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Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)

Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)
Literature review current through: Jan 2024.
This topic last updated: Nov 30, 2022.

INTRODUCTION — Autoinflammatory diseases are conditions of pathogenic chronic or recurrent inflammation mediated by antigen-independent hyperactivation of the immune system [1]. A broad spectrum of autoinflammatory diseases is now recognized, differing markedly from one another in pathogenesis and clinical manifestations. This topic review covers autoinflammatory diseases that originate in aberrant interferon (IFN) production and signaling, also termed the interferonopathies [2,3]. A general discussion of autoinflammatory diseases is available separately. (See "The autoinflammatory diseases: An overview".)

Additional topics cover other specific autoinflammatory diseases:

(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

(See "Cryopyrin-associated periodic syndromes and related disorders".)

(See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)

(See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

(See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)".)

(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)".)

OVERVIEW OF PATHOGENESIS — IFNs are cytokines involved in immune defense. Defects in IFNs affect the innate immune response and can also result in autoimmunity.

Three families of IFNs are recognized (figure 1) [4-6]:

Type I IFNs – The type I IFNs are IFN-alpha (13 isoforms), IFN-beta, IFN-epsilon, IFN-kappa, and IFN-omega. Cytokines in this large family are produced by almost all nucleated cells as a key element of antiviral defense. They bind the IFN-alpha receptor (IFNAR; a dimer of the proteins IFNAR1 and IFNAR2). IFN-beta can also signal though IFNAR1 alone. IFNAR is expressed broadly and transduces signals via the intracellular tyrosine kinases Janus kinase (JAK) 1 and tyrosine kinase (TYK) 2 to modulate gene transcription via a transcription factor complex consisting of signal transducer and activator of transcription (STAT) 1, STAT2, and IFN regulatory factor (IRF) 9. Type I IFNs also signal via STAT3 and through STAT-independent pathways [5]. Type I IFNs induce fever by stimulating prostaglandin production in the hypothalamus, though they are weaker pyrogens than interleukin (IL) 1 [7].

Type II IFNs – The type II IFNs are limited to IFN-gamma. This cytokine is produced by T cells (T helper type 1 [Th1] CD4 cells and CD8 cells), natural killer (NK) cells, natural killer T (NKT) cells, and some innate lymphoid cells. It binds the widely expressed receptor IFN-gamma receptor (IFNGR; a dimer of IFNGR1 and IFNGR2). IFN-gamma activates multiple effector functions in macrophages, including antigen presentation via class I and class II major histocompatibility complex (MHC) molecules, and promotes Th1 differentiation in CD4 T cells, among many other effects [6]. IFNGR signals via JAK1 and JAK2, generating a STAT1 dimer as its downstream transcription factor.

Type III IFNs – The type III IFNs are the four isoforms of IFN-lambda. These cytokines can be produced by both stromal and immune cells and are less well understood than type I and II IFNs. They bind a receptor formed from the heterodimer of IL-10 receptor 2 (IL10R2) and IFN-lambda receptor 1 (IFNLR1), expressed predominantly by epithelial cells and neutrophils. Downstream signaling is shared with type I IFNs, JAK1 and TYK2, leading to formation of the STAT1/STAT2/IRF9 transcription factor complex, although, in some contexts, TYK2 appears dispensable [8]. Compared with type I IFN, signals from type III IFN are less explosive but more sustained and play a role in host protection at skin and mucosal barriers and in the central nervous system (CNS) [5].

IFNs modulate expression of up to 10 percent of human genes with consequences including blockade of viral entry, replication, and survival [4,9]. Expression of a core set of these genes, many conserved across species, represents an "IFN signature" that can help in the recognition of the interferonopathies, although signaling overlap between the different IFN classes limits specificity [10,11].

