Version May 2024
INTRODUCTION — The concept of autoinflammation was introduced in 1999 to describe a category of systemic inflammation, exemplified by the monogenic periodic fever syndromes, that was distinct from autoimmunity [1]. As related biologic mechanisms have been elucidated, it has become clear that antigen-independent immune activation plays a central role in a wide variety of diseases in which inflammation contributes to tissue injury [2].
An overview of autoinflammatory diseases is presented here, with a focus on shared pathogenic and pathophysiologic mechanisms. While some disorders are discussed briefly in this topic review, more detailed descriptions of the clinical manifestations, diagnosis, and treatment of the major autoinflammatory diseases are presented elsewhere. Classification and genetic testing for inborn errors of immunity are also discussed in detail separately:
●(See "Inborn errors of immunity (primary immunodeficiencies): Classification".)
●(See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)
●(See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)
●(See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity".)
●(See "Autoinflammatory diseases mediated by miscellaneous mechanisms".)
●(See "Deficiency of adenosine deaminase 2 (DADA2)".)
●(See "Cryopyrin-associated periodic syndromes and related disorders".)
●(See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)
●(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)
●(See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)
OVERVIEW OF PATHOGENESIS — Immune defense requires both antigen-specific and antigen-independent mechanisms. The antigen-specific arm of the immune response, referred to as adaptive immunity, is based upon learned self/nonself discrimination mediated by selective expansion of T and B cell clones in which genetic recombination has generated antigen-specific receptors. (See "The adaptive cellular immune response: T cells and cytokines".)
These "learned" responses are not the only mechanism of immune defense. Innate immunity refers to a network of cells and proteins that respond to infection or tissue injury through genetically "hard-wired" recognition of foreign molecules (eg, bacterial cell wall components) or host molecules produced or released by damaged cells (eg, interleukin [IL] 1 and uric acid crystals). Neutrophils, macrophages, mast cells, and natural killer cells are among the principal cellular effectors of innate immunity. Complement, a set of proteins that recognize and bind nonself targets, exemplifies a noncellular arm of the innate immune response. (See "An overview of the innate immune system" and "Complement pathways" and "Toll-like receptors: Roles in disease and therapy".)
Innate and adaptive immune mechanisms work closely together. Recognition of danger signals by innate immune mechanisms directs the development of adaptive immune responses, while lack of recognition favors tolerance. Established adaptive immune responses recruit innate immunity to assist with the effector response. As examples, T cells can recruit neutrophils, and B cell-derived antibodies target bacteria for lysis by complement.
Autoimmune diseases, such as rheumatoid arthritis, myasthenia gravis, and type 1 diabetes, represent mistakes in self/nonself discrimination by adaptive immune mechanisms. Hallmarks include the presence of autoantibodies, a female predominance for most of these diseases, and an association with specific alleles in the major histocompatibility complex (MHC), whose proteins are responsible for presenting peptides to T cells.
By contrast, autoinflammatory diseases arise through inappropriate activation of antigen-independent inflammatory mechanisms. Thus, they may broadly be considered to represent primary diseases of innate immunity, although cells more typically associated with adaptive immunity (eg, T lymphocytes) may also contribute to autoinflammation [1,2]. Accordingly, these diseases typically lack autoantibodies or MHC associations and occur as commonly in males as in females. (See "Overview of autoimmunity".)
Many autoinflammatory diseases are rare and therefore (with the exception of familial Mediterranean fever [FMF] and the presumed autoinflammatory condition periodic fever with aphthous stomatitis, pharyngitis, and adenitis [PFAPA]) are unlikely to be encountered in routine clinical practice. However, they illustrate the important principle that the mechanisms controlling innate immunity are critical to regulation of inflammation. More subtle variants in these mechanisms likely contribute to the presentation of other, much more common diseases.
