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Reumatismo, 2018; 70 (3): 187-198 REVIEW

Histopathology of the skin in rheumatic diseases

M.S. Chimenti1, A. Di Stefani2, P. Conigliaro1, A. Saggini3, S. Urbani1, A. Giunta4, M. Esposito4, L. Bianchi4, K. Peris2, R. Perricone1 1Rheumatology, Allergology and Clinical Immunology, Department of Medicina dei Sistemi, University of Rome Tor Vergata, Rome; 2Institute of Dermatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome; 3Department of Biomedicine and Prevention, Anatomic Pathology, University of Tor Vergata, Rome; 4Dermatology, Department of Medicina dei Sistemi, University of Rome Tor Vergata, Rome, Italy

SUMMARY Rheumatological systemic autoimmune diseases, such as connective tissue diseases, rheumatoid arthritis or spondyloarthritis, are characterized by the presence of joint involvement associated with extra-articular manifestations. Among them, cutaneous diseases are often the most relevant and representative clinical onlymanifesta- tion, as in psoriatic arthritis, scleroderma or systemic lupus erythematosus. In this context, it is useful for rheumatologists to understand better skin diseases and their histopathological features. Evaluation of skin biopsy specimens can be helpful not only to confirm the diagnosis in both classic and clinically atypical variants, but also to improve further our knowledge of the pathogenetic mechanisms and the close linkuse between skin and articular diseases. In this review, we discuss the clinical features, diagnostic evaluation and the histopathological features of skin manifestation of the most relevantvant rheumatological autoimmune diseases. Key words: Histopathology; cutaneous diseases; autoimmune diseases; skin.

Reumatismo, 2018; 70 (3): 187-198

n INTRODUCTION n PSORIASIS utoimmune rheumatological diseases Psoriasis is a chronic inflammatory im- Aare characterized by the presence of mune-mediated skin disease, affecting both joint and extra-articular manifesta- 1-3% of Caucasians, characterized by ex- tions. Among them, skin involvement is cessive growth and aberrant differentiation one of the most frequent signs.Non-commercial In a large of keratinocytes (1). proportion of cases, skin lesions may be There are various clinical subtypes includ- the first manifestation of the disease, having chronic plaque (or psoriasis vulgaris), ing a spy role for rheumatological systemic guttate, erythrodermic, and pustular psoria- diseases such as, for example scleroderma, sis. Clinically, psoriatic lesions consist of lupus erythematosus, dermatomyositis or erythemato-squamous patches and plaques psoriatic arthritis. covered by silvery scales (1). Psoriatic ar- Histopathological evaluation of skin biopsy thritis is a chronic inflammatory arthropa- samples may be useful to confirm the clini- thy typically associated with psoriasis. cal diagnosis but also to understand better Psoriasis is a complex multifactorial dis- and improve our knowledge of the patho- ease related to a combination of genetic, genesis of systemic autoimmune diseases. environmental and immunological factors, In this review, we provide an overview of involving both innate and adaptive im- Corresponding author: Maria Sole Chimenti the clinical features, diagnostic evaluation mune systems (2, 3). Keratinocytes play a Rheumatology, and the histopathological features of skin key role in the recruitment and activation Allergology and Clinical Immunology, University of Rome Tor Vergata manifestation of the most relevant rheuma- of T cells in psoriatic lesions and T cells Via Montpellier, 1 - 00133 Rome, Italy tological autoimmune diseases (Table I). are fundamental in the maintenance of the E-mail: [email protected]

