Ab0162 Diversity of Immune Regulatory Defects: Insights From a Tertiary Care Rheumatology Centre in Northern India

Background: Primary immune regulatory disorders (PIRDs) are inborn errors of immunity resulting in severe and recurrent infections as well as traits like autoinflammation, autoimmunity, lymphoproliferation, and susceptibility to malignancies. Due to diverse clinical presentations, they present to multiple specialities, often leading to delayed diagnoses and morbidity. Early detection and initiating targeted therapies are crucial. The spectrum of these disorders is expanding and data from North India is sparse. This study is aimed to describe the clinical spectrum and outcomes of immune regulatory defects from North India. Objectives: To describe the clinical spectrum, genetic etiology and outcomes of patients with primary immune regulatory defects. Methods: A retrospective analysis of patients suspected of having immune regulatory defects at our hospital between 2013 and 2023 was conducted. Patient data, including clinical profiles and genetic test results were compiled from case records and electronic databases. Results: Of the 25 suspected cases, 12 had a confirmed genetic diagnosis. 19 patients had the characteristic phenotype (Male: Female= 2.1:1) presenting at a median age of 12 months (3-54). The median age of onset was 36 months (50-120), with a median delay in diagnosis of 6 (1.75- 24) months. A history of consanguinity and sibling deaths due to similar illnesses was reported in 6 cases each (31.5%). Among the 14 individuals who underwent whole exome sequencing, the diagnosis was confirmed in 12 cases. One patient was admitted for evaluation with suspected congenital hemophagocytic lymphohistiocytosis (HLH) due to death of 3 siblings with history of fever, rash and cytopenia, whose genetic analysis report is awaited. Another patient with Very Early Onset Inflammatory Bowel Disease (VEOIBD) exhibited a NOD2 heterozygous mutation categorized as a Variant of Uncertain Significance (VUS) (Table 1). Primary manifestations included fever (12,63.1%), hepatosplenomegaly (9,47.3%), lymphadenopathy (5,26.3%), and inflammatory Bowel Disease (IBD) (6,31.5%). Notably, 8 patients (42.1%) each experienced infections and had cytopenia, 12 (63.1%) exhibited failure to thrive, while 5 (26.3%) had HLH and 2 (10.5%) had interstitial lung disease. 2 patients (10.5%) each had recurrent pneumonia, septicaemia and infective diarrhoea while subcutaneous abscess and urinary tract infection were seen in 1 patient (5.2%) each. Diagnoses varied from Autoimmune Lymphoproliferative Syndrome (ALPS), Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome, SOCS1 haploinsufficiency, to familial Macrophage Activation Syndrome (MAS) (Refer to Table 1). Regarding treatment response, 10 patients (52.6%) received immunosuppression, 3 (15.7%) received chemotherapy according to HLH protocol and 1 patient (5.2%) underwent HSCT. 7 patients (36.8%) positively responded, while 7 (36.8%) succumbed to the illness, and 5 (26.3%) were lost to follow-up. (Table 1). Survival at 1 year and 5 years was 71.2% (52.5%-96.6%) and 56.9% (36.9%-87.9%) respectively. Patients with any episode of HLH had worse survival, however no significant association of increased mortality was seen with infections. Conclusion: The spectrum of immune regulatory defects is rapidly expanding. Maintaining a heightened clinical suspicion and a low threshold for genetic testing is crucial for early identification. This early recognition is pivotal for initiating targeted treatment strategies and facilitating genetic counselling. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.