As an example, most heterozygous carriers for pathogenic variants in the FMF gene (MEFV) do not manifest frank FMF, but they may demonstrate more subtle manifestations of increased inflammation. These include frequent fevers; more dramatic sepsis physiology; increased susceptibility to juvenile idiopathic arthritis, ankylosing spondylitis, and certain vasculitides; and more severe rheumatoid arthritis [3-8]. The emerging picture is that many disorders generally regarded as autoimmune probably also include aspects that could be considered autoinflammatory [9]. In addition, common diseases such as gout, pseudogout, and atherosclerotic coronary artery disease engage autoinflammatory mechanisms [10,11]. Chronic activation of related mechanisms may even contribute to age-associated diseases such as hypertension [12]. Thus, the canonical autoinflammatory diseases represent the "tip of the iceberg" of the relevance of related mechanisms for human health and disease.
CATEGORIES OF AUTOINFLAMMATORY DISEASES — Autoinflammatory diseases may be grouped into working categories based upon major pathogenic themes (table 1). Diseases within each category can share overlapping clinical features (table 2). Importantly, many diseases engage mechanisms not limited to a single category.
Disorders of inflammasomes and related IL-1 family cytokines — The inflammasomes are large intracellular protein complexes that cleave inactive pro-interleukin (IL) 1-beta into its highly inflammatory mature form. Aberrant activation of these complexes results in inappropriate generation of IL-1-beta, triggering inflammation with fever since IL-1-beta is a potent endogenous pyrogen. Other proteins cleaved by inflammasomes are IL-18, a cytokine that potentiates interferon gamma production, and gasdermin D, a protein that forms pores within the cell membrane that allow release of mature IL-1-beta and IL-18 and cause a proinflammatory form of cell death called pyroptosis.
There are at least seven known inflammasome complexes, each built around a distinct protein that serves as a danger sensor and provides a scaffold for inflammasome assembly when triggered [13]. Mutations affecting these protein complexes cause the inflammasome-mediated autoinflammatory diseases, sometimes called the inflammasomopathies. For example, familial Mediterranean fever (FMF) and hyperimmunoglobulin D (IgD) syndrome (HIDS) arise from aberrant activation of the pyrin inflammasome while familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disorder (NOMID) arise from aberrant activation of the cryopyrin inflammasome. Clinical features of this family of diseases include fever, rash, arthralgias, and symptoms affecting the chest and abdomen.
The IL-1 family consists of 11 members, including IL-1-beta and IL-18, but also the proinflammatory cytokine IL-36 and the antiinflammatory cytokine blocker IL-1 receptor antagonist (IL-1RA). Disorders clinically similar to the inflammasome disorders, though typically without fever, can arise through deficiency of IL-1RA or of an antagonist of IL-36 signaling. (See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)".)
Diseases of interferon production and signaling — The interferons are a family of cytokines that mediate cell-cell signaling to coordinate the immune response to infection. Activation of these pathways results in multisystem inflammation, usually but not always featuring fever. Associated autoinflammatory diseases can arise from genetic defects anywhere along the interferon pathway, from cytokine overproduction to aberrant signaling through the interferon receptor. Often called "interferonopathies," this growing family of diseases includes Aicardi-Goutières syndrome and STING-associated vasculitis with onset in infancy (SAVI). These syndromes are clinically diverse, but suggestive features include skin vasculitis affecting areas exposed to cold (finger, nose, external ears), interstitial lung disease, and calcification of the basal ganglia. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)
Diseases of NFkB activation — Nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) represents a final common pathway for many cell-activating stimuli. The proteins that make up the NFkB complex reside in inactive form in the cytoplasm. When released from inhibition, this complex migrates to the nucleus to induce transcription of a network of proinflammatory genes. Some autoinflammatory diseases arise from inappropriate activation of this pathway, including Blau syndrome and haploinsufficiency of A20/tumor necrosis factor alpha-induced protein 3 (TNFAIP3). Related diseases with overlapping but distinct manifestations arise through defects in TNF signaling or production, including TNF receptor 1 associated periodic syndrome (TRAPS). (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity".)