The known interferonopathies are primarily due to aberrant production or signaling of type I IFNs [3,12]. A broad range of genetic defects can cause exaggerated type I IFN signaling. Each mutation will also lead to additional clinical manifestations specific to the gene and the host context. Under normal circumstances, these cytokines are generated in response to viral infection. Viruses engulfed in vesicles are sensed via Toll-like receptors (TLRs) located in endosomes (TLR3 for double-stranded ribonucleic acid [dsRNA], TLR7 and TLR8 for single-stranded RNA, TLR9 for cytosine-phosphodiester bond-guanine deoxyribonucleic acid [CpG DNA] motifs). Viruses that penetrate into the cytoplasm are detected by RNA sensors such as retinoic acid inducible gene I (RIGI) and melanoma differentiation-associated gene 5 (MDA5) and by DNA sensors such as the cyclic guanosine monophosphate-adenosine monophosphate synthetase-stimulator of IFN genes (cGAS-STING) pathway [13,14]. Interferonopathies arise when these pathways are engaged in the absence of viral infection [3,12]. This happens in four major ways:

Mutations that enable autonomous activation of sensor pathways, such as gain-of-function mutations in STING.

Failure to degrade or otherwise process endogenous nucleotides, leading to accumulation of host DNA (including mitochondrial DNA) or RNA that triggers sensor proteins. Examples include mutations affecting the DNA-degrading enzyme three-prime repair exonuclease (TREX) 1.

Mutations affecting the clearance of damaged proteins via the proteasome, leading to cellular stress. Examples include defects in proteasome subunit beta (PSMB) type 8 (PSMB8) leading to chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE).

Loss of negative regulation of IFN signaling, as by mutations in ubiquitin-specific peptidase 18 (USP18).

Although autoinflammatory diseases are typically conceptualized as innate immune defects, elevated type I IFN signaling is observed in autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, dermatomyositis, and scleroderma [15]. Indeed, TREX1 deficiency can present as SLE [16]. Correspondingly, patients with genetically confirmed interferonopathies can develop autoantibodies including antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), rheumatoid factor (RF), anticyclic citrullinated peptide (CCP), lupus anticoagulant, anticardiolipin, and the antineutrophil cytoplasmic antibodies (ANCA) anti-myeloperoxidase and anti-proteinase 3 [17,18]. This family of diseases therefore illustrates the interconnectedness of innate and adaptive immunity, with autoinflammation and autoimmunity as a spectrum rather than a dichotomy [1].

DIAGNOSIS — The manifestation of specific interferonopathies is presented below (see 'Selected interferonopathies' below). In general, an interferonopathy should be considered in patients presenting with manifestations including the following:

Persistent systemic inflammation with fever, reflecting the role of type I IFNs as endogenous pyrogens.

Cutaneous small-vessel vasculitis with acral localization (fingers, toes, ears, nose, cheeks). Initial lesions can resemble chilblains (see "Pernio (chilblains)"). The localization appears to reflect exacerbation of inflammation by cool temperatures.

Basal ganglia calcifications resembling those observed in in utero infection with TORCH organisms (Toxoplasmosis, Other [syphilis], Rubella, Cytomegalovirus [CMV], Herpes simplex virus). These calcifications can cause seizures or neurocognitive impairment but may also be asymptomatic.

Unexplained recurrent inflammation affecting the lung, colon, and/or skin.

Poor response of clinical manifestations to interleukin (IL) 1 inhibition.

Laboratory studies — Routine laboratory tests are nonspecific. Inflammatory markers are typically elevated, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelet count. Anemia is common, observed in almost 70 percent in one series [17]. Levels of the IFN-induced chemokine C-X-C motif chemokine ligand 10 (CXCL10; also termed IFN-gamma-induced protein 10 [IP-10]) can correlate with disease activity [17]. Autoantibodies are commonly noted.

Levels of IFNs are difficult to measure directly in blood without highly refined experimental methods [19]. However, evidence for their presence can be obtained through the detection of a so-called "IFN signature" in circulating leukocytes, either in whole-blood messenger RNA (mRNA) or in mRNA extracted from purified peripheral blood mononuclear cells (PBMCs). Multiple groups have identified panels of IFN-stimulated genes (ISGs) that reliably reflect cytokine exposure. For example, one signature is based upon the genes IFN-alpha inducible protein 27 (IFI27), IFN-induced protein 44 like (IFI44L), IFN-induced protein with tetratricopeptide repeats 1 (IFIT1), ISG15 ubiquitin-like modifier (ISG15), radical S-adenosyl methionine domain containing 2 (RSAD2), and sialic acid binding Ig-like lectin 1 (SIGLEC1), while another employs 28 genes [10,11]. Expression in patients is compared with that in healthy controls. This test is not available on a commercial basis, though it is routinely conducted by research laboratories in many major medical centers.

