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Dermatologic Manifestations of Noninflammasome-Mediated Autoinflammatory Diseases

Open AccessPublished:December 15, 2022DOI:https://doi.org/10.1016/j.xjidi.2022.100176
      Autoinflammatory diseases (AIDs) arise from disturbances that alter interactions of immune cells and tissues. They give rise to prominent (auto)inflammation in the absence of aberrant autoantibodies and/or autoreactive T cells. AIDs that are predominantly caused by changes in the inflammasome pathways, such as the NLRP3- or pyrin-associated inflammasome, have gained substantial attention over the last years. However, AIDs resulting primarily from other changes in the defense system of the innate immune system are less well-studied. These noninflammasome-mediated AIDs relate to, for example, disturbance in the TNF or IFN signaling pathways or aberrations in genes affecting the IL-1RA. The spectrum of clinical signs and symptoms of these conditions is vast. Thus, recognizing early cutaneous signs constitutes an important step in differential diagnoses for dermatologists and other physicians. This review provides an overview of the pathogenesis, clinical presentation, and available treatment options highlighting dermatologic aspects of noninflammasome-mediated AIDs.

      Abbreviations:

      AID (autoinflammatory disease), ANCA (antineutrophil cytoplasmic antibody), AOSD (adult-onset Still disease), BASDAI (Bath Ankylosing Spondylitis Activity Index), CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), CAPS (cryopyrin-associated periodic syndrome), CRD (cysteine-rich domain), DIRA (deficiency of IL-1RA), DITRA (deficiency of IL-36RA), ER (endoplasmic reticulum), ESR (erythrocyte sedimentation rate), FMF (familial Mediterranean fever), MAS (macrophage activation syndrome), M-CSF (macrophage colony-stimulating factor), NET (neutrophil extracellular trap), NOS (nitrous oxide), NSAID (nonsteroidal anti-inflammatory drug), NUD (neutrophilic urticarial dermatosis), PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), PRAAS (proteosome-associated autoinflammatory disease), PKR (protein kinase R), SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis syndrome), SAVI (STING-associated vasculopathy with onset in infancy), SchS (Schnitzler syndrome), STAT (signal transducer and activator of transcription), sTNFR (soluble TNF receptor), Th17 (T helper 17), TNFR (TNF receptor), TRAPS (TNF receptor‒associated autoinflammatory disease), VAS (Visual Analog Scale)

      Introduction

      Most patients with autoinflammatory diseases (AIDs) present with recurrent flares of fever, showing several additional systemic and cutaneous signs and symptoms. Because skin findings encompass a wide range of possible rashes and often overlap with nonautoinflammatory conditions, physicians encountering AIDs should be aware of common skin lesions in the disease course. In addition, knowledge of the underlying pathogenic mechanism and clinical presentation shortens the time of diagnosis and therefore lessens the disease burden for patients. In this paper, we present a comprehensive review of cutaneous lesions seen in noninflammasome-mediated AIDs and discuss the general clinical presentation of affected patients as well as the underlying mechanism leading to the pathophysiology of the disease.

      Cutaneous Signs seen in Noninflammasome-Mediated AIDs

      AIDs predominantly driven by gain-of-function mutations in one of the inflammasome platforms (e.g., NLRP3 inflammasome leading to cryopyrin-associated periodic syndrome [CAPS] or the pyrin inflammasome leading to familial Mediterranean fever [FMF]) commonly show high levels of IL-1β resulting from the immediate impact of the mutation on the function of the inflammasome (
      • Sangiorgi E.
      • Rigante D.
      The clinical chameleon of autoinflammatory diseases in children.
      ). We recently reviewed cutaneous signs seen in inflammasome-mediated AIDs (
      • Borst C.
      • Symmank D.
      • Drach M.
      • Weninger W.
      Cutaneous signs and mechanisms of inflammasomopathies.
      ). Although the inflammasome can be triggered through various factors, noninflammasome-mediated AIDs show no direct mutation in the building blocks of the inflammasome. Symptoms seen in noninflammasome-mediated AIDs are instead underlined by the disruption of various cytokine signaling pathways or receptors with effects on tissue-resident cells as well as infiltrating immune cells (Figure 1). The commonly observed overproduction of proinflammatory cytokines may have detrimental effects on tissues. The TNF, IFNs, and the IL-1 family are three of the key cytokine pathways involved in the pathophysiology of AIDs. Because AIDs present with diverse symptoms, diagnosis requires an interdisciplinary workup of the patient. Skin findings can range from migratory, erythematous patches and plaques (TNF receptor‒associated autoinflammatory disease [TRAPS]) over a unique combination of progressive lipodystrophy, violaceous plaques with raised borders, and violaceous swellings of the lips and eyelids (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature [CANDLE] and generalized erythema with studded pustules—deficiency of IL-36RA [DITRA]) to urticaria-like lesions (Schnitzler syndrome [SchS]) (Table 1). Histopathological findings of skin biopsies can be found in Table 2. We aim to highlight the dermatologic aspects of these diseases and provide a working tool for physicians in clinical skin examination.
      Figure thumbnail gr1
      Figure 1Cytokine (receptor) associated AIDs. The circle in the middle shows the skin (epidermis + dermis) as well as immune cells traveling in the vessels. Top panel: IL-1RA family‒associated disease includes DITRA (left top panel), mainly affecting keratinocytes, and DIRA (right top panel), affecting myeloid cells as well as other cell types. In DITRA, IL-36RA hinders the binding of IL-36 to the receptor, which provides a mechanism regulating proinflammatory cytokine release. Without IL-36RA, IL-36 binds to the receptor and signals in a MyD88-dependent manner. Proinflammatory cytokine production is elevated through the NF-kB and MAPK pathways. A similar mechanism is seen for the loss of IL-1RA in DITRA. Middle panel: TNF receptor‒associated disease TRAPS (right middle panel) shows the upregulation of ROS through processes inside the mitochondrion as well as the UPR induced by the accumulation of misfolded (red shining receptors with teal filling) TNF receptors. Other possible theories related to the pathophysiology of TRAPS are explained in detail in . Bottom panel: Interferonopathies show CANDLE (left bottom panel) and SAVI (right bottom panel). CANDLE shows a failed proteasomal degradation of ubiquitinated proteins, which is sensed by protein kinase R owing to the accumulation of IL-24. Inflammation leads to the damage of proteins and further to an upregulated de novo synthesis of proteins and type 1 IFN (mainly IFN-α/γ), which leads to a vicious cycle of autostimulation. It also stimulates surrounding cells. SAVI shows a constitutional activation of the viral sensor STING, which is bound to the endoplasmic reticulum. Activated STING wanders through the Golgi apparatus near the nucleus, upregulating type 1 IFNs production through IRF3. In both cases, type I IFN binds to the IFN receptor and signals through the Jak‒STAT pathway to amplify the inflammatory response. AID, autoinflammatory disease; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; DIRA, deficiency of IL-1RA; DITRA, deficiency of IL-36RA; SAVI, STING-associated vasculopathy with onset in infancy; STAT, signal transducer and activator of transcription; TRAPS, TNF receptor‒associated autoinflammatory disease; UPR, unfolded protein response.
      Table 1Cutaneous Signs in Noninflammasome-Mediated AIDs
      Cytokine (Receptor) Associated AIDsCutaneous SignLocalizationOnsetDuration of FlareTrigger of FlareClass
      Class: classification based on Figueras-Nart et al. (2019): (1) maculopapular rashes or inflammatory plaques; (2) urticarial rashes; (3) pustular, pyogenic, or neutrophilic dermatosis-like rashes; (4) panniculitis or subcutaneous nodules; (5) vasculitis or vasculopathy; (6) hyperkeratotic lesions; (7) hyperpigmented lesions; (8) bullous lesions; and (9) aphthous lesions.
      TRAPSMigratory erythematous plaques and patches; periorbital edemaTrunk, extremities, faceChildhood2‒3 weeksUnprovoked or by stress, exercise, infection, injury, hormonal changes(1)
      IFN associated
      CANDLEErythematous to violaceus, edematous maculae; erythematous or violaceous, pruritic plaques; edema; lipodystrophyAcra; face, trunk, extremities; lips, eyelids; initially in the face, then progression to trunk and extremitiesNeonatal period1 dayStress, cold temperature, infections(1)
      SAVIErythematous to violaceous, infiltrated plaques, ulcers, tissue loss; erythema, ear, and saddle-nose deformitiesAcra, extremities; faceInfancyUndefinedCold temperature, unprovoked(5)
      IL receptor signaling defects
      DIRAErythematous plaques with pustules, nail dystrophyGeneralized, nailsBirth, neonatal periodUndefinedTrauma (pathergy), unprovoked(3)
      DITRAErythematous plaques with pustules; nail dystrophy; benign migratory glossitis, scrotal tongueGeneralized; nails, tongueNeonatal period, infancy, childhood, adulthoodFew days to 1 weekInfection, stress, drug intake, drug withdrawal, menstruation, pregnancy, red wine, surgery(3)
      Other or Polygenic Autoinflammatory DiseasesCutaneous SignLocalizationOnsetDuration of FlareTrigger of FlareClass
      Class: classification based on Figueras-Nart et al. (2019): (1) maculopapular rashes or inflammatory plaques; (2) urticarial rashes; (3) pustular, pyogenic, or neutrophilic dermatosis-like rashes; (4) panniculitis or subcutaneous nodules; (5) vasculitis or vasculopathy; (6) hyperkeratotic lesions; (7) hyperpigmented lesions; (8) bullous lesions; and (9) aphthous lesions.
      SAPHOPustules; acnePalms, soles; face, neck, trunk, and extremitiesAdulthoodUndefinedUnknown(3)
      AOSDEvanescent, salmon-colored macular or maculopapular rash; papules, plaques, (erythematous, urticaria-like, heliotrope-like, lichenoid)Trunk, extremities; head, trunk, extremitiesAdulthoodFew hoursInfection, unprovoked(1)
      SchSUrticarial rashTrunk, extremities, rarely head or neckAdulthood12-48 hoursStress, physical work, alcohol, spicy food, cold or hot temperatures(2)
      PFAPAAphtaeEnoralInfancy, childhood1‒10 daysunknown(9)
      Abbreviations: AID, autoinflammatory syndrome; AOSD, adult-onset Still disease; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; DIRA, deficiency of IL-1RA; DITRA, deficiency of IL-36RA; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome; SAVI, STING-associated vasculopathy with onset in infancy; SchS, Schnitzler syndrome; TRAPS, TNF receptor‒associated autoinflammatory disease.
      The table provides an overview of discussed AIDs. The onset and localization of cutaneous lesions as well as the duration and the trigger of flare-up of the disease are listed. Each AID is sorted into the classification schemata proposed by
      • Figueras-Nart I.
      • Mascaró J.M.
      • Solanich X.
      • Hernández-Rodríguez J.
      Dermatologic and dermatopathologic features of monogenic autoinflammatory diseases.
      .
      1 Class: classification based on
      • Figueras-Nart I.
      • Mascaró J.M.
      • Solanich X.
      • Hernández-Rodríguez J.
      Dermatologic and dermatopathologic features of monogenic autoinflammatory diseases.
      : (1) maculopapular rashes or inflammatory plaques; (2) urticarial rashes; (3) pustular, pyogenic, or neutrophilic dermatosis-like rashes; (4) panniculitis or subcutaneous nodules; (5) vasculitis or vasculopathy; (6) hyperkeratotic lesions; (7) hyperpigmented lesions; (8) bullous lesions; and (9) aphthous lesions.
      Table 2Histopathological Presentation of Noninflammasome-Mediated Autoinflammatory Diseases
      Autoinflammatory DiseaseHistopathological Signs
      TNF associated
      TRAPSNo specific pattern can be observed histopathologically; findings are rather unspecific. Most frequently, a perivascular infiltrate affecting the upper and the mid-dermal plexus can be observed, composed of lymphocytes and histiocytes (
      • Schmaltz R.
      • Vogt T.
      • Reichrath J.
      Skin manifestations in tumor necrosis factor receptor-associated periodic syndrome (TRAPS).
      ).
      IFN associated
      CANDLEThe entire dermis shows a perivascular and interstitial infiltrate consisting of mononuclear cells, neutrophils, eosinophils, and atypical myeloid cells, which could be proven (characterized) by immunohistochemistry (
      • Torrelo A.
      • Colmenero I.
      • Requena L.
      • Paller A.S.
      • Ramot Y.
      • Richard Lee C.C.
      • et al.
      Histologic and immunohistochemical features of the skin lesions in CANDLE syndrome.
      ).
      SAVIIn early lesions, dermal capillaries show signs of vasculitis with no evidence of affection of medium-sized vessels. Older lesions show signs of a vaso-occlusive disease (
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ).
      IL-1 family associated
      DIRASkin biopsy reveals a subcornear pustule accompanied by a suprabasal acantholysis. In addition, neutrophil eccrine hidradenitis could be observed (
      • Minkis K.
      • Aksentijevich I.
      • Goldbach-Mansky R.
      • Magro C.
      • Scott R.
      • Davis J.G.
      • et al.
      Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis.
      ).
      DITRAIrregularly arranged acanthosis, hyperkeratosis, and parakeratosis associated with intraepidermal spongiform pustules. Mixed superficial perivascular infiltrate (
      • Marzano A.V.
      • Damiani G.
      • Genovese G.
      • Gattorno M.
      A dermatologic perspective on autoinflammatory diseases.
      ).
      Polygenic
      SAPHOTwo main patterns can be recognized: (i) palms and soles show a psoriasiform epidermal hyperplasia with intraepidermal abscess formation accompanied by a superficial perivascular chronic inflammatory infiltrate and (ii) head and neck as well as trunk show a neutrophil-rich folliculitis and perifolliculitis (
      DermNet
      SAPHO syndrome.
      ).
      AOSDIn florid lesions, apoptotic keratinocytes especially located in the upper layer of the epidermis can be observed. The Upper to mid-dermis shows a perivascular infiltrate consisting of lymphocytes and neutrophils (
      • Lee J.Y.-Y.
      • Yang C.C.
      • Hsu M.M.-L.
      Histopathology of persistent papules and plaques in adult-onset Still’s disease.
      ).
      SchSVariable dense dermal infiltrate consisting of neutrophils arranged alongside collagen bundles without evidence of vasculitis (
      • Lipsker D.
      The Schnitzler syndrome.
      ).
      PFAPANo reports on histopathological findings.
      Abbreviations: AOSD, adult-onset Still disease; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; DIRA, deficiency of IL-1RA; DITRA, deficiency of IL-36RA; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome; SAVI, STING-associated vasculopathy with onset in infancy; SchS, Schnitzler syndrome.
      The table provides an overview of the histopathological presentation of noninflammasome-mediated autoinflammatory diseases.