Autoinflammation via other mechanisms — Normal inflammatory responses are mediated by many pathways, and the range of genetic defects leading to dysregulated inflammation is correspondingly diverse. Some autoinflammatory disorders fail to fit comfortably into the categories above. These include deficiency of adenosine deaminase 2 (DADA2), COPA syndrome, and autoinflammatory PLC-gamma-2-associated antibody deficiency and immune dysregulation (APLAID) (see "Deficiency of adenosine deaminase 2 (DADA2)" and "Autoinflammatory diseases mediated by miscellaneous mechanisms"). Disorders of aberrant activation of complement, including atypical hemolytic uremic syndrome, age-related macular degeneration, and paroxysmal nocturnal hemoglobinuria, are sometimes considered autoinflammatory and are discussed separately. (See "Complement-mediated hemolytic uremic syndrome in children" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
HALLMARKS OF THE AUTOINFLAMMATORY DISEASES — Autoinflammatory diseases should be suspected in patients with recurrent or persistent inflammation unexplained by another cause, such as infection or malignancy. Manifestations may include fever, rash, serositis (pleuritis or peritonitis), arthritis, meningitis, and uveitis. Lymphadenopathy and splenomegaly may also occur, and secondary (amyloid A [AA]) amyloidosis can complicate longstanding disease. As the spectrum of recognized autoinflammatory disease has expanded, other presenting features have also been recognized, including enterocolitis, vasculitic rash, basal ganglia calcifications, stroke including cerebrovascular hemorrhage, and interstitial lung disease. Most patients develop earliest disease manifestations in childhood, although milder or atypical forms can present de novo in adults.
A particularly useful clue to the presence of autoinflammation is the stereotyped character of febrile episodes and their failure to behave like common infections. As an example, fevers may occur at regular intervals, exhibit a standard duration, occur without upper respiratory symptoms and in the absence of illness in other members of the household, and fail to respond to antibiotics.
Inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), are usually elevated during disease flares and may sometimes remain abnormal between episodes. In contrast to autoimmune diseases, high-titer autoantibodies are usually absent, although interferonopathies may be accompanied by antibodies typically encountered in systemic lupus erythematosus and in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis.
DIAGNOSIS — Patients who present with a history of inflammatory episodes that recur or persist over months or years in the absence of another cause should be evaluated for an autoinflammatory disease after unusual infections and malignancy are first excluded. The family history is then assessed. A family history of a similar syndrome suggests a heritable disorder such as monogenic autoinflammatory diseases (although recessive or de novo mutations will often lack such a history). The evaluation then seeks a clinical pattern consistent with one of the major autoinflammatory disorders, reviewed in detail in a chart maintained by the Autoinflammatory Alliance [14]. Classification criteria for major autoinflammatory diseases have been developed for patients with available genetic testing (cryopyrin-associated periodic fever syndromes [CAPS], Familial Mediterranean fever [FMF], tumor necrosis factor [TNF] receptor-1 associated periodic syndrome [TRAPS], mevalonate kinase deficiency [MKD]) (table 2) and also in patients for whom only clinical data are available (periodic fever with aphthous stomatitis, pharyngitis, and adenitis [PFAPA]; CAPS; FMF; TRAPS; MKD) (table 3) [15,16]. Empiric therapeutic trials using glucocorticoids, colchicine, interleukin (IL) 1 blockade (typically with recombinant IL-1 receptor antagonist [IL-1RA], anakinra), or inhibitors of interferon signaling can be informative [2].
