A Dermatologic Perspective on Autoinflammatory Diseases A.V

A dermatologic perspective on autoinflammatory diseases A.V. Marzano1, G. Damiani1, G. Genovese1, M. Gattorno2

1Dipartimento di Fisiopatologia ABSTRACT regulation of the innate immunity and Medico-Chirurgica e dei Trapianti, Autoinflammatory diseases (AIDs) en- clinically characterised by recurrent ep- Università degli Studi di Milano, compass a heterogeneous group of dis- isodes of sterile inflammation in affect- Unità Operativa di Dermatologia, orders pathogenetically related to an ed organs in the absence of infection, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, abnormal activation of the innate im- allergy, and high titre of circulating au- Milano, Italy; munity and clinically characterised by toantibodies or autoreactive T cells (1, 2UOC Pediatria 2, G. Gaslini Institute, aseptic inflammation in the affected or- 2). The skin is one of the major organs Genova, Italy. gans in the absence of high titre of cir- involved in classic monogenic AIDs, Angelo V. Marzano, MD culating autoantibodies or autoreactive with a wide range of cutaneous lesions Giovanni Damiani, MD T cells. In classic monogenic AIDs, the occurring. Monogenic AIDs, for which Giovanni Genovese, MD skin is frequently involved with a wide a typical example is the cryopyrin-as- Marco Gattorno, MD range of cutaneous lesions. Monogenic sociated periodic syndromes (CAPS), Please address correspondence to: AIDs result from different mutations in are due to different mutations involv- Angelo V. Marzano, MD, a single gene, which regulates the in- ing a single gene regulating the innate Dipartimento di Fisiopatologia nate immunity. These mutations cause Medico-Chirurgica e dei Trapianti, immune response (3-8). In CAPS, these Università degli Studi di Milano, an uncontrolled activation of the in- mutations cause an aberrant activation Unità Operativa di Dermatologia, flammasome, leading to an overexpres- of the inflammasome, which is a mo- IRCCS Fondazione Ca’ Granda, sion of interleukin (IL)-1β. IL-1β is the lecular platform that plays a pivotal role Ospedale Maggiore Policlinico, pivotal cytokine which is responsible in autoinflammation as it induces the via Pace 9, 24125 Milano, Italy. for the exaggerated production of cy- overexpression of the key proinflamma- E-mail: [email protected] tokines and chemokines that induce the tory cytokine, interleukin (IL)-1β (3-8). Received on November 27, 2017; accepted recruitment of neutrophils, key cells in Excessive amounts of IL-1β triggers on December 7, 2017. autoinflammation. Paradigmatic auto- the uncontrolled release of a number of Clin Exp Rheumatol 2018; 36 (Suppl. 110): inflammatory forms are the cryopyrin- cytokines and chemokines, which act S32-S38. associated periodic syndromes (CAPS), synergistically with IL-1β inducing the © Copyright Clinical and whose skin involvement consists of urti- autoinflammatory process. The autoin- Experimental Rheumatology 2018. carial lesions. Similar IL-1β-mediated flammatory process is mainly mediated autoinflammatory pathomechanisms via the recruitment and activation of Key words: autoinflammation, also occur in deficiency of IL-1 receptor neutrophils, which are central mecha- autoinflammatory monogenic antagonist (DIRA) and deficiency of IL- nistic components of the AIDs (3-8). syndromes, cryopyrin-associated 36 receptor antagonist (DITRA), whose Urticarial lesions, which present along- periodic syndromes, deficiency of cutaneous appearance is characterised side periodic fever and other systemic IL-1 receptor antagonist, deficiency by pustular lesions, as well as in pyo- symptoms and signs characteristic of of IL-36 receptor antagonist, pyogenic genic arthritis, pyoderma gangrenosum CAPS, may be regarded as the skin arthritis, pyoderma gangrenosum, acne and acne (PAPA) syndrome. Pyoderma hallmark of these conditions (9). A sim- gangrenosum, which is the cutaneous ilar inflammatory scenario occurs as a hallmark of the PAPA syndrome, is a consequence of inherited gain-of-func- prototypic neutrophil-mediated skin tion mutations in genes encoding the Funding: this paper is part of a disease, manifesting as single or multi- IL-1 receptor antagonist (IL-1RA) (10) supplemental issue