      TNF receptor‒associated AIDs

      The TNF receptor (TNFR) is an essential player in the innate immune system, regulating inflammation and cell death (
      • Wang X.
      • Lin Y.
      Tumor necrosis factor and cancer, buddies or foes?.
      ). The cytokine TNFα mediates essential functions influencing cell proliferation, immune regulation, as well as cell death and survival. These functions are facilitated through the signaling of a family of TNFRs, which, if dysregulated, can lead to a wide variety of undesired symptoms (
      • Lobito A.A.
      • Gabriel T.L.
      • Medema J.P.
      • Kimberley F.C.
      Disease causing mutations in the TNF and TNFR superfamilies: focus on molecular mechanisms driving disease.
      ). The autoinflammatory TNF-associated disease (TRAPS) is associated with autosomal dominant missense mutations of the TNFRSF1A on chromosome 12 (
      • McDermott M.F.
      • Aksentijevich I.
      • Galon J.
      • McDermott E.M.
      • Ogunkolade B.W.
      • Centola M.
      • et al.
      Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.
      ). TNFRSF1A codes for the type I transmembrane protein TNFR1, and over 180 low- and high-penetrance mutations have been reported (
      • Milhavet F.
      • Cuisset L.
      • Hoffman H.M.
      • Slim R.
      • El-Shanti H.
      • Aksentijevich I.
      • et al.
      The infevers autoinflammatory mutation online registry: update with new genes and functions.
      ). Whereas low-penetrance mutations are associated with none or only mild signs of TRAPS, high-penetrance mutations are always disease-causing variants showing a fulminant phenotype (
      • Cantarini L.
      • Rigante D.
      • Merlini G.
      • Vitale A.
      • Caso F.
      • Lucherini O.M.
      • et al.
      The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
      ;
      • Gaggiano C.
      • Vitale A.
      • Obici L.
      • Merlini G.
      • Soriano A.
      • Viapiana O.
      • et al.
      Clinical features at onset and genetic characterization of pediatric and adult patients with TNF-α receptor-associated periodic syndrome (TRAPS): A series of 80 cases from the AIDA network.
      ;
      • Lachmann H.J.
      • Papa R.
      • Gerhold K.
      • Obici L.
      • Touitou I.
      • Cantarini L.
      • et al.
      The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
      ;
      • McDermott M.F.
      • Aksentijevich I.
      • Galon J.
      • McDermott E.M.
      • Ogunkolade B.W.
      • Centola M.
      • et al.
      Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.
      ;
      • Ruiz-Ortiz E.
      • Iglesias E.
      • Soriano A.
      • Buján-Rivas S.
      • Español-Rego M.
      • Castellanos-Moreira R.
      • et al.
      Disease phenotype and outcome depending on the age at disease onset in patients carrying the R92Q low-penetrance variant in TNFRSF1A gene.
      ). They disrupt structural important disulfide bonds on the protein’s ectodomain, affecting three of the four cysteine-rich domains (CRDs), which are encoded on exons 2‒6 (
      • Banner D.W.
      • D’Arcy A.
      • Janes W.
      • Gentz R.
      • Schoenfeld H.J.
      • Broger C.
      • et al.
      Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: implications for TNF receptor activation.
      ;
      UniProt Consortium
      UniProt: a worldwide hub of protein knowledge.
      ). These CRDs are essential for the initial homotrimerization (CRD1) of the receptor and its binding to TNFα (CRD2 and 3) (
      • Rebelo S.L.
      • Bainbridge S.E.
      • Amel-Kashipaz M.R.
      • Radford P.M.
      • Powell R.J.
      • Todd I.
      • et al.
      Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function.
      ).
      TNFR1 is translated into the endoplasmic reticulum (ER) and stored in the Golgi apparatus until it is transported toward the cell surface. It is either cleaved by TNFα-converting enzyme and other metalloproteases to act as a soluble TNFR (sTNFR), regulating the balance of available TNFα, or it homotrimerizes with other TNFR1 (
      • D’Alessio A.
      • Esposito B.
      • Giampietri C.
      • Ziparo E.
      • Pober J.S.
      • Filippini A.
      Plasma membrane microdomains regulate TACE-dependent TNFR1 shedding in human endothelial cells.
      ;
      • Porteu F.
      • Hieblot C.
      Tumor necrosis factor induces a selective shedding of its p75 receptor from human neutrophils.
      ). After homotrimerization, TFNR1 can bind to TNFα and associate with additional adapter proteins through lateral movement on the cell surface to initiate the signaling complex (
      • Morton P.E.
      • Perrin C.
      • Levitt J.
      • Matthews D.R.
      • Marsh R.J.
      • Pike R.
      • et al.
      TNFR1 membrane reorganization promotes distinct modes of TNFα signaling.
      ). This subsequently leads either to the activation of NF-κB and the production of proinflammatory cytokines or to caspase-induced apoptosis through the death domain of TNFR1. Endocytosis of TNFR1 stops the signaling and downmodulates available TNFR1 on the surface of the cell (Figure 2a, left panel) (
      • Jarosz-Griffiths H.H.
      • Holbrook J.
      • Lara-Reyna S.
      • McDermott M.F.
      TNF receptor signalling in autoinflammatory diseases.
      ;
      • Lobito A.A.
      • Gabriel T.L.
      • Medema J.P.
      • Kimberley F.C.
      Disease causing mutations in the TNF and TNFR superfamilies: focus on molecular mechanisms driving disease.
      ). Although the pathophysiology of TRAPS is not yet fully understood, several studies suggest multiple mechanisms leading to the hyperinflammatory state seen in this condition. These theories can be divided into four categories: mechanisms related to (i) faulty regulation and protein folding and (ii) dysregulated actions involving the TNFR1 at the cell surface as well as processes disrupting (iii) the signaling pathway or the (iv) degradation of the protein (Figure 2a, right panel).
      Figure thumbnail gr2
      Figure 2Pathogenesis of TRAPS and its associated mutations. (a) The lifecycle of the TNFR1 is depicted (left panel) with its associated possible pathogenic disruptions (right panel) through circles 1‒4. After transcription, TNFR1 is translated into the ER and is properly folded (1). TNFR1 is stored in the Golgi apparatus until it is transported toward the cell surface. One possible mechanism of TRAPS includes the misfolding of the protein, leading to ER stress, and the production of ROS and UPR. This theory seems to be involved in most pathogenic mutations, whereas the following mechanism seems to be seen in only some variants. Properly folded TNFR1 reaches the cell surface and is either cleaved by TNF-α‒converting enzyme and other metalloproteases to act as an sTNFR or homotrimerizes to bind TNF-α (2). A defective shedding of TNFR1 as sTNFR1 was seen in some patients with TRAPS. Another theory includes an autoactivation or overactivation of the TNFR1. After binding to TNF-α, TNFR1 associates with further adaptor proteins through lateral mobility to initiate the signaling complex (3). This subsequently leads either to the activation of NF-kB and the production of proinflammatory cytokines or to caspase-induced apoptosis through the death domain of TNFR1. Patients with TRAPS showed elevated microRNA important for the regulation of gene silencing. A heightened stimulation of NF-kB could also be a mechanism of TRAPS. Endocytosis of TNFR1 stops the signaling and downmodulates available TNFR1 on the surface of the cell (4). In TRAPS, not all TNFR1 mutants may be cleared through the proteasome and accumulate in the cytosol, which could lead to ligand-independent signaling processes. (b) TRAPS rash is migratory. Erythematous, nonpruritic, tender maculae and papules on the trunk progressively coalesce into patches and plaques and spread toward the limbs. Periorbital edema and less common skin manifestations are not shown. B denotes the back view, and F denotes the front view. ER, endoplasmic reticulum; sTNFR1, soluble TNFR1; TRAPS, TNF receptor‒associated autoinflammatory disease; UPR, unfolded protein response.
      Even though nearly all pathogenic mutations influence the protein’s extracellular domain, the pathogenesis proves to be an interwoven net of multiple processes influencing each other with significant variability depending on the variant.

