Cutaneous Vasculitis: Review on Diagnosis and Clinicopathologic Correlations PDF

Clinical Reviews in Allergy & Immunology (2021) 61:181–193 https://doi.org/10.1007/s12016-020-08788-4 Cutaneous Vasculitis: Review on Diagnosis and Clinicopathologic Correlations Laure Frumholtz 1 & Sara Laurent-Roussel 2 & Dan Lipsker 3,4 & Benjamin Terrier 5,6 Published online: 6 May 2020 # Spri...

Clinical Reviews in Allergy & Immunology (2021) 61:181–193 https://doi.org/10.1007/s12016-020-08788-4 Cutaneous Vasculitis: Review on Diagnosis and Clinicopathologic Correlations Laure Frumholtz 1 & Sara Laurent-Roussel 2 & Dan Lipsker 3,4 & Benjamin Terrier 5,6 Published online: 6 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Cutaneous vasculitis is an inflammatory disease affecting the dermal blood vessel walls. The skin is a privileged organ in the setting of vasculitis since it is easily accessible for physical examination and safe biopsy, allowing an accurate characterization of inflammatory lesions. The skin is often involved. Also, cutaneous vasculitis can reflect a cutaneous component of a systemic vasculitis, a skin-limited or skin-dominant expression or variant of a systemic vasculitis, or be a single-organ vasculitis per se. Vasculitis lesions are multiple and polymorphic. They may induce a wide spectrum of clinical manifestations depending on the location and the size of the vessels involved. The depth of affected vessels is correlated with the type of cutaneous lesions. Involvement of small superficial vessels results mostly in urticarial, but relatively persistent plaques, papules, and palpable purpura. Involvement of vessels in the dermohypodermic junction or hypodermis results in ulcers, nodules, or livedo. The type of inflammatory infiltrate is also a key finding for the diagnosis of cutaneous vasculitis. Leukocytoclastic vasculitis is not a disease per se but the result of a pathophysiological process common to different causes. A better knowledge of the vascular anatomy of the skin, elementary lesions, and histological characteristics of dermatologic manifestations would allow a more relevant and more efficient diagnostic approach. We also propose a list of additional exams to be performed in front of skin lesions suggestive of vasculitis. The aim of our article is to provide an overview of elementary skin lesions and clinicopathologic correlations in cutaneous and systemic vasculitis. Keywords Skin. Cutaneous vasculitis. Nodules. Purpura. Livedo Electronic supplementary material The online version of this article Introduction (https://doi.org/10.1007/s12016-020-08788-4) contains supplementary material, which is available to authorized users. Vasculitis is a heterogeneous group of diseases characterized by the presence of inflammation of blood vessels. In 1990, the * Laure Frumholtz American College of Rheumatology established diagnostic [email protected] criteria for seven vasculitis based on clinical, biological, and * Benjamin Terrier histologic findings, namely polyarteritis nodosa (PAN) , [email protected] granulomatosis with polyangiitis (GPA) formerly named 1 Department of Dermatology, Saint-Louis Hospital, Assistance Wegener’s granulomatosis , eosinophilic granulomatosis Publique-Hôpitaux de Paris (AP-HP), 1 Avenue Claude Vellefaux, with polyangiitis (GEPA) formerly named Churg-Strauss syn- 75010 Paris, France drome , hypersensitivity angiitis , IgA vasculitis former- 2 Department of Pathology, Saint-Louis Hospital, AP-HP, ly named Henoch-Schönlein purpura , giant cell arteritis Paris, France (GCA) , and Takayasu arteritis. The first International 3 Department of Dermatology and Dermatopathology, Nouvel Hôpital Chapel Hill Consensus Conference (CHCC) on the Civil, Strasbourg, France Nomenclature of Systemic Vasculitides in 1994 reached con- 4 Faculté de médecine de Strasbourg, Strasbourg, France sensus on names and definitions for the most common forms 5 Department of Internal Medicine, National Referral Center for Rare of vasculitis , with an update in 2012 to improve the previ- Systemic Autoimmune Diseases, Hôpital Cochin, AP-HP, 27, rue du ous nomenclature, change names and definitions, and add Faubourg Saint-Jacques, 75679 Paris Cedex 14, France categories of vasculitis that were not included in the 6 Faculté de Médecine, Université Paris-Descartes, Sorbonne Paris CHCC1994. Vasculitis may affect a wide range of tissues Cité, Paris, France at the same time or during the follow-up or predominantly 182 Clinic Rev Allerg Immunol (2021) 61:181–193 affect one organ more than the others as various expression of by venules to reach the plexus. Therefore, the subpapillary a systemic vasculitis. In contrast, vasculitis can be limited to a plexus feeds the superficial