Cutaneous manifestations of systemic autoinflammatory disorders

Clinics in Dermatology (2015) 33, 520–526

Cutaneous manifestations of systemic autoinflammatory disorders Bediha Bölükbasi, MD a , Karoline Krause, MD b,c,⁎ a

Department of Internal Medicine, Müllroser Chaussee 7, 15236 Frankfurt (Oder), Germany Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany 2 c Autoinflammation Reference Center Charité (ARC ), Charité, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany b

Abstract Rare systemic autoinflammatory diseases (sAIDs) are driven by cytokine-mediated uncontrolled inflammation that results from activation of innate immune pathways. sAIDs present with recurrent fever episodes, fatigue, musculoskeletal symptoms, gastrointestinal, neurologic, and skin manifestations. They include hereditary monogenic and acquired multifactorial disorders, show a significant morbidity and usually persist for life. Due to the limited awareness of sAIDs, they are often associated with a considerable delay in diagnosis. Within the last decade, the use of cytokineneutralizing therapies has been shown to improve the clinical symptoms of many patients with different sAIDs. Because skin involvement, such as urticarial, pustular, or ulcerative eruptions, is common in a variety of autoinflammatory disorders, dermatologists should be aware of the most important diseases and their skin phenotypes. This review gives an overview on prototype sAIDs with focus on cutaneous manifestations, clinical clues, and diagnostic approaches. Effective treatment options, such as anti–interleukin-1–targeted therapies, are discussed. © 2015 Elsevier Inc. All rights reserved.

Introduction Systemic autoinflammatory diseases (sAIDs) are heterogenous chronic disorders, characterized by an abnormal inflammatory phenotype that is mediated via innate immune pathways. As opposed to autoimmune diseases, antigenspecific T cells and autoantibodies are lacking in sAIDs. The term autoinflammatory disease was introduced in 1999 by ⁎ Corresponding author. Tel.: +49 30 450 518 438; fax: +49 30 450 518 959. E-mail address: [email protected] (K. Krause). http://dx.doi.org/10.1016/j.clindermatol.2015.05.002 0738-081X/© 2015 Elsevier Inc. All rights reserved.

Mc Dermott et al, following the discovery of the underlying mutation in the tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a rare hereditary inflammatory disease.1 Within the last decade, many new sAIDs have been described; however, disease awareness is still limited, resulting in a diagnostic delay of many years or even decades.2 Delay in diagnosis goes along with considerable quality-of-life impairment and may cause irreversible long-term complications (eg, amyloidosis) and death.3 Typical clinical features of sAIDs include recurrent fever episodes, fatigue, and musculoskeletal, gastrointestinal, neurologic, and skin manifestations. The inflammation in many sAIDs is mediated via an overactive

Cutaneous manifestations of autoinflammatory disorders Table 1

521

Classification of selected systemic autoinflammatory diseases (sAIDs)

Monogenic sAIDs

Multifactorial acquired sAIDs

Common diseases with autoinflammatory aspects

Overlapping immune-mediated diseases

Disease/gene

Proposed mechanism

FMF/MEFV TRAPS/TNFRSF1 A MKD/MVK CAPS/NLRP3 PAPA syndrome/PSTPIP1 DIRA/IL-1 RN DITRA/IL36 RN Blau syndrome/NOD2 FCAS2/NLRP12 Majeed syndrome/LPIN2 SchS/complex sJIA/complex AOSD/complex PFAPA/complex Behçet disease/complex Gout/complex Diabetes mellitus/complex Alzheimer disease/complex Cardiac injury/complex PRAAS/PSMB8 PLAID/PLCG2