supported by an ple ulcers with undermined, raised ery- and the IL-36 receptor antagonist (IL- unrestricted grant from Novartis Farma, thematous to violaceous borders. This 36RA); these mutations give rise to two Italy through a service agreement with review is focused on the CAPS, DIRA/ disorders known as deficiency of the in- Health Publishing & Services Srl. Health DITRA and PAPA syndromes with em- terleukin-1 receptor antagonist (DIRA) Publishing & Services Srl provide phasis on their cutaneous manifesta- and deficiency of interleukin thirty- editorial assistance. Article Processing tions, as well as their histology and six–receptor antagonist (DITRA), re- Charges were also funded by Novartis Farma, Italy pathophysiology. spectively (11). Similar to CAPS, the cutaneous picture of DIRA and DITRA Competing interests: M. Gattorno has received speaker’s fees, consultancies Introduction is monomorphic but is characterised by and unrestricted grants from Novartis Autoinflammatory diseases (AIDs) are a pustular presentation (10, 11). There and SOBI. The other authors declare no a heterogeneous group of disorders that is an increasing body of evidence that competing interests. are pathogenetically related to a dys- autoinflammation is the physiopatho-

S-32 Clinical and Experimental Rheumatology 2018 Dermatology of autoinflammatory diseases / A.V. Marzano et al. logical explanation of many polygenic cutaneous diseases, and in particular neutrophilic dermatoses. These are a spectrum of disorders hallmarked by an accumulation of neutrophils in the skin and rarely in internal organs, which are clinically characterised by polymorphic skin lesions (12-14). Pyoderma gangrenosum (PG), the prototype of neutrophilic dermatoses, also occurs in the context of syndromic forms, one of which, namely pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), Fig. 1. Cryopyrin-associated periodic syndromes (CAPS). (A) Urticarial rash characterised by erythematous and confluent wheals on the thighs of an adolescent is a well-known monogenic autoin- with Muckle-Wells syndrome. Notably, lesions have a symmetrical distribution. (B) Histopathological flammatory syndrome (15-18). In this aspects: dense neutrophilic perivascular and interstitial inflammatory infiltrate. Courtesy of Dr Angelo review, we will focus on CAPS, DIRA/ Cassisa. DITRA and syndromic PG, with em- phasis on cutaneous manifestations as macules or slightly elevated papules or the term “neutrophilic urticarial derma- well as their histopathological features plaques that predominantly involve the tosis” (Fig. 1B) to define the clinico- and pathophysiological mechanisms. trunk and less frequently the lower and pathological features which character- upper limbs. The lesions may some- ise the skin involvement in CAPS but Cryopyrin-associated periodic times display an annular configuration are also seen in association with lupus syndrome (CAPS) and a peripheral halo of vasoconstric- erythematosus and adult-onset Still’s CAPS is an umbrella term for three tion can rarely be seen. Individual le- disease (25, 26). Finally, non-specific phenotypes that increase in severity sions usually heal within 24 to 48 hours histological aspects occur in CAPS pa- from familial cold autoinflammatory without scarring or residual hyperpig- tients presenting with only flat wheals syndrome (FCAS), Muckle-Wells syn- mentation; more solid and persistent or erythema (9). drome to chronic infantile neurologi- lesions, that mimic the wheals in urti- cal, cutaneous and articular syndrome carial vasculitis, can also develop (Fig. Differential diagnosis (CINCA), which is also known as ne- 1A). The lesions often have a sym- Urticarial vasculitis and common urti- onatal-onset multisystem inflammatory metrical distribution and, similarly to caria are the main differential diagno- disease (NOMID) (3-7, 19-22). These urticarial vasculitis, they are associated ses of CAPS urticarial lesions. Urticar- three entities of the CAPS group repre- with pain or burning sensation rather ial vasculitis is a small vessel vasculitis sent a clinical continuum of autosomal than itching; pruritus, if present, is only with predominant skin involvement dominant disorders caused by a number slight. The skin