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Table I - Main histological features of skin manifestations in rheumatologic diseases. Rheumatological Skin manifestation and histological features disease Psoriasis S: erythemato-squamous patches and plaques covered by silvery scales H: parakeratosis of cornified layer, hypogranulosis, neutrophils within epidermis and parakeratotic foci, thinned suprapapillary plates, increased number of mitotic figures in the basal and suprabasal layers, ectatic and tortuous papillary blood vessels LE S: SLE, DLE, SCLE, bullous LE, chilblain lupus, lupus tumidus, lupus panniculitis H: vacuolar degeneration of basal layer of epidermis with variable number of Civatte bodies; dermal lymphocytic infiltrate (superficial in SLE, superficial and deep and periadnexal in DLE); interstitial mucin deposition in dermis; possible dermal neutrophils with leukocytoclasis in SLE; hyperkeratosis, atrophy of spinous layer, and follicular keratotic plugging in DLE DM S: erythematous, scaly lesions with a predilection for sun-exposed areas, poikiloderma, periungual erythema and telangiectases, Gottron papules, heliotrope rash H: indistinguishable from SLE; vacuolar degeneration of basal layer of epidermis with rare Civatte bodies; superficial lymphocytic infiltrate in dermis; interstitial mucin deposition in dermis; possible dermal neutrophils with leukocytoclasis Sclerodermia S: painless, discolored, sclerotic skin (morphea or systemic scleroderma) H: thickened dermis, broad sclerotic collagen bundles, pilosebaceous unit atrophy, dermal lymphoplasmacytic infiltrate in early lesions ANCA- MPA S: purpura and petechiae, livedo reticularis, andonly erythema associated H: perivascular lymphocyte infiltration in the upper dermis and infiltration of vasculitides lymphocytes, few neutrophils around small arteries in the middle to deep dermis and diffuse infiltration of histiocytes and lymphocytes in the middle dermis GPA S: purpura and petechiae use H: leukocytoclastic vasculitis, necrotizing granulomas EGPA S: subcutaneous nodules, and purpura H: leukocytoclastic vasculitis, extravascular granulomas, eosinophils in inflammatory infiltrate Urticarial S: recurrent episodes of urticaria (wheals causing burning pain, lasting greater than 24 h and vasculitis leaving residual hyperpigmentation) H: lymphocytic infiltrate with eosinophils and red blood cell extravasation, leukocytoclastic vasculitis Cryoglo- S: orthostatic palpable purpura bulinemic H: eosinophilic refractile deposits within vessel lumina with extension into the intima, vasculitis leukocytoclastic vasculitis Behçet S: oral and genital ulcers, skin hyperreactivity, erythema nodosum-like lesions, papulopustular disease lesions, hemorrhagic blisters, infiltrated erythema, Sweet’s syndrome-like eruptions and extragenital ulcerations H: dermal lymphohistiocytic infiltrate with neutrophils; at times leukocytoclastic vasculitis; Non-commercialseptal and/or lobular panniculitis; dense perivascular neutrophil infiltrate with no fibrinoid changes in pathergic lesions Rheumatoid S: rheumatoid vasculitis, rheumatoid nodules, granulomatous skin disorders, and neutrophilic arthritis dermatoses H: leukocytoclastic vasculitis; palisading necrobiotic granulomas in rheumatoid nodules Lyme S: erythema migrans, acrodermatitis chronica atrophicans disease H: superficial and deep chronic inflammatory cell infiltrate in the dermis with lymphocytes and plasma cells; prominent eosinophils at the tick bite site; atrophy of the dermis and loss of elastic fibers in acrodermatitis chronica atrophicans Sarcoidosis S: papular sarcoidosis, plaques, lupus pernio, erythema nodosum H: sarcoidal granulomas (epithelioid histiocytes and giant cells surrounded by a thin rim of lymphocytes and plasma cells, naked granulomas) Pyoderma S: necrotic ulcers with distinctively ragged, undermined, erythematous borders gangrenosum H: follicular and perifollicular inflammation with intradermal abscesses, ulceration, superficial edema at the advancing edge, tight perivascular lymphoplasmacytic infiltrate, occasionally leukocytoclastic vasculitis S, skin manifestations; H, histopathological features; SLE, systemic lupus erythematosus; DM, dermatomyositis; ANCA, antineutrophil cytoplasmic antibodies; MPA, microscopic polyangiitis; GPA, granulomatosis with polyangiitis; EGPA, eosinophilic granulomatosis with polyangiitis.

