Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience

Abstract

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation.Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India.Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed.Results: Data on 107 patients with SAID were collated—of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 (DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 (NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness.Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.

Variant in the PLCG2 Gene May Cause a Phenotypic Overlap of APLAID/PLAID: Case Series and Literature Review

“…Of the thirty-one sequence variants in the PLCG2 gene listed in Infevers [ 7 ], two pathogenic, one variant of unknown significance (VUS), one likely benign, and five so far not classified PLCG2 gene variants displayed an APLAID phenotype and three not classified PLCG2 gene variants presented a PLAID phenotype [ 3 , 5 , 8 , 9 , 10 , 11 , 12 , 13 ]. In addition, five other papers were identified in the PubMed search, which fulfilled the inclusion criteria [ 14 , 15 , 16 , 17 , 18 ]. Data fulfilling inclusion criteria were analyzed for genetic, clinical and immunology characteristics ( Table 2 and Table 3 ).…”

“…Several patients diagnosed as PLAID had evidence for cold-induced urticaria, increased susceptibility for recurrent infections, signs of autoimmunity and allergic diseases and immunologic findings (reduced immunoglobulins, low numbers of circulating class switched memory B-cells, reduced NK cells) [ 3 , 10 , 18 ]. Several patients diagnosed as APLAID had the following clinical and laboratory characteristics: cutaneous findings (rashes, erythema, granulomas, cutis laxa and vesiculo-pustular lesions), eye inflammation, recurrent infections, abdominal pain and inflammatory bowel disease, musculoskeletal complaints, immunologic findings (reduced/normal immunoglobulins, reduced circulating class-switched CD27+ memory B-lymphocytes and decreased/normal NK cells) [ 5 , 8 , 9 , 12 , 14 , 15 , 16 , 17 , 18 ]. Data were compared with patients’ characteristics from our case series, highlighting an overlap of characteristics previously reported for the PLAID and APLAID syndrome.…”

“…All five patients in this case series had clinical and laboratory similarities with previously described patients diagnosed as PLAID/APLAID. The patients in this case series showed PLAID characteristics, such as cold-induced urticaria [ 3 , 10 ] and APLAID characteristics, such as eye inflammation, musculoskeletal complaints and no circulating antibodies [ 5 , 8 , 9 , 12 , 14 , 15 , 16 ]. All patients had recurrent upper airway infections, abdominal pain, episodic diarrhea and normal T-cell function, as previously described in several PLAID and APLAID patients [ 3 , 5 , 8 , 9 , 12 , 14 , 15 , 16 ].…”

“…The patients in this case series showed PLAID characteristics, such as cold-induced urticaria [ 3 , 10 ] and APLAID characteristics, such as eye inflammation, musculoskeletal complaints and no circulating antibodies [ 5 , 8 , 9 , 12 , 14 , 15 , 16 ]. All patients had recurrent upper airway infections, abdominal pain, episodic diarrhea and normal T-cell function, as previously described in several PLAID and APLAID patients [ 3 , 5 , 8 , 9 , 12 , 14 , 15 , 16 ]. In addition, they had normal NK cells, similar to several APLAID patients [ 5 , 8 , 9 , 14 ].…”

Profile of 208 Patients With Inborn Errors of Immunity at a Tertiary Care Center in South India

“…Interestingly, we had a family with FCAS-1 with 10 affected family members across 4 generations! [23].…”