Genetic testing is the mainstay of diagnosis and, given the relatively low cost of genetic panels testing for multiple disorders, should represent an early step in the evaluation of a patients with suspected autoinflammation. Where a specific diagnosis is strongly suspected on the basis of presentation and epidemiology, for example a patient with classic FMF, targeted single-gene sequencing can be more cost effective. PFAPA remains a clinical diagnosis without genetic correlate and may be diagnosed with confidence in the absence of genetic testing to exclude other conditions in the appropriate clinical context (eg, an otherwise well child with monthly fevers lasting four to six days that resolve with a single dose of glucocorticoids). (See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation" and "Fever of unknown origin in adults: Etiologies" and "Fever of unknown origin in adults: Evaluation and management" and 'Differential diagnosis' below and "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)
Autoinflammatory syndromes associated with fever include:
●Familial Mediterranean fever (FMF)
●TNF receptor-1 associated periodic syndrome (TRAPS)
●Hyperimmunoglobulin D syndrome (HIDS)
●Cryopyrin-associated periodic fever syndromes (CAPS; includes familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome [MWS], and neonatal-onset multisystem inflammatory disorder [NOMID])
Autoinflammatory disorders that do not present with fever as a major manifestation of the disease include:
●Deficiency of the IL-1RA (DIRA) that causes osteomyelitis with periostitis and pustulosis
●Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome
●Blau syndrome (juvenile systemic granulomatosis)
●Deficiency of adenosine deaminase 2 (DADA2) that can present with stroke
●Deficiency of the IL-36 receptor antagonist (DITRA) that causes generalized pustular psoriasis
For diseases that present with fever, the most useful discriminators are the duration and periodicity of febrile episodes. In both febrile and afebrile autoinflammatory conditions, additional historical and clinical features that can narrow down the differential diagnosis include Mediterranean descent in FMF and presence of associated clinical features. As an example, the following findings were noted in a study of 228 Italian patients with periodic fever [17]:
●Detection of a relevant mutation was more likely in patients with a family history of periodic fever, early age at disease onset, and clinical manifestations of abdominal pain (which was the strongest positive predictor), chest pain, or diarrhea. In contrast, the presence of aphthous ulcers (also known as canker sores) was a negative predictor (odds ratio 0.2).
●Two features were helpful in distinguishing among the disorders: the duration of fever, which is shortest in FMF (mean two to three days) and longest in TRAPS (mean 15 days in severe disease and 5 to 9 days in mild disease), and the presence of vomiting or splenomegaly, which may be seen in HIDS.
The diagnostic evaluation should be informed by the epidemiology of each condition. FMF and PFAPA are common, but the other periodic fever syndromes are rare. As an example, the prevalence of CAPS in France was calculated at 1:360,000 [18]. In addition, certain syndromes are more common in specific populations. Gene carriage of FMF-related mutations, for example, exceeds 10 percent in specific populations of Armenians, Turks, and Ashkenazi Jews. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)", section on 'Epidemiology' and "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis", section on 'Epidemiology'.)
Diagnosis is important because of potential implications for therapy, monitoring for the development of secondary (amyloid A [AA]) amyloidosis [19], and the need for genetic counseling [20]. However, many patients still defy diagnostic classification despite advances in diagnostic testing [21-23]. In such patients, reconsideration of the full differential diagnosis is essential. If an autoinflammatory disease still appears likely, empiric therapy patterned on that employed in other autoinflammatory diseases is often warranted, including colchicine, anakinra, and potentially Janus kinase (JAK) inhibitors to block interferon signaling [24]. These patients should be referred, if possible, to a center with appropriate expertise to guide empiric treatment trials and select appropriate genetic tests, including evaluation for mosaicism (presence of a mutant gene in some cells but not others) (see 'Mosaicism' below), or other targeted investigation that may lead to a definitive diagnosis. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of periodic fevers includes unusual infections such as relapsing fever, malignancy and premalignant states (eg, acute lymphoblastic leukemia, neuroblastoma, Hodgkin lymphoma [Pel-Ebstein fever], Schnitzler syndrome), cyclic neutropenia, systemic juvenile idiopathic arthritis (sJIA)/adult-onset Still's disease (AOSD), and periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. (See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation" and "Fever of unknown origin in adults: Etiologies" and "Fever of unknown origin in adults: Evaluation and management".)
●Relapsing fever – Relapsing fever is similar in name to periodic fever syndromes. However, relapsing fever is an arthropod-borne infectious disease caused by spirochetes of the Borrelia genus, not an autoinflammatory disease. It is also characterized by recurrent episodes of fever. The first febrile episode is the most severe and ends with a crisis phase. This phase lasts 15 to 30 minutes; consists of rigors, a further elevation in temperature, and increased pulse and blood pressure; and is followed by profuse diaphoresis, falling temperature, and hypotension, which usually persist for several hours. (See "Clinical features, diagnosis, and management of relapsing fever".)
