Monogenic inborn errors of immunity in autoimmune disorders

Abstract

To estimate the prevalence of monogenic inborn errors of immunity in patients with autoimmune diseases. This was a retrospective and prospective cohort study. The study included 56 subjects (Male:Female ratio: 1.07) with mean age of onset of autoimmunity of 7 years (4months-46 years). 21/57 (37.5%) had polyautoimmunity. 5/56 patients met the JMF criteria for PID. The different AID referred were hematological (42%) > GI (16%) > Skin (14%) > Endocrine (10%) > Rheumatological (8%) > Renal (6%) > Neurological (2%). 36/57 (63%) reported recurrent infections. 27/56 were on polytherapy, 46 had received steroids. 18/52 (35%) had CD19 lymphopenia, 24/52(46%) had CD4 lymphopenia, 11/52(21%) had CD8 lymphopenia, 14/48 (29%) had NK lymphopenia. 20/50 (42%) had hypogammaglobinemia. 28/56 (50%) were found to have pathogenic variants among PIRD genes (LRBA:6, STAT1 GOF: 3, CTLA4: 2, ACP5: 2, 1 each with NFKB1, NLRP12, CARD11 GOF, STAT3 GOF, RTEL1, NCF2, ATM, RAG1, BTK, IL12RB1, CR2 and CD55 microdeletion/CHAPEL, FOXP3, PIK3CD, CD40L, ADA2). These 28 patients had 41 autoimmune diseases. Hematological AID was most common (50%)>GI (16%)>Endocrine (9%)>Skin (11%)>Rheumatological (7%)>Renal and neurological (1%). Hematological AID is most common manifestation in almost 75% of children with PIRD. Positive predictive value of abnormal immunological tests was 50% and sensitivity of 70%. JMF criteria had specificity of 100% in identifying PIRD but sensitivity was only 17%. Polyautoimmunity had a positive predictive value of 35% and sensitivity of only 40%. Avg age at initial presentation with autoimmunity in patients with underlying PIRD was 7.4 years vs 6.4 years in those without PIRD. 11/28 of these children were offered transplant out of whom 4 have successful transplants. 8/28 were started on sirolimus, 2/28 on abatacept, 3/28 on baracitinib, 2/29 on ruxolitinib after diagnosis that led to steroid withdrawal. 4 have died. Conclusion: 50% of children with AID have underlying PIRD. LRBA deficiency and STAT1 GOF were the most common PIRD. Age at presentation, number of autoimmunity, routine immunological tests and JMF criteria are not predictive of underlying PIRD. Early diagnosis with exome sequencing alters the prognosis and opens new therapeutic avenue.