      Clinical signs and symptoms

      From the clinical perspective, TRAPS is characterized by periodic fevers, painful erythematous migratory rashes, and periorbital edema as stipulated by the Eurofever criteria (
      • Gattorno M.
      • Hofer M.
      • Federici S.
      • Vanoni F.
      • Bovis F.
      • Aksentijevich I.
      • et al.
      Classification criteria for autoinflammatory recurrent fevers.
      ). Arthralgia, myalgia, abdominal pain, and malaise are additionally common findings together with conjunctivitis, pleuritic chest pain, headache, and lymphadenopathy. In 10% of untreated cases, secondary AA amyloidosis is possible (
      • Lachmann H.J.
      • Papa R.
      • Gerhold K.
      • Obici L.
      • Touitou I.
      • Cantarini L.
      • et al.
      The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
      ;
      • Papa R.
      • Lane T.
      • Minden K.
      • Touitou I.
      • Cantarini L.
      • Cattalini M.
      • et al.
      INSAID variant classification and Eurofever criteria guide optimal treatment strategy in patients with TRAPS: data from the Eurofever registry.
      ;
      • Toro J.R.
      • Aksentijevich I.
      • Hull K.
      • Dean J.
      • Kastner D.L.
      Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations.
      ). Disease onset is usually in childhood with a median age of 4.3 years. In 9.1% of patients, initial symptoms occur after the age of 30 years (
      • Lachmann H.J.
      • Papa R.
      • Gerhold K.
      • Obici L.
      • Touitou I.
      • Cantarini L.
      • et al.
      The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
      ). The underlying trigger can only be identified in about a third of flare ups. Common triggers include (emotional) stress; infection; injury; and hormonal changes, such as the menstrual cycle, whereas pregnancy is thought to be a mitigating factor (
      • Kimberley F.C.
      • Lobito A.A.
      • Siegel R.M.
      • Screaton G.R.
      Falling into TRAPS--receptor misfolding in the TNF receptor 1-associated periodic fever syndrome.
      ;
      • Kriegel M.A.
      • Hüffmeier U.
      • Scherb E.
      • Scheidig C.
      • Geiler T.
      • Kalden J.R.
      • et al.
      Tumor necrosis factor receptor-associated periodic syndrome characterized by a mutation affecting the cleavage site of the receptor: implications for pathogenesis.
      ;
      • Lachmann H.J.
      • Papa R.
      • Gerhold K.
      • Obici L.
      • Touitou I.
      • Cantarini L.
      • et al.
      The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
      ;
      • Papa R.
      • Lane T.
      • Minden K.
      • Touitou I.
      • Cantarini L.
      • Cattalini M.
      • et al.
      INSAID variant classification and Eurofever criteria guide optimal treatment strategy in patients with TRAPS: data from the Eurofever registry.
      ). The duration of flares varies from a few days to months, with a typical duration of 2 weeks. Flares usually occur every 6‒12 weeks. Extended periods without flares up are possible (
      • Kimberley F.C.
      • Lobito A.A.
      • Siegel R.M.
      • Screaton G.R.
      Falling into TRAPS--receptor misfolding in the TNF receptor 1-associated periodic fever syndrome.
      ;
      • Lachmann H.J.
      • Papa R.
      • Gerhold K.
      • Obici L.
      • Touitou I.
      • Cantarini L.
      • et al.
      The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
      ;
      • Papa R.
      • Lane T.
      • Minden K.
      • Touitou I.
      • Cantarini L.
      • Cattalini M.
      • et al.
      INSAID variant classification and Eurofever criteria guide optimal treatment strategy in patients with TRAPS: data from the Eurofever registry.
      ). Laboratory findings during flares include leukocytosis, elevated acute-phase reactants (CRP, serum amyloid A, haptoglobin, fibrinogen), and an increased erythrocyte sedimentation rate (ESR) (
      • Kastner D.L.
      Hereditary periodic fever syndromes.
      ;
      • Shwin K.W.
      • Lee C.-C.R.
      • Goldbach-Mansky R.
      Dermatologic manifestations of monogenic autoinflammatory diseases.
      ;
      • Toro J.R.
      • Aksentijevich I.
      • Hull K.
      • Dean J.
      • Kastner D.L.
      Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations.
      ;
      • Williamson L.M.
      • Hull D.
      • Mehta R.
      • Reeves W.G.
      • Robinson B.H.
      • Toghill P.J.
      Familial Hibernian fever.
      ).

      Cutaneous signs

      TRAPS rash is characterized by migratory, erythematous, nonpruritic, tender patches or plaques with underlying myalgias and periorbital edema (
      • Romano M.
      • Arici Z.S.
      • Piskin D.
      • Alehashemi S.
      • Aletaha D.
      • Barron K.S.
      • et al.
      The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist.
      ;
      • Toro J.R.
      • Aksentijevich I.
      • Hull K.
      • Dean J.
      • Kastner D.L.
      Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations.
      ;
      • Williamson L.M.
      • Hull D.
      • Mehta R.
      • Reeves W.G.
      • Robinson B.H.
      • Toghill P.J.
      Familial Hibernian fever.
      ). Early signs of a flare include macules and papules on the trunk that progressively coalesce into patches and plaques and spread toward the limbs (
      • Schmaltz R.
      • Vogt T.
      • Reichrath J.
      Skin manifestations in tumor necrosis factor receptor-associated periodic syndrome (TRAPS).
      ). Other manifestations include urticaria, erysipelas-like rash, small-vessel vasculitis, angioedema, and annular as well as serpiginous plaques (Figure 2b) (
      • Cattalini M.
      • Meini A.
      • Monari P.
      • Gualdi G.
      • Arisi M.
      • Pelucchi F.
      • et al.
      Recurrent migratory angioedema as cutaneous manifestation in a familiar case of TRAPS: dramatic response to anakinra.
      ;
      • Dodé C.
      • André M.
      • Bienvenu T.
      • Hausfater P.
      • Pêcheux C.
      • Bienvenu J.
      • et al.
      The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome.
      ;
      • Jain A.
      • Misra D.P.
      • Sharma A.
      • Wakhlu A.
      • Agarwal V.
      • Negi V.S.
      Vasculitis and vasculitis-like manifestations in monogenic autoinflammatory syndromes.
      ;
      • Schmaltz R.
      • Vogt T.
      • Reichrath J.
      Skin manifestations in tumor necrosis factor receptor-associated periodic syndrome (TRAPS).
      ;
      • Yao Q.
      • Englund K.A.
      • Hayden S.P.
      • Tomecki K.J.
      Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: case report and literature review.
      ;
      • Zhao M.
      • Luo Y.
      • Wu D.
      • Yang Y.
      • Sun Y.
      • Wang R.
      • et al.
      Clinical and genetic features of Chinese adult patients with tumour necrosis factor receptor-associated periodic fever syndrome.
      ).

      Treatment

      The major treatment goals of TRAPS are symptom control during flare ups, reduction of flare frequency, and prevention of secondary AA amyloidosis (
      • Romano M.
      • Arici Z.S.
      • Piskin D.
      • Alehashemi S.
      • Aletaha D.
      • Barron K.S.
      • et al.
      The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist.
      ). Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are used to gain control over symptoms during acute flare ups and are both given on demand (
      • Ter Haar N.M.
      • Oswald M.
      • Jeyaratnam J.
      • Anton J.
      • Barron K.S.
      • Brogan P.A.
      • et al.
      Recommendations for the management of autoinflammatory diseases.
      ,
      • Ter Haar N.
      • Lachmann H.
      • Özen S.
      • Woo P.
      • Uziel Y.
      • Modesto C.
      • et al.
      Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review.
      ). However, corticoid-sparing agents are usually required as maintenance therapy. The treatment of choice is IL-1 blockade with canakinumab, which is licensed for TRAPS treatment, with anakinra being a possible alternative (
      • Papa R.
      • Lane T.
      • Minden K.
      • Touitou I.
      • Cantarini L.
      • Cattalini M.
      • et al.
      INSAID variant classification and Eurofever criteria guide optimal treatment strategy in patients with TRAPS: data from the Eurofever registry.
      ;
      • Romano M.
      • Arici Z.S.
      • Piskin D.
      • Alehashemi S.
      • Aletaha D.
      • Barron K.S.
      • et al.
      The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist.
      ;
      • Ter Haar N.M.
      • Oswald M.
      • Jeyaratnam J.
      • Anton J.
      • Barron K.S.
      • Brogan P.A.
      • et al.
      Recommendations for the management of autoinflammatory diseases.
      ,
      • Ter Haar N.
      • Lachmann H.
      • Özen S.
      • Woo P.
      • Uziel Y.
      • Modesto C.
      • et al.
      Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review.
      ). Owing to its short half-life, anakinra can also be given on demand (
      • Grimwood C.
      • Despert V.
      • Jeru I.
      • Hentgen V.
      On-demand treatment with anakinra: a treatment option for selected TRAPS patients.
      ). Less beneficial treatment options include the IL-6 inhibitors tocilizumab and colchicine (
      • Kuemmerle-Deschner J.B.
      • Gautam R.
      • George A.T.
      • Raza S.
      • Lomax K.G.
      • Hur P.
      Systematic literature review of efficacy/effectiveness and safety of current therapies for the treatment of cryopyrin-associated periodic syndrome, hyperimmunoglobulin D syndrome and tumour necrosis factor receptor-associated periodic syndrome.
      ). Etanercept can be helpful in some patients. However, its effects diminish over time. Other TNFα inhibitors, such as infliximab or adalimumab, showed no clear benefit (
      • Kuemmerle-Deschner J.B.
      • Gautam R.
      • George A.T.
      • Raza S.
      • Lomax K.G.
      • Hur P.
      Systematic literature review of efficacy/effectiveness and safety of current therapies for the treatment of cryopyrin-associated periodic syndrome, hyperimmunoglobulin D syndrome and tumour necrosis factor receptor-associated periodic syndrome.
      ;
      • Ter Haar N.
      • Lachmann H.
      • Özen S.
      • Woo P.
      • Uziel Y.
      • Modesto C.
      • et al.
      Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review.
      ).

      IFN-Associated AIDs

      IFNs are the base of a complex innate immune response system to battle viral attacks. Type 1 IFNs, especially IFN-α and IFN-β, increase the resistance of cells against the replication of viruses. They also augment the presentation of viral factors for the activation of antigen-presenting cells such as dendritic cells and macrophages and activate NK cells. These mechanisms ensure that banal viral infections are often resolved without influencing the host’s daily life. In patients with interferonopathies, this vital response system is dysregulated, leading to autoinflammation and an abnormal response to viral infections and other stressors.
      In CANDLE, the IFN response system is influenced by a failed degradation mechanism caused by the reduction of the proteolytic activity of the proteasome (Figure 1, bottom left) (
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ). The steady autoinflammation is easily seen by a characteristic combination of cutaneous lesions involving violaceous plaques, edema of eyelids and lips, as well as progressive lipodystrophy present on the skin since infancy (
      • Torrelo A.
      CANDLE syndrome as a paradigm of proteasome-related autoinflammation.
      ). In contrast, STING-associated vasculopathy with onset in infancy (SAVI) is induced by a gain-of-function mutation in a viral sensor, leading to the overactivation of the IFN response system (Figure 1, bottom right) (
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ). It shows vasculitic lesions often associated with ulcers and gangrene eventually leading to loss of the acra. Although many more IFN-related AIDs are known, these two mechanistically different diseases CANDLE and SAVI present with memorable cutaneous signs starting in early infancy.