188 Reumatismo 3/2018 Clinical and histopathological features of cutaneous manifestations in rheumatic diseases REVIEW

disease. Inflammatory myeloid dendritic and form spongiform pustules of Kogoj cells release interleukin (IL)-23 and IL-12 and extend further into the overlying stra- in order to activate T helper (Th) 1 cells, tum corneum, resulting in the development IL-17-producing T cells (Th17), and Th22 of Munro’s microabscesses; parakeratosis cells to produce cytokines such as IL-17, becomes confluent. The scales can be de- interferon (IFN)-g, tumor necrosis factor tached, together with the extremely thin su- (TNF)-a, and IL-22. These cytokines in- prapapillary area, by mild scraping, causing duce keratinocytes to amplify and further fine bleeding points of papillary capillaries support the psoriatic inflammatory process (i.e. the pathognomonic Auspitz’s sign). Ad- (2-4). ditional dermal features are papilledema and From a histopathological point of view, a moderately dense perivascular infiltrate psoriasis is the prototype of the psoriasi- predominantly composed of lymphocytes form tissue reaction pattern, morphologi- (5-8) (Figure 1). In stable psoriatic plaques cally defined as epidermal hyperplasia with the rete-ridges may exhibit some thickening elongation of the rete ridges (5). Additional at their base, and the amount of parakerato- specific features are: parakeratosis of the sis diminishes. With rubbing or scratching, cornified layer, hypogranulosis, the pres- changes of lichen simplex chronicus may be ence of neutrophils within the epidermis observed. Late lesions (resolvingonly or treated and parakeratotic foci, thinned suprapap- plaques) show the presence of compact illary plates, increased number of mitotic orthokeratosis, focal hypergranulosis and figures in the basal and suprabasal layers, thickening of suprapapillary plates, while ectatic and tortuous papillary blood vessels both psoriasiform hyperplasiause and the in- (Figure 1). flammatory infiltrate are significantly less Psoriasis is a dynamic process, with a conspicuous (6-8). natural course characterized by different As mentioned above, there are variants of clinical stages (early onset, stabilization, psoriasis with particular clinical and histo- regression, reactivation). Therefore, the histopathological findings will morpho- logically mirror these changes (6, 7) and may be influenced by several factors such as duration of lesions, psoriasis variant, lesion size and topography, and administered treatment (1, 6-8). In the early phase, psoriatic lesions show non-specific histological changes such as dilatation and congestion of blood vessels in the papillary dermis and a Non-commercialsparse, perivascular, lymphocytic infiltrate (6-8). The fol- lowing phase is characterized by the development of focal mounds of parakeratosis with loss of the underlying granular layer as well as exocytosis of neutrophils through the epidermis. Progression in the inflammatory cascade leads to the active lesion with epidermal acanthosis, regularly elongated rete-ridges and increased number of mitoses in the basal and suprabasal layers. Papil- lary capillaries show increased length and Figure 1 - Histopathological features of psoriasis. Presence of regular tortuosity, leading to the so-called squirt- epidermal hyperplasia with hypogranulosis, parakeratosis and neu- ing papillae (i.e. formation of a suprapap- trophils within the stratum corneum; tortuous papillary blood vessels illary exudate and parakeratosis) (6-8). and lympho-monocytic dermal infiltrate (Haematoxylin & eosin stain; Neutrophils migrate into the spinous layer original magnification: x200).

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logical features. In pustular psoriasis there is Lupus erythematosus (LE) is a chronic a remarkable increase in the number of neu- autoimmune disorder of unknown aetiol- trophils, with several intraepidermal spongi- ogy mainly affecting fertile young women form pustules of Kogoj and Munro’s micro- (12). Conventionally, three clinical sub- abscesses in the overlying parakeratotic layer. types are recognized: systemic LE (SLE), Erythrodermic psoriasis may exhibit mild cutaneous-limited chronic (discoid) LE parakeratosis since continuous shedding of (DLE), and subacute LE (SCLE), which scales and superficial dermal blood vessels is characterized by the association be- tend to be more prominently dilated (1, 7, 8). tween specific skin lesions and variable, Histological aspects of psoriatic lesions usually mild, systemic involvement (11, are also influenced by the anatomic loca- 12). Additionally, less common cutane- tion: mucosal lesions show less epidermal ous variants of LE have been recognized hyperplasia and scaling; in flexural areas including bullous LE, chilblain lupus, lu- (inverse psoriasis) the scaly component is pus tumidus, neonatal LE, and lupus pan- generally lacking; on acral skin, spongiotic niculitis (12). Overlap may occur between and crusted aspects are prevalent. In con- histopathological changes observed in cu- trast, a significant scaling plaque formation taneous lesions of the three main LE clini- is frequent on the scalp (6-8). cal variants,only with the lichenoid reaction The epidermal hyperplasia observed in pattern (i.e., interface dermatitis) being psoriasis reflects a profound alteration of a significant feature in most of cutaneous the balance between the proliferation and LE biopsies (13). differentiation of keratinocytes, as shown useSkin lesions of SLE are characterized by up to 27 times increased mitotic activ- by prominent vacuolar degeneration of ity and a greater than 7-fold increase in the the epidermal basal layer with only rare epidermal turnover time. Such changes are Civatte bodies; a sparse lymphocytic in- associated with striking variations in the filtrate is seen in the superficial dermis, keratin profile expressed by keratinocytes, along with edema and mild red blood with overexpression of keratin 16, indicat- cell extravasation (14). Perivascular and ing hyperproliferation of keratinocytes (9). interstitial neutrophils may be present in Immunohistochemistry studies provide the superficial dermis in early lesions of evidence that psoriatic lesions contain in- SLE as well as leukocytoclasis with no creased numbers of T cells that are CD3+ clear small vessel vasculitis (13, 15). DLE CD2+ CD45RO+ CLA+, with a subset is characterized by a superficial and deep having activation markers CD25, HLADR, lymphohistiocytic inflammatory infiltrate and CD27; several CD4+ T cells produce with stereotypical lichenoid reaction pat- IFN-gamma,Non-commercial IL-17, and IL-22; some CD8+ tern (i.e., prominent vacuolar change of cells and an increased number of BDCA- the epidermis and scattered Civatte bod- 1 CD11c+ inflammatory dermal dendritic ies) and adnexotropism (11, 12). Ad- cells (2, 3, 10). ditional histological features of DLE include hyperkeratosis with atrophy of the spinous layer, and keratotic plugging n CONNECTIVE TISSUE of hair follicles. Marked hyperkeratosis DISEASES and epidermal hyperplasia are distinc- Autoimmune connective tissue disor- tive features of hypertrophic lesions of ders encompass a heterogeneous group of DLE (16). The histopathological features immune-mediated diseases with a vari- of SCLE are linked to those of DLE and able potential for cutaneous involvement. SLE. Compared to DLE, typical lesions Skin manifestations of such diseases are of SCLE exhibit a diminished amount of changeable, with occasional clinical and inflammatory cells and epidermal/follicu- histopathological overlapping, thus requir- lar changes, with concomitant increasing ing appropriate clinicopathological corre- dermal edema and mucin deposition (13) lation (11). (Figure 2).