part of the dermis and the capillary single organ and define a single-organ vasculitis. Cutaneous network surrounding superficial annexes. Conversely, the vasculitis reflects the inflammation of dermal blood vessels epidermis is not vascularized and is nourished by imbibition and may induce a wide spectrum of clinical manifestations from the capillary networks of the dermal papillae. Such depending on the location and the size of the affected vessels. vascular anatomy is important because cutaneous inflamma- Along with this line, a dermatologic addendum to the tory infiltrates during vasculitis are located along these CHCC2012 was proposed in 2018 to standardize the names vessels, as localized, regrouped and perivascular infiltrates, and definitions for cutaneous vasculitis and provide a standard differentiating them histologically from diffuse inflammatory framework both for clinicians. The aim of our article is infiltrates. However, it is common not to visualize the wall of to provide an overview of elementary skin lesions and the vessels because of their destruction or the infiltrates. clinicopathologic correlations in cutaneous and systemic In terms of classification, it is important to note that vasculitis. medium-sized vessels according to the CHCC nomenclature are not present in the skin. However, there are in the deep layers of the skin some vessels with a smooth muscle wall which are considered medium-sized vessels. Nevertheless, it Vascular Anatomy of the Skin seems more accurate to talk about small vessels and vessels with smooth muscular wall in the skin. Better knowledge of the vascular anatomy of the skin is re- Finally, the cutaneous functional vascular unit is a cone- quired to understand the different clinical aspects of cutaneous shaped zone for which the base is at the surface of the epider- vasculitis (Fig. 1). The vascular system of the skin consists of mis and the apex at the level of the nourishing artery at the two interconnected plexuses: a deep plexus and a superficial dermohypodermic junction. This vascular anatomy explains plexus. Nourishing arteries of the skin are located in the the clinical aspect of livedo, where the obstruction of the hypodermis and engage into the deep dermis where arterioles nourishing artery leads to a venous stasis drawing the contours and venules communicate to form the deep vascular plexus. of the cone and assuming a reticulated aspect. The deep plexus is at the dermohypodermic junction and is also called cutaneous plexus. The branches of this plexus irrigate the adipose tissue of hypodermis, the deep part of dermis, and the capillary network surrounding hair follicles, Details on Histologic Features for the Analysis deep sebaceous glands, and sweat glands. Then, these of Vasculitis branches pass vertically through the dermis (candelabrum-like arteries). In the superficial dermis, arterioles and venules form Type of Inflammatory Infiltrate a second plexus, the superficial or subpapillary plexus, from which an arteriole ascends towards the most superficial part of The type of inflammatory infiltrate is a key finding for the the dermis, in front of the dermal papillae, and then descends diagnosis of cutaneous vasculitis. Fig. 1 Vascular anatomy of the skin Clinic Rev Allerg Immunol (2021) 61:181–193 183 Leukocytoclastic Vasculitis vasculitis associated with a mixed or neutrophilic infiltrates should suggest an infectious origin, especially if Leukocytoclastic vasculitis is not a disease per se but the leukocytoclasia is absent. result of a pathophysiological process common to different causes. Leukocytoclastic vasculitis reflects a damage relat- Granulomatous Vasculitis ed to circulating immune complexes that are deposited in the wall of small vessels and activate the complement Predominance of macrophages with or without giant cells cascade. Cutaneous lesions related to leukocytoclastic characterizes granulomatous vasculitis. Granuloma may be vasculitis are mostly localized in the lower limbs due to located into the vessel wall like in GCA, or be extra-vascular venous stasis. like in GPA. Differential diagnoses include infectious and Histological differential diagnoses of leukocytoclastic vas- non-infectious disorders such as sarcoidosis, cutaneous metas- culitis are infections and neutrophilic dermatoses. Diagnosis tasis, and Crohn’s disease. of neutrophilic dermatosis is based on dermal infiltrates composed of neutrophils with or without leukocytoclasia pictures. Some neutrophilic dermatoses such as pyoderma Direct Skin Immunofluorescence gangrenosum or Sweet’s syndrome may be accompanied by foci of vasculitis as an epiphenomenon, but the density and the Direct skin immunofluorescence may reveal immunoglobu- absence