      CANDLE

      The rapid response to a viral threat leads to the production of proinflammatory cytokines, chemokines, other proteins, and small molecules such as ROS or nitrous oxide (NOS) to aid the overall microbiocidal activity. Although these factors help to eliminate the intruder or inform neighboring cells of the threat, they may have profound consequences for the cell itself. Especially, ROS and NOS may irreversibly damage proteins inside the cell (
      • Johnston-Carey H.K.
      • Pomatto L.C.D.
      • Davies K.J.A.
      The immunoproteasome in oxidative stress, aging, and disease.
      ). These damaged proteins need to be cleared in a coordinated manner to reduce stress and ensure the cell’s survival. In homeostasis, waste proteins get degraded by the proteasome after ubiquitination. In inflammation, the constitutively active proteasome gets help from the immune proteasome (
      • Ciechanover A.
      Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting.
      ;
      • Ebstein F.
      • Kloetzel P.M.
      • Krüger E.
      • Seifert U.
      Emerging roles of immunoproteasomes beyond MHC class I antigen processing.
      ;
      • Johnston-Carey H.K.
      • Pomatto L.C.D.
      • Davies K.J.A.
      The immunoproteasome in oxidative stress, aging, and disease.
      ;
      • Kasahara M.
      • Flajnik M.F.
      Origin and evolution of the specialized forms of proteasomes involved in antigen presentation.
      ). This immunoproteasome is mainly induced in hematopoietic cells through type I IFNs and helps the cell to meet the elevated demand for degrading waste proteins in a state of inflammation (
      • Aki M.
      • Shimbara N.
      • Takashina M.
      • Akiyama K.
      • Kagawa S.
      • Tamura T.
      • et al.
      Interferon-gamma induces different subunit organizations and functional diversity of proteasomes.
      ;
      • Ebstein F.
      • Kloetzel P.M.
      • Krüger E.
      • Seifert U.
      Emerging roles of immunoproteasomes beyond MHC class I antigen processing.
      ). It also heightens the degradation of pathogen-related proteins to present them on the cell’s surface through major histocompatibility complex I (
      • Ebstein F.
      • Kloetzel P.M.
      • Krüger E.
      • Seifert U.
      Emerging roles of immunoproteasomes beyond MHC class I antigen processing.
      ). The building blocks of proteosomes consist of a subunit specialized in recognizing ubiquitinated proteins transporting it to a core subunit specialized in proteolytic degradation (
      • Baumeister W.
      • Walz J.
      • Zühl F.
      • Seemüller E.
      The proteasome: paradigm of a self-compartmentalizing protease.
      ;
      • Johnston-Carey H.K.
      • Pomatto L.C.D.
      • Davies K.J.A.
      The immunoproteasome in oxidative stress, aging, and disease.
      ). In CANDLE, a proteosome-associated autoinflammatory disease (PRAAS), mutations of genes involved in the assembly or the proteasome’s function lead to the loss of the ability to degrade waste (Figure 1, bottom left) (
      • Torrelo A.
      CANDLE syndrome as a paradigm of proteasome-related autoinflammation.
      ). The first mutation associated with CANDLE was detected nearly 10 years ago in the gene PSMB8 (
      • Liu Y.
      • Ramot Y.
      • Torrelo A.
      • Paller A.S.
      • Si N.
      • Babay S.
      • et al.
      Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.
      ). It adds a crucial chymotrypsin-like activity to the core subunit and might also play a role in assembling the immunoproteasome (
      • Johnston-Carey H.K.
      • Pomatto L.C.D.
      • Davies K.J.A.
      The immunoproteasome in oxidative stress, aging, and disease.
      ;
      • Torrelo A.
      CANDLE syndrome as a paradigm of proteasome-related autoinflammation.
      ). Various other variants of genes such as PSMB4, PSMB9, PSMA3, and the recently discovered loss-of-function mutation in PSMB10 (
      International Society of Systemic Auto-Inflammatory Diseases
      10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID).
      ) as well as PSMG2 (
      • de Jesus A.A.
      • Brehm A.
      • VanTries R.
      • Pillet P.
      • Parentelli A.S.
      • Montealegre Sanchez G.A.
      • et al.
      Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy Candle/PRAAS4.
      ) affect either the immunoproteasome directly or general parts of the proteasome subunits or its assembly. A recent study (
      • Davidson S.
      • Yu C.H.
      • Steiner A.
      • Ebstein F.
      • Baker P.J.
      • Jarur-Chamy V.
      • et al.
      Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24.
      ) identified protein kinase R (PKR) as a sensor recognizing proteotoxic stress because of the accumulation of IL-24 in a human cell line model. IL-24 is constitutively secreted by the ER and might act as a control mechanism for a functional proteasome degradation system. Patients with PRAAS exhibited increased levels of phosphorylated PKR and IL24 as well as smaller isoforms of IL24 mRNA (
      • Davidson S.
      • Yu C.H.
      • Steiner A.
      • Ebstein F.
      • Baker P.J.
      • Jarur-Chamy V.
      • et al.
      Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24.
      ). The highly reduced function of the degradation of waste products further induces proinflammatory reactions leading to a vicious cycle and an overall heightened type I IFN production even after trivial viral infections and other stressors (
      • Brehm A.
      • Liu Y.
      • Sheikh A.
      • Marrero B.
      • Omoyinmi E.
      • Zhou Q.
      • et al.
      Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
      ;
      • Ebstein F.
      • Kloetzel P.M.
      • Krüger E.
      • Seifert U.
      Emerging roles of immunoproteasomes beyond MHC class I antigen processing.
      ;
      • McCarthy M.K.
      • Weinberg J.B.
      The immunoproteasome and viral infection: a complex regulator of inflammation.
      ). Plasmacytoid dendritic cells produce high amounts of type I IFN in cutaneous lesions of patients with CANDLE (
      • Jegalian A.G.
      • Facchetti F.
      • Jaffe E.S.
      Plasmacytoid dendritic cells: physiologic roles and pathologic states.
      ;
      • Torrelo A.
      • Colmenero I.
      • Requena L.
      • Paller A.S.
      • Ramot Y.
      • Richard Lee C.C.
      • et al.
      Histologic and immunohistochemical features of the skin lesions in CANDLE syndrome.
      ). Type I IFN mRNA can be used as a biomarker in patients with CANDLE, and the inhibitors directly targeting the IFN-induced Jak‒signal transducer and activator of transcription (STAT) pathway seem to ameliorate symptoms (
      • Sanchez G.A.M.
      • Reinhardt A.
      • Ramsey S.
      • Wittkowski H.
      • Hashkes P.J.
      • Berkun Y.
      • et al.
      JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.
      ).

      Clinical signs and symptoms

      Clinically, CANDLE is an AID characterized by a combination of symptoms with multiorgan involvement (
      • Arima K.
      • Kinoshita A.
      • Mishima H.
      • Kanazawa N.
      • Kaneko T.
      • Mizushima T.
      • et al.
      Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome.
      ;
      • Brehm A.
      • Liu Y.
      • Sheikh A.
      • Marrero B.
      • Omoyinmi E.
      • Zhou Q.
      • et al.
      Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
      ;
      • de Jesus A.A.
      • Brehm A.
      • VanTries R.
      • Pillet P.
      • Parentelli A.S.
      • Montealegre Sanchez G.A.
      • et al.
      Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy Candle/PRAAS4.
      ;
      International Society of Systemic Auto-Inflammatory Diseases
      10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID).
      ;
      • Liu Y.
      • Ramot Y.
      • Torrelo A.
      • Paller A.S.
      • Si N.
      • Babay S.
      • et al.
      Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.
      ). The true prevalence of this rare AID is still unknown, with more than 45 cases found in the medical literature (
      • Torrelo A.
      CANDLE syndrome as a paradigm of proteasome-related autoinflammation.
      ). The first signs of disease usually occur within the neonatal period, whereas disease onset at higher age is rare but possible (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ;
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ). Patients present with almost daily recurring fevers, pruritic rashes, and edema of the lips and eyelids. Stress, cold temperatures, or viral infections are possible triggers for fever attacks and cutaneous lesions (
      • Torrelo A.
      CANDLE syndrome as a paradigm of proteasome-related autoinflammation.
      ). During the further course of the disease, patients develop eponymous lipodystrophy. Failure to thrive commonly occurs; however, the presence of developmental delay is rare (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ). Other disease symptoms include arthralgias, clubbing of the fingers and toes, myositis, chronic chondritis leading to ear and saddle-nose deformities, conjunctivitis, nodular episcleritis, aseptic meningitis, calcification of the basal ganglia, metabolic syndrome, hepatosplenomegaly with a prominent abdomen, and inflammation of other organs (
      • Brehm A.
      • Liu Y.
      • Sheikh A.
      • Marrero B.
      • Omoyinmi E.
      • Zhou Q.
      • et al.
      Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
      ;
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ). If left untreated, CANDLE results in progressive organ damage eventually leading to early mortality (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ). Laboratory analysis shows hypochromic anemia, leukocytosis, thrombocytosis, increased ESR, and increased levels of CRP. Occasionally, liver enzymes can be elevated (
      • Brehm A.
      • Liu Y.
      • Sheikh A.
      • Marrero B.
      • Omoyinmi E.
      • Zhou Q.
      • et al.
      Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
      ;
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ). An elevated peripheral blood IFN signature is also a typical but not disease-specific sign of CANDLE (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ).

      Cutaneous signs

      The combination of dermatologic findings in CANDLE is unique. In the first few months of life, patients present with perniotic, red-to-violaceus, edematous lesions occurring on the acral digits with cold exposure as a possible trigger (
      • Arima K.
      • Kinoshita A.
      • Mishima H.
      • Kanazawa N.
      • Kaneko T.
      • Mizushima T.
      • et al.
      Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome.
      ;
      • Torrelo A.
      CANDLE syndrome as a paradigm of proteasome-related autoinflammation.
      ). During infancy or childhood, annular, flat, erythematous or violaceous, pruritic plaques with raised borders ranging from 1 to 5 cm in diameter start to develop. They are usually located on the face and trunk but may also involve the extremities, including hands, palms, feet, and soles. New lesions develop weekly or every few weeks and gradually resolve over the course of a few weeks, occasionally resulting in hyperpigmentation. In addition, patients develop persistent, erythematous to violaceous swellings of the lips and eyelids (Figure 3a) (
      • Arima K.
      • Kinoshita A.
      • Mishima H.
      • Kanazawa N.
      • Kaneko T.
      • Mizushima T.
      • et al.
      Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome.
      ;
      • Brehm A.
      • Liu Y.
      • Sheikh A.
      • Marrero B.
      • Omoyinmi E.
      • Zhou Q.
      • et al.
      Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
      ;
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ). Eczema and flare-related urticaria have been reported to occur as well (
      • Schwartz D.M.
      • Kitakule M.M.
      • Dizon B.L.
      • Gutierrez-Huerta C.
      • Blackstone S.A.
      Burma AM, et al. Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features.
      ). Lipodystrophy has its onset in early childhood, with progressive subcutaneous fat loss starting at the face and progressing to the trunk and limbs with the upper typically more affected than the lower extremities (
      • Brehm A.
      • Liu Y.
      • Sheikh A.
      • Marrero B.
      • Omoyinmi E.
      • Zhou Q.
      • et al.
      Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
      ;
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ).
      Figure thumbnail gr3
      Figure 3Cutaneous signs of IFN-associated AIDs. (a) CANDLE: a unique combination of dermatologic findings: perniotic, edematous lesions on acra in the first few months of life; later flat, erythematous or violaceous plaques with raised borders (diameter 1‒5 cm) on the face, trunk, and extremities; persistent, erythematous to violaceous swellings of the lips and eyelids; lipodystrophy starting at the face and progressing to the trunk and limbs. (b) SAVI: erythematous to violaceous, infiltrated, ulcerating plaques on the acra, dorsum of the hands, thighs, and soles; facial erythema resembling malar rash; and telangiectatic lesions on the cheeks, nose, and extremities. Other findings (e.g., gangrene, saddle-nose deformity) are not shown. B denotes the back view, and F denotes the front view. AID, autoinflammatory disease; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; SAVI, STING-associated vasculopathy with onset in infancy.

      Treatment

      Treatment focuses on controlling disease activity to prevent organ damage or its progression. However, optimal treatment of CANDLE remains challenging with both methotrexate and corticosteroids leading to a partial improvement of fever attacks and cutaneous lesions. In some cases, NSAIDs can be used to control fever attacks (
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ). Jak1/2 inhibitors represent a promising new treatment approach with improved efficacy compared with IL-1 inhibitors, TNFα inhibitors, colchicine, azathioprine, ciclosporin, dapsone, or intravenous Ig (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ;
      • Torrelo A.
      • Patel S.
      • Colmenero I.
      • Gurbindo D.
      • Lendínez F.
      • Hernández A.
      • et al.
      Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.
      ). In a case report, treatment with Jak1/2 inhibitor baricitinib led to sufficient disease control because fever attacks stopped, skin rashes improved, periorbital swelling disappeared, musculoskeletal symptoms resolved, and growth velocity increased (
      • Boyadzhiev M.
      • Marinov L.
      • Boyadzhiev V.
      • Iotova V.
      • Aksentijevich I.
      • Hambleton S.
      Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome.
      ). In a case series, Jak1/2 inhibitor baricitinib led to improved disease control with remission occurring in 50% of patients (
      • Sanchez G.A.M.
      • Reinhardt A.
      • Ramsey S.
      • Wittkowski H.
      • Hashkes P.J.
      • Berkun Y.
      • et al.
      JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.
      ).

