Diagnostic and therapeutic algorithms for monogenic autoinflammatory diseases presenting with recurrent fevers among adults

Abstract

Autoinflammatory diseases (AIDs) are defined as disorders of innate immunity. They were initially defined in contrast to autoimmune diseases because of the lack of involvement of the adaptive immune system and circulating autoantibodies. The four monogenic AIDs first described are called the “historical” AIDs and include: Familial Mediterranean Fever (associated with MEFV mutations), cryopyrinopathies (associated with NLRP3 mutations), Tumor Necrosis Factor Receptor-associated Periodic Syndrome (associated with TNFRSF1A mutations) and Mevalonate Kinase Deficiency (associated with MVK mutations). In the last 10 years, >50 new monogenic AIDs have been discovered due to genetic advances. The most important discovery for adult patients is VEXAS syndrome associated with somatic UBA1 mutations leading to an autoinflammatory disease affecting mostly elderly men. Diagnosis of monogenic AIDs is based on personal and family history and detailed analysis of symptoms associated with febrile attacks, in the context of elevated peripheral inflammatory markers. This review proposes a practical approach of the diagnosis of the main monogenic AIDs among adult patients to guide the clinician.

Update on autoinflammatory diseases

“…Due to the rarity and phenotypic variability of many of the SAIDs, randomized, double-blind controlled drug trials are often unattainable. Fortunately, for many established autoinflammatory diseases, consensus-generated diagnosis and management recommendations have been published and can help rheumatologists diagnose, treat, and monitor patients with many of these disorders [50][51][52]. There are also global efforts to increase collaborations through established groups such as Eurofever and childhood arthritis and rheumatology research alliance (CARRA).…”

Deciphering the relationship between temperature and immunity

“…The most common disease in this category, adult-onset Still’s disease, rose in incidence in these clinical cohorts from 38% to 75% over the 15-year study (1998–2012). This rise is part of a larger trend of growing prevalence in autoinflammatory disease, a delineation of disorders that often present with recurrent fever [ 76 ]. In contrast to autoimmune diseases, which are primarily dysregulation of the adaptive immune system, autoinflammatory diseases stem from dysregulation of the innate immune system [ 14 , 15 , 76–78 ].…”

“…This rise is part of a larger trend of growing prevalence in autoinflammatory disease, a delineation of disorders that often present with recurrent fever [ 76 ]. In contrast to autoimmune diseases, which are primarily dysregulation of the adaptive immune system, autoinflammatory diseases stem from dysregulation of the innate immune system [ 14 , 15 , 76–78 ]. Clinically, they differ markedly in that 78% of those diagnosed with autoimmune diseases are female [ 77 ], while some autoinflammatory diseases, such as FCAS (familial cold autoinflammatory syndrome), can disproportionately affect males 2:1 [ 78 ].…”

“…Autoinflammatory diseases can be divided into two main categories: polygenic diseases, such as adult-onset Still’s disease, and monogenic diseases, such as FCAS. Research in monogenic diseases is rapidly growing due to more widespread availability of whole exome sequencing, in fact >50 new monogenic autoinflammatory disorders have been described in the last 10 years [ 76 ]. Notably among these, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) was discovered in 2020 and is now recognized as one of the most frequent monogenic causes of recurrent fevers, worldwide [ 76 ].…”

“…Research in monogenic diseases is rapidly growing due to more widespread availability of whole exome sequencing, in fact >50 new monogenic autoinflammatory disorders have been described in the last 10 years [ 76 ]. Notably among these, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) was discovered in 2020 and is now recognized as one of the most frequent monogenic causes of recurrent fevers, worldwide [ 76 ]. Unique in its pathology, VEXAS is not inherited but acquired through somatic mutations in the UBA1 gene [ 79 ].…”