of angiocentricity of the neutrophilic infiltrate allow lins (IgA, IgM, IgG), complement (C3, C1q), or fibrinogen correct diagnosis. deposits within the vessel wall. All leukocytoclastic vasculitis are the consequence of immune complex deposits into the Lymphocytic Vasculitis vessel wall, and therefore with positive direct immunofluores- cence on skin biopsy. Nevertheless, such deposits evolve over Lymphocytic vasculitis may correspond to an evolutionary time and the biopsy of a lesion more than 72 h old usually stage of leukocytoclastic vasculitis, marking the transition reveals only C3 deposits on the vascular wall. Therefore, from an acute to a subacute stage. However, some vasculitis negative direct immunofluorescence does not eliminate can be primarily lymphocytic, as seen in macular lymphocytic leukocytoclastic vasculitis. Direct immunofluorescence may arteritis. True lymphocytic vasculitis must be differentiated be an additional feature supporting the diagnosis of IgA from perivascular lymphocytic infiltrates without fibrinoid ne- vasculitis in case of predominant IgA deposits into the crosis of the vessel wall. capillary wall, though it is not specific. Also, IgM deposits are not specific and are conventionally mentioned Necrotizing Vasculitis in the presence of rheumatoid factor or cryoglobulinemia. Conversely, immunoglobulin deposits into the vascular Necrotizing vasculitis is defined by vasculitis accompanied wall without any evidence of vasculitis have no pathological by fibrinoid necrosis. Tissue necrosis is called fibrinoid significance. necrosis when it is associated with a homogeneous, eosin- ophilic, periodic acid-Schiff-positive extracellular substance, due to the penetration into the vascular wall Diagnostic Approach According to the Size and the interstitial tissue of serum proteins, like fibrin, im- of the Affected Vessels and the Elementary munoglobulins, or complement, especially when immune Lesions complexes are present. Fibrinoid necrosis may not be always visible, mainly because of the segmental or focal Cutaneous lesions have a major interest for the diagnosis of involvement as in PAN or the thinness of the wall of the vasculitis but they do not allow etiological diagnosis. affected vessel compared with the intensity of inflammato- Lesions are multiple and polymorphic, but they can provide ry infiltrates as in leukocytoclastic vasculitis. some valuable information on the size of the affected vessels and the type of vasculitis involved. Approximately Thrombosing Vasculopathy half patients with cutaneous vasculitis with dermal or hy- podermic vessel involvement have systemic vasculitis. During an inflammatory process, various consequences can Conversely, half patients with systemic vasculitis will be observed, as the extravasation of red blood cells or the develop cutaneous manifestations. The depth of affected secondary thromboses due to endothelial cell damage. vessels is correlated with the type of cutaneous lesions. However, thrombosing vasculopathy may also result from Involvement of small superficial vessels results mostly in a primary thrombotic process causing necrosis that will urticarial, but relatively persistent plaques, papules, and secondarily induce inflammation. Also, a thrombosing palpable purpura. Involvement of vessels i n t he 184 Clinic Rev Allerg Immunol (2021) 61:181–193 Fig. 2 Clinicopathologic correlations of nonthrombocytopenic purpura dermohypodermic junction or hypodermis results in ulcers, Nonpurpuric Papules nodules, or livedo. Within vasculitis, papules usually reflect the involvement PORPORA of small-sized vessels of the dermis. Papules correspond to Involvement of Small Vessels PAPULE palpable and solid lesions measuring of less than 1 cm. Vasculitis lesion becomes palpable due to the intensity of PUSTOLE Purpura the inflammatory infiltrate, usually within the perivascular superficial and/or deep areas. These lesions are almost al- Purpura is the clinical expression of red blood cell extravasa- ways erythematous because of vasodilatation caused by the tion in the dermis (Fig. 2). Purpura is not always synonymous perivascular infiltrate. Also, associated edema of the der- with vasculitis related to damage of the vessel wall. Purpura mis may be responsible by itself of the palpable lesion, as it may occur in the absence of inflammation of the vessel wall. is in urticaria, or coexist with a cellular infiltration. Papules A purpura not initially palpable, dark, with necrotic evolution, may also reflect granulomatous lesions associated with translates more often thrombosing vasculopathy than vasculi- vasculitis, especially during GPA or GEPA. In these situa- tis (Table 1). In contrast, a palpable purpura usually reflects