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Systemic lupus erythematosus (SLE) is an autoimmune disease whose pathophysiology remains incompletely understood, involving genetic and epigenetic factors. However, an increasing small subset of patients present with monogenic lupus, providing insight into the pathogenesis of the disease. This systematic review focuses on SLE associated with A20 haploinsufficiency (HA20), a monogenic disorder associated with tumor necrosis factor alpha-induced protein 3 gene (TNFAIP3) variants. Besides the mainly auto-inflammatory phenotypic expression of HA20 mimicking Behçet's disease spectrum, some of its clinical and biological manifestations are part of the spectrum of autoimmune diseases, including glomerulonephritis as well as the frequent presence of antinuclear antibodies, sometimes with anti-DNA specificity. Among all the 191 HA20 patients reported in the literature, we identified 16 patients (8.4 %) with a compatible diagnosis of SLE. When estimable, the SLICC 2012 and EULAR/ACR 2019 classification criteria were positive for 92.9 % of them. A majority had multi-system involvement, mainly cutaneous (81.3 %), musculoskeletal (56.3 %), and/or renal (56.3 %) manifestations. They also seemed to exhibit differences compared to other SLE patients: higher prevalence of fever, chronic cutaneous lupus erythematosus, oral and genital ulcers, neuropsychiatric manifestations, autoimmune cytopenia, and elevated biologic inflammatory markers. This review highlights the necessity of considering TNFAIP3 variants in SLE patients with early-onset disease, familial history, and/or specific clinical manifestations suggestive of autoinflammatory diseases. Recognizing HA20-SLE patients may improve our understanding of SLE pathogenesis and lead to better therapeutic strategies for these patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A20 Haploinsufficiency (HA20) is a monogenic autoinflammatory disease associated with an autosomal dominant mutation in the TNFAIP3 gene. It induces a defect in the inactivation of the pro-inflammatory NF-κB pathway. Less than 200 cases have been described worldwide. The clinical picture of the disease is essentially based on the association of recurrent fever and/or biologic inflammatory syndrome, aphtosis, often bipolar, and cutaneous folliculitis. However, the clinical spectrum of HA20 is very broad, including gastrointestinal (mainly colonic ulceration), articular, cutaneous, pericardial and lymph node involvement, as well as frequent association with organ-specific or non-specific autoimmune manifestations and/or autoantibodies, including antinuclear antibodies and anti-dsDNA. As a result, the diagnosis of a number of systemic or organic disorders, most notably Behçet's disease, Crohn's disease, and sometimes even systemic lupus, has been corrected to HA20 by molecular research for a heterozygous mutation with functional deficiency of TNFAIP3. Although the first signs of the disease often appear in the first years of life, the diagnosis is often made in adulthood and requires the involvement of both paediatric and adult physicians. Treatment for HA20 is not codified and relies on conventional or biological immunomodulators and immunosuppressants adapted to the patient's symptomatology. This review highlights the enormous diagnostic challenges in this autoinflammatory disease., (Copyright © 2023 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

A20 haploinsufficiency is an autoinflammatory disease caused by defective inactivation of the NF-κB pathway. We conducted a systematic literature review of articles reporting patients with TNFAIP3 sequence variants from 2016 to August 2023 following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data from 177 patients from 65 articles were retrieved (108 women). The principal features were mucosal ulcers (n = 129); fever (n = 93) followed by gastrointestinal (n = 81); skin features (n = 76); autoimmunity (n = 61), including thyroiditis (n = 25) and lupus (n = 16); and joint involvements (n = 54). Five patients had died at the time of publication. In 54 of 63 patients, CRP was significantly elevated during flares, with a median of 51 mg/l. The most commonly used treatment included corticosteroids and nonsteroidal anti-inflammatory drugs (n = 32), TNF blockers (n = 29), colchicine (n = 28), and methotrexate (n = 14). TNFAIP3 variants impacted the ovarian tumor domain in 92 cases and a Zinc finger domain in 68 cases. Geographic origin, reported sex, and variant type significantly impacted phenotype. A better understanding of the wide A20 haploinsufficiency phenotype could facilitate the diagnosis process. Much remains to be elucidated about pathogenesis and treatment to improve outcome in patients with A20 haploinsufficiency., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)