      SAVI

      There are numerous sensor and adapter proteins that help cells in combating invading viruses. STING is one of them and was found to acquire a gain-of-function mutation in patients with SAVI. STING is anchored at the membrane of the ER and gets indirectly activated by viral DNA and abnormal DNA derived from bacteria or damaged cells (
      • Liu Y.
      • Lu X.
      • Qin N.
      • Qiao Y.
      • Xing S.
      • Liu W.
      • et al.
      STING, a promising target for small molecular immune modulator: a review.
      ;
      • Sun W.
      • Li Y.
      • Chen L.
      • Chen H.
      • You F.
      • Zhou X.
      • et al.
      Eris, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization.
      ). After activation, STING travels to the Golgi complex and the perinuclear compartment, where it further interacts with several proteins, ultimately leading to the translocation of the IRF3 to the nucleus and the induction of type I IFNs (Figure 1, bottom right) (
      • Tsuchiya Y.
      • Jounai N.
      • Takeshita F.
      • Ishii K.J.
      • Mizuguchi K.
      Ligand-induced ordering of the C-terminal tail primes STING for phosphorylation by TBK1.
      ;
      • Zhao B.
      • Shu C.
      • Gao X.
      • Sankaran B.
      • Du F.
      • Shelton C.L.
      • et al.
      Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins.
      ). Although the activation mechanism between DNA and RNA viruses varies (
      • Liu Y.
      • Lu X.
      • Qin N.
      • Qiao Y.
      • Xing S.
      • Liu W.
      • et al.
      STING, a promising target for small molecular immune modulator: a review.
      ), SAVI-associated mutations of TMEM173, the gene coding for STING, lead to a constitutional activated STING protein and subsequently a heightened production of IFN-β and autoinflammation similar to that in other interferonopathies (
      • Ergun S.L.
      • Fernandez D.
      • Weiss T.M.
      • Li L.
      STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition.
      ).
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      showed the constitutive activation of the STING pathway in peripheral blood monocytes and the upregulation of the reactivity to stimulating factors in fibroblast of patients with SAVI. In these fibroblasts, the Jak1/2 inhibitor baricitinib inhibiting the IFN pathway shows promising results (
      • Kim H.
      • Brooks K.M.
      • Tang C.C.
      • Wakim P.
      • Blake M.
      • Brooks S.R.
      • et al.
      Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients.
      ;
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ;
      • Sanchez G.A.M.
      • Reinhardt A.
      • Ramsey S.
      • Wittkowski H.
      • Hashkes P.J.
      • Berkun Y.
      • et al.
      JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.
      ).

      Clinical signs and symptoms

      As the name suggests, SAVI is an AID with onset in early infancy with a median age of symptom onset <6 months. Only 1 of 60 reported cases had adulthood disease onset (
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      ). The exact prevalence of this rare AID is unknown (
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      ). SAVI is characterized by small-vessel vasculitis with recurrent cutaneous rashes and sometimes cartilage damage reflected as ear and/or saddle-nose deformities; interstitial lung disease with dyspnea, tachypnea and/or, cough eventually leading to respiratory failure; systemic inflammation; recurrent fevers; failure to thrive, and arthritis or arthralgia (
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      ;
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ). Rarely, neuroimaging shows basal ganglia calcifications (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ). CRP levels and ESR are usually increased (
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ). The peripheral blood IFN signature is also elevated, similar to that in CANDLE (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ). In addition, >50% of patients with SAVI are positive for antinuclear antibodies (35 of 56 patients), antineutrophil cytoplasmic antibodies (ANCAs) (15 of 21 patients) (perinuclear ANCA and cytoplasmic ANCA), and rheumatoid factor (17 of 30 patients) (
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      ). Leukopenia and thrombocytosis occur frequently (
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ). Levels of IgG and IgA are elevated, and levels of IgM and complement are shown to be within the reference range (
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ).

      Cutaneous signs

      Skin lesions can be present at disease onset or develop months afterward (
      • Tang S.
      • Li S.
      • Zheng S.
      • Ding Y.
      • Zhu D.
      • Sun C.
      • et al.
      Understanding of cytokines and targeted therapy in macrophage activation syndrome.
      ). As shown in a large case series published by
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      , 86% of patients exhibit cutaneous lesions. Patients usually present with erythematous to violaceous, infiltrated plaques on the digits and nose and ears, dorsum of the hands, thighs, and soles (Figure 3b). Plaques ulcerate in most of the patients. Patients also exhibit facial erythema resembling malar rash and telangiectatic lesions on the cheeks, nose, and extremities. In addition, nailfold capillary tortuosity, alopecia, livedo, urticarial lesions on the upper extremity, oral aphthosis, and gingivostomatitis have been described (
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      ;
      • Schwartz D.M.
      • Kitakule M.M.
      • Dizon B.L.
      • Gutierrez-Huerta C.
      • Blackstone S.A.
      Burma AM, et al. Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features.
      ;
      • Tang S.
      • Li S.
      • Zheng S.
      • Ding Y.
      • Zhu D.
      • Sun C.
      • et al.
      Understanding of cytokines and targeted therapy in macrophage activation syndrome.
      ). In severe cases (19% of patients), SAVI leads to extensive tissue loss because of vascular occlusion resulting in ear deformity, nasal septum perforation, saddle-nose deformity, loss of nails, and gangrene and consecutive loss of fingers or toes (
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      ;
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ).

      Treatment

      As seen in CANDLE, inhibition of the Jak/STAT pathway through Jak inhibitors is a promising treatment option, whereas treatment with immunomodulators such as glucocorticoid monotherapy, conventional synthetics (e.g., methotrexate, leflunomide), or biologic disease-modifying drugs (e.g., etanercept, infliximab, anakinra, belimumab, rituximab, tocilizumab), hydroxychloroquine, mycophenolate motefil, cyclophosphamide, intravenous Ig, colchicine, or thalidomide led to no or incomplete response (
      • Cetin Gedik K.
      • Lamot L.
      • Romano M.
      • Demirkaya E.
      • Piskin D.
      • Torreggiani S.
      • et al.
      The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: Candle/PRAAS, SAVI and AGS.
      ;
      • Liu Y.
      • Jesus A.A.
      • Marrero B.
      • Yang D.
      • Ramsey S.E.
      • Sanchez G.A.M.
      • et al.
      Activated STING in a vascular and pulmonary syndrome.
      ). Treatment with Jak inhibitors such as ruloxitinib and baricitinib, initially in combination with systemic corticosteroids, allowed for a reduction of disease severity (
      • Frémond M.L.
      • Hadchouel A.
      • Berteloot L.
      • Melki I.
      • Bresson V.
      • Barnabei L.
      • et al.
      Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.
      ;
      • Sanchez G.A.M.
      • Reinhardt A.
      • Ramsey S.
      • Wittkowski H.
      • Hashkes P.J.
      • Berkun Y.
      • et al.
      JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.
      ). Jak inhibitor tofacitinib was associated with unsatisfactory treatment response (
      • Tang X.
      • Xu H.
      • Zhou C.
      • Peng Y.
      • Liu H.
      • Liu J.
      • et al.
      STING-associated vasculopathy with onset in infancy in three children with new clinical aspect and unsatisfactory therapeutic responses to tofacitinib.
      ).

      IL-1 Family Receptor Antagonist‒Associated AIDs

      The IL-1 family includes many cytokines and receptors facilitating the response against harmful pathogens. One of the most prominent agents is IL-1β. As seen in, for example, inflammasome-mediated AIDs, the massive IL-1β release can lead to the destruction of the surrounding tissues and needs to be tightly controlled. The IL-1RA prevents a vicious cycle of autocrine stimulation between IL-1β and the IL-1 receptor (
      • Lennard A.C.
      lnterleukin-1 Receptor Antagonist.
      ). When this mechanism fails, a chronic inflammatory state leads to a rare, life-threatening disease called deficiency of IL-1RA (DIRA) (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ). Because the IL-1 family spans a wide range of cytokines with a similar regulatory mechanism, DIRA is not the only AID known to be the outcome of a failed receptor antagonist. DITRA describes patients with a defect in the IL-36RA (
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ).

      DIRA

      Binding of IL-1β to the IL-1 receptor leads to heterodimerization and the activation of a potent proinflammatory signal cascade (
      • Fields J.K.
      • Günther S.
      • Sundberg E.J.
      Structural basis of IL-1 family cytokine signaling.
      ;
      • Wang D.
      • Zhang S.
      • Li L.
      • Liu X.
      • Mei K.
      • Wang X.
      Structural insights into the assembly and activation of IL-1β with its receptors.
      ), priming the cell for further production of pro‒IL-1β (
      • Avolio E.
      • Gianfranceschi G.
      • Cesselli D.
      • Caragnano A.
      • Athanasakis E.
      • Katare R.
      • et al.
      Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction.
      ). Because this can lead to a circle of autocrine stimulation, cells that produce IL-1β (in particular, monocytes and macrophages, neutrophils, dendritic cells, and epithelial cells) also code the antagonistic partner IL-1RA (
      • Eisenberg S.P.
      • Brewer M.T.
      • Verderber E.
      • Heimdal P.
      • Brandhuber B.J.
      • Thompson R.C.
      Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism.
      ). IL-1RA binds with high affinity to the IL-1 receptor without inducing the conformational change needed for proinflammatory signaling (
      • Eisenberg S.P.
      • Brewer M.T.
      • Verderber E.
      • Heimdal P.
      • Brandhuber B.J.
      • Thompson R.C.
      Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism.
      ;
      • Fields J.K.
      • Günther S.
      • Sundberg E.J.
      Structural basis of IL-1 family cytokine signaling.
      ). This way, IL-1RA competitively inhibits the activation of the IL-1 receptor and lays the groundwork for a controlled inflammatory response. Patients with DIRA show missense or nonsense mutation in the gene IL1RN, which codes for IL-1RA (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ). More than 15 mutations with varying pathogenic potentials are registered at InFevers, and sequencing efforts continuously uncover new variants (
      • Milhavet F.
      • Cuisset L.
      • Hoffman H.M.
      • Slim R.
      • El-Shanti H.
      • Aksentijevich I.
      • et al.
      The infevers autoinflammatory mutation online registry: update with new genes and functions.
      ). A recent study reported a new mutation leading to DIRA in Brazil (
      • Mendonça L.O.
      • Grossi A.
      • Caroli F.
      • de Oliveira R.A.
      • Kalil J.
      • Castro F.F.M.
      • et al.
      A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of interleukin-1 receptor antagonist (DIRA).
      ), after additions from Turkey (
      • Sözeri B.
      • Gerçeker-Türk B.
      • Yıldız-Atıkan B.
      • Mir S.
      • Berdeli A.
      A novel mutation of interleukin-1 receptor antagonist (IL1RN) in a DIRA patient from Turkey: diagnosis and treatment.
      ) and India (
      • Mendonca L.O.
      • Malle L.
      • Donovan F.X.
      • Chandrasekharappa S.C.
      • Montealegre Sanchez G.A.
      • Garg M.
      • et al.
      Deficiency of interleukin-1 receptor antagonist (DIRA): report of the first Indian patient and a novel deletion affecting IL1RN.
      ) in 2018 and 2017, respectively. As far as reported, these mutations lead to a faulty protein expression or to no production of the protein at all (Figure 1, top right) (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ). Monocytes affected with DIRA-associated mutations showed elevated production of several proinflammatory cytokines, including IL-1, IL-6, TNF, and MIP-1α (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ;
      • Reddy S.
      • Jia S.
      • Geoffrey R.
      • Lorier R.
      • Suchi M.
      • Broeckel U.
      • et al.
      An autoinflammatory disease due to homozygous deletion of the IL1RN locus.
      ). IL-6 is a typical proinflammatory cytokine heightening the production of acute-phase proteins as well as inducing neutrophilia and T helper 17 (Th17) T-cell differentiation, both seen in the inflamed skin of patients affected by DIRA (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ;
      • Naseem S.
      • Iqbal R.
      • Munir T.
      Role of interleukin-6 in immunity: a review.
      ;
      • Suwa T.
      • Hogg J.C.
      • English D.
      • Van Eeden S.F.
      Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow.
      ). The impact of IL-1RA to regulate inflammatory responses can be nicely shown through the effect of recombinant IL-1RA because the response to the treatment stops with discontinuation of the therapy.