tions, papules are erythematous or purple, located on the the presence of an inflammatory cell infiltrate. Papulous elbow and finger extension areas, and usually multiple and or polymorphic purpura is usually the clinical expression of symmetrical (Fig. 3). These lesions may resemble to vesi- leukocytoclastic vasculitis. However, some vasculitis may re- cles, nodules, or ulcerations. Histologically, there is an en- sult in nonpalpable purpura. dothelial necrosis with an extra-vascular granulomatous Clinic Rev Allerg Immunol (2021) 61:181–193 185 Table 1 Main causes of nonpalpable purpura and palpable purpura Involvement of Smooth Muscle Wall Vessels (adapted from ) (Medium-sized Vessel) Nonpalpable purpura Bacteremia et septicemia Nodules Purpuric and pigmentary capillaritis NODULI LIVEDO ISCHEMICHE Disseminated intravascular coagulation Purpuric annular granuloma Nodules correspond to palpable and solid lesions measuring Langerhans cell histiocytosis of more than 1 cm. Usually, nodules are located in the dermis Paraproteinemia (cryoglobulinemia) Parvovirus B19 (and other viruses) or hypodermis. In the context of vasculitis, they reflect the Stasis involvement of vessels of the dermohypodermic junction or Rickettsiosis the hypodermis (Supplementary data Fig. 2). Nodules can be Talon noir located alongside an artery or a superficial vein, and can Thrombocytopenia Drug reactions evolve into an ulcer or necrosis. For an adequate pathological evaluation of a nodule, a deep Ecchymotic lesions (with or without petechiae) biopsy with the scalpel, carrying out the hypodermis, is re- Amyloidosis Disseminated intravascular coagulation quired. Vasculitis associated with cutaneous nodules involves Ehler Danlos syndrome vessels with a smooth muscle wall as in PAN, or vasculitis Angioimmunoblastic T cell lymphoma involving both capillary and smooth muscle wall vessels as Pseudohematoma Mechanic purpura (Bateman) ANCA-associated vasculitis. Thrombotic livedo Superficial pyoderma gangrenosum Scurvy Thrombocytopenia Livedo Anticoagulant Traumatism Livedo corresponds to a reticulate (network-like) erythema Vasculitis of vascular origin (Fig. 4). Livedo is secondary to vasomo- Palpable purpura tor disturbances or obstructive vascular pathology, with or Vasculitis lesions without parietal involvement (Table 2). It is not Bacteremia Langerhans cell histiocytosis synonymous with vasculitis. Clinically, there are different Paraproteinemia types of livedo: Rickettsia, typhus… IgA vasculitis – Livedo reticularis, with fine, regular, and closed meshes, Leukocytoclastic vasculitis Granulomatous vasculitis frequently physiological; – Livedo racemosa (branched livedo), with broken, Nonvasculitis lesions branched, discontinuous, and irregular meshes, always Angioma Kaposi’s disease pathological and characteristic of the Sneddon Angiokeratoma syndrome; Pyogenic granuloma – Livedo with infiltrated meshes, frequently encountered during vasculitis (PAN); – Purpuric livedo or retiform purpura which directs towards infiltrate composed of eosinophils, lymphocytes, and his- a thrombosing pathology of the dermal vessels such as a tiocytes, and necrobiosis of collagen bundles is usually disseminated intravascular coagulation or catastrophic basophilic in GPA and eosinophilic in GEPA. antiphospholipid syndrome. Overall, livedo reticularis is most often physiological, Pustules whereas a livedo racemosa is always pathological and requires a thorough assessment. The skin biopsy is not systematic and Pustules are caused by the detachments of the epidermis its interest remains debated. There is no interest of skin biopsy whose content is made of neutrophils (Supplementary data in livedo reticularis, whereas in livedo racemosa with infiltra- Fig. 1). Pustules are sometimes secondary to purpura and the tion or necrosis, the biopsy of the infiltrated zone sometimes intensity of the inflammatory infiltrate. Follicular or can reveal vasculitis. In the presence of a non-infiltrated and nonfollicular pustules with purpuric contour reflect small- non-necrotic livedo racemosa, limited to the lower limbs, the vessel vasculitis, and are typically observed in Behcet’s dis- biopsy is frequently not contributive but may sometimes show ease or inflammatory bowel diseases. They may also a picture of endarteritis obliterans directing towards a diagno- occur during infectious endocarditis or gonococcemia. sis of Sneddon syndrome, or an intense hyaline fibrinoid 186 Clinic Rev Allerg Immunol (2021) 61:181–193 Fig. 3 Clinicopathologic correlations of papules. Picture showing papules of the elbow in a patient with granulomatosis with polyangiitis; histopathologically, there is a circumscribed area in the upper part of the dermis with