Imaging — Imaging studies typically correspond to the clinical manifestations and are nonspecific, although basal ganglia calcifications in a patient without a history of TORCH infections strongly suggests an interferonopathy.

Therapeutic trial — Another approach to diagnosis is by therapeutic trial with a Janus kinase (JAK) 1 inhibitor, analogous to the use of IL-1 blockade with anakinra in the inflammasomopathies (see "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)"). Type I IFNs signal in part via JAK1. Thus, patients with a type I interferonopathy would be expected to respond to JAK inhibition with one of the commercially available agents (tofacitinib, JAK1 and JAK3; ruxolitinib and baricitinib, JAK1 and JAK2; or upadacitinib, JAK1). Such response was observed in a study of baricitinib treatment in patients with an interferonopathy [17]. Determining the IFN signature can identify patients who may benefit from JAK inhibition [20]. However, some diseases that are not overtly interferonopathies respond to these agents (eg, rheumatoid arthritis). Partial responses may be diagnostically difficult to interpret, and treatment of interferonopathy mimics, such as infection or malignancy, could potentially be unsafe. An empiric therapeutic trial should therefore be pursued with caution.

Molecular testing — Definitive diagnosis of the interferonopathies is via gene sequencing. Multiple companies now offer targeted sequencing of genes implicated in the autoinflammatory diseases, including the interferonopathies, typically with a turnaround time measured in weeks. Patients who express clinical features suggestive of an interferonopathy, but in whom commercial testing fails to establish a diagnosis, may have a mosaic or nongermline mutation. In such cases, consultation with genetics experts and/or referral to a center with expertise in these disorders is advised.

SELECTED INTERFERONOPATHIES — Aberrant type I IFN production can result from disordered nucleic acid sensing, failure to degrade or modify endogenous nucleic acids, defective protein degradation by the proteasome, and impaired control of IFN signaling. More than 20 diseases in this family are recognized, and new interferonopathies are regularly identified [12]. We discuss here representative disorders in each group.

Enhanced nucleic acid sensing

STING-associated vasculopathy with onset in infancy (SAVI) — Stimulator of IFN genes (STING) associated vasculopathy with onset in infancy (SAVI; MIM #615934) is an autoinflammatory disease caused by gain-of-function mutations in the gene encoding STING (transmembrane protein 173 [TMEM173]) [21]. Under normal conditions, STING is engaged by cyclic dinucleotides generated from viral DNA by cyclic guanosine monophosphate-adenosine monophosphate synthetase (cGAS), leading to induction of type I IFN production [14]. STING can also sense pathogens directly [22]. Constitutive activation of STING leads to maximal upregulation of IFN-beta transcription and IFN-regulated gene expression, with constitutive phosphorylation of signal transducer and activator of transcription (STAT) 1. In a murine model, T cells, but not cGAS or IFN-alpha receptor (IFNAR), mediate lung disease [23].

Patients generally present in early infancy with tachypnea and/or rashes (telangiectasia, pustules, and/or blisters) on the face, hand, and feet that worsen with cold exposure and may ulcerate [21,24,25]. Most patients have recurrent low-grade fevers and develop marked vascular inflammation resulting in tissue damage. Pulmonary manifestations include interstitial lung disease, paratracheal or hilar lymphadenopathy, and lung fibrosis. Notably, the central nervous system (CNS) is typically spared. Basal ganglia calcifications occur but are less common than with other interferonopathies. Autoantibodies are common, including antinuclear antibodies (ANAs), rheumatoid factor (RF), and anti-neutrophil cytoplasmic antibodies (ANCA) [25]. Patients have not responded to systemic glucocorticoids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), or biologic agents. Blockade of IFN signaling with a Janus kinase (JAK) inhibitor is a potential therapeutic strategy, although response is typically partial [17,25].

Dysregulated trafficking of STING and associated enhanced IFN production have been observed in patients with mutations affecting coatomer protein subunit alpha (COPA) [26-28]. The resulting condition, presenting as arthritis and lung disease, is often categorized with the interferonopathies, but, because of alterations in thymic selection and associated T cell autoreactivity, the mechanisms of disease remains uncertain [29]. COPA is discussed separately. (See "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'COPA syndrome'.)