      Clinical signs and symptoms

      DIRA is a rare AID of unknown global prevalence but was estimated to occur in 1 case per 6,300 inhabitants in Puerto Rico (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ). The disease usually presents at birth or during the neonatal period and is typically characterized by chronic inflammation with occasionally occurring flare ups (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ). Clinical features include a pustular skin rash triggered by mechanical stress, nail changes, oral mucosal lesions, sterile osteomyelitis, periostitis, balloon-like widening of bones, swollen joints, and severe bone pain. Hepatosplenomegaly and abdominal distention with a caput medusae are other possible signs of the disease. However, fever is uncommon (
      • Romano M.
      • Arici Z.S.
      • Piskin D.
      • Alehashemi S.
      • Aletaha D.
      • Barron K.S.
      • et al.
      The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist.
      ). DIRA is usually fatal if left untreated. Laboratory studies show elevated levels of acute-phase reactants, leukocytosis, thrombocytosis, and anemia (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ;
      • Brau-Javier C.N.
      • Gonzales-Chavez J.
      • Toro J.R.
      Chronic cutaneous pustulosis due to a 175-kb deletion on chromosome 2q13: excellent response to anakinra.
      ;
      • Reddy S.
      • Jia S.
      • Geoffrey R.
      • Lorier R.
      • Suchi M.
      • Broeckel U.
      • et al.
      An autoinflammatory disease due to homozygous deletion of the IL1RN locus.
      ).

      Cutaneous signs

      Cutaneous manifestations can either be mild with erythematous plaques and sterile follicular pustules limited to one area or severe with generalized pustulosis or ichthyosiform lesions. Sparing of the palms and soles has been reported. A positive skin pathergy test, oral mucosal lesions (ulcers, stomatitis), and nail involvement (pitting, onychomadesis) are possible findings (Figure 4a) (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ;
      • Brau-Javier C.N.
      • Gonzales-Chavez J.
      • Toro J.R.
      Chronic cutaneous pustulosis due to a 175-kb deletion on chromosome 2q13: excellent response to anakinra.
      ;
      • Goldbach-Mansky R.
      Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1.
      ;
      • Minkis K.
      • Aksentijevich I.
      • Goldbach-Mansky R.
      • Magro C.
      • Scott R.
      • Davis J.G.
      • et al.
      Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis.
      ;
      • Reddy S.
      • Jia S.
      • Geoffrey R.
      • Lorier R.
      • Suchi M.
      • Broeckel U.
      • et al.
      An autoinflammatory disease due to homozygous deletion of the IL1RN locus.
      ;
      • Romano M.
      • Arici Z.S.
      • Piskin D.
      • Alehashemi S.
      • Aletaha D.
      • Barron K.S.
      • et al.
      The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist.
      ).
      Figure thumbnail gr4
      Figure 4Cutaneous signs of DIRA and DITRA. (a) DIRA: erythematous plaques studded with sterile follicular pustules limited to one area or with generalized location and nail involvement (pitting). Other findings (e.g., ichthyosiform lesions, stomatitis) were not shown. (b) DITRA: generalized erythematous plaques studded with sterile pustules with consecutive desquamation, scrotal tongue, and nail dystrophy. Benign migratory glossitis is not shown. B denotes the back view, and F denotes the front view. DIRA, deficiency of IL-1RA; DITRA, deficiency of IL-36RA.

      Treatment

      Inhibition of IL-1α appears to be important in stopping bone inflammation. Hence, anakinra and rilonacept are the mainstays of treatment because they block both IL-1α and IL-1β as opposed to canakinumab, which only inhibits IL-1β (
      • Romano M.
      • Arici Z.S.
      • Piskin D.
      • Alehashemi S.
      • Aletaha D.
      • Barron K.S.
      • et al.
      The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist.
      ). As shown in a report on the basis of the Eurofever Registry, anakinra induced complete remission in the majority of patients (
      • Ter Haar N.
      • Lachmann H.
      • Özen S.
      • Woo P.
      • Uziel Y.
      • Modesto C.
      • et al.
      Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review.
      ). Canakinumab has been used successfully in one patient, whereas another patient continued to experience flare ups while on therapy (
      • Mendonça L.O.
      • Grossi A.
      • Caroli F.
      • de Oliveira R.A.
      • Kalil J.
      • Castro F.F.M.
      • et al.
      A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of interleukin-1 receptor antagonist (DIRA).
      ;
      • Ulusoy E.
      • Karaca N.E.
      • El-Shanti H.
      • Kilicoglu E.
      • Aksu G.
      • Kutukculer N.
      Interleukin-1 receptor antagonist deficiency with a novel mutation; late onset and successful treatment with canakinumab: a case report.
      ). Disease-modifying antirheumatic drugs and corticosteroids appear to be only partially effective (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ).

      DITRA

      Similar to DIRA, DITRA involves the regulation of the proinflammatory effect of an IL-1 family cytokine through its receptor antagonist. DITRA shows a mutation in the gene IL36RN, which codes for IL-36RA (Figure 1, top left) (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ;
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ). Mutations in IL36RN are not specific for DITRA because they can also lead to palmoplantar pustulosis and acrodermatitis continua of Hallopeau, both being pustular entities related to psoriasis (
      • Setta-Kaffetzi N.
      • Navarini A.A.
      • Patel V.M.
      • Pullabhatla V.
      • Pink A.E.
      • Choon S.E.
      • et al.
      Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.
      ). The three different IL-36 (α, β, and γ) are lesser known members of the IL-1 family and are, similar to their antagonist IL-36RA, primarily expressed in epithelial tissues of barrier sites such as the skin (
      • Bassoy E.Y.
      • Towne J.E.
      • Gabay C.
      Regulation and function of interleukin-36 cytokines.
      ;
      • Zhou L.
      • Todorovic V.
      Interleukin-36: structure, signaling and function.
      ). A general proinflammatory state could be observed in DITRA because monocytes from patients showed a heightened production of IL-1β, IL-1α, IL-6, IL-8, and TNF similar to monocytes from patients with DIRA (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ;
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ). IL-36, which was shown to be highly elevated in skin lesions from patients with DITRA, stimulates keratinocytes and drives the Th17/23 cell axis, which is essential to protect the body’s outer layers against pathogens. Its high expression in epithelial tissues might be the reason for the more skin-specific hyperinflammation and negligible systemic involvement seen in DITRA compared with those seen in DIRA (
      • Aksentijevich I.
      • Masters S.L.
      • Ferguson P.J.
      • Dancey P.
      • Frenkel J.
      • van Royen-Kerkhoff A.
      • et al.
      An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
      ;
      • Guglani L.
      • Khader S.A.
      Th17 cytokines in mucosal immunity and inflammation.
      ;
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Zhou L.
      • Todorovic V.
      Interleukin-36: structure, signaling and function.
      ).

      Clinical signs and symptoms

      DITRA presents with recurrent flares of generalized erythematous patches studded with pustules (pustular psoriasis), high bouts of fever, and systemic inflammation (
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ). Malaise and organ involvement in terms of hepatosplenomegaly with ascites and pericardial and pleural effusion can also occur (
      • Ellingford J.M.
      • Black G.C.M.
      • Clayton T.H.
      • Judge M.
      • Griffiths C.E.M.
      • Warren R.B.
      A novel mutation in IL36RN underpins childhood pustular dermatosis.
      ;
      • Körber A.
      • Mössner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      ;
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ). The prevalence of generalized pustular psoriasis is estimated to be two per one million persons (
      • Körber A.
      • Mössner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      ). The exact prevalence of DITRA is unknown, with about 200 cases being reported in the medical literature (
      • Hospach T.
      • Glowatzki F.
      • Blankenburg F.
      • Conzelmann D.
      • Stirnkorb C.
      • Müllerschön C.S.
      • et al.
      Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents.
      ).
      • Mössner R.
      • Wilsmann-Theis D.
      • Oji V.
      • Gkogkolou P.
      • Löhr S.
      • Schulz P.
      • et al.
      The genetic basis for most patients with pustular skin disease remains elusive.
      detected IL36RN mutations in 20 of 61 (33%) investigated patients with generalized pustular psoriasis. The disease onset is varying, ranging from an age of 1 week to age of 72 years, with a mean age of 33.4 ± 22.4 years (
      • Körber A.
      • Mössner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      ;
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Mössner R.
      • Wilsmann-Theis D.
      • Oji V.
      • Gkogkolou P.
      • Löhr S.
      • Schulz P.
      • et al.
      The genetic basis for most patients with pustular skin disease remains elusive.
      ). The course of the disease is usually episodic, less often continuous (
      • Mössner R.
      • Wilsmann-Theis D.
      • Oji V.
      • Gkogkolou P.
      • Löhr S.
      • Schulz P.
      • et al.
      The genetic basis for most patients with pustular skin disease remains elusive.
      ). A recent study reported the flare duration of a few days to a week (
      • Salik D.
      • Zoghaib S.
      • Dangoisse C.
      • Sass U.
      • Kolivras A.
      • Soblet J.
      • et al.
      New variant in deficiency of interleukin-36 receptor antagonist syndrome (DITRA).
      ). In cases of episodic DITRA, flare ups occur at irregular time intervals (
      • Mössner R.
      • Wilsmann-Theis D.
      • Oji V.
      • Gkogkolou P.
      • Löhr S.
      • Schulz P.
      • et al.
      The genetic basis for most patients with pustular skin disease remains elusive.
      ). Disease flares can be triggered by viral or bacterial infections (e.g., urinary tract infection; gastroenteritis; upper respiratory tract infections such as bronchitis, common cold, and sinusitis), stress, drug intake (penicillin, sulfonamides, codeine, paracetamol, metamizole, acetylsalicylic acid, verapamil), withdrawal of drugs (retinoid, methotrexate, corticosteroids), menstruation, pregnancy, red wine, and surgical interventions (
      • Körber A.
      • Mössner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      ;
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Mössner R.
      • Wilsmann-Theis D.
      • Oji V.
      • Gkogkolou P.
      • Löhr S.
      • Schulz P.
      • et al.
      The genetic basis for most patients with pustular skin disease remains elusive.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ). Blood tests show elevated levels of CRP, increased ESR, and leukocytosis with neutrophilia (
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ).

      Cutaneous signs

      Patients present with generalized erythematous plaques studded with sterile pustules. In most patients, skin manifestations occur episodically with a sudden onset and subsequent desquamation (
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ). Involvement of the tongue (benign migratory glossitis, scrotal tongue) and nail dystrophy can additionally occur (Figure 4b) (
      • Körber A.
      • Mössner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      ;
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ).

      Treatment

      Treatment options include acitretin; corticosteroids; methotrexate; ciclosporin; and TNFα, IL-1, IL-12/23, and IL-17 inhibitors (
      • Hospach T.
      • Glowatzki F.
      • Blankenburg F.
      • Conzelmann D.
      • Stirnkorb C.
      • Müllerschön C.S.
      • et al.
      Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ). Acitretin with or without concomitant methotrexate has been used successfully in a few published cases (
      • Ellingford J.M.
      • Black G.C.M.
      • Clayton T.H.
      • Judge M.
      • Griffiths C.E.M.
      • Warren R.B.
      A novel mutation in IL36RN underpins childhood pustular dermatosis.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ). There is also evidence for the beneficial effect of corticosteroids and ciclosporin (
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ). Treatment with TNF-α inhibitors induced a complete remission in 7 of 12 flares (58%). IL-1, IL-12/23, and IL-17 led to a complete remission of one of eight (13%), four of four (100%), and four of four (100%) flares, respectively (
      • Hospach T.
      • Glowatzki F.
      • Blankenburg F.
      • Conzelmann D.
      • Stirnkorb C.
      • Müllerschön C.S.
      • et al.
      Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents.
      ). Targeted therapy inhibiting the IL-36 pathway might be a promising treatment in the future (
      • Bachelez H.
      • Choon S.E.
      • Marrakchi S.
      • Burden A.D.
      • Tsai T.F.
      • Morita A.
      • et al.
      Inhibition of the Interleukin-36 pathway for the treatment of generalized pustular psoriasis.
      ).

