CIC Edizioni Internazionali. Cutaneous vasculitides and vasculopathies. Review. Giampiero Girolomoni Paolo Rosina. severity.

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1 Review Cutaneous vasculitides and vasculopathies Giampiero Girolomoni Paolo Rosina Department of Medicine Section of Dermatology University of Verona, Italy Address for correspondence: Paolo Rosina, MD Department of Medicine Section of Dermatology University of Verona Piazzale A. Stefani Verona, Italy Phone: Fax: paolo.rosina@univr.it Summary Cutaneous vasculopathies are classified into four main forms: inflammatory vasculitides, livedoid vasculopathies, capillary chronic pigmented purpura and endothelitis. These conditions may have quite similar presentations, and sometimes they are overlapping. Cutaneous vasculitides are a heterogeneous group of inflammatory disorders affecting skin blood vessels. They may be triggered by several factors, such as infection or drug, or may be related to underlying disease, notably connective tissue or malignancies. The most widely used classification of cutaneous vasculitides is based on the size of the vessels concerned, and makes a distinction between small-vessel, small- and medium-vessel, medium-to-large vessel and largest-vessel vasculitis. The most common form is small-vessel vasculitis, that is clinically characterized by the presence of purpuric papules, sometimes accompanied by hemorrhagic bullae or necrotic areas, mostly localized in the lower extremities. Some forms of vasculitis are characterized by the presence of an infiltrate with a prevalent lymphocyte composition, and this is the reason why they are called lymphocytic vasculitis. A crucial step for confirmation of diagnosis is the histologic examination, to be performed on recentonset lesions. The extent of the disease beyond the skin should be also assessed. Treatment requires elimination of the cause when possible, as well as therapy with nonsteroidal anti-inflammatory drugs, corticosteroids or other immunosuppressive agents, depending on disease severity. KEY WORDS: skin vasculitis, diagnosis, therapy. Vasculitides and cutaneous vasculopathies are classified into four main forms: inflammatory vasculitides (with a typical cutaneous manifestation), livedoid vasculopathies (of non-inflammatory and microthrombotic nature), capillary chronic pigmented purpura and endothelitis (most frequently caused by viral infections, typically due to Parvovirus B19). These conditions may have quite similar presentations, and sometimes they are overlapping. Cutaneous vasculitides are a specific pattern of skin vessel inflammation; they may be limited to the skin, develop at first at the skin level and then proceed to systemic involvement, or be a cutaneous manifestation of a systemic vasculitis. Both the arterial and the venous districts can be affected, with varying clinical manifestations that often require histological confirmation (1-4). They may affect the arteries and the veins, with a great clinical variability. The most widely used classification of cutaneous vasculitides is based on the size of the vessels concerned, and makes a distinction between small-vessel, small- and mediumvessel, medium-to-large vessel and largest-vessel vasculitis (arteritis) (Table 1). Small-vessel vasculitis The most common form is small-vessel vasculitis, that is clinically characterized by the presence of purpuric papules, sometimes accompanied by hemorrhagic bullae or necrotic areas, mostly localized in the lower extremities (Figures 1, 2). Small-vessel vasculitis may also present as petechiae and, less frequently, as persistent orticarioid lesions with hyperpigmentation, vesicles and pustules (5). The typical histopathological finding of these forms is a leukocytoclastic vasculitis, with fibrinoid necrosis of the vessel wall, a neutrophil-rich inflammatory infiltrate sometimes also with eosinophils with nuclear dust. It is usually recommended to perform a biopsy of recently developed palpable lesions, within hours from appearance. If a biopsy of a less recent lesion is performed, there may be a different presentation because lesions are of evolutive nature: in a late stage of leukocytoclastic vasculitis, a more pronounced lymphomonocyte component may be detected. The pathogenetic mechanism involves a damage Clinical Dermatology 2013; 1 (2):