Failure to degrade endogenous nucleic acids

Aicardi-Goutières syndrome — Aicardi-Goutières syndrome (AGS) was the first disease recognized as an interferonopathy [30]. AGS represents a family of conditions with related clinical presentations, most commonly reflecting failure to properly degrade host RNA or DNA. Accumulated nucleic acids trigger intracellular sensor proteins, engaging host antiviral defense mechanisms in the absence of the ability to clear the offending "pathogen." Patients may present very early in life or in a delayed fashion. Manifestations include fevers, acral vasculopathy/chilblains, and CNS inflammation, with seizures, basal ganglia calcifications, and progressive neurocognitive impairment. Multiple genetic causes have been recognized:

AGS1 (MIM #225750) – Three-prime repair exonuclease 1 (TREX1), DNA degradation.

AGS2 (MIM #610181) – Ribonuclease H2 endonuclease complex subunit B (RNASEH2B), RNA degradation.

AGS3 (MIM #610329) – Ribonuclease H2 endonuclease complex subunit C (RNASEH2C), RNA degradation.

AGS4 (MIM #610333) – Ribonuclease H2 endonuclease complex subunit A (RNASEH2A), RNA degradation.

AGS5 (MIM #612952) – SAM domain and HD domain 1 (SAMHD1), DNA degradation.

AGS6 (MIM # 615010) – Adenosine deaminase acting on RNA 1 (ADAR1), RNA degradation.

AGS7 (MIM #615846) – IFN-induced helicase C domain-containing protein 1 (IFIH1), encoding the protein melanoma-differentiation-associated protein 5 (MDA5) involved in sensing of cytoplasmic double-stranded RNA (dsRNA). Some patients may present with reduced antiviral immunity due to impaired recognition of viral nucleic acids [31].

AGS 1 through 6 are believed to reflect loss of gene function. AGS6 arises through an impaired ability to neutralize RNA generated from endogenous retroviruses [32]. AGS7 represents a genetic gain of function and so bears closer pathophysiologic resemblance to SAVI than to the other forms of AGS. Patients with pathogenic variants in IFIH1 (encoding the cytoplasmic RNA sensor MDA5) may present as AGS with neurologic and cutaneous symptoms, but some are asymptomatic or can express a genetic syndrome of valvular calcification, dental anomalies, osteopenia, and acroosteolysis termed Singleton-Merton syndrome. Affected members of a family with atypical Singleton-Merton syndrome were found to have pathogenic variants in another cytoplasmic RNA sensor, retinoic acid inducible gene I (RIGI) [33].

DNase II deficiency — DNase II is a DNA-degrading enzyme localized to the lysosome. Patients with pathogenic variants affecting the gene DNASE2 develop exaggerated IFN signaling, as well as elevation in proinflammatory cytokines including tumor necrosis factor (TNF) alpha. They present with neonatal pancytopenia, intermittent fevers, cholestatic hepatitis, proteinuria, and arthritis [34].

PNPase deficiency — Abnormal activation of IFN signaling has been reported in four patients with pathogenic variants in polyribonucleotide nucleotidyltransferase 1 (PNPT1), encoding the enzyme polynucleotide phosphorylase (PNPase). This protein is responsible for degrading double-stranded mitochondrial RNA [35]. Excess RNA is sensed by MDA5 and RIGI, triggering type I IFN production. Patients presented in childhood with failure to thrive and neurologic compromise; the presence of fevers and systemic inflammation was not reported.

Defective proteasome function

CANDLE — Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE; MIM #256040) is one of several overlapping disorders resulting from mutations affecting PSMB8 or related proteasome proteins, including those encoded by the genes proteasome subunit alpha type 3 (PSMA3), PSMB4, and PSMB9. Pathogenic variants in proteasome maturation protein (POMP) cause a CANDLE-like immune dysregulatory syndrome [36]. CANDLE is also known as proteasome-associated autoinflammatory syndrome (PRAAS). Most patients exhibit homozygous or compound heterozygous deficiency of a single gene, but patients bearing heterozygous mutations in two of these genes have been reported (digenic inheritance) [37-40]. Proteasome dysfunction results in a cellular unfolded protein response, leading to inappropriate production of type I and type II IFNs, as well as elevation in interleukin (IL) 6 [39,41]. Immune activation exacerbates these conditions because activated immune cells exhibit accelerated protein synthesis and reactive oxygen species production, increasing the "load" of defective or damaged proteins requiring proteasome-mediated disposal [42].