a mixed interstitial infiltrate and necrobiotic collagen bundles (courtesy Dr. François Chasset) aspect of the wall of a muscular arteriole observed in macular Other Manifestations Associated with Vasculitis lymphocytic arteritis. Pyoderma Gangrenosum Ischemic Manifestations: Gangrene or Necrosis Pyoderma gangrenosum is a painful cutaneous ulceration, of the Extremities, the Scalp, or the Tongue locating predominantly in the lower limbs, with progres- sive centrifugal extension that can reach more than Skin necrosis results from the occlusion of skin vessels. The extent 10 cm, and which initially starts as a pustule or subcuta- of necrosis depends on the type and depth of the affected vessels. neous nodule de novo or after a mild trauma, with Necrotic lesions are frequently seen in type I cryoglobulinemia inflammatory and purplish raised borders and some zones , where the main mechanism is a thrombosing vasculop- with purulent hutches. Pyoderma gangrenosum often athy. Such lesions can also be observed during ANCA-associated occurs in patients with inflammatory bowel disease, but vasculitis and necrotizing digital arteritis during PAN. Necrosis of it can also occur in patients with GPA and Takayasu the scalp and/or the tongue occurs in GCA. arteritis. Clinic Rev Allerg Immunol (2021) 61:181–193 187 Fig. 4 Clinicopathologic correlations of livedo. Picture showing a livedo in a patient with PAN Superficial Thrombophlebitis Oral, Genital, or Anal Ulcers Superficial thrombophlebitis must be distinguished from deep Oral ulcers are rare manifestations of vasculitis, except for thrombophlebitis and varicose vein thrombosis. The clinical Behçet’s disease in which it represents the most common man- picture includes sensitive nodules, sometimes as a deep linear ifestation. Oral ulcers can also be observed rarely in GPA (5% lesion or poorly limited cord. Such lesions can be seen in of patients) or in relapsing polychondritis, especially within thrombophilic disorders as antiphospholipid syndrome or the mouth and genital ulcers with inflamed cartilage (MAGIC) protein C or S deficiency, or in vasculitis, mainly Behçet’s syndrome. disease. Elsewhere, they may be the revealing mode of solid cancers, especially the stomach or the pancreas. Splinter Hemorrhages Gingival Hypertrophy Splinter hemorrhages, small areas of hemorrhages under the fingernails or toenails, are rare in vasculitis and are more likely Gingival hypertrophy, displaying a raspberry appearance, was to be due to thromboembolic or thrombotic pathology, espe- described as a mucosal manifestation of GPA, which is the cially during catastrophic antiphospholipid syndrome or infec- only vasculitis associated with this feature. tious endocarditis. 188 Clinic Rev Allerg Immunol (2021) 61:181–193 Table 2 Mechanisms and causes of livedo (adapted from ) Vasomotor disorder: most often livedo reticularis Physiological State of shock, low circulatory flow Pheochromocytoma, carcinoids Medicinal: amantadine , noradrenaline , gemcitabine Heart dermatitis or erythema ab igne Pellagra Hypothyroidism, Cushing’s syndrome Central nervous system disorders: multiple sclerosis, encephalitis, poliomyelitis, Parkinson’s disease, stroke, cerebral traumatism... Livedo of inflammatory origin Sarcoidosis Susac syndrome , Systemic lupus erythematosus Macular lymphocytic arteritis PAN, cutaneous PAN ANCA-associated vasculitis: GPA, EGPA, MPA Cryofibrinogenemia, cold agglutinates Hypocomplementemic urticarial vasculitis Subcutaneous injection of buprenorphine Basin’s disease or nodular vasculitis Livedo of emboligenous origin: livedo purpuric and purpura Embolism of cholesterol crystals Adenopathy emboligene Crude embolisms (associated with myxoma of the atrium and endocarditis) Gas emboli Infectious endocarditis Malignant embolism: angiotropic lymphomas, visceral cancers Paradoxical embolisms on foramen oval Intra-lymphatic histiocytosis (associated with rheumatoid arthritis) Emboli of hydrophilic polymer after vascular catheterization Nicolau’s Disease Livedo of thromboembolic origin Antiphospholipid syndrome Cryoglobulin Disseminated intravascular coagulation Livedo of infectious origin Capnocytophaga canimorsuss, due to an ICDD Escherichia coli Blood hyper viscosity: branched livedo Myeloproliferative syndrome (essential thrombocythemia, Vaquez’s disease, myeloid leukemia, myeloid splenomegaly) Cryoglobulinemia, cryofibrinogenemia Cold agglutinins Pancreatitis Crystal deposits: purpura retiform Calciphylaxis Oxaluria, homocystinuria Livedo of thrombotic origin: ADA2 deficiency White cutaneous atrophy Sneddon syndrome Monoclonal cryoglobulinemia Raynaud’s Phenomenon Interstitial Granulomatous Dermatitis Raynaud’s phenomenon is mainly seen in connective