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Bullous LE is an uncommon but distinctive sociated with, or follow the occurrence of manifestation of SLE with striking clin- any cutaneous or systemic manifestation of icopathological similarities to dermatitis LE. Histological hallmarks of LE profun- herpetiformis such as subepidermal blis- dus include a lobular panniculitis charac- ters with edema and a superficial inflam- terized by a lymphoplasmacytic infiltrate matory infiltrate composed of neutrophils and occasional lymphoid follicles, often and lymphocytes (17). Histopathological associated with mild epidermal and dermal findings in chilblain lupus include perivas- changes of cutaneous LE (22). cular, superficial and deep lymphocytic Special stains may be useful to highlight infiltrate with overlying vacuolar degen- thickening of the basement membrane zone eration of the epidermal basal layer (18). and dermal interstitial mucin deposition in Tumid lesions of chronic LE (i.e., lupus LE cutaneous lesions, irrespectively of the tumidus) have an increased deposition of clinical variant (23). Clusters of CD123+ dermal mucin with subepidermal edema plasmacytoid dendritic cells may be ob- and perivascular lymphocytic infiltrate of served by means of immunohistochemis- variable density and only rare epidermal try, although the sensitivity and specificity involvement (19, 20). Histological changes of this finding are variable and depend on observed in neonatal cutaneous LE resem- the clinical presentation (24). onlyAddition- ble those observed in SCLE (21). Lupus ally, in LE direct immunofluorescence of panniculitis (i.e., LE profundus), a chronic, involved skin (i.e., lupus band test) may recurrent panniculitis, may precede, be as- show IgG and IgM depositionuse at the base-

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Figure 2 - Histopathological features of skin manifestations during systemic lupus erythematosus. A, B) Cutaneous lesion of SLE with vacuolar degeneration of the epidermal basal layer, only rare Civatte bodies, sparse lymphocytic infiltrate in the superficial dermis, dermal edema and mild red blood cell extravasation (Haematoxylin & eosin stain; original magnification: x100). C, D) scalp lesion of DLE with superficial and deep lymphohistiocytic inflammatory infiltrate with interface dermatitis (vacuolar change of the epidermis and scattered Civatte bodies) and marked adnexotropism (Hae- matoxylin & eosin stain; original magnification: x100). E, F) lesion of SCLE with superficial lymphohistiocytic inflammatory infiltrate with lichenoid arrangement, vacuolar change of epidermis with scattered Civatte bodies, hyperkeratosis with intermittent atrophy of the spinous layer (Haematoxylin & eosin stain; original magnification: x100).

