantial reduction of corticosteroids.
Diagnosis of XIAP deficiency was established by strongly reduced expression of XIAP in peripheral blood mononuclear cells assessed by flow cytometry. Sanger sequencing of the corresponding gene BIRC4 identified a heterozygous nonsense mutation (c.664C>T; p.Arg222*). An extremely skewed x-inactivation with wildtype inactivation nearly 100% of cells was revealed by HUMARA assay. Introducing the IL-6 antibody tocilizumab lead to substantial reduction of inflammatory activity. SCT from a matched unrelated donor as curative treatment is planned.
Tocilizumab may be considered as treatment alternative in children with XIAP-deficiency. It may help to reduce inflammation and IBD symptoms.