eruption generally oc- manifesting as wheals that persist for of different mutations in a single gene, curs as recurrent crops but may also fol- more than 24 hours (9, 28). In urticarial NLRP3 (nucleotide-binding oligom- low a chronic course in some patients. vasculitis, the wheals resolve leaving erisation domain [NOD]-like receptor It is notable that in FCAS, the urticarial an ecchymotic-hyperpigmented patch; family, pyrin domain containing 3). eruption is triggered by cold exposure other cutaneous manifestations, includ- More than 175 different mutations in and accompanied by fever spikes, head- ing livedo reticularis, purpura, bullae, NLRP3, mainly concentrated in exon ache, and fatigue as well as arthralgia and necrotic-ulcerative lesions, may 3, have been associated with the three and conjunctivitis (25). also be present. Skin biopsy is crucial CAPS phenotypes and reported in the for a differential diagnosis since the registry of hereditary autoinflammato- Histopathological aspects urticarial vasculitis histology shows a ry disorder mutations, Infevers (http:// The histological pattern of the CAPS pattern typical of leukocytoclastic vas- fmf.igh.cnrs.fr/ISSAID/infevers/) (23, urticarial lesions consists of a dense culitis. Common urticaria is a frequent 24). NLRP3 encodes the protein, cry- neutrophilic perivascular and inter- disease that is subdivided into acute opyrin, which is responsible for the un- stitial inflammatory infiltrate (25-27). and chronic forms. Chronic spontane- controlled overproduction of IL-1β via Leukocytoclasia is frequently observed ous urticaria cases resistant to conven- the inflammasome (23). but fibrinoid necrosis of dermal small tional antihistamine treatment may be vessel wall is always absent, which is difficult to differentiate from CAPS Cutaneous features: an important clue to differentiate the cases. However, unlike chronic sponta- urticarial presentation histology of CAPS from that of ur- neous urticaria patients, CAPS patients The urticarial rash affects almost all pa- ticarial vasculitis. Dermal oedema, generally do not suffer from intense tients with CAPS and shows similar as- which is the typical finding of chronic itching, lack wheals with surrounding pects in all three CAPS phenotypes (25, spontaneous urticaria histology, is also flare and their urticarial lesions tend to 26). Individual lesions are rose or red absent. Lipsker and colleagues coined be symmetrically distributed. Histol-

Clinical and Experimental Rheumatology 2018 S-33 Dermatology of autoinflammatory diseases / A.V. Marzano et al.

Fig. 2. Deficiency of IL-36 receptor antagonist (DITRA). (A) Widespread eruption consisting of erythematous, polycyclic lesions covered by pustules. (B) Detail of the pustular lesions. (C) Histology showing parakeratotic hyperkeratosis and acanthosis associated with intraepidermal spongiform pustules. Courtesy of Dr Raffaele Gianotti. ogy, as previously mentioned, as well tion via nuclear factor kappa B (NFkB) ballooning of long bones, anterior rib- as the presence of systemic symptoms and mitogen activated protein (MAP) end widening, periosteal elevation of and signs in CAPS are important clues kinases (29). Deficiency of IL-36RA long bones, and multifocal osteolytic le- for a differential diagnosis (9). leads to an exaggerated inflammatory sions. Central nervous system involve- response, analogous to that resulting ment manifesting as vasculitis may Deficiency of IL-1 receptor from IL-1RA deficiency in patients rarely be seen (10). DITRA is clinically antagonist (DIRA) and deficiency of with DIRA, and further implicates the suspected when, early in childhood, a IL-36 receptor antagonist (DITRA) relevance of these pathways in pustular patient displays recurrent and severe In 2009, DIRA was described both clin- disease pathogenesis (11). Mutations in generalised pustular psoriasis that is ically and genetically as an autosomal IL-36RN have been reported to account enriched by systemic symptoms such recessive autoinflammatory disorder for 46% to 82% of cases of generalised as fever, asthenia, and laboratory mark- (10) in which a homozygous mutation pustular psoriasis without associated ers including neutrophilia and elevated led to a loss of function in