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ment membrane in a variable percentage n SYSTEMIC VASCULITIDES of cases depending on the clinical subtype, with highest rates of positivity being re- Systemic vasculitides are a group of rare corded in SLE (25). diseases characterized by inflammation of Cutaneous manifestations of dermatomy- the arterial or venous vessel wall, causing ositis (DM) include nonspecific erythe- stenosis or thrombosis. Clinical symptoms matous, scaly lesions with a predilection may be limited to the skin or other organs, for sun-exposed areas, poikilodermatous or may involve multiple manifestations as changes, periungual erythema and telan- systemic conditions (31). Primitive vas- giectases, Gottron papules, and heliotrope culitides have been recently re-classified. rash (26). Histologically, DM skin le- Among the small vessel vasculitides, the sions exhibit features of cutaneous SLE, antineutrophil cytoplasmic antibodies namely vacuolar changes of the basal layer (ANCA)-associated vasculitides (AAV) with scant apoptotic keratinocytes, a mild are granulomatosis with polyangiitis (We- chronic infiltrate in the superficial dermis, gener, GPA), eosinophilic granulomatosis edema and interstitial mucin deposition with polyangiitis (Churg-Strauss, EGPA) (14, 26). Indeed, in most cases, cutane- and Microscopic polyangiitis (MPA), while ous lesions of DM and SLE appear to be the immuneonly complex (IC) vasculitides are histologically indistinguishable (14, 26). IgA vasculitis (Henoch–Schönlein), cryo- Gottron papules are distinguished by the globulinemic vasculitis (CV), urticarial presence of epidermal hyperkeratosis and vasculitis (UV) and anti-glomerular base- acanthosis, while poikilodermatic skin is usement membrane (GBM) disease (32). Skin characterized by the combination of inter- findings such as palpable purpura, nodules, face dermatitis with the triad of epidermal urticaria, ulcers, and infarction are clues atrophy, melanin incontinence, and superfi- to the presence of vasculitis. Histological cial vessel dilatation (26, 27). findings of fibrinoid necrosis, infiltration The term scleroderma (Sc) refers to a by neutrophils or lymphocytes, and depo- heterogeneous group of diseases distin- sition of complement and immunoglobu- guished by abnormal collagen deposition lin may be helpful in reaching a specific in the skin (28). Two major subtypes of Sc diagnosis. However, there is considerable are recognized, namely localized Sc (i.e., overlap across different conditions. The morphea; linear Sc) and systemic Sc (SSc). more relevant skin manifestations will be Regardless of the clinical variant, the his- described in the next paragraphs (32). topathological hallmarks of Sc include a The AAV is a group of systemic vascu- striking increase in dermal thickness with litis associated with ANCA specific for broadeningNon-commercial of sclerotic collagen bundles, myeloperoxidase (MPO) or proteinase-3 also replacing the periadnexal adipose tis- (PR3), characterized by predominant in- sue and extending into the subcutis (29). flammation of small vessels. Three mecha- Atrophy of follicular units is a frequent nisms of vascular inflammatory damage finding, while eccrine coils appear at a can be considered: IC deposition, ANCAs higher level than normal in the dermis due (humoral response), and T-lymphocyte to underlying collagen deposition and der- response with granuloma formation (cell- mal sclerosis (30). Epidermal changes are mediated response) (33) leading to activa- nonspecific, with prevalence of epidermal tion of endothelial cell, with subsequent atrophy. A perivascular lymphoplasmacyt- vessel obstruction and ischemia of depend- ic infiltrate may be seen through the mid- ent tissue, and consequent haemorrhage in and lower dermis and subcutis, especially the surrounding tissues with weakening of at the borders of lesions. Indeed, early le- the vessel wall, and aneurysm formation sions are characterized by a more promi- (Figure 3). nent degree of inflammation, while late le- MPA is histologically characterized by sions are dominated by collagen deposition small-vessel involvement. Anti-myeloper- and dermal sclerosis (29). oxidase antibodies (MPO-ANCA) are of-

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ten positive in serum. The skin is affected nodosum, granuloma annulare, chronic in 20-70% of patients with purpuric lesions, inflammation, and acute inflammatory le- petechiae, livedo reticularis, and erythema. sions without vasculitis (35). Histological findings showed perivascular EGPA is a multisystemic disorder defined lymphocyte infiltration in the upper dermis as an eosinophil-rich and granulomatous and infiltration of lymphocytes and a few inflammation. Among the most frequent neutrophils around small arteries in the skin manifestations, subcutaneous nodules mid to deep dermis and diffuse infiltration and purpura (especially involving the legs) of histiocytes and lymphocytes in the mid represent a clinical hallmark of the vascu- dermis (34). litic phase. A skin biopsy of purpuric le- While no cutaneous lesion is specific for sions generally shows a leukocytoclastic GPA, several histopathological entities vasculitis. Extravascular granulomas, small can be observed, including, in decreasing and medium-sized vessels vasculitis, and order: leukocytoclastic vasculitis, granu- the eosinophilic infiltrates are the typical lomatous inflammation, nonspecific ul- features. Interstitial and vascular granulo- ceration, superficial dermal and epidermal mas are composed of eosinophilic necrotic necrosis without inflammation, erythema matrix surrounded by giant cells and pali- only use