Interstitial granulomatous dermatitis may clinically pres- tissue diseases, mainly systemic scleroderma, mixed ent as linear cords of axillary regions, but also papules connective tissue disease, and inflammatory myopathy. and plaques. Histologically, deep dermal necrobiosis In vasculitis, Raynaud’s phenomenon directs towards foci are typically observed, affecting one or a few colla- cryoglobulinemic vasculitis, in up to 30% of patients gen bundles and surrounded by histiocytes organized in with in type I cryoglobulinemia , and roughly 20% rosettes. This entity is nosologically related to the so- in mixed cryoglobulinemic vasculitis. called Churg-Strauss granulomas and is associated with Clinic Rev Allerg Immunol (2021) 61:181–193 189 many disorders, such as GEPA and MPA , rheumatoid criteria correctly classifies a patient as having IgA vasculitis arthritis, systemic lupus erythematosus, and adult onset in 87%: palpable purpura not related to thrombocytopenia, Still disease. post-prandial diffuse abdominal pain typically associated with bloody diarrhea, gastrointestinal hemorrhage, hematuria, age less than 20 years, and absence of drugs at the beginning of the Description of the Main Cutaneous Vasculitis disease that could have precipitated the affection. Histologically, IgA vasculitis displays no specificity, showing Skin Small-Vessel Vasculitis typical leukocytoclastic vasculitis. However, direct immunoflu- orescence reveals predominant IgA deposits in the capillary Cutaneous Leukocytoclastic Angiitis wall. Thus, predominance of perivascular IgA deposits on skin biopsy is an additional positive argument for the diagnosis of The hypersensitivity vasculitis or cutaneous leukocytoclastic IgA vasculitis, without being specific , since other vasculitis angiitis has been individualized in the CHCC1994 and the as cryoglobulinemic vasculitis may have IgA deposits. CHCC2012 and belongs to the single-organ vasculitis. Clinically, cutaneous manifestations of cutaneous leukocytoclastic angiitis are polymorphic and include purpu- Cryoglobulinemic Vasculitis ra, urticarial plaques, nodules, vesicles or bulla, pustules, and/ or ulceration. Cryoglobulinemia is defined by the presence of immunoglob- ulins which precipitate with cold temperatures and Urticarial Vasculitis resolubilize with warming. Classification is based on the im- munochemical analysis, defining three types. Type I Urticarial vasculitis is defined histologically by inflammation cryoglobulins are single monoclonal immunoglobulins al- of capillaries of the dermis and post-capillary venules, and is ways linked to a B cell lymphoproliferative disorder. Type II divided into 2 groups accord the complement fraction level: cryoglobulins consist of polyclonal IgG with monoclonal IgM normocomplementemic urticarial vasculitis and with rheumatoid factor activity. Type III cryoglobulins are hypocomplementemic urticarial vasculitis. comprised of polyclonal IgG and polyclonal IgM with rheu- Lesions of urticarial vasculitis differ from classical urticaria matoid factor activity. Type II and III are often referred to as because they are more fixed, they are less pruriginous, and mixed cryoglobulinemia (MC), and may be linked to B cell they persist for more than 24 h. They have a chronic evolution, lymphoproliferative disorder, autoimmune disorders, and/or leaving hyperpigmented maculas, and are associated with an- infections. gioedema in half cases, purpura in one third, and livedo in Mixed cryoglobulinemia is responsible for vasculitis with 14%. Extra-cutaneous manifestations may occur, mainly cryoglobulin immune deposits affecting small vessels (capil- arthralgias, and ocular, pulmonary, gastrointestinal, and/or re- laries, venules, or arterioles). Vascular purpura is the most nal involvement. Most normocomplementemic urticarial vas- frequent manifestation, often indicative of the disease, where- culitis are idiopathic, whereas hypocomplementemic urticarial as peripheral neuropathy occurred in half patients and renal vasculitis are frequently associated with connective tissue dis- involvement in one third of patients. In contrast, type I mono- eases. Urticarial vasculitis must be distinguished from neutro- clonal cryoglobulinemia is responsible for vascular occlusion philic urticarial dermatosis, as many cases of UV have been with frequent Raynaud phenomenon, ulcers and distal necro- reclassified as NUD during the last decade. sis, pain and swelling in the extremities, or hyperviscosity syndrome. Histologically, cryoglobulinemia presents mostly IgA Vasculitis (Henoch-Schönlein Purpura) with a perivascular mononuclear cell infiltrate, without affect- ing the vessel wall by itself. However, leukocytoclastic vas- IgA vasculitis is