●Cyclic neutropenia – Other than PFAPA, fever in autoinflammatory disorders is episodic rather than truly periodic. Thus, the presence of a predictable recurrent fever pattern should trigger consideration of cyclic neutropenia, which may be of childhood or adult onset. (See "Cyclic neutropenia".)
●Schnitzler syndrome – Schnitzler syndrome is an acquired autoinflammatory syndrome that presents with chronic urticaria associated with monoclonal immunoglobulin M (IgM) gammopathy (most often IgM kappa). Additional features may include bone pain, skeletal hyperostosis, arthralgias, lymphadenopathy, and intermittent fevers. Patients are at increased risk of hematologic malignancies. There is no specific test for Schnitzler syndrome, and clinicians must maintain a high index of suspicion in patients with chronic urticaria and a monoclonal IgM gammopathy. Most patients respond well to inhibition of the interleukin (IL) 1 pathway. Schnitzler syndrome is discussed in greater detail separately. (See "Urticarial vasculitis", section on 'Differential diagnosis'.)
●Systemic juvenile idiopathic arthritis/adult-onset Still's disease – A further diagnostic consideration is the febrile-onset arthritis known in childhood as systemic juvenile idiopathic arthritis (sJIA) and in adults as adult-onset Still's disease (AOSD). Patients with these conditions present with features including high-spiking fevers, rash, serositis, and lymphadenopathy. Arthritis is often evident at onset but may sometimes lag for weeks, months, or even years. These clinical features, as well as brisk response to IL-1 antagonism in many patients, has led many to conclude that sJIA/ASD also belong to the family of autoinflammatory diseases, although important differences remain [25,26]. These diseases are discussed in detail separately. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of adult-onset Still's disease".)
●PFAPA syndrome – PFAPA is a relatively common entity compared with the other periodic fever syndromes. The etiology of PFAPA has not been defined, but further investigation may ultimately identify it as autoinflammatory.
Briefly, PFAPA is characterized by febrile episodes beginning in early childhood that recur approximately every three to four weeks. These episodes are associated with typical clinical features, and another cause is not identifiable. Episodes are abrupt in onset, last three to six days, and may be accompanied by one or more of the following:
•Pharyngitis (exudative or nonexudative)
•Mild aphthous ulcerations
•Lymphadenopathy
•Chills (rigors)
•Fatigue
•Headache
•Mild abdominal pain
Despite its acronym, recurrent fevers are the only prominent clinical finding in many patients. Leukocytosis and elevation of inflammatory markers occur acutely during episodes and return to normal between episodes. Patients are otherwise healthy and grow normally. Most patients with PFAPA outgrow the febrile episodes with time, and no long-term consequences have been identified. PFAPA syndrome is discussed in greater detail separately. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)
TREATMENT — Treatment is focused on blocking the primary inflammatory pathway involved in each disease. Biologic agents blocking various cytokines have been used to treat autoinflammatory diseases. Nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids may play important ancillary roles. Patients should be monitored for inflammation both during flares and in periods of remission. Persistent elevation of markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) during asymptomatic periods may reflect residual uncontrolled inflammation indicative of inadequate disease control.
Interleukin (IL) 1 blockade is effective in disorders mediated primarily through IL-1-beta, including the inflammasomopathies, deficiency of the IL-1 receptor antagonist (DIRA), and tumor necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS). TNF blockade may be effective in TRAPS and is typically effective in deficiency of adenosine deaminase 2 (DADA2), as well as congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) syndrome and the autoinflammatory-like disease chronic nonbacterial osteomyelitis (CNO). Diseases mediated by interferon may respond to blockade of the intracellular Janus kinase (JAK) proteins that mediate interferon signaling. Treatment of these syndromes is discussed in greater detail in the individual disease-specific topics.
MOSAICISM — Pathogenic variants resulting in autoinflammatory diseases are not necessarily present in all cells. Some patients exhibit autoinflammatory symptoms on the basis of mosaicism, referring to the presence of cells of distinct genotypes within a single individual [27]. Mosaicism has been identified in patients with late-onset, mild, or otherwise atypical autoinflammatory diseases in the spectrum of cryopyrin-associated periodic syndromes (CAPS); tumor necrosis factor (TNF) alpha receptor-1 associated syndrome (TRAPS); Nod-like receptor family, caspase recruitment domain-containing 4 (NLRC4) related disease; Blau syndrome; and the VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) [28-32].