Patients typically present in the first months of life, developing recurrent skin eruptions with infiltrating neutrophils and mononuclear cells, hepatomegaly, arthralgias/arthritis, and systemic inflammation, sometimes including fevers. Lipodystrophy develops subsequently. Basal ganglia calcifications may occur. Despite elevation in IL-6 levels, blockade of the IL-6 receptor with tocilizumab is ineffective, as is antagonism of IL-1 [41]. Treatment with JAK inhibition can be effective [17]. (See 'Treatment' below.)

Defective regulation of interferon signaling

Pseudo-TORCH syndrome — Ubiquitin-specific peptidase 18 (USP18) is an IFN-induced protein that provides negative feedback on type I IFN signaling by blocking IFNAR2 binding to JAK1 [43]. Deficiency of USP18 presents in infancy with clinical features resembling congenital TORCH infection, including microcephaly, basal ganglia calcifications, and neurocognitive impairment [44]. A ubiquitin-like modifier, ISG15, is another negative regulator of IFN signaling that acts by promoting the longevity of USP18. Patients lacking ISG15 present similarly to patients lacking USP18, but in a milder form [45].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of the interferonopathies includes unusual infections such as relapsing fever, malignancy and premalignant states (eg, Schnitzler syndrome), cyclic neutropenia, and systemic juvenile idiopathic arthritis (sJIA)/adult-onset Still's disease (AOSD) (see "The autoinflammatory diseases: An overview"). Specific to the interferonopathies, the differential diagnosis includes other diseases manifested by elevated IFN and its consequences. Thus, interferonopathies may mimic congenital TORCH (Toxoplasmosis, Other [syphilis], Rubella, Cytomegalovirus [CMV], Herpes simplex virus) infections; acute or chronic viral infection (human immunodeficiency virus [HIV], Epstein-Barr virus [EBV], CMV, hepatitis viruses); and the rheumatic diseases (systemic lupus erythematosus [SLE], rheumatoid arthritis, dermatomyositis, scleroderma, and overlap syndromes including mixed connective tissue disease). Small- and medium-vessel vasculitides, including cryoglobulinemia, drug-induced vasculitis, and antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, may present with a cutaneous vasculopathy similar to that of interferonopathies. Autoantibodies associated with SLE (including antinuclear antibody [ANA], anti-double-stranded DNA [dsDNA], lupus anticoagulant, and antiphospholipid antibodies); rheumatoid arthritis (rheumatoid factor [RF] and anticyclic citrullinated peptide [CCP]); and vasculitis (ANCA, both anti-myeloperoxidase [MPO] and antiproteinase 3 [PR3]) also can be observed in patients with an interferonopathy [17,18].

Interferonopathies should be considered when symptoms of autoimmune conditions develop at an uncommonly early age, are unusually severe, do not respond to routine treatments, or are found in multiple family members. Similarly, organ involvement not usually seen in viral infections or rheumatologic diseases, such as hepatitis, encephalopathy, basal ganglia calcifications, and pneumonitis, can suggest that the patient does not have one of the more common polygenic autoimmune diseases. Confirmation usually requires genetic testing for pathogenic variants in interferonopathy-associated genes.

TREATMENT — Glucocorticoids have been the mainstay of interferonopathy management but are accompanied by substantial toxicity (see "Major adverse effects of systemic glucocorticoids"). Prednisone at a dose of 1 mg/kg twice daily is still often the initial treatment until the specific interferonopathy is identified. Patients in extremis initially may be treated with pulsed-dose methylprednisolone (30 mg/kg/day, maximum 1000 mg). As soon as is clinically appropriate, more specific antiinflammatory agents are added to allow tapering of glucocorticoids. As an example, with chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE) syndrome, methotrexate may provide some steroid-sparing effect, but interleukin (IL) 1 and IL-6 blockade are largely ineffective [41]. Given the role of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling downstream of the IFN-alpha receptor (IFNAR), JAK inhibitors are now the mainstay of treatment for the interferonopathies [46].

In one study, 18 patients with an interferonopathy received the JAK1/2 inhibitor baricitinib over a mean of three years [17]. Results were as follows:

Ten patients with CANDLE – Nine patients exhibited a meaningful clinical response, including of 5 of 10 (50 percent) who achieved clinical remission off glucocorticoids.