IL1RN, the plaque psoriasis (30, 31), suggesting inflammatory markers (11). Although gene encoding the IL-1RA (29). Muta- there is an overlap between DITRA and the disease usually occurs in childhood, tion provokes a lack of contrasting IL-1 the generalised variant of pustular pso- its occurrence in some adults has also signalling, resulting in an uncontrolled riasis. been described. Mortality is a possible systemic inflammation. Heterozygous complication due to the large disrup- carriers are asymptomatic (29). Patients Cutaneous features: tion of the skin barrier and consequent present in the neonatal period with pustular presentation septicaemia (10, 11). Interestingly, DI- systemic inflammation, manifested by Both DIRA and DITRA manifest as TRA patients do not experience other elevations of acute phase reactants, as clearly defined, raised bumps on the subtypes of psoriasis consolidating the well as bone and skin inflammation. skin that are filled with pus (pustules) view that the causative mutation pro- One third of children are born small for (10, 11). Skin pathergy may be eluci- vokes a specific clinical phenotype. their gestational age, with evidence of dated by mechanical injury on the skin an intrauterine onset. Infants can also and leads to the development of the Histopathological aspects develop a life-threatening systemic pustular lesions. Severity of cutaneous Histology shows intraepidermal spongi- inflammatory response syndrome due presentation ranges from rare pustules form pustules with clusters of neutro- to uncontrolled escalating inflamma- to a disseminated pustulosis resembling phils consolidated in microabscesses tion. In 2011, a mutation in the IL-36 the generalised variant of pustular pso- (Fig. 2C). Parakeratosis, acanthosis receptor antagonist gene (IL-36RN) riasis (Figs. 2A and 2B). Psoriatic nail with elongation of rete ridges and der- was identified in nine Tunisian families changes, such as pitting and onycho- mal neutrophilic infiltration are also (11). The mutation had an autosomal madesis, may also be present. Ich- seen (10, 11). recessive behaviour which lead to a thyosis may also enrich the cutaneous clinical phenotype suggesting gener- findings (10, 11). Interestingly, DIRA Differential diagnosis alised pustular psoriasis. The gene IL- pustular eruption can anticipate sys- DIRA and DITRA must be differenti- 36RN is located on chromosome 2 and temic complications such as respiratory ated from variants of pustular psoriasis encodes the IL-36RA, which binds the insufficiency and thrombotic events. which occur outside the setting of au- IL-36R causing a negative feedback in However, mortality secondary to multi- toinflammation, including generalised IL-36 signalling (11). IL-36 belongs to organ failure has rarely been reported. pustular psoriasis, palmoplantar pus- the IL-1 family cytokine and by binding Bone changes are typical clinical find- tulosis, and acrodermatitis continua of the IL-36 receptor enables the transduc- ings of DIRA and include epiphyseal Hallopeau. Bone and central nervous

S-34 Clinical and Experimental Rheumatology 2018 Dermatology of autoinflammatory diseases / A.V. Marzano et al. system involvements, as seen in DIRA, are relevant clinical clues for differential diagnosis. The other differential diagnosis is acute generalised exanthematous pustulosis which, however, has a predilection for the major flexures and is triggered in the vast majority of cases by medications, particularly antibiotics, antimycotics, and anticon- vulsants (32). The identification and withdrawal of the offending drug are both helpful for differential diagnosis and the essential first therapeutic step. Fig. 3. Pyoderma gangrenosum. (A) Typical ulcer of pyoderma gangrenosum. (B) Histology showing Syndromic pyoderma gangrenosum a dense dermal-hypodermal inflammatory infiltrate consisting of lymphocytes, histiocytes and neutro- (PG) phils. Courtesy of Dr Raffaele Gianotti. Neutrophilic dermatoses are a heterogeneous group of conditions characterised neutrophilic dermatoses in general (37, severe nodulocystic presentation; both clinically by polymorphic skin lesions, 39, 40), with all these forms thus repre- conditions may persist into adulthood including