Inflammasome activation Protein misfolding Inflammasome activation Intrinsic inflammasomopathy Inflammasome activation Absence of negative IL-1α or IL-1β regulator Absence of negative IL-36α, IL-36β, or IL-36γ regulator NFκB activation disorder NFκB activation disorder Unknown Inflammasome activation Inflammasome activation Inflammasome activation Unknown Unknown Crystal-induced inflammasome activation Hyperglycemia-induced inflammasome activation Inflammasome activation by DAMPS, amyloid, ROS Inflammasome activation by DAMPS Altered immunoproteasome function Signaling abnormalities in multiple leukocyte subsets

AOSD, adult-onset Still`s disease; CAPS, cryopyrin-associated periodic syndrome; DAMPS, danger-associated molecular patterns; DIRA, deficiency of IL-1 receptor antagonist; DITRA, deficiency of IL-36 receptor antagonist; FCAS2, familial cold autoinflammatory syndrome 2; FMF, familial Mediterranean fever; IL, interleukin; MEFV, Mediterranean fever gene; MKD, mevalonate kinase deficiency; MVK, mevalonate kinase; NOD2, nucleotide oligomerization domain 2; NLRP, nucleotide binding domain-like receptor protein; PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; PLAID, phospholipase Cγ2–associated antibody deficiency; PRAAS, proteasome-associated autoinflammatory syndrome; PSTPIP1, proline-serine-threonine phosphatase interacting protein 1; ROS, reactive oxygen species; SchS, Schnitzler´s syndrome; sJIA, systemic juvenile idiopathic arthritis; TRAPS, TNF receptor–associated periodic syndrome.

inflammasome and subsequent cytokine release. Both single mutations in inflammasome-related genes and other tissuespecific factors, such as microbes, oxidative stress, and crystals, may account for the uncontrolled inflammasome activation in autoinflammatory disorders.4

Spectrum of autoinflammatory diseases sAIDs can be divided into hereditary monogenic disorders and multifactorial acquired disorders. Among them are the well-known hereditary periodic fever syndromes (HPFs), characterized by chronic recurrent fever attacks as one of the leading clinical manifestations. HPFs include TRAPS, cryopyrin-associated periodic syndrome (CAPS), mevalonate kinase deficiency (MKD), and familial Mediterranean fever (FMF) (Table 1). Except for FMF, which has a higher prevalence in Eastern Mediterranean countries, all periodic fever syndromes are very rare disorders. The list of other rare sAIDs with monogenic inheritance is constantly growing. Representatives of such sAIDs are Blau syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), and pyogenic

arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, which share an early disease onset within the first years of life. Multifactorial acquired sAIDs may develop in childhood, like systemic juvenile idiopathic arthritis (sJIA), or in adulthood, like adult-onset Still disease (AOSD) and Schnitzler´s syndrome (SchS) (Table 1). The etiology of acquired sAIDs is still unknown. Several studies in AOSD suggest a combination of genetic predisposition and infectious triggers, which contribute to the clinical presentation.5–7 Recently, inflammasome activation via innate immune pathways has also been linked—at least in part—to the pathogenesis of common inflammatory disorders, such as gout,8 diabetes mellitus,9 neurodegenerative diseases including Alzheimer’s,10 and even malignancies.11 Also, there are the co-existence of autoinflammatory and autoimmune mechanisms (eg, in proteasome-associated autoinflammatory disease [PRAAS])12 and the coincidence with autoimmune and immunodeficiency features (as in phospholipase Cγ2–associated antibody deficiency [PLAID]).13 The apparent overlap of immune features led to the concept of a disease continuum, in which defective innate and adaptive immune mechanisms are located on two ends of a spectrum of immune-mediated diseases.4

522 Table 2

B. Bölükbasi, K. Krause Cutaneous manifestations in sAIDs

Skin phenotype

Disease

Urticarial/maculopapular lesions

CAPS FCAS2 PLAID MKD TRAPS SchS sJIA AOSD DIRA DITRA PAPA syndrome PAPA PASH Behçet disease MKD PFAPA Blau syndrome FMF Majeed syndrome PRAAS

