A Case of Adult-Onset Still’s Disease Caused by a Novel Splicing Mutation in TNFAIP3 Successfully Treated With Tocilizumab

Abstract

TNFAIP3 encodes the NF-κB regulatory protein A20. High-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20 (HA20), inadequate inhibition of NF-κB pathway, and an early onset autoinflammatory disorder. However, the clinical phenotype of patients with HA20 varies greatly and clinical diagnoses prior to establishing the genetic cause, included both autoimmune and autoinflammatory conditions. Here, we present the first patient with HA20, who was previously diagnosed with AOSD but was later found to have a novel heterozygous variant in TNFAIP3 and who was successfully treated with anti-IL6 receptor biologic tocilizumab (RoActemra). We discovered a novel heterozygous mutation in TNFAIP3 c.1906C>T, not previously found in ExAC database. Further analysis shows that this single-nucleotide variant at the terminal residue of TNFAIP3 exon 7 produces an alternatively spliced mRNA resulting in p.His636fsTer1. Additional genetic analysis of family members shows that this variant does segregate with the inflammatory clinical phenotypes. Subsequent functional test show that NF-κB activation, measured as intracellular phosphorylation of p65 in CD14 + monocytes, was more enhanced in the patient compared with healthy controls (HC) following stimulation with LPS. This was associated with higher production of inflammatory cytokines by the patients PBMC in response to LPS and ATP and enhanced activation of NLRP3 inflammasome complex. Furthermore, increased activation of NLRP3 inflammasome was evident systemically, since we detected higher levels of ASC specks in patients’ sera compared with HC. Finally, we used population genetics data from GnomAD to construct a map of both genetic conservation and most probable disease-causing variants in TNFAIP3 which might be found in future cases of HA20.

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

“…To date, anti-IL-6 therapy has been widely used to treat autoimmune diseases, including rheumatic arthritis ( 69 ), giant cell arteritis ( 70 ), and adult-onset Still's disease (AOSD) ( 71 ). Our results suggest that blocking IL-6 with JAK1/2 inhibitors or inhibiting fibroblast proliferation might represent a beneficial IgG4-RD treatment.…”

Cardioprotection of Ginkgolide B on Myocardial Ischemia/Reperfusion-Induced Inflammatory Injury via Regulation of A20-NF-κB Pathway

“…Zinc finger protein A20, also described as the TNF-α-induced protein 3 (TNFAIP3), is a widely expressed cytoplasmic signaling protein, commonly deemed as an anti-inflammatory, nuclear factor-kappa B (NF-κB) inhibitory, and anti-apoptotic molecule (5, 6). A20 was one key part of the mechanisms involved in multiple autoimmune and inflammatory diseases, such as coronary artery disease, psoriasis, systemic sclerosis, coeliac disease, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis.…”

Genetic Basis of Myocarditis: Myth or Reality?

“…The A20 protein, which is encoded by the TNFAIP3 gene, is a critical inhibitor of pro-inflammatory signaling pathways and is involved in negative regulation of auto-inflammation and autoimmunity [263]. The clinical phenotypes associated with HA20 are heterogeneous, including autoimmune diseases (Behçet's disease, hereditary fever-like condition, juvenile idiopathic arthritis, systemic lupus erythematosus, and rheumatoid arthritis) and, recently, AOSD: a splice site mutation on the TNFAIP3 gene has been identified in a patient previously diagnosed with adult-onset Stills' disease (AOSD) [264]; once correctly diagnosed, the patient was successfully treated with anti-IL6 receptor biologic tocilizumab [265]. Myocarditis has been repeatedly reported in AOSD, presenting as myocarditispericarditis [265][266][267][268][269][270][271][272][273][274], with pericarditis occurring in more than 50% of cases [265].…”