Mosaicism arises through the development of disease-causing mutations after the single-cell stage of embryogenesis. The proportion and distribution of cells bearing the mutation vary depending upon when the mutation occurs. If the mutation arises at an early stage, the resulting cells can be widely distributed, potentially even encompassing the germ cells and thus transmissible to future offspring (so-called gonosomal mosaicism). Genetic divergence arising later is usually restricted to nongonadal cells (somatic mosaicism) and even to specific cell populations. In such cases, the mutation can be missed if screening is restricted to a cell population different from the ones affected or if the mutated cell population is only a small fraction of the cells tested, such that the "signal" from cells bearing the mutation is swamped by a larger fraction of nonmutant cells. Detection of such cases may require specialized techniques, including next-generation deoxyribonucleic acid (DNA) sequencing (deep sequencing), testing of multiple tissues, and generation of clones from different tissues from the same patient [27,28].
SUMMARY AND RECOMMENDATIONS
●Definition – The autoinflammatory diseases constitute a family of disorders characterized by aberrant activation of inflammatory pathways in the absence of antigen-directed autoimmunity. Classically, periodic fevers are the common presenting manifestation. However, the spectrum of autoinflammatory disorders continues to expand and now includes disorders in which recurrent fevers may be absent. (See 'Introduction' above.)
●Pathogenesis – Autoinflammatory diseases can be organized by pathogenic mechanism (table 1). Major categories include diseases mediated by the inflammasome and related interleukin (IL) 1 family cytokines, by interferons, and by nuclear factor kappa B (NFkB) and tumor necrosis factor (TNF). Other autoinflammatory diseases are mediated by mechanisms distinct from these or by processes yet to be determined. There is growing appreciation that autoinflammatory pathways contribute to and modulate the presentation of common diseases. (See 'Overview of pathogenesis' above and 'Categories of autoinflammatory diseases' above.)
●Clinical manifestations and diagnosis – Autoinflammatory diseases should be suspected when a patient presents with recurrent episodes of inflammation over months or years unexplained by another cause. Most patients develop their first disease manifestations in childhood. Manifestations may include fever, rash, serositis (pleuritis or peritonitis), arthritis, meningitis, uveitis, enterocolitis, vasculitis, and basal ganglia calcifications. The clinical pattern is evaluated to determine if it is consistent with one of the major autoinflammatory disorders. Genetic testing is typically then employed to confirm a clinically suspected entity. (See 'Hallmarks of the autoinflammatory diseases' above and 'Diagnosis' above.)
•Disorders associated with fever – Autoinflammatory syndromes associated with fever include familial Mediterranean fever (FMF), TNF receptor-1 associated periodic syndrome (TRAPS), the hyperimmunoglobulin D syndrome (HIDS), and the cryopyrin-associated periodic fever syndromes (CAPS; includes familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome [MWS], and neonatal-onset multisystem inflammatory disorder [NOMID]). (See 'Diagnosis' above.)
•Disorders not associated with fever – Autoinflammatory disorders that do not present with fever as a major manifestation of the disease include deficiency of the interleukin (IL) 1 receptor antagonist (DIRA) that causes osteomyelitis with periostitis and pustulosis; the syndrome of pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA); Blau syndrome (juvenile systemic granulomatosis); deficiency of adenosine deaminase 2 (DADA2) that can present with stroke; and deficiency of the IL-36 receptor antagonist (DITRA) that causes generalized pustular psoriasis. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis includes unusual infections such as relapsing fever, malignancy, cyclic neutropenia, and systemic juvenile idiopathic arthritis (sJIA)/adult-onset Still's disease (AOSD). It also includes periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA), a relatively common syndrome of recurrent unexplained fever in children. (See 'Differential diagnosis' above.)
●Treatment – Treatment is focused on blocking the primary inflammatory pathway involved in each disease with biologic agents that inhibit various cytokines. Nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids may play important ancillary roles. (See 'Treatment' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
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