      Polygenic Autoinflammatory Syndromes

      Polygenic AIDs are defined by an overactive cytokine production of the innate immune system with no underlying monogenic driver. In many cases, infectious triggers or mutations predisposing to the disease are being discussed, but owing to the multifactorial influence, consistent pathogenesis is often missing. Synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO); periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA), SchS, and adult-onset Still disease (AOSD) represent some of these polygenic AIDs showing a wide variety of cutaneous signs.

      SAPHO

      SAPHO is a complex inflammatory disease with predominantly autoinflammatory characteristics bearing additional autoimmune features and signs of infectious disease. No clear genetic background has been described, but reported familial aggregation (
      • Dumolard A.
      • Gaudin P.
      • Juvin R.
      • Bost M.
      • Peoc’h M.
      • Phelip X.
      SAPHO syndrome or psoriatic arthritis? A familial case study.
      ;
      • Ferguson P.J.
      • Lokuta M.A.
      • El-Shanti H.I.
      • Muhle L.
      • Bing X.
      • Huttenlocher A.
      Neutrophil dysfunction in a family with a SAPHO syndrome-like phenotype.
      ) and association with certain SNVs (
      • Assmann G.
      • Wagner A.D.
      • Monika M.
      • Pfoehler C.
      • Pfreundschuh M.
      • Tilgen W.
      • et al.
      Single-nucleotide polymorphisms p53 G72C and Mdm2 T309G in patients with psoriasis, psoriatic arthritis, and SAPHO syndrome.
      ;
      • Xu D.
      • Liu X.
      • Lu C.
      • Luo J.
      • Wang C.
      • Gao C.
      • et al.
      Reduction of peripheral natural killer cells in patients with SAPHO syndrome.
      ) indicate an underlying genetic susceptibility for the disease. High levels of proinflammatory cytokines strongly stress the autoinflammatory component, but differences in cytokine expression between patients and studies complicate the description of coherent pathogenesis. Elevated IL-6, IL-8, and IL-17 as well as low TNFβ serum levels were observed in SAPHO (
      • Hurtado-Nedelec M.
      • Chollet-Martin S.
      • Nicaise-Roland P.
      • Grootenboer-Mignot S.
      • Ruimy R.
      • Meyer O.
      • et al.
      Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome.
      ;
      • Przepiera-Będzak H.
      • Fischer K.
      • Brzosko M.
      Serum interleukin-18, fetuin-A, soluble intercellular adhesion Molecule-1, and endothelin-1 in ankylosing spondylitis, psoriatic arthritis, and SAPHO syndrome.
      ,
      • Przepiera-Będzak H.
      • Fischer K.
      • Brzosko M.
      Serum IL-6 and IL-23 levels and their correlation with angiogenic cytokines and disease activity in ankylosing spondylitis, psoriatic arthritis, and SAPHO syndrome.
      ;
      • Zhang S.
      • Li C.
      • Zhang S.
      • Li L.
      • Zhang W.
      • Dong Z.
      • et al.
      Serum levels of proinflammatory, anti-inflammatory cytokines, and RANKL/OPG in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.
      ).
      • Zhang S.
      • Li C.
      • Zhang S.
      • Li L.
      • Zhang W.
      • Dong Z.
      • et al.
      Serum levels of proinflammatory, anti-inflammatory cytokines, and RANKL/OPG in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.
      correlated IL-6, IL-8, as well as the IL-17/TNFα quotient to clinical scores measuring disease activity (Visual Analog Scale [VAS] and Bath Ankylosing Spondylitis Activity Index [BASDAI]). The elevation of TNF-α observed in bone biopsies and high levels of Propionibacterium acnes were reported to influence the manifestation of the disease (
      • Assmann G.
      • Simon P.
      The SAPHO syndrome--are microbes involved?.
      ;
      • Gupta L.
      • Ahmed S.
      • Singh B.
      • Prakash S.
      • Phadke S.
      • Aggarwal A.
      Novel NLRP12 variant presenting with familial cold autoimmunity syndrome phenotype.
      ;
      • Wagner A.D.
      • Andresen J.
      • Jendro M.C.
      • Hülsemann J.L.
      • Zeidler H.
      Sustained response to tumor necrosis factor alpha-blocking agents in two patients with SAPHO syndrome.
      ). P. acnes, a Gram-positive commensal skin bacterium (
      • Brüggemann H.
      • Henne A.
      • Hoster F.
      • Liesegang H.
      • Wiezer A.
      • Strittmatter A.
      • et al.
      The complete genome sequence of Propionibacterium acnes, a commensal of human skin.
      ), is found in nearly 50% of bone biopsies, and treatment of colonized skin lesions with antibiotics showed improvement in some patients with SAPHO, suggesting that P. acnes might be an infectious trigger of the disease (
      • Assmann G.
      • Kueck O.
      • Kirchhoff T.
      • Rosenthal H.
      • Voswinkel J.
      • Pfreundschuh M.
      • et al.
      Efficacy of antibiotic therapy for SAPHO syndrome is lost after its discontinuation: an interventional study.
      ;
      • Assmann G.
      • Simon P.
      The SAPHO syndrome--are microbes involved?.
      ;
      • Berthelot J.-M.
      • Corvec S.
      • Hayem G.
      SAPHO, autophagy, IL-1, FoxO1, and propionibacterium (Cutibacterium) acnes.
      ). The effect of antibiotic treatment was often lost after discontinuation (
      • Assmann G.
      • Wagner A.D.
      • Monika M.
      • Pfoehler C.
      • Pfreundschuh M.
      • Tilgen W.
      • et al.
      Single-nucleotide polymorphisms p53 G72C and Mdm2 T309G in patients with psoriasis, psoriatic arthritis, and SAPHO syndrome.
      ;
      • Hurtado-Nedelec M.
      • Chollet-Martin S.
      • Nicaise-Roland P.
      • Grootenboer-Mignot S.
      • Ruimy R.
      • Meyer O.
      • et al.
      Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome.
      ). Some phylotypes of P. acnes were associated with high IL-1β production (
      • Berthelot J.-M.
      • Corvec S.
      • Hayem G.
      SAPHO, autophagy, IL-1, FoxO1, and propionibacterium (Cutibacterium) acnes.
      ), which is a known proinflammatory cytokine and a driving force in many other AIDs (
      • Liao H.J.
      • Chyuan I.T.
      • Wu C.S.
      • Lin S.W.
      • Chen K.H.
      • Tsai H.F.
      • et al.
      Increased neutrophil infiltration, IL-1 production and a SAPHO syndrome-like phenotype in PSTPIP2-deficient mice.
      ). Although heightened IL-1β release after stimulation was indeed observed in a patient with SAPHO (
      • Colina M.
      • Pizzirani C.
      • Khodeir M.
      • Falzoni S.
      • Bruschi M.
      • Trotta F.
      • et al.
      Dysregulation of P2X7 receptor-inflammasome axis in SAPHO syndrome: successful treatment with anakinra.
      ), there was no difference in the IL-1 plasma serum levels compared with that in the healthy controls (
      • Zhang S.
      • Li C.
      • Zhang S.
      • Li L.
      • Zhang W.
      • Dong Z.
      • et al.
      Serum levels of proinflammatory, anti-inflammatory cytokines, and RANKL/OPG in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.
      ). Interestingly, IL-1 inhibition showed significant alleviation of musculoskeletal manifestations but no change in the severity of skin lesions (
      • Daoussis D.
      • Konstantopoulou G.
      • Kraniotis P.
      • Sakkas L.
      • Liossis S.N.
      Biologics in SAPHO syndrome: a systematic review.
      ). The impact of IL-1 and P. acnes on SAPHO remains largely obscure and demands further studies.
      Other cytokines provide a more coherent but not complete insight into the disease. IL-6 is a classical proinflammatory cytokine known for its bone resorbing characteristics because it stimulates osteoclastogenesis by influencing osteoblast’s expression of RANKL, which was elevated in patients with a high disease activity score (VAS/BASDAI ≥ 4) (
      • Tamura T.
      • Udagawa N.
      • Takahashi N.
      • Miyaura C.
      • Tanaka S.
      • Yamada Y.
      • et al.
      Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6.
      ;
      • Wu Q.
      • Zhou X.
      • Huang D.
      • Ji Y.
      • Kang F.
      IL-6 enhances osteocyte-mediated osteoclastogenesis by promoting JAK2 and RANKL activity in vitro.
      ). RANKL is a key player in bone metabolism, which can also influence the immune system (e.g., in skin inflammation or thymus development) (
      • Ono T.
      • Hayashi M.
      • Sasaki F.
      • Nakashima T.
      RANKL biology: bone metabolism, the immune system, and beyond.
      ). Abundant TNF-α and RANKL were observed at sites of inflammatory bone erosions, with TNF-α further stimulating RANKL-induced osteoclastogenesis (
      • Zhang Y.H.
      • Heulsmann A.
      • Tondravi M.M.
      • Mukherjee A.
      • Abu-Amer Y.
      Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways.
      ).
      • Zhang S.
      • Li C.
      • Zhang S.
      • Li L.
      • Zhang W.
      • Dong Z.
      • et al.
      Serum levels of proinflammatory, anti-inflammatory cytokines, and RANKL/OPG in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.
      suspected that these processes are highly involved in the generation of bone lesions seen in SAPHO, in accordance with the aggressive bone erosions seen in psoriatic arthritis (
      • Ritchlin C.T.
      • Haas-Smith S.A.
      • Li P.
      • Hicks D.G.
      • Schwarz E.M.
      Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis.
      ). TNF blockers showed promising response rates for musculoskeletal and skin manifestation in SAPHO (
      • Daoussis D.
      • Konstantopoulou G.
      • Kraniotis P.
      • Sakkas L.
      • Liossis S.N.
      Biologics in SAPHO syndrome: a systematic review.
      ). The key cytokine connecting innate immunity with adaptive immunity in SAPHO seems to be IL-17. IL-17 is known to connect T cells to neutrophil activation, and its pro-osteoclastogenic properties contribute to the pathogenesis of many rheumatic diseases (
      • Miossec P.
      Update on interleukin-17: a role in the pathogenesis of inflammatory arthritis and implication for clinical practice.
      ;

      Zenobia C, Hajishengallis G. Basic biology and role of interleukin-17 in immunity and inflammation. Periodontol 2000 2015;69:142–159.

      ). IL-17‒producing T cells (Th17 cells) are induced by IL-6 and IL-1β and were shown to be elevated in the serum of patients with SAPHO (
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • Sallusto F.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ;
      • Firinu D.
      • Murgia G.
      • Lorrai M.M.
      • Barca M.P.
      • Peralta M.M.
      • Manconi P.E.
      • et al.
      Biological treatments for SAPHO syndrome: an update.
      ). Recently,
      • Daoussis D.
      • Konstantopoulou G.
      • Kraniotis P.
      • Sakkas L.
      • Liossis S.N.
      Biologics in SAPHO syndrome: a systematic review.
      connected IL-17 to all hallmark symptoms of the disease: synovitis, acne, pustulosis, hyperostosis, and osteitis. Biopsies of patients with acne and palmoplantar pustulosis showed high levels of IL-17 (
      • Daoussis D.
      • Konstantopoulou G.
      • Kraniotis P.
      • Sakkas L.
      • Liossis S.N.
      Biologics in SAPHO syndrome: a systematic review.
      ). IL-17 also has a great impact on neutrophil migration and, together with IL-8, an early-phase chemokine, which strongly attracts neutrophils and to a lesser amount T cells and basophils, could explain the increased infiltration of neutrophils seen in skin biopsies of patients with SAPHO (
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • Sallusto F.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ;
      • DeForge L.E.
      • Preston A.M.
      • Takeuchi E.
      • Kenney J.
      • Boxer L.A.
      • Remick D.G.
      Regulation of interleukin 8 gene expression by oxidant stress.
      ;
      • Ferguson P.J.
      • Lokuta M.A.
      • El-Shanti H.I.
      • Muhle L.
      • Bing X.
      • Huttenlocher A.
      Neutrophil dysfunction in a family with a SAPHO syndrome-like phenotype.
      ). In addition, RNA sequencing of neutrophils revealed an enhancement of neutrophil migration and adhesion markers in SAPHO (
      • Sun Y.
      • Li C.
      • Zhu M.
      • Zhang S.
      • Cao Y.
      • Yang Q.
      • et al.
      Enhanced migration and adhesion of peripheral blood neutrophils from SAPHO patients revealed by RNA-Seq.
      ). IL-17 inhibitors showed varying response rates with a greater impact on skin manifestations than on musculoskeletal symptoms. It is suspected that the diversity in the efficacy of IL-17 inhibitors could be dependent on the Th17 count (
      • Assmann G.
      • Tajali A.
      • Bamberger S.
      • Pfreundschuh M.
      • Schormann C.
      • Neumann F.
      AB0039 reduction of TH17+ lymphocytes in part of sapho patients on treatment with secukinumab.
      ). More data are needed to evaluate the effectiveness of these newer biologics targeting the IL-17/IL23 axis (
      • Daoussis D.
      • Konstantopoulou G.
      • Kraniotis P.
      • Sakkas L.
      • Liossis S.N.
      Biologics in SAPHO syndrome: a systematic review.
      ).