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Figure 3 - ANCA-associated vasculitis. Pathogenetic mechanisms proposed for anti-neutrophil cytoplasmic auto-antibody (ANCA)-mediated vascular inflammation. Neutrophils are primed by cytokines to express ANCA antigens (myeloperoxidase and proteinase-3) at the cell surface and then adhere to susceptible endothelium and ANCA antibodies interact with the ANCA antigens, resulting in neutrophil activation. The ANCA-activated neutrophils release factors (e.g. properdin, factor B, proteases, ROS and MPO) cause damage to vascular endothelium and activate the alternative complement pathway with the generation of the powerful neutrophil chemoattractant C5a. This causes an amplification of neutrophil influx and activation with severe necrotizing inflammation of the vessel wall. B, B cells; Th, T helper; IL-1β, interleukin 1 beta; TNFa, tumour necrosis factor alpha; PMN, polymorphonuclear cells; MPO, myeloperoxidase; PR3, proteinase 3; ROS, oxygen radicals.

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sading lymphocytes. The vasculitic process classification diagnostic criteria, oral and mainly affects small and medium vessels genital ulcers and skin hyperreactivity are (especially small arteries) and is charac- included. The skin pathergy test is consid- terized by fibrinoid necrosis of the vessel ered highly sensitive and specific for BD wall associated or not with granuloma or (42). Together with oral and genital ulcers, eosinophilic infiltrates (36). various cutaneous lesions can be observed, Urticarial vasculitis (UV) is character- such as: erythema nodosum-like lesions ized by a cutaneous presentation resem- (15-78%) and papulopustular lesions (28- bling urticaria; skin biopsy often shows a 96%). Lesions such as hemorrhagic blisters, predominantly lymphocytic infiltrate with infiltrated erythema, Sweet’s syndrome- eosinophils and red blood cell extravasa- like eruptions and extragenital ulcerations tion. Occasionally, a true leukocytoclas- may also be observed (42). Combinations tic vasculitis, mainly involving capillaries of various skin lesions are commonly seen and venules, is encountered (37). Peculiar in the same patient. characteristics of the lesions associated Histological features include: leukocy- with laboratory findings, such as low levels toclastic vasculitis and lymphocytic vas- of C3, C4 and C1q, presence of anti-C1q culitis with extension to focal localized antibodies, high erythrocyte sedimentation fibrinoid onlynecrosis of vessel walls. Mucocu- rate, suggest diagnosis of UV, although a taneous lesions often present features of skin biopsy is required for a definitive di- leukocytoclastic vasculitis or, in many cas- agnosis. es, a neutrophilic vascular reaction without usetrue vasculitis (43, 44). Cryoglobulinemic vasculitides Cryoglobulins are monoclonal or poly- n OTHER SKIN clonal immunoglobulins that share the MANIFESTATIONS common property of precipitating at tem- IN RHEUMATOLOGICAL peratures of less than 37°C and re-dissolv- DISEASES ing on warming (38). The consequent deposition of circulating IC (cryoglobulins and Rheumatoid arthritis (RA) is a systemic in- complement) together with hemodynamic flammatory disorder that primarily affects and local factors are the main components the joints, but may exhibit extra-articular of the disease pathogenesis (39). Essential manifestations, including cutaneous ones mixed cryoglobulinemia (MC) shows a that are the most frequent, and often the prominent association with HCV infection initial feature of extra-articular involve- (>90%). It is a systemic vasculitis (leuko- ment in RA patients (45). They include cytoclasticNon-commercial vasculitis) affecting cutaneous rheumatoid vasculitis, rheumatoid nodules, vessels and multiple visceral organs. CV granulomatous skin disorders, and neutro- are characterized by the presence of pal- philic dermatoses. Rheumatoid vasculitis pable purpura (40). The histological char- displays features of both cutaneous ne- acteristics include: occlusive thrombotic crotizing venulitis (leukocytoclastic vas- diathesis comprising eosinophilic refractile culitis) and cutaneous polyarteritis nodosa. deposits within vessel lumina with exten- Associations with mononeuritis multiplex sion into the intima, with or without asso- and bowel involvement has a fatal progno- ciated characteristic granulomatous vascu- sis, while patients with superficial dermal litic component (41). venulitis without other extra-articular involvement may have a favourable progno- Behçet disease sis (45-47). Behçet’s disease (BD) is an inflammatory Histopathology of rheumatoid nodules is multisystem disease of unknown aetiol- characterized by granulomatous tissue re- ogy with unpredictable exacerbations and action pattern. Well-formed necrobiotic remissions. Mucocutaneous lesions con- granulomas appear within the dermis fre- stitute the hallmark of the disease. Among quently with deep extension. There is a

