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 polymor- phic 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, pyo- derma 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