2 G. Girolomoni et al. In te Small vessel vasculitis CSVV Henoch-Schönlein purpura (IgA) Urticarial vasculitis (hypocomplementemic) Erythema elevatum diutinum Secondary to: infections, drug exposure, hematologic malignancies Associated with connective tissue vascular disease (e.g. SLE, RA, juvenile DM) zio na li Table 1 - Classification of cutaneous vasculitis. small-vessel vasculitis include: infections (hepatitis B and C, infectious mononucleosis, Lyme disease), drugs (diltiazem, cimetidine, procarbazine, fluoxetine, etanercept, methotrexate), hematological diseases (leukemia, lymphoma, polycythemia, etc.). A particular form of leukocytoclastic vasculitis is SchönleinHenoch purpura, a common form in children, characterized by perivascular deposits of IgA and a tendency to extra-cutaneous involvement with arthritis and gastrointestinal and renal manifestations. A not so rare form in very young children usually below two years of age is acute hemorrhagic edema of infancy: it is characterized by hemorrhagic lesions particularly in the face and extremities, and creates great anxiety among parents (7). In spite of the appearance, it is a benign condition, usually secondary to infections, and resolves spontaneously without any therapy (Figure 3). Some forms of vasculitis are characterized by the presence of an infiltrate with a prevalent lymphocyte composition, and this is the reason why they are called lymphocytic vasculitis (8, 9). In this case, too, there is a wide pathogenic spectrum, but the most typical forms are those associated with Rickettsiosis, use of certain drugs, or to conditions that may appear during connective tissue diseases or other disorders (Table 2). Sneddon disease, which mainly affects young women, is a rare condition characterized by findings of a lymphocytic vasculitis associated with livedo racemosa and relapsing cerebrovascular complications. If a vasculitis is clinically suspected, a crucial step for confirmation of diagnosis is the histologic examination, to be performed as previously said on recent-onset lesions. The extent of the disease beyond the skin should be also assessed, i.e. possible involvement of the kidneys, nervous system (also the peripheral system which is often the main cause of pain), joints, gastrointestinal tract and pleuropericardial district. The next step is to determine etiology: this disease is most frequently caused by infections, drugs or associated conditions that induce the production of immunocomplexes, e.g. connective tissue diseases, tumors, or rn a mediated by circulating immunocomplexes, with neutrophil-predominant vessel wall damage. Urticarial vasculitis can be either hypocomplementemic or normocomplementemic: hypocomplementemic forms are often associated with a systemic involvement, especially at kidney and pulmonary level (6). Hypocomplementemia is not necessarily detected steadily, as it may vary over time. Urticarial vasculitis especially hypocomplementemic forms is sometimes associated with connective tissue diseases: a proportion of these cases may fulfill the criteria for a diagnosis of systemic lupus erythematosus. Other conditions that may cause or be associated with ni Small and medium-sized vessel vasculitis Cryoglobulinemia (type I and II) ANCA-associated: microscopic polyangiitis, Wegener s granulomatosis, Churg-Strauss syndrome Secondary to infection, inflammatory disorders (AI-CTD) izi o Medium-sized vessel vasculitis Polyarteritis nodosa Classic (systemic) PAN and cutaneous PAN Nodular vasculitis CI C Ed Largest Vessel Vasculitis Giant cell (temporal) arteritis Takayasu arteritis Figure 1 - Cutaneous clinical manifestations in patients with small-vessel vasculitis: hemorrhagic papules (palpable purpura). Figure 2 - Small-vessel vasculitis: hemorrhagic papules and bullae, necrotic areas. 94 Figure 3 - Acute hemorrhagic edema of infancy: clinical features. Table 2 - Lymphocytic vasculitis. Infections Drugs Malignancies (hematologic) Collagen vascular disease Pityriasis lichenoides Degos disease Sneddon disease (some forms) Clinical Dermatology 2013; 1 (2): 93-97

3 Cutaneous vasculitides and vasculopathies Table 3 - Clinical evaluation of patients with vasculitis. Confirm clinical diagnosis histopathologically Punch biopsy of a lesion at the appropriate stage Realize that lesions have life spans and that therapy affects the histopathologic findings Incisional biopsy for larger vessel vasculitis Assess extent of disease General Myalgias Arthralgias Fever Kidney glomeruli Proteinurea/hematuria Nervous System Central or peripheral Diffuse or local findings Attempt to establish etiology Drugs Infections (viral, bacterial, fungal, other) Diseases associated with immune complexes (e.g. connective tissue vascular diseases, malignancy, inflammatory bowel disease, chronic active hepatitis, etc.) Idiopathic - 50% chronic inflammatory diseases (8-10). Over 50% of cases usually remain idiopathic (Table 3). From a therapeutic point of view, data from controlled studies on small-vessel cutaneous vasculitis are relatively limited. Overall, this is a rather rare disease, and therefore most treatment recommendations are based on case series; generally, the starting therapy is colchicine, pentoxifylline or cortisone, sometimes methotrexate; in the most severe forms, cyclophosphamide is the most frequently used drug. Small- and medium-sized vessel cutaneous vasculitis Small- and medium-sized vessel cutaneous vasculitis include cryoglobulinemia (Table 4). This condition is characterized by three subtypes: monoclonal type I (more frequently IgM), associated with B-cell lymphoproliferative disorders (multiple