      Clinical signs and symptoms

      SAPHO is a rare AID with an estimated prevalence of 100‒400 cases per million (
      • Huhn C.K.
      • Schauer F.
      • Schempp C.M.
      • Venhoff N.
      • Finzel S.
      Skin inflammation associated with arthritis, synovitis and enthesitis. Part 1: psoriatic arthritis, SAPHO syndrome, Still’s disease, Behçet’s disease.
      ). It is characterized by cutaneous and osseoarticular manifestations. A total of 54% of skin manifestations occur before involvement of bones and joints (
      • Li C.
      • Zuo Y.
      • Wu N.
      • Li L.
      • Li F.
      • Zhang W.
      • et al.
      Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.
      ). Dermatologic manifestations include palmoplantar pustulosis, severe acne, and psoriasis vulgaris. The type of cutaneous manifestation depends on various epidemiological factors. Patients with severe acne are usually younger at the onset, with a median age of 20 years, and are predominantly male. Patients with palmoplantar pustulosis are usually female with a median disease onset of 37 years (
      • Li Y.
      • Li C.
      • Wu N.
      • Li F.
      • Wu Z.
      • Sun X.
      • et al.
      Demographic, clinical, and scintigraphic comparison of patients affected by palmoplantar pustulosis and severe acne: a retrospective study.
      ). Clinical features of articular involvement include joint pain; tenderness; swelling; as well as occasional erythema because of hyperostosis, osteitis, and arthritis (
      • Huhn C.K.
      • Schauer F.
      • Schempp C.M.
      • Venhoff N.
      • Finzel S.
      Skin inflammation associated with arthritis, synovitis and enthesitis. Part 1: psoriatic arthritis, SAPHO syndrome, Still’s disease, Behçet’s disease.
      ). Nearly all patients with SAPHO suffer from anterior chest wall pain. Radiologic evaluation shows abnormalities, such as osteolysis, sclerosis, and hyperostosis, in 90% of patients. Other common sites of involvement include the lumbosacral regions and peripheral joints (
      • Li C.
      • Zuo Y.
      • Wu N.
      • Li L.
      • Li F.
      • Zhang W.
      • et al.
      Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.
      ). In laboratory analysis, ESR and CRP levels are increased in more than half of the patients (
      • Li C.
      • Zuo Y.
      • Wu N.
      • Li L.
      • Li F.
      • Zhang W.
      • et al.
      Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.
      ).

      Cutaneous signs

      Skin manifestations of SAPHO include mainly severe acne and/or palmoplantar pustulosis, with psoriasis vulgaris rarely occurring as well (
      • Li C.
      • Zuo Y.
      • Wu N.
      • Li L.
      • Li F.
      • Zhang W.
      • et al.
      Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.
      ). About 70% of patients suffer from palmoplantar pustulosis only, and 7% exhibit acne lesions only. The remainder manifests with combinations of palmoplantar pustulosis, acne, and/or psoriasis vulgaris (
      • Li C.
      • Zuo Y.
      • Wu N.
      • Li L.
      • Li F.
      • Zhang W.
      • et al.
      Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.
      ). Severe acne can present as acne conglobata, acne fulminans, and/or hidradenitis suppurativa. Acne conglobata is characterized by cystic lesions, with interconnecting sinuses and scarring occurring on the face, neck, upper trunk, upper arms, thighs, and buttock (Figure 5a). Acne fulminans refers to a highly inflammatory form of acne with ulcerative lesions. Hidradenitis suppurativa manifests as inflammatory nodules, cysts, abscesses, and sinus tracts usually in the axillary, anogenital, and/or groin area (
      • Kahn M.F.
      • Khan M.A.
      The SAPHO syndrome.
      ). Acne occurs predominantly in male patients with SAPHO (
      • Li Y.
      • Li C.
      • Wu N.
      • Li F.
      • Wu Z.
      • Sun X.
      • et al.
      Demographic, clinical, and scintigraphic comparison of patients affected by palmoplantar pustulosis and severe acne: a retrospective study.
      ). Palmoplantar pustulosis is characterized by an abrupt eruption of multiple sterile pustules typically 2‒4 mm in diameter occurring on the palms and soles. Occasionally, lesions can be found on the dorsal aspect of the hands and feet as well (
      • Kahn M.F.
      • Khan M.A.
      The SAPHO syndrome.
      ). Palmoplantar pustulosis occurs mainly in female patients with SAPHO syndrome (
      • Li Y.
      • Li C.
      • Wu N.
      • Li F.
      • Wu Z.
      • Sun X.
      • et al.
      Demographic, clinical, and scintigraphic comparison of patients affected by palmoplantar pustulosis and severe acne: a retrospective study.
      ).
      Figure thumbnail gr5
      Figure 5Cutaneous signs of SAPHO and PFAPA. (a) SAPHO: acne fulminans on the upper trunk (A and B) healing with scarring (C). Hidradenitis suppurativa, psoriasis vulgaris, and palmoplantar psoriasis are not shown. (b) PFAPA: small oral aphthae surrounded by erythema on the nonkeratinized oral (A) and pharyngitis (B). Skin rash is not shown. The patient gave consent to the publication of his photographs. B denotes the back view, and F denotes the front view. PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome.

      Treatment

      The choice of a therapeutic agent is based on the disease manifestations. Patients with predominant joint involvement are initially treated with NSAIDs or corticosteroids (
      • Colina M.
      • Govoni M.
      • Orzincolo C.
      • Trotta F.
      Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects.
      ;
      • Hayem G.
      • Bouchaud-Chabot A.
      • Benali K.
      • Roux S.
      • Palazzo E.
      • Silbermann-Hoffman O.
      • et al.
      SAPHO syndrome: a long-term follow-up study of 120 cases.
      ;
      • Li C.
      • Zuo Y.
      • Wu N.
      • Li L.
      • Li F.
      • Zhang W.
      • et al.
      Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.
      ). Patients who do not respond to the initial treatment can be switched to methotrexate, followed by TNF-α inhibitors alone or in combination with methotrexate (
      • Daoussis D.
      • Konstantopoulou G.
      • Kraniotis P.
      • Sakkas L.
      • Liossis S.N.
      Biologics in SAPHO syndrome: a systematic review.
      ;
      • Li C.
      • Zuo Y.
      • Wu N.
      • Li L.
      • Li F.
      • Zhang W.
      • et al.
      Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.
      ). Less commonly used treatments are bisphosphonates; phosphodiesterase 4 inhibitor apremilast; and inhibitors of IL-1, IL-17, and IL-12/-23 (
      • Aljuhani F.
      • Tournadre A.
      • Tatar Z.
      • Couderc M.
      • Mathieu S.
      • Malochet-Guinamand S.
      • et al.
      The SAPHO syndrome: a single-center study of 41 adult patients.
      ;
      • Colina M.
      • Govoni M.
      • Orzincolo C.
      • Trotta F.
      Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects.
      ;
      • Daoussis D.
      • Konstantopoulou G.
      • Kraniotis P.
      • Sakkas L.
      • Liossis S.N.
      Biologics in SAPHO syndrome: a systematic review.
      ;
      • Wendling D.
      • Prati C.
      • Aubin F.
      Anakinra treatment of SAPHO syndrome: short-term results of an open study.
      ,
      • Wendling D.
      • Aubin F.
      • Verhoeven F.
      • Prati C.
      IL-23/Th17 targeted therapies in SAPHO syndrome. A case series.
      ). SAPHO-related acne can be treated with oral antibiotics such as azithromycin and doxycycline (
      • Aljuhani F.
      • Tournadre A.
      • Tatar Z.
      • Couderc M.
      • Mathieu S.
      • Malochet-Guinamand S.
      • et al.
      The SAPHO syndrome: a single-center study of 41 adult patients.
      ) or isotretinoin (
      • Galadari H.
      • Bishop A.G.
      • Venna S.S.
      • Sultan E.
      • Do D.
      • Zeltser R.
      Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome treated with a combination of isotretinoin and pamidronate.
      ).

      PFAPA

      Pathogenesis of PFAPA is broadly based on an overactivated innate immune system dysregulating T-cell activity. Various hypotheses for the pathogenesis of PFAPA were postulated in the last decade, but none could be proven yet. Neither a monogenic background nor an infectious trigger could be identified. A recent study (
      • Yildiz M.
      • Adrovic A.
      • Ulkersoy I.
      • Gucuyener N.
      • Koker O.
      • Sahin S.
      • et al.
      The role of Mediterranean fever gene variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.
      ) proposed that the disease onset or attack duration might be influenced by MEFV gene variants. MEFV, the gene responsible for the monogenic AID FMF, and several other genes associated with inflammasomopathies or the activation of the inflammasome (e.g., ALPK1 [
      • Sangiorgi E.
      • Azzarà A.
      • Molinario C.
      • Pietrobono R.
      • Rigante D.
      • Verrecchia E.
      • et al.
      Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.
      ]) were reported in PFAPA, but no mutation could be found consistently (
      • Berkun Y.
      • Levy R.
      • Hurwitz A.
      • Meir-Harel M.
      • Lidar M.
      • Livneh A.
      • et al.
      The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome.
      ;
      • Dagan E.
      • Gershoni-Baruch R.
      • Khatib I.
      • Mori A.
      • Brik R.
      MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA.
      ;
      • Di Gioia S.A.
      • Bedoni N.
      • von Scheven-Gête A.
      • Vanoni F.
      • Superti-Furga A.
      • Hofer M.
      • et al.
      Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.
      ;
      • Kolly L.
      • Busso N.
      • von Scheven-Gete A.
      • Bagnoud N.
      • Moix I.
      • Holzinger D.
      • et al.
      Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production.
      ;
      • Manthiram K.
      • Preite S.
      • Dedeoglu F.
      • Demir S.
      • Ozen S.
      • Edwards K.M.
      • et al.
      Common genetic susceptibility loci link PFAPA syndrome, Behçet’s disease, and recurrent aphthous stomatitis.
      ;
      • Yildiz M.
      • Adrovic A.
      • Ulkersoy I.
      • Gucuyener N.
      • Koker O.
      • Sahin S.
      • et al.
      The role of Mediterranean fever gene variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.
      ,
      • Yildiz M.
      • Haslak F.
      • Adrovic A.
      • Gucuyener N.
      • Ulkersoy I.
      • Koker O.
      • et al.
      Independent risk factors for resolution of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome within 4 years after the disease onset.
      ). Cytokine levels vary massively between flare-up and remission states and often between different studies. Several reports detected an elevation of IL-18 observed in both states of disease activity and especially high IL-6 during flare ups (
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