characterized by palpable purpura, arthralgia, culitis is possible, especially within the skin, with fibrinoid and abdominal pain, and accounts for 10% of cutaneous vas- necrosis of the wall of small-sized vessels and inflammatory culitis. IgA vasculitis is the most frequent vasculitis in infiltrate of neutrophils, some of them being pycnotic childhood, with an annual incidence of 3 to 26 per 100,000 (leukocytoclasia). Intravascular hyaline deposits can be ob- children, often occurring between 4 and 7 years. The served, with the presence of immunoglobulin and comple- disease is less common in adults, with an estimated incidence ment deposition using direct immunofluorescence. between 0.1 and 1.8 per 100,000 individuals. The derma- tologic manifestation of both leukocytoclastic vasculitis and IgA vasculitis is palpable purpura. Michel et al. described clinical criteria for differentiating IgA vasculitis and cutaneous leukocytoclastic angiitis. Presence of 3 of the following 6 190 Clinic Rev Allerg Immunol (2021) 61:181–193 Skin Small-Vessel and Smooth Muscle Wall Vessel neutrophilic infiltrate frequently responsible for vascular Vasculitis thrombosis. The disease can be systemic with cutaneous in- volvement (systemic PAN), and limited to the skin as a single- Association of vasculitis lesions of small vessels and vessels organ vasculitis (cutaneous PAN); in the latter, regional neu- with smooth muscle wall is strongly suggestive of ANCA- rological involvement nevertheless frequently occurs. associated vasculitis, i.e., GPA, MPA, and EGPA. Skin manifestations of systemic PAN are described in al- most 50% of cases, dominated by purpura (19%), livedo Granulomatosis with Polyangiitis (17%), nodules (15%), urticaria (6%), and ulcers or cutaneous necrosis (4%). Although purpura is often mentioned in Granulomatosis with polyangiitis is histologically character- clinical studies, it is incompatible with the current definition of ized by inflammation of the vessel wall with peri- or extra- the CHCC2012 since it is a manifestation of small-vessel vas- vascular granulomas. Clinically, GPA is characterized by ear, culitis, the type of vessel which are spared in PAN. Possible nose, and throat manifestations, pulmonary involvement, and explanations would be that these PAN with purpura would be glomerulonephritis. ANCA are positive in more than 90% of MPA or cryoglobulinemic vasculitis, or conversely, an inac- cases, directed against proteinase 3. Yes the most common curate definition of PAN in CHCC2012. skin finding is palpable purpura related to leukocytoclastic During cutaneous PAN, skin manifestations are mainly vasculitis. livedo, nodules, and ulcers predominantly affecting the lower limbs. Other manifestations were described, including Microscopic Polyangiitis atrophie blanche , Raynaud’s phenomenon, and inflam- matory plaques surrounded by nodules. Triggering factors of Microscopic polyangiitis is responsible for a segmental and cutaneous PAN have been identified, such as viral, bacterial or focal necrotizing glomerulonephritis, associated with mycobacterial infection, inflammatory bowel disease, or extracapillary proliferation, and no extra-vascular granuloma. drugs (minocycline). Other clinical manifestations include arthralgias, peripheral Another entity, called macular lymphocytic arteritis (MLA) neuropathy, alveolar hemorrhage, or gastrointestinal manifes- or macular arteritis or lymphocytic thrombophilic arteritis, tations. ANCA are positive in more than 80% of cases, direct- was described in 2003. Authors initially reported the associa- ed against myeloperoxidase. tion of a macular and pigmented rash with lymphocytic arter- itis in the hypodermis or deep dermis on skin biopsy. Eosinophilic Granulomatosis with Polyangiitis Clinically, skin lesions are erythematous and/or pigmented mac- ules, reticulated, sometimes associated with nodules and purpu- Eosinophilic granulomatosis with polyangiitis is a necrotizing ra. Lesions are always located in the lower limbs and less fre- vasculitis defined by the association of asthma, blood and quently in the upper limbs (44%) and more rarely in the trunk. tissue eosinophilia, and systemic vasculitis. Clinical manifes- MLA preferentially occurs in women in 70–80% and median tations include multiple mononeuropathy or polyneuropathy, age is 40 years. Histologically, the epidermis and dermis are non-fixed pulmonary infiltrates, sino-nasal abnormalities, and normal; a dense peri- and intravascular lymphocytic infiltrate cardiomyopathy. Cutaneous manifestations are frequent oc- surrounding small arterioles in the reticular dermis or hypoder- curring in up to 50% of patients , especially purpura, sub- mis is observed. No destruction nor necrosis is