myeloma, Waldenstrom macroglobulinemia), clinically characterized by manifestations of gangrene, ulcers, acrocyanosis and Raynaud s phenomenon; type II, composed of polyclonal IgG and monoclonal IgM with rheumatoid factor activity, associated with infections (HCV, HIV), autoimmune diseases and lymphoproliferative diseases (11). Type II is clinically characterized by the development of palpable purpura, sometimes accompanied by arthralgia, peripheral neuropathy and glomerulonephritis. Type III is composed of polyclonal IgG and IgM, the latter with a rheumatoid factor activity. In addition to leukocytoclastic presentations with neutrophil-rich infiltrates around the vessel and fibrinoid necrosis of the wall cryoglobulinemias may also present non-inflammatory conditions (especially of type 1) with vessel occlusions due to cryoprecipitates, although vasculitis is not necessarily present. In this case, the clinical presentation is not inflammatory but directly of the ulcerative type. The most relevant of medium-sized vessel vasculitides is polyarteritis nodosa (12). Classical polyarteritis nodosa is a very rare systemic disease characterized by a number of symptoms including fever, myalgia, fatigue with body weight loss, necrotizing glomerulonephritis, ischemic cardiac disease, hypertension, polyneuritis and ocular involvement. Cutaneous involvement may be observed in 20-30% of cases, with typical painful nodules in lower extremities with a tendency to ulceration palpable purpura, livedo reticularis and digital gangrenes. Besides this classical form, there is also a cutaneous polyarteritis nodosa that presents with systemic symptoms as well, including low-grade fever, myalgia, arthralgia and peripheral neuropathy, but especially with very painful erythematous nodules in the legs that have an ulcerative progression and leave pigmentation and scars; it is more common during infancy and has a benign nature, although a chronic and relapsing course can be reported, and is associated with infections (HBV, HIV, Parvovirus B19) and bowel chronic inflammatory diseases (Table 5). Table 4 - Cutaneous small and medium-sized vessel vasculitides. Cryoglobulinemia: type I: monoclonal IgM > IgG (B cell proliferative disease). Retiform purpura, gangrene, ulcers, acrocyanosis, Raynaud s type II: polyclonal IgG (HCV, HIV, autoimmune diseases, lymphoproliferative diseases) with monoclonal IgM with rheumatoid factor activity. Palpable purpura, arthralgia, peripheral neuropathy, GN. Type III: polyclonal IgG and polyclonal IgM with RF activity. ANCA-associated: microscopic polyangiitis, Wegener s granulomatosis, Churg-Strauss syndrome Secondary to infection, inflammatory disorders (AI-CTD) Table 5 - Polyarteritis nodosa (PAN): main cutaneous and systemic clinical features. Classical (systemic) PAN Systemic disorder (fever, myalgias, asthenia, weight loss, necrotizing glomerulonephritis, cardiac ischemic disease, hypertension, neuritis, ocular involvement) Skin (20-30%) Erythematous and painful nodules (legs) which may ulcerate; palpable purpura, livedo reticularis, digital gangrene Cutaneous PAN Mild fever myalgias, arthralgia, asthenia, peripheral neuropathy Erythematous and painful nodules (legs), ulcers, palpable purpura, livedo reticularis, digital gangrene Most common form in children Benign but chronic relapsing course Associated with infection (Strep; Parvovirus B19, HBV, HIV) and IBD Clinical Dermatology 2013; 1 (2):

4 G. Girolomoni et al. Livedoid vasculopathies Livedoid vasculopathies develop in patients with a predisposing thrombophilic state at baseline (13, 14). This may be of different origin, since there are inherited and acquired thrombophilic forms, all characterized (from a pathogenic point of view) by a tendency to generate microthrombi in small skin vessels. A microthrombus can be histologically documented, without inflammatory events affecting the vessels. It is important to document the microthrombus histologically with intravascular fibrin deposition: biopsy should be performed on the healthy skin around the ulcerative lesions, presumably next to the obstructed vessel that runs through the surrounding skin. The examination reveals ulcerative manifestations that leave ivory-white stellate scars with peripheral telangiectasias (atrophie blanche), often associated with livedo reticularis, intense pain, more frequently in young patients (in this case, they are often inherited thrombophilias) and particularly affecting the lower extremities. Typical manifestations include livedo reticularis or racemosa, with a large and highly irregular branching pattern, possibly accompanied by ulcerations; they usually affect very young patients who do not have a history of venous insufficiency or thrombophlebitis. Table 6 shows the main inherited and acquired causes of venous thrombosis. The treatment is based on antiplatelet, anticlotting or antithrombotic therapy: in case of severe forms, the Table 6 - Causes of venous thrombosis. Inherited Common: G1691A mutationi factor V gene (Factor V Leiden) G20210A mutation prothrombin (factor II) gene Homozygous C677T mutation MTHFR gene Increased levels of factor VIII, factor IX, or fibrinogen* (Probably inherited) Rare: Antithrombin deficiency Protein C deficiency Protein S deficiency Very rare: Dysfibrinogenemia Homozygous homocystinuria Increased levels of factor XI Acquired Surgery and trauma Prolonged immobilization Older age Cancer Myeloproliferative disorders Previous thrombosis Pregnancy and the puerperium Obesity Contraception or hormone-replacement therapy Resistance to activated protein C (that is not due to alterations in the factor V gene) Antiphosfolipid antibodies (primary and acquired antiphospholipid syndrome) Mild-to-moderate hyperhomocysteinemia initial treatment is heparin followed by anticlotting agents. Pigmented purpuric dermatosis The most common forms of pigmented purpuric dermatosis include Schamberg disease and lichen aureus (a localized, unilateral and well-circumscribed form) (Table 7). They are characterized by the appearance of flat, non-palpable macular lesions that begin as erythematous forms and then evolve into hyperpigmentation, usually in lower extremities; they are common in young women but also in elderly males. These forms are usually mistaken for vasculitis, but in fact they are chronic capillaritis (15). There is no vasculitis, but a perivascular inflammatory infiltrate with red blood cell extravasation that results into hemosiderin deposition and hyperpigmentation. These forms usually resolve spontaneously within a few months (but are sometimes relapsing) and do not need to be investigated from a systemic point of view like for vasculitis. The most typical diagnostic criteria include a superficial perivascular inflammatory infiltrate without vascular damage, with red blood cell extravasation and the presence of melanophages. In the majority of cases, viral endothelitis is caused by parvovirus B19, which typically infects endothelial cells and determines several hemorrhagic conditions that include fifth disease, papular-purpuric gloves and sock syndrome (Figure 4), or purpuric manifestations with or without an association with vasculitis and with an atypical localization (16). These forms present as a viral infection, with polyarthralgias, fever, malaise, fatigue and possible neurological manifestations. From a clinical Table 7 - Pigmented purpuric dermatoses. Schamberg disease Purpura annularis teleangectodes of Majocchi Pigmented purpuric lichenoid dermatitis of Gougerot and Blum Lichen aureus Eczematide-like purpura of Ducas and Kapetanakis Linear pigmented purpura Granulomatous pigmented purpura Figure 4 - Papular-purpuric gloves and socks syndrome: clinical manifestations. 96 Clinical Dermatology 2013; 1 (2): 93-97

5 Cutaneous vasculitides and vasculopathies cutaneous point of view, they appear as superficial, non-palpable purpuric lesions, sometimes spreading on acral sites, with a possible involvement of mucous membranes and with the appearance of petechiae and hyperemia that is particularly evident in the oral cavity and the pharynx. The histological examination shows a perivascular inflammatory infiltrate mainly consisting of lymphocytes, with no signs of vasculitis and with red blood cell extravasation into the dermis. References 1. Chen KR, Carlson JA. Clinical approach to cutaneous vasculitis. Am J Clin Dermatol 2008;9: Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol 2003;48: Carlson JA. The histological assessment of cutaneous vasculitis. Histopathology 2010;56: Marzano AV, Vezzoli P, Berti E. Skin involvement in cutaneous and systemic vasculitis. Autoimmun Rev 2013;12: Lotti T, Ghersetich I, Comacchi C, Jorizzo JL. Cutaneous small-vessel vasculitis. J Am Acad Dermatol 1998;39: Peroni A, Colato C, Zanoni G, Girolomoni G. Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria: part II. Systemic diseases. J Am Acad Dermatol 2010;62: Sites LY, Woodmansee CS, Wilkin NK, Hanson JW, Skinner RB Jr, Shimek CM. Acute hemorrhagic edema of infancy: case reports and a review of the literature. Cutis 2008;82: Kluger N, Francès C. Cutaneous vasculitis and their differential diagnoses. Clin Exp Rheumatol 2009;27:S Guillevin L. Infections in vasculitis. Best Pract Res Clin Rheumatol 2013;27: Buggiani G, Krysenka A, Grazzini M, Vašků V, Hercogová J, Lotti T. Paraneoplastic vasculitis and paraneoplastic vascular syndromes. Dermatol Ther 2010;23: Terrier B, Cacoub P. Cryoglobulinemia vasculitis: an update. Curr Opin Rheumatol 2013;25: Morgan AJ, Schwartz RA. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol 2010;49: Gonzalez-Santiago TM, Davis MD. Update of management of connective tissue diseases: livedoid vasculopathy. Dermatol Ther 2012;25: Gaffo AL. Thrombosis in vasculitis. Best Pract Res Clin Rheumatol 2013;27: Carlson JA, Chen KR. Cutaneous pseudovasculitis. Am J Dermatopathol 2007;29: Katta R. Parvovirus B19: a review. Dermatol Clin 2002;20: Clinical Dermatology 2013; 1 (2):