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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.
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 (
). 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 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 Figure 2. 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.
Stress, physical work, alcohol, spicy food, cold or hot temperatures
(2)
PFAPA
Aphtae
Enoral
Infancy, childhood
1‒10 days
unknown
(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
Table 2Histopathological Presentation of Noninflammasome-Mediated Autoinflammatory Diseases
Autoinflammatory Disease
Histopathological Signs
TNF associated
TRAPS
No 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 (
The 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 (
In 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 (
Two 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 (
In 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 (
). 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 (
). 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 (
The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
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.
The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
). 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 (
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 (
). 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 (
). 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) (
). 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 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 (
). 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 (
The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
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 (
Tumor necrosis factor receptor-associated periodic syndrome characterized by a mutation affecting the cleavage site of the receptor: implications for pathogenesis.
The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international 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 (
The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.
). Laboratory findings during flares include leukocytosis, elevated acute-phase reactants (CRP, serum amyloid A, haptoglobin, fibrinogen), and an increased erythrocyte sedimentation rate (ESR) (
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.
). Other manifestations include urticaria, erysipelas-like rash, small-vessel vasculitis, angioedema, and annular as well as serpiginous plaques (Figure 2b) (
Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: case report and literature review.
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 (
). 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 (
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.
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 (
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.
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) (
). 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 (
). 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) (
). 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 (
). 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 (
Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting.
). 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 (
). The building blocks of proteosomes consist of a subunit specialized in recognizing ubiquitinated proteins transporting it to a core subunit specialized in proteolytic degradation (
). 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) (
Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.
) 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 (
). 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 (
). 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 (
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 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.
). 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 (
). During the further course of the disease, patients develop eponymous lipodystrophy. Failure to thrive commonly occurs; however, the presence of developmental delay is rare (
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 (
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.
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.
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 (
). 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) (
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 (
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 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 (
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 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 (
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 (
). 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) (
), 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 (
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 (
Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients.
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 (
). 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 (
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.
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) (
, 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 (
Burma AM, et al. Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features.
). 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 (
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 (
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.
). Treatment with Jak inhibitors such as ruloxitinib and baricitinib, initially in combination with systemic corticosteroids, allowed for a reduction of disease severity (
STING-associated vasculopathy with onset in infancy in three children with new clinical aspect and unsatisfactory therapeutic responses to tofacitinib.
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 (
). 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 (
). 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 (
). 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 (
) 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) (
). Monocytes affected with DIRA-associated mutations showed elevated production of several proinflammatory cytokines, including IL-1, IL-6, TNF, and MIP-1α (
). 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 (
). 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 (
). The disease usually presents at birth or during the neonatal period and is typically characterized by chronic inflammation with occasionally occurring flare ups (
). 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 (
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 (
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) (
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.
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 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.
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 (
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.
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) (
). 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 (
). 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 (
). 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 (
). 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 (
DITRA presents with recurrent flares of generalized erythematous patches studded with pustules (pustular psoriasis), high bouts of fever, and systemic inflammation (
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 (
). 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 (
Patients present with generalized erythematous plaques studded with sterile pustules. In most patients, skin manifestations occur episodically with a sudden onset and subsequent desquamation (
). 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 (
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 (
) 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 (
Serum IL-6 and IL-23 levels and their correlation with angiogenic cytokines and disease activity in ankylosing spondylitis, psoriatic arthritis, and SAPHO syndrome.
Serum levels of proinflammatory, anti-inflammatory cytokines, and RANKL/OPG in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.
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 (
), 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 (
Serum levels of proinflammatory, anti-inflammatory cytokines, and RANKL/OPG in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.
). 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) (
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 (
). 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 (
Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
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 (
). 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 (
Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
). 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 (
). It is characterized by cutaneous and osseoarticular manifestations. A total of 54% of skin manifestations occur before involvement of bones and joints (
). 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 (
). Clinical features of articular involvement include joint pain; tenderness; swelling; as well as occasional erythema because of hyperostosis, osteitis, and arthritis (
). 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 (
). 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 (
). 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 (
). 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 (
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.
The choice of a therapeutic agent is based on the disease manifestations. Patients with predominant joint involvement are initially treated with NSAIDs or corticosteroids (
Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects.
). 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 (
Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects.
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 (
) 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 [
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 (