seen within the cutaneous nodules, and urticaria. Less frequent manifestations arterial wall, but a very homogenous fibrinous and hyaline cir- were reported, as Wells cellulitis , Kimura disease, and cumferential arterial ring is characteristic of MLA. Lever granuloma, all belonging to the spectrum of eosinophil- Autoantibodies can be found, mainly anticardiolipin and antinu- ic dermatoses. Histologically, Wells phenomenon may be clear antibodies, sometimes with anti-SSA specificity. However, present, as the eosinophilic flame figures corresponding to this entity remains controversial and a real distinction between collagen destruction by degranulation of eosinophils. ANCA cutaneous PAN and MLA has not been established. In 2015, are positive in only 30–40%, usually directed against Buffiere-Morgada et al. retrospectively and blindly assessed the myeloperoxidase. frequency of clinical and histologic features of MLA in patients given the diagnosis of cutaneous PAN. Predominantly lympho- Skin Vasculitis of the Smooth Muscle Wall Vessels cytic arteritis, a paucity of neutrophils, concentric fibrin ring, and absence of internal lamina elastic disruption were present in Polyarteritis Nodosa 60%, 20%, 18%, and 23% of patients, respectively. The inci- dence of complete remission was not different between patients Polyarteritis nodosa is a segmental and focal necrotizing vas- having a predominant lymphocyte infiltrate or few neutrophils. culitis affecting medium and small arteries and arterioles of These data did not favor the classification of cutaneous PAN and the deep dermis and septums, with an inflammatory MLA as distinct entities. Clinic Rev Allerg Immunol (2021) 61:181–193 191 Kawasaki Disease (a) Recent drugs initiation? (b) Recent infection? Kawasaki disease is a vasculitis of large and medium vessels, (c) Neoplasia, malignant hemopathy? of unknown etiology, affecting preferentially children of less (d) Laboratory tests: CBC, platelets, CRP, PT, APTT, than 5 years, and more rarely adult. Kawasaki disease results fibrinogen, serum electrolytes, urea, creatinine, liver in febrile adenocutaneous-mucosal syndrome. Its severity is function tests, serum protein electrophoresis, HIV, related to cardiac involvement and the development of coro- HBV, and HCV serologies, parvovirus B19 serology nary aneurysms. (and/or other viruses according to clinical and epide- miological setting), cryoglobulin, rheumatoid factor, Behçet’s Disease complement fractions levels, antinuclear antibodies and if positive anti-ENA, ANCA testing, proteinuria, Behçet’s disease is a multisystemic inflammatory vasculitis and urine analysis affecting the arteries and veins of variable size, and preferen- (e) Morphological investigations: chest X-ray tially young men aged around 30 years. Besides frequent buc- (f) Investigations to discuss depending on clinical con- cal and genital ulcers, cutaneous manifestations include in- text and disease course: blood cultures, echocardiog- flammatory nodules locating in the lower limbs and resem- raphy, CT scan and sinuses, brain imaging and lum- bling erythema nodosum, “pseudofolliculitis,” and superficial bar puncture. thrombophlebitis. Ocular, gastrointestinal, vascular, or central nervous system attacks are less frequent but much more serious. Conclusion Drug-Induced Vasculitis with Immune Complex Cutaneous vasculitis constitutes a large and heterogeneous Deposition group of diseases, for which the analysis of cutaneous elemen- tary lesions and skin biopsy provide important findings on the Drug-induced vasculitis with immune complex deposition has size of the affected vessel and possibly on the type of been individualized in the CHCC2012 as a vasculitis of de- vasculitis. fined cause. It occurs most often within 7–21 days after initi- ation of the suspected drug. Drugs most frequently involved Compliance with Ethical Standards are fosphenytoin, quinidine, sulfonamides, penicillins, allopu- rinol, or granulocyte-colony stimulating factor. Overall, Conflict of Interest The authors declare that they have no conflict of approximately 15–20% of cutaneous vasculitis are drug- interest. induced. Informed consent Yes. Research Involving Human Participants and/or Animals None. How I Manage a Patient with Suspected Cutaneous Vasculitis References When a cutaneous vasculitis is suspected, a careful diagnostic approach is mandatory to look for potentially severe organ 1. Lightfoot RW, Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, manifestations and to establish as quickly as possible the eti- McShane DJ et al (1990) The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis ological diagnosis : Rheum 33(8):1088–1093 2. 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