Pustular lesions

Pyoderma gangrenosum lesions Aphthous lesions

Granulomatous lesions Erysipelas-like lesions Painful papules/Sweet-like lesions Lipodystrophy

AOSD, adult-onset Still´s disease; CAPS, cryopyrin-associated periodic syndrome; DIRA, deficiency of IL-1 receptor antagonist; DITRA, deficiency of IL-36 receptor antagonist; FCAS2, familial cold autoinflammatory syndrome 2; FMF, familial Mediterranean fever; IL, interleukin; MKD, mevalonate kinase deficiency; NLRP, nucleotide binding domain-like receptor protein; PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne; PASH, pyoderma gangresosum, acne, and suppurative hidradenitis; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; PLAID, phospholipase Cγ2–associated antibody deficiency; PRAAS, proteasome-associated autoinflammatory syndrome; SchS, Schnitzler´s syndrome; sJIA, systemic juvenile idiopathic arthritis; TRAPS, TNF receptor–associated periodic syndrome.

Skin manifestations in autoinflammatory diseases Cutaneous manifestations are common and may even represent the leading clinical findings in autoinflammatory diseases. Cutaneous findings include urticarial or maculopapular eruptions, pustules, ulcerative lesions (aphthae and pyoderma gangrenosum), and granulomatous and erysipelas-like lesions (Table 2). None of these are specific for any disorder, and the extent of skin involvement varies among patients and diseases.

Autoinflammatory diseases presenting with urticarial eruptions Cryopyrin-associated periodic Schnitzler's syndrome (CAPS) CAPS is a very rare hereditary autosomal-dominant disorder with an estimated population frequency of 1 to 3 per million.14 A positive family history can be found in nearly half of patients. Most cases have been reported in Western

European countries and North America, but the disease is known in other parts of the world as well.2 Disease pathogenesis in CAPS, a direct inflammasomopathy, is mediated via a gain of function mutation in the gene encoding for nucleotide binding–like receptor protein 3 (NLRP3).15 NLRP3 is part of the inflammasome, a cytosolic multiprotein complex that controls the activity of caspase-1 via the adaptor apoptosis speck protein (ASC). Active caspase-1 acts on interleukin-1β [IL-1β] cytokine family members, including IL-1β and IL-18, which are produced in the cytosol as biologically inactive pro-forms. After caspase-1 activation, pro–IL-1β cytokines are proteolytically processed and thereby become biologically active. The NLRP3 mutation in CAPS results in an overactivated inflammasome followed by IL-1β–mediated inflammation. Based on the clinical phenotype, CAPS may be divided into three subtypes. Familial cold autoinflammatory syndrome (FCAS) represents the mildest form, followed by Muckle-Wells syndrome (MWS), the intermediate subtype, and neonatal-onset multisystem inflammatory disorder (NOMID), the most severe subtype (Table 3). Disease onset is usually in early childhood, appearing from the first days of life to early adulthood.14 In a majority of patients, the urticarial eruption in CAPS is symmetrically distributed on the trunk and extremities and occurs on a daily basis (Figure 1). It may have diurnal variations with a maximum intensity in the evening. In contrast to common urticaria, the skin lesions are usually not itchy and do not respond to antihistamine treatment.16 In FCAS and MWS, cold is a major trigger of skin and systemic inflammatory findings.17 Other clinical features in CAPS include recurrent fever episodes, malaise, and joint, ocular, and neurologic manifestations.18,19 Feared long-term complications are amyloidosis and hearing loss.3,20

