Severe Hyperinflammation and Evans Syndrome in Patient with RelA Deficiency Successfully Treated with Infliximab

IntroductionRelA deficiency is a recently recognized inborn error of immunity (IEI) caused by mutations in the RELA gene. RelA is a transcriptional factor in the NF-kB pathway. Deficiency of RelA leads to impaired downregulation of anti-apoptosis in fibroblasts, leading to TNF-induced cell death. Clinical presentation includes mucocutaneous ulcerations and Bechet’s-like disease along with autoimmunity.Additionally, dominant-negative mutations can cause type 1 interferonopathy. Our case highlights effective treatment of RelA-associated autoimmune hemolytic anemia (AIHA)/Evans syndrome and severe dysregulated hyperinflammatory state with infliximab.CaseA 20-year-old previously healthy female was diagnosed with severe and relapsing AIHA at age 12. AIHA was refractory to multiple immunomodulators, including prednisone, rituximab, mycophenolate mofetil, abatacept, and sirolimus. While on sirolimus and abatacept, she developed vaginal ulcerations resembling Bechet’s disease requiring interruption of therapy. She was in full remission following 8 doses of daratumumab. Approximately 11 months into remission, she was hospitalized for a fever of unknown origin. Labs showed exacerbation of her AIHA, new immune thrombocytopenia, and markedly elevated inflammatory markers, including ferritin (125,803 ng/mL), CXCL9 (19,343 pg/mL), and Il-18 (188,985 pg/mL), consistent with macrophage activation syndrome. Infectious evaluation was negative. PET scan showed hypermetabolic lymphadenopathy in her neck/chest. Bone marrow biopsy was negative for malignancy but revealed hemophagocytosis.Excisional lymph node biopsy showed reactive lymph nodes with paracortical expansion by macrophages. She received methylprednisolone (1,000 mg) for 3 days, followed by a prednisone wean with cessation of fevers after 13 consecutive days. Genetics revealed a heterozygous pathogenic variant in RELA c.592C>T (p.Arg198*). Given worsening cytopenias and inflammatory markers with steroid wean, she was initiated on Infliximab. Interestingly, her mother had a history of oral ulcers as a teenager, and her older sister was recently diagnosed with inflammatory bowel disease.ConclusionEvaluation of IEI should be pursued in patients with refractory/chronic cytopenias. Careful consideration of RelA deficiency should be taken in patients with autoimmunity. Our patient developed life-threatening hyperinflammation that was effectively treated with steroids followed by TNF inhibition. Additionally, she has had resolution of her ulcerations and cytopenias. She remains on monotherapy infliximab with stable disease.