Four patients with stimulator of IFN genes (STING) associated vasculopathy with onset in infancy (SAVI) – Partial response in three of four patients.

Four patients with another interferonopathy, two without genetic diagnosis – Partial response in two of four patients, including one patient with Aicardi-Goutières syndrome type 5 (AGS5; homozygous SAMHD1 deletion).

The clinical response to baricitinib correlated with markers of attenuated IFN signaling, including improvement in the peripheral blood IFN signature, STAT1 phosphorylation, and levels of circulating C-X-C motif chemokine ligand 10 (CXCL10). Correspondingly, excess IFN signaling proved more easily controlled in CANDLE than in SAVI. Toxicities observed include upper respiratory tract infection, herpes zoster (two patients), and viremia with the BK polyomavirus (nine patients). There are also case reports of clinical improvement after treatment with the JAK inhibitors ruxolitinib (JAK1/2 inhibitor) and tofacitinib (JAK1/3 inhibitor) [47-51]. Small-molecule inhibitors of STING are in development, as are inhibitors of tyrosine kinase (TYK) 2, which could offer additional selectivity by blocking type I IFN signaling but not that of type II or type III IFNs [8,52].

BK virus reactivation has been reported in patients with interferonopathies treated with JAK inhibitors, posing a potential risk for BK nephropathy. Guidelines recommend BK viral load measurement in blood and urine at baseline and at each follow-up visit, together with urinalysis and blood urea nitrogen (BUN)/creatinine assessment, with consideration to limiting immunosuppression to moderate any detected viremia [46]. Interferonopathies may affect the kidney directly or in synergy with other infectious or genetic factors (in particular the inherited apolipoprotein L1 [APOL1] high-risk genotypes), further underscoring the importance of monitoring kidney function in these patients [53].

Other experimental approaches for interferonopathies include the use of reverse transcriptase inhibitors to decrease expression of endogenous retroviruses and acceleration of autophagy-mediated clearance of cytoplasmic nucleic acids via inhibition of mammalian (mechanistic) target of rapamycin (mTOR) [12]. The role of gene therapy and hematopoietic cell transplantation remains unknown, although successful transplantation has been reported [36].

SUMMARY

Definition – The autoinflammatory diseases constitute a family of disorders characterized by hyperactivation of inflammatory pathways in the absence of antigen-directed autoimmunity. (See 'Introduction' above.)

Pathogenesis – Autoinflammatory diseases mediated by mutations affecting interferon (IFN) signaling are called the interferonopathies. IFNs are a family of proinflammatory cytokines that mediate defense against viruses, along with other immune roles. Most interferonopathies reflect excessive type I IFN signaling. (See 'Overview of pathogenesis' above.)

Clinical presentation and diagnosis – An interferonopathy should be suspected in patients presenting with inflammation recurrent or persistent over months or years unexplained by another cause. Most patients develop initial disease manifestations in childhood. Features can include fever; vasculitic rashes, especially in areas exposed to cold (fingers, nose, ears, cheeks); interstitial lung disease; and basal ganglia calcifications resembling congenital TORCH (Toxoplasmosis, Other [syphilis], Rubella, Cytomegalovirus [CMV], Herpes simplex virus) infections. Unlike most other autoinflammatory diseases, the interferonopathies may feature circulating autoantibodies including rheumatoid factor (RF), cyclic citrullinated peptide (CCP), antinuclear antibody (ANA), and antineutrophil cytoplasmic autoantibody (ANCA). Definitive diagnosis of the interferonopathies is by genetic testing. Research laboratories can assess the expression of IFN-stimulated genes in peripheral blood leukocytes, though commercial testing for this "IFN signature" is not yet available. (See 'Diagnosis' above and 'Selected interferonopathies' above.)

Differential diagnosis – The differential diagnosis includes unusual infections such as congenital TORCH infections and relapsing fever, malignancy, cyclic neutropenia, systemic juvenile idiopathic arthritis (sJIA)/adult-onset Still's disease (AOSD), and rheumatic diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, and ANCA-associated vasculitis. (See 'Differential diagnosis' above.)

Treatment – Treatment of the interferonopathies varies with etiology. Glucocorticoids can be effective in the short term. Blockade of Janus kinases (JAKs) provides substantial relief for many patients. (See 'Treatment' above.)

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Topic 116307 Version 7.0

References

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