pustules, bullae, abscesses, senting polygenic AIDs. (42, 44, 45, 48). PG generally presents papules, nodules, and ulcers, and his- with its typical skin ulcer displaying tologically by a neutrophil-rich inflam- Pyogenic arthritis, pyoderma undermined, elevated erythematous-vi- matory infiltrate (13, 33, 34). The pos- gangrenosum and acne (PAPA syndrome) olaceous borders and usually involves sible involvement of almost any organ PAPA syndrome is a rare autosomal the legs, however, pustular, bullous or system gave rise a number of years ago dominant disease first described by vegetating lesions can coexist or re- to the term “neutrophilic disease” (14). Lindor et al. in 1997 (41). Clinically, place the classic ulcer. Painful, recur- The prototype of neutrophilic derma- it is characterised by sterile inflamma- rent aseptic monoarticular arthritis with toses is PG, which, in its classic pres- tion of the skin and joints (42). PAPA a neutrophil-rich infiltrate generally oc- entation, manifests as single or multiple syndrome is due to different mutations curs in childhood and may also be the skin ulcers with undermined, raised er- on chromosome 15q involving the first manifestation of the disease, pos- ythematous to violaceous borders (Fig. PSTPIP1 gene (43, 44). The originally sibly leading to joint erosion and de- 3A); it may also present with pustular, identified mutations, namely A230T struction (48). It is noteworthy that in bullous, and vegetating plaque-type le- and E250A, as well as others more re- young adults articular symptoms tend sions (18, 33, 34). PG may be isolated cently found, interfere with the ability to decrease while cutaneous manifesta- or associated with systemic conditions, of PSTPIP1 to phosphorylate proin- tions become more prominent. In a re- including inflammatory bowel diseases, flammatory pyrin domains eventually cent clinical trial, PASH was described rheumatological disorders, lymphopro- leading to an altered assembly and ac- and proposed to be an autoinflamma- liferative forms or other haemopathies. tivation of the inflammasome and con- tory syndrome (Figs. 4A, 4B, and 4C) It is noteworthy that PG may also mani- sequent release of IL-1β (44-46). The (37, 40). Presence of HS and absence of fest as syndromic PG, occurring in the overexpression of IL-1β induces an un- aseptic arthritis distinguish PASH syn- context of autoinflammatory forms such controlled production of several proin- drome from PAPA syndrome; however, as PAPA (35), PASH (PG, acne, and flammatory cytokines and chemokines, the combination of sterile arthritis with suppurativa hidradenitis, also known which are responsible for the recruit- symptoms of PASH has been reported as hidradenitis suppurativa [HS]) (36- ment and activation of mature neutro- and christened PAPASH (39). HS is a 38), or other more recently described phils, leading to a neutrophil-mediated chronic inflammatory disease involving syndromes such as pyogenic arthritis, inflammatory scenario (15, 46-48). the terminal portion of the hair follicle, acne, PG, and suppurativa hidradenitis clinically characterised by nodules, of- (PAPASH) (39). While PAPA is a clas- Cutaneous features: ten ulcerating, abscesses and fistulas, sic monogenic autoinflammatory syn- polymorphic presentation evolving into retracting or hypertrophic drome due to mutations in a single gene PG may occur early in life with pos- scars in apocrine gland-bearing sites regulating innate immunity, namely sible preceding events that act as trig- (49), such as the axillary, inguinal, and PSTPIP1 (proline-serine-threonine gering factors; these may include vac- anogenital regions. phosphatase-interacting protein 1) (35, cination or minimal trauma, according 39), there is increasing evidence that to the so-called pathergy phenomenon. Histological aspects of pyoderma mutations in different genes involved in However, PG tends more frequently to gangrenosum autoinflammation are associated with develop around puberty and to be ac- Histopathological features of PG, albeit PASH as well as with isolated PG and companied by acne, often in its more non-specific, are helpful in excluding

Clinical and Experimental Rheumatology 2018 S-35 Dermatology of autoinflammatory diseases / A.V. Marzano et al.

