Undifferentiated autoinflammatory diseases: a systematic review

Undifferentiated autoinflammatory diseases (uAIDs) represent a newly recognized category of AIDs that fail to meet the diagnostic criteria for established monogenic or polygenic AIDs. This systematic review aims to clarify the prevalence of uAIDs and summarize the clinical features and treatment responses of affected patients.

A systematic literature review of PubMed, Web of Science, EMBASE, Cochrane and Scopus was performed in accordance with the 2020 PRISMA guidelines. English-language studies mentioning uAIDs were included for analysis. The classification criteria used for the diagnosis of uAIDs, as well as the demographic data, clinical manifestations and treatment responses of patients, were extracted and analyzed. Study quality was assessed via the tool developed by Hoy et al. The primary outcome, the pooled prevalence of uAIDs, was calculated via common- or random-effects meta-analyses, as appropriate.

Thirty-five articles were included. Although termed variably, the definition of uAIDs consistently includes the following key points: patients with clinical signs and symptoms of systemic inflammation; patients who fail to meet the criteria for any well-defined polygenic AIDs; next-generation sequencing is negative or inconclusive; and other confounding conditions are excluded. The pooled prevalence of uAIDs among patients with AIDs was 21% (95% confidence interval: 14-29). Fever, arthralgia and abdominal pain were the most common clinical manifestations. Colchicine was the most frequently reported immunosuppressant in the literature, while interleukin (IL)-1-targeted biologics achieved remission in 70% of treated patients.

A diagnosis of uAIDs should be considered in patients who present with autoinflammatory features, such as fever, arthralgia and abdominal pain and who do not meet the diagnostic criteria for monogenic or polygenic AIDs or other confounding conditions. The responsiveness to IL-1-targeted biologics implies that the IL-1 pathway may be a potential gateway in uAIDs. Future prospective studies with standardized criteria are needed to overcome current limitations of exclusion-based diagnosis and study heterogeneity in uAIDs research.