Schnitzler's syndrome (SchS) SchS is a prototype late-onset sAID that begins about the age of 50. Around 250 cases have been reported so far, generally in Europe21; however, the estimated number of undiagnosed cases is thought to be much higher. Although the pathogenesis of SchS is widely unknown, changes in the expression of inflammasome components ASC and P2X7 and increased cellular IL-1β secretion place SchS in the group of inflammasomopathies.22 Interestingly, disease-causing somatic CAPS mutations and NLRP3 polymorphisms of unknown significance have been detected in single patients with SchS.23,24 The clinical phenotype in SchS is characterized by recurrent urticarial eruptions (Figure 2), associated with a monoclonal gammopathy (IgM or rarely IgG). Additional symptoms are episodes of fever, myalgias, and bone and joint pain. In general, the findings resemble an adult form of CAPS. Due to the monoclonal gammopathy, lymphoproliferative disorders, such as Waldenström's disease, develop in up to 15% of patients, even after years or decades.25

Cutaneous manifestations of autoinflammatory disorders Table 3

523

Clinical spectrum of CAPS subtypes

CAPS, cryopyrin-associated periodic syndrome; MWS, Muckle-Wells syndrome; NOMID, neonatal-onset multisystem inflammatory disease.

Autoinflammatory diseases presenting with pustular lesions Deficiency of the IL-1 receptor antagonist (DIRA) DIRA is a neonatal-onset autoinflammatory disease that has been reported in very few patients, generally from Europe, the Middle East, North America, and Central America. The disease is caused by homozygous mutations in the IL-1RN gene, which encodes the IL-1 receptor antagonist, a competitor of IL-1β at the IL-1 receptor.26 The mutated IL-1 receptor antagonist cannot bind to the receptor, resulting in loss of its IL-1β inhibitory function.

Fig. 1 Urticarial eruption in 54-year old man with Muckle-Wells syndrome.

Clinically, newborns present with localized or generalized sterile pustules. There may also be ichthyosiform lesions and nail changes, plus joint swellings, osteomyelitis, skeletal malformations, and hepatosplenomegaly. As opposed to HPFs, recurrent fever episodes are not typical features of DIRA, although the pronounced inflammation may lead to multiorgan failure and significant childhood mortality.26,27

Fig. 2 Urticarial eruption in 51-year-old man with Schnitzler`s syndrome.

524

Autoinflammatory diseases presenting with ulcerative lesions Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome PAPA syndrome is another ultra-rare autosomal-dominant disease with about 40 published case reports. The underlying mutation in PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) enhances inflammasome activation via pyrin that results in caspase-1-driven IL-1β accumulation.28 Patients develop painful sterile pyogenic arthritis, beginning in early childhood. Cutaneous findings include severe nodulocystic acne and painful pyoderma gangrenosum lesions, usually developing during puberty, often leading to severe scarring and significant psychosocial impairment.29 By adulthood, the arthritis may diminish, but the skin lesions worsen.

B. Bölükbasi, K. Krause matory diseases (eg, CAPS, SchS, AOSD)34 as well as pustular and ulcerative diseases (eg, DIRA and PAPA syndrome).26,35 Although dermal neutrophil accumulation is not specific for sAIDs, it may be a further hint toward autoinflammation. After exclusion of other inflammatory conditions, genetic testing is recommended to confirm the diagnosis of monogenic sAID in patients with early disease onset and/or positive family history; however, it has to be noted that up to 40% of patients with a clear phenotype of monogenic autoinflammatory disease are mutation-negative,2 suggesting the existence of other unknown germ-line mutations or somatic mutations.36 The diagnosis of multifactorial acquired sAIDs is usually made on the basis of combined clinical criteria. Additional serum markers (eg, serum-immune fixation to confirm monoclonal gammopathy in patients with suspected Schnitzler´s syndrome) should follow the individual clinical phenotype.