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surrounding palisade of histiocytes and a pus pernio. In a small percentage of cases, mixed infiltrate of lymphocytes, plasma it results in a mucous infiltration obstruct- cells, multinucleated giant cells and occa- ing the upper respiratory airways (54). The sional eosinophils (48). lesions can develop in pre-existent areas of Lyme disease is a disorder caused by Bor- trauma and scars and can be confused with relia burgdorferi infection and may in- keloids (55). The most common aspecific volve many organs, including the skin. lesion is erythema nodosum. It is a benign The early skin lesion around the tick bite condition with >80% complete regression is an expanding area of redness on the within two years (56). Less common pres- skin, known as erythema migrans. It shows entations of cutaneous sarcoidosis are ver- edema, vascular dilatation, extravasation of rucous, annular, lichenoid, psoriasiform, erythrocytes and an inflammatory infiltrate subcutaneous, ichthyosiform ulcerative, of neutrophils. If the causative organisms atrophic, hypopigmented, erythrodermic, persist in the skin, there is a superficial and nail and the alopecia associated variants deep perivascular and interstitial infiltrate (57-59). The great clinical variety of le- of lymphocytes and, in many cases, plasma sions also reflects the variety of histopatho- cells and rare eosinophils, especially at the logical characteristics examined. Granu- site of tick bite (49). A special stain is the lomas are characterized by an infiltrateonly of Warthin-Starry silver, used to identify the lymphocytes, epithelioid cells, giant cells, spirochetes in the papillary dermis at the neutrophils and plasma cells. In many cas- dermoepidermal junction. Diagnosis may es Schaumann bodies, necrosis and fibrosis be confirmed by using an indirect immu- can been found. Epidermaluse changes include nofluorescence or immunoperoxidase tech- atrophy, parakeratosis, acanthosis and tel- niques (49). angiectasia (60). The number of granulo- Sarcoidosis is a systemic disease character- mas is not related to the extension or sever- ized by non-caseating granulomas that can ity of the disease (61). No differences have involve any tissues or organs. Cutaneous been found in the depth and cellular density sarcoidosis develops in 20-35% of patients of granulomas between patients with pap- with systemic sarcoidosis although it may ules and those with plaques. In both groups represent the only clinical manifestation the infiltrate appears to be superficial with of the disease. Recognition of cutaneous moderate density. In contrast, in patients involvement is important because it pro- with nodules, granulomas are deeper, while vides an easier and fast diagnosis since the patients with scar sarcoidosis seem to have skin represents an accessible tissue source both deeper and heavier infiltrates (62). for histological examination. The lesions Pyoderma gangrenosum (PG) is an im- may show different morphologies,Non-commercial so that mune-mediated cutaneous disease, charac- differential diagnosis can be difficult, the terized by the development of one or more disease being known as the great imitator necrotic ulcers with distinctively ragged, (50). The cutaneous eruptions are divided undermined, erythematous borders (63, into specific, distinguished by classic non- 64). Ulceration may be preceded by the caseating granulomas, and aspecific when occurrence of papulopustular or nodular they arise as a reactive process without lesions (65). Development of PG lesions granuloma formation. Among the former, may occur on sites of previous trauma (i.e., the most common clinical manifestation is pathergy) (64). Clinical subtypes of PG in- papular sarcoidosis, which usually appears clude the common ulcerative presentation on the face although it can occur anywhere. as well as the bullous, pustular, vegeta- Papules are often associated with acute dis- tive, and the rare superficial granulomatous ease (51). The plaques, instead, are local- variants (66). Histopathological findings ized at the trunk, face and extensor surfaces in PG are variable, being contingent on of the arms and legs and they often arise lesion duration and anatomic location; ac- during chronic and extrathoracic sarcoido- cordingly, a diagnosis of PG or exclusion sis (52, 53). Some patients may present lu- thereof should not rely only on histological