Fig. 4. Pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH). (A) Inflammatory acne presenting with papules, nodules, and pustules on the nape.(B) Hidradenitis suppurativa: erythematous ulcerated nodules, abscesses and fistulas with hypertrophic scarring on the buttocks and intergluteal fold. (C) Ulcerative pyoderma gangrenosum associated with cribriform scarring on the back. other causes of ulceration. The time particularly palpable purpura and live- and can trigger the autoinflammatory and site of the biopsy must be care- do reticularis, and the typical histology cascade leading to the development of fully selected. It is recommended to showing a leukocytoclastic vasculitis PG (53). IL-17 is another key cytokine take an elliptic specimen that includes pattern are lacking (51). A rare PG-like which is involved in the regulation of the border and the floor of the ulcer. presentation of granulomatosis with the innate immunity. IL-17 also plays an The typical histology of ulcerative polyangiitis (Wegener’s granulomato- important role in autoinflammation via PG shows epidermal ulceration and a sis) has also to be considered; however, the recruitment and activation of neu- dermal-hypodermal inflammatory infil- anti-neutrophil cytoplasmic antibodies trophils, which stimulates the produc- trate mainly consisting of neutrophils; (ANCA) negativity and the absence tion of cytokines and chemokines that leukocytoclasia may also be seen but of granulomatous aspects on histology amplify the accumulation of neutro- fibrinoid necrosis of vessel wall isal- allows the exclusion of this diagnosis phils into the skin and the inflammatory ways absent (13, 34, 50). In late phases (52). Neoplastic causes of ulceration, network (53). IL-1β, IL-17, and TNF-α of the disease, lymphocytes, histio- namely basal cell carcinoma, squamous are also overexpressed in lesional skin cytes, and macrophages predominate in cell carcinoma or lymphoma, may be of other neutrophilic dermatoses, in- the infiltrate, with possible presence of ruled out on the basis of the histology. cluding HS that is a leading player in plasma cells and giant cells, the latter Finally, factitial ulcers may be excluded the PASH syndrome (17, 54-59). These forming sometimes granulomas (Fig. by means of a psychiatric evaluation. cytokines also increase the production 3B). Special histochemical stains and of matrix metalloproteinases, which are microbiological cultures are negative; Pathophysiology of autoinflammation important effectors in inducing tissue this finding is of paramount diagnostic in pyoderma gangrenosum and its damage in PG (17). Recently, various relevance. syndromes mutations have been reported in genes A recent comprehensive immunologi- encoding signalling molecules, which Differential diagnosis of pyoderma cal investigation, which used skin sam- are involved in triggering the innate gangrenosum ples of lesions occurring on patients immunity (60). In particular, gain-of- For the diagnosis of ulcerative PG, other with PG and on patients with PASH, function mutations in the NLRP3 gene causes of ulceration must be ruled out. identified a constant inflammatory pro- have been identified as an aetiologi- Microbiological analysis must always file showing overexpression of IL-1β, cal factor of CAPS. In the monogenic be performed to exclude more common tumour necrosis factor (TNF)-α, IL-8, syndrome presenting with PG, PAPA, bacterial infections or rare fungal infec- and the chemokines C-X-C motif ligand mutations involving the PSTPIP1 gene tions such as blastomycosis, a deep and (CXCL)1/2/3 and CXCL16 (40). Over- lead to decreased inhibition of the in- severe mycosis with ulcerative presen- expression of IL-1β in PG suggests that flammasome and consequent activation tation. Colour Doppler ultrasonography autoinflammation occurs through the of caspase-1; this proteolytic enzyme and/or other more specific instrumen- activation of the inflammasome simi- cleaves pro-IL-1β into its biologically tal examinations may exclude vascu- larly to the PG-associated syndromes, active isoform, IL-1β, with exagger- lar causes of ulceration. An important such as the monogenic autoinflamma- ated production of this cytokine that differential diagnosis is cutaneous tory syndrome PAPA (44). Dysfunction drives the autoinflammation associated small vessel vasculitis, the most com- or altered activation of the inflammas- with the PAPA triad of symptoms (61). mon form of vasculitis in dermatology; ome depends on genetic alterations, and A recent comprehensive analysis of the however, the latter may be ruled out if in particular gene mutations as occurs main genes involved in autoinflamma- coexisting cutaneous manifestations, in the autoinflammatory syndromes, tion demonstrated that both isolated PG

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