Treatment options Diagnostic approach A diagnosis of autoinflammatory disease is usually made after exclusion of various other inflammatory conditions. Based on the leading clinical findings the differential diagnoses of sAIDs may include autoimmune diseases, infections, and other inflammatory disorders. In patients with recurrent urticarial eruptions, histamine-mediated urticaria would be the most common condition; however, in the presence of systemic symptoms, such as arthralgia and fatigue, urticarial autoinflammatory syndromes (eg, CAPS and SchS) or urticarial vasculitis may be the underlying condition.30 The latter presents with damage to small dermal vessels and/or fibrinoid deposits in perivascular and interstitial locations. SAIDs with pustular lesions should be distinguished from pustular psoriasis, acute generalized exanthematous pustulosis (AGEP), and isolated areas of hidradenitis suppurativa. Mucous membrane and skin ulcers are common findings in many inflammatory conditions. Aphthous lesions may be a sign of infection, autoimmune disease, immunodeficiency, or autoinflammation. Pyoderma gangrenosum lesions may be idiopathic or linked to inflammatory bowel disease, hematologic disorders, or rare monogenic sAIDs, including PAPA syndrome.31 Step one in the diagnostic algorithm consists of a detailed medical history, including family history and age of onset. Because erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA) are elevated either during disease attacks or constantly in sAIDs, these laboratory tests should be part of the diagnostic workup. In addition, continuously high SAA levels are associated with an increased risk for amyloidosis.3 S100 proteins (S100 A8/9, S100 A12) have been reported to be useful markers in detecting subclinical inflammation in sAIDs.32,33 So far, autoinflammatory skin biomarkers are not available. Skin histopathology studies revealed the existence of dermal neutrophil-rich cell infiltrates in urticarial autoinflam-

Since the early 1970s, colchicine has been successfully used in the treatment of FMF patients.37 The treatment of other sAIDs has been limited to poorly effective nonsteroidal antiphlogistics and immunosuppressives. Based on a better understanding of innate immune responses, new treatment options have emerged. For the majority of sAIDs, cytokine-blocking agents have had good efficacy. Clinical trials with IL-1–neutralizing drugs in CAPS have revealed a highly significant improvement of clinical symptoms and inflammation markers and led to the approval of anti–IL-1β blockers for CAPS.38–40 Recently, anti–IL-1 treatment was also approved for therapy-resistant cases of sJIA41 and gout.42 Patients with other autoinflammatory conditions, such as FMF, SchS, DIRA, and PAPA syndrome have also been reported, in small open-label studies and case series, to benefit from anti–IL-1 treatment.26,43–46 Based on the excellent efficacy of anti–IL-1 treatment in rare sAIDs, IL-1–neutralizing drugs are successfully used in clinical trials to treat common inflammatory conditions including diabetes mellitus, post–myocardial infarction inflammation, and heart failure.47–49 Anti-IL-6 blockade represents another promising treatment option in sAIDs. Anti-IL-6 treatment is approved for sJIA50 and has been found to have good efficacy in single patients with SchS51 and TRAPS,52 too. Also, anti-TNF blockers can be helpful in the treatment of MKD,53 TRAPS,54 and PAPA syndrome.55

Conclusions SAIDs are severe and disabling inflammatory conditions that start in early childhood (eg, CAPS and FMF) or adulthood (eg, AOSD and SchS) and persist for life. If not treated properly, these diseases lead to irreversible long-term complications,

Cutaneous manifestations of autoinflammatory disorders including amyloidosis (FMF, CAPS, SchS), hearing loss, and destructive arthropathy (CAPS), as well as malignant lymphoma (SchS).20,25,56 Autoinflammatory disorders are associated with a high burden for patients and society. Although the treatment of sAIDs has much improved by the use of cytokine-targeted therapies, it is still not satisfactory for many patients. CAPS and sJIA are the only rare sAIDs for which approved therapies, namely anti–IL-1 blockers (CAPS and sJIA) and anti–IL-6 blockers (sJIA), exist. Unfortunately, anticytokine therapies for other sAIDs are dependent on the reimbursement policies of individual health insurance providers. With the rarity of autoinflammatory disorders, only very few randomized clinical trials have been reported to provide support for obtaining insurance approval. Future efforts should aim at (1) increasing the awareness of autoinflammatory diseases and (2) enabling access to effective treatment options such as cytokine-targeted therapies for all patients with rare sAIDs.

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