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findings, but it always requires appropriate biopsy specimens can be helpful not only correlation with clinical and anamnestic to confirm the diagnosis of skin disease in data (64, 66). both classic and atypical clinical variants, A histological classification of PG has but also to further improve knowledge of been proposed, which identifies ulcera- the pathogenesis and the close link be- tive, pustular, bullous, and vegetative PG tween skin and articular diseases (70). lesions (67). Such histological subtypes, however, may be interpreted as different stages of the same disease, accounting for n REFERENCES significant overlapping observed between 1. Chimenti S. Psoriasis. Florence: SEE Editrice; different subtypes. Early lesions of PG are 2005. characterized by follicular and perifollicu- 2. Kim J, Krueger JG. The immunopathogenesis lar inflammation along with development of psoriasis. Dermatol Clin. 2015; 33: 13-23. of intradermal abscesses (65). Later, ne- 3. Carubbi F, Chimenti MS, Blasetti G, et al. As- crosis of superficial dermis and epidermis sociation of psoriasis and/or psoriatic arthritis with autoimmune diseases: the experience of ensues, resulting in ulceration (65). Fully two Italian integrated Dermatology/Rheuma- developed PG ulcers are almost indistin- tology outpatient clinics. J Eur Acad Dermatol guishable from ulcers due to other causes, Venereol.only 2015; 29: 2160-8. with mixed inflammatory cells and abscess 4. Novelli L, Chimenti MS, Chiricozzi A, Perricone formation being observed at the base of R. The new era for the treatment of psoriasis and psoriatic arthritis: Perspectives and validated the lesion (63, 65). Superficial edema at strategies. Autoimmun Rev. 2014; 13: 64-9. the advancing edge is a frequent finding, use5. Ackerman AB. Histologic diagnosis of inflam- along with a tight perivascular lymphop- matory skin diseases. Philadelphia: Lea & Fe- lasmacytic infiltrate, at times with signs of biger; 1978. evident vasculitis. Pustular lesions of PG 6. Ackermann AB, Ragaz A. The lives of the le- are characterized by subepidermal edema sions chronology in dermatopathology. New York: Masson Publishing. 1984. and a diffuse dense neutrophilic infiltrate, 7. Murphy M, Kerr P, Grant-Kels JM. The his- resulting in subcorneal pustules formation topathologic spectrum of psoriasis. Dermatol (63, 64); in bullous lesions of PG, con- Clin. 2007; 25: 524-8. versely, massive subepidermal edema leads 8. Cribier BJ. Psoriasis under the microscope. J to subepidermal bullae with neutrophils Eur Acad Dermatol Venereol. 2006; 20: 3-9. (67). Finally, a special acknowledgement 9. Chimenti MS, Triggianese P, Nuccetelli M, et al. Auto-reactions, autoimmunity and psoriatic should be given to the vegetating subtype, arthritis. Autoimmun Rev. 2015; 14: 1142-6. the distinctive features of which include 10. Chiricozzi A, Romanelli M, Panduri S, et pseudoepitheliomatous hyperplasia, der- al. Relevance of in vitro 3-D skin models in mal abscesses with sinus tracts formation, dissecting cytokine contribution to psoriasis and Non-commercialan associated palisading granuloma- pathogenesis. Histol Histopathol. 2017; 32: 893-98. tous infiltrate (63, 64, 67). 11. Sepehr A, Wenson S, Tahan SR. Histopatho- logic manifestations of systemic diseases: the n CONCLUSIONS example of cutaneous lupus erythematosus. J Cutan Pathol. 2010; 37: 112-24. Rheumatological systemic autoimmune 12. Crowson AN, Magro C. The cutaneous pathol- diseases include, in most instances, skin ogy of lupus erythematosus: a review. J Cutan Pathol. 2001; 28: 1-23. manifestations as a key component of the 13. Callen JP. Subacute cutaneous lupus erythe- disease. Rheumatologists often have the matosus versus systemic lupus erythematosus. primary privileged position of suspecting, J Am Acad Dermatol. 1999; 40: 129-31. recognizing and treating extra-articular 14. Magro CM, Segal JP, Crowson AN, Chadwick manifestations of autoimmune diseases P. The phenotypic profile of dermatomyositis as skin diseases (68). In this context, it is and lupus erythematosus: a comparative analysis. J Cutan Pathol. 2010; 37: 659-71. useful for the rheumatologist to better un- 15. Brinster NK, Nunley J, Pariser R, Horvath B. derstand skin diseases and their histopatho- Nonbullous neutrophilic lupus erythematosus: logical features (69). Evaluation of skin a newly recognized variant of cutaneous lupus

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