Systemic Autoinflammatory Diseases: A Growing Family of Disorders of Overlapping Immune Dysfunction

Abstract

Systemic autoinflammatory diseases (SAIDs) are characterized by unprovoked exaggerated inflammation on a continuum from benign recurrent oral ulceration to life-threatening strokes or amyloidosis, with renal failure as a potential sequela. The ability to discriminate these diagnoses rests on the genetic and mechanistic defect of each disorder, considering potential overlapping autoinflammation, autoimmunity, and immune deficiency. A comprehensive and strategic genetic investigation influences management as well as the consequential expected prognoses in these subsets of rare diseases. The ever-expanding therapeutic armamentarium reflects international collaborations, which will hasten genetic discovery and consensus-driven treatment.

Keywords: Autoinflammatory disease; Immune dysfunction; Immune dysregulation; Inborn errors of immunity; Periodic fevers; Systemic autoinflammatory disease.

Fig. 1.

Age of onset and inheritance of SAIDs. The age of disease onset is characteristic of several SAIDs. Abbreviations: NLRP3-AID, NLRP3-associated autoinflammatory disease; MKD, Mevalonate Kinase Deficiency; FMF, Familial Mediterranean Fever; PAPA, Pyogenic arthritis, pyoderma gangrenosum and acne; LPIN2-CNO, LPIN2-chronic non-bacterial osteomyelitis; DITRA, Deficiency of the IL36 receptor antagonist; PFIT, Periodic fever, immunodeficiency and thrombocytopenia; AGS, Aicardi-Goutieres syndrome; SAVI, STING-associated vasculopathy with onset in infancy; PRAAS; Proteosome-associated autoinflammatory syndromes; OAS1 Oligoadenylate Synthetase 1; SMS Singleton-Merten syndrome; TRAPS, Tumor Necrosis Factor Receptor-associated periodic syndrome; DADA2, Deficiency of Adenosine Deaminase 2; HA20, A20 haploinsufficiency; ORAS, OTULIN-related autoinflammatory syndrome; CRIA Cleavage-resistant RIPK1-induced autoinflammatory syndrome; CAMPS CARD14-mediated psoriasis; SFID, Sideroblastic anemia with B-cell immunodeficiency; PLAID, PLCG2-associated antibody deficiency and immune dysregulation; APLAID, Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation; VEXAS Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome; sJIA, Systemic Juvenile Idiopathic Arthritis; PFAPA, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis.

Fig. 2.

Autoinflammation in the spectrum of immunologic diseases. A growing number of autoinflammatory disorders present with overlapping types of immune dysfunction. Abbreviations: FMF, Familial Mediterranean Fever; TRAPS, Tumor Necrosis Factor Receptor-associated periodic syndrome; PFAPA, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis; sJIA, Systemic Juvenile Idiopathic Arthritis; AOSD, Adult-onset Still’s Disease; NLRP3-AID, NLRP3-associated autoinflammatory disease; NLRC4-AID, NLRC4-associated autoinflammatory disease; NLRP12-AID, NLRP12-associated autoinflammatory disease, PAPA, Pyogenic arthritis, pyoderma gangrenosum and acne; SDCM, SH3BP2 deficiency with multilocular cystic disease of the mandibles; LPIN2-CNO, LPIN2-chronic non-bacterial osteomyelitis; DIRA, Deficiency of the Interleukin-1 receptor antagonist; CAMPS, CARD14-mediated psoriasis syndrome; DITRA, Deficiency of the IL36 receptor antagonist; ORAS, OTULIN-related autoinflammatory syndrome; SIFD, Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; XLPDR, X-linked reticulate pigmentary disorder; PFIT, Periodic fever, immunodeficiency and thrombocytopenia; SPENCDI, Spondyloenchondroplasia with immune dysregulation syndrome; HA20, A20 haploinsufficiency; PLAID, PLCG2-associated antibody deficiency and immune dysregulation; APLAID, Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation; DADA2, Deficiency of Adenosine Deaminase 2; CEBPE, C/EBPε-associated autoinflammation and immune impairment of neutrophils; AGS, Aicardi-Goutieres syndrome; SLE, Systemic Lupus Erythematosus; SAVI, STING-associated vasculopathy with onset in infancy; def, deficiency.

Fig. 3.

Approach to the patient with suspected SAID.

Fig. 4.

Comparison of sequencing methods employed in the diagnosis of SAIDs. Nontargeted approaches, such as WES and WGS, provide increased coverage of genomic regions and may identify pathogenic variants in known or novel-disease associated genes. Nonetheless, cost, reporting time, need for storage space, frequency of secondary findings, and detection of variables of unknown significance (VUS) parallels the number of genomic regions examined.