Cutaneous arteriolitis: A novel cutaneous small vessel vasculitis disorder clinicopathologically different from cutaneous polyarteritis nodosa and cutaneous venulitis

Cutaneous vasculitis can be classified into two types based on the affected vessel size: small vessel vasculitis predominantly affecting dermal venules, and muscular vessel vasculitis as found in cutaneous arteritis predominantly affecting arteries located at the dermal-subcutaneous junction. We describe two cases with a novel small vessel vasculitis disorder, which exclusively affected arterioles in the mid-dermis, and show clinical and pathological difference distinct from cutaneous polyarteritis nodosa and cutaneous venulitis. Both patients were male, and presented with painful infiltrative plaques, involving the palms, soles, and thighs without extracutaneous involvement except for fever and arthralgia. Histopathological examination revealed vasculitis in the mid-dermis characterized by a predominant infiltration of neutrophils with vessel wall fibrinoid necrosis and leukocytoclasia identical to the features of leukocytoclastic vasculitis, except that the affected vessels were arterioles rather than venules. Serological examinations showed normal levels of serum complements, immune complexes, and antineutrophil cytoplasmic antibodies, and vasculitis disorders associated with systemic diseases were excluded in both patients. The patients showed a good response to short-term treatment with prednisolone up to 30 mg. This novel cutaneous arteriolitis clinicopathologically different from both cutaneous venulitis and cutaneous arteritis appears to be a skin-limited disorder.     

Cutaneous vasculitis update: neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes

Most biopsies of cutaneous vasculitis will exhibit a small vessel neutrophilic vasculitis [leukocytoclastic vasculitis (LCV)] that is associated with immune complexes on direct immunofluorescence examination or, less commonly, antineutrophilic cytoplasmic antibodies (ANCA) by indirect immunofluorescence testing. Is in uncommon for skin biopsy to reveal solely a neutrophilic arteritis signifying the presence of cutaneous polyarteritis nodosa or, if accompanied by significant lobular panniculitis, nodular vasculitis/erythema induratum. In other cases, cutaneous vascular damage (fibrinoid necrosis, muscular vessel wall disruption, or endarteritis obliterans) will be mediated by a nonneutrophilic inflammatory infiltrate. Eosinophilic vasculitis can be a primary (idiopathic) process that overlaps with hypereosinophilic syndrome, or it can be a secondary vasculitis associated with connective tissue disease or parasite infestation. Authentic cutaneous granulomatous vasculitis (versus vasculitis with extravascular granulomas) can represent a cutaneous manifestation of giant cell arteritis, an eruption secondary to systemic disease such as Crohn's disease or sarcoidosis, or a localized disorder, often a post-herpes zoster (HZ) phenomenon. Lymphocytic vasculitis is a histologic reaction pattern that correlates with broad clinical differential diagnosis, which includes connective tissue disease - mostly systemic lupus erythematosus (SLE), endothelial infection by Rickettsia and viruses, idiopathic lichenoid dermatoses such as perniosis or ulcerative necrotic Mucha-Habermann disease, and angiocentric cutaneous T-cell lymphomas. Skin biopsy extending into the subcutis, identifying the dominant inflammatory cell and caliber of vessels affected, extravascular histologic clues such as presence of lichenoid dermatitis or panniculitis, and correlation with clinical data allows for accurate diagnosis of these uncommon vasculitic entities.     

Histologie der kutanen Vaskulitiden

Identification of vasculitis by skin biopsy represents the diagnostic gold standard. Skin biopsies should be taken from fresh lesions or from margin of an ulceration and should contain all layers of the skin including subcutis. Classification of vasculitis is based on histological criteria considering the size of the predominantly affected vessel, the distribution of vasculitis in the dermis and subcutis, and the predominant inflammatory cell-type. In cutaneous vasculitis, small and medium-sized vessels of the arterial and/or venous system are predominant affected. Vasculitis of the larger-sized blood vessels is based on inflammatory cells within the wall of the vessel; in small vessel vasculitis, additional features include fibrin within the vessel wall and/or an intraluminal thrombus and/or perivascular and interstitial infiltrates of neutrophils, nuclear dust and extravasated erythrocytes are required for the diagnosis of vasculitis. Leukocytoclastic vasculitis is the most common form of cutaneous vasculitis. An correct diagnosis requires careful correlation of medical history, the clinical, serological, imaging and direct immunofluorescence data, and histologic findings.     

Histology of cutaneous vasculitides

Identification of vasculitis by skin biopsy represents the diagnostic gold standard. Skin biopsies should be taken from fresh lesions or from margin of an ulceration and should contain all layers of the skin including subcutis. Classification of vasculitis is based on histological criteria considering the size of the predominantly affected vessel, the distribution of vasculitis in the dermis and subcutis, and the predominant inflammatory cell-type. In cutaneous vasculitis, small and medium-sized vessels of the arterial and/or venous system are predominant affected. Vasculitis of the larger-sized blood vessels is based on inflammatory cells within the wall of the vessel; in small vessel vasculitis, additional features include fibrin within the vessel wall and/or an intraluminal thrombus and/or perivascular and interstitial infiltrates of neutrophils, nuclear dust and extravasated erythrocytes are required for the diagnosis of vasculitis. Leukocytoclastic vasculitis is the most common form of cutaneous vasculitis. An correct diagnosis requires careful correlation of medical history, the clinical, serological, imaging and direct immunofluorescence data, and histologic findings.     

Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid arthritis

BACKGROUND: Cutaneous manifestations are the most frequent, and often the initial feature of extra-articular involvement in patients with rheumatoid vasculitis. OBJECTIVES: The purpose of the study was to evaluate the clinical and histological spectrum of cutaneous vasculitis and the associated systemic involvement in patients with rheumatoid vasculitis. METHODS: Among 525 patients with rheumatoid arthritis, 20 tissue specimens with histologically proven cutaneous necrotizing vasculitis from 11 patients were investigated by studying the types and levels of affected vessels and related clinical features. RESULTS: Small-vessel vasculitis identified as dermal necrotizing venulitis was found in 10 patients, clinically characterized by palpable purpura, maculopapular erythema, erythema elevatum diutinum and haemorrhagic blisters. Arteritis histologically resembling cutaneous polyarteritis nodosa, clinically characterized by subcutaneous nodules, livedo reticularis, atrophie blanche and deep ulcers was identified in four patients all with systemic complications. Coexistence of venulitis and arteritis was identified in three patients. Different cutaneous vasculitic manifestations often coexisted and recurred in the same patient. Three patients with systemic complications of mononeuritis multiplex (two of three), interstitial pulmonary fibrosis (two of three) and abdominal microaneurysms (one of three) died within 1 year of onset of the cutaneous vasculitis. Immunofluorescence demonstrated vessel wall deposition of IgM and/or complement in six of the seven patients examined. CONCLUSIONS: Features of cutaneous rheumatoid vasculitis overlapping both the characteristics of cutaneous necrotizing venulitis and cutaneous polyarteritis nodosa together with coexistence of these different type of vasculitis in the same or different lesional skin account for the associated diverse cutaneous vasculitic manifestations. Although dermal venulitis (leucocytoclastic vasculitis) was the most common presentation, the presence of leucocytoclastic vasculitis in rheumatoid patients did not necessarily indicate a favourable prognosis. Associations with mononeuritis multiplex and bowel involvement had a fatal prognosis, while patients with superficial dermal venulitis without other extra-articular involvement may follow a favourable prognosis.     

New algorithm (KAWAKAMI algorithm) to diagnose primary cutaneous vasculitis

Palpable purpura tends to indicate involvement of small vessel vasculitis in the upper dermis. Livedo racemosa, nodular lesion and skin ulceration are indicative of involvement of small to medium-sized vessel vasculitis in the lower dermis to subcutaneous fat. We set out to establish a new algorithm (KAWAKAMI algorithm) for primary cutaneous vasculitis based on the Chapel Hill Consensus Conference classification and our research results, and apply to the diagnosis. The first step is to measure serum antineutrophil cytoplasmic antibodies (ANCA) levels. If myeloperoxidase-ANCA is positive, Churg–Strauss syndrome or microscopic polyangiitis can be suspected, and if the patient is positive for proteinase 3-ANCA, Wegener's granulomatosis is most likely. Next, if cryoglobulin is positive, cryoglobulinemic vasculitis should be suspected. Third, if direct immunofluorescence of the skin biopsy specimen reveals immunoglobulin A deposition within the affected vessels, Henoch–Schönlein purpura is indicated. Finally, the presence of anti-phosphatidylserine–prothrombin complex antibodies and/or lupus anticoagulant and histopathological necrotizing vasculitis in the upper to middle dermis (leukocytoclastic vasculitis) indicates cutaneous leukocytoclastic angiitis, whereas if necrotizing vasculitis exists in the lower dermis and/or is associated with the subcutaneous fat, cutaneous polyarteritis nodosa is indicated. The KAWAKAMI algorithm may allow us to refine our earlier diagnostic strategies and allow for efficacious treatment of primary cutaneous vasculitis. In cutaneous polyarteritis nodosa, warfarin or clopidogrel therapies should be administrated, and in cases that have associated active inflammatory lesions, corticosteroids or mizoribine (mycophenolate mofetil) therapy should be added. We further propose prophylactic treatment of renal complications in patients with Henoch–Schönlein purpura.     

Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis

Vasculitis, inflammation of the vessel wall, can result in mural destruction with hemorrhage, aneurysm formation, and infarction, or intimal-medial hyperplasia and subsequent stenosis leading to tissue ischemia. The skin, in part due to its large vascular bed, exposure to cold temperatures, and frequent presence of stasis, is involved in many distinct as well as un-named vasculitic syndromes that vary from localized and self-limited to generalized and life-threatening with multi-organ disease. To exclude mimics of vasculitis, diagnosis of cutaneous vasculitis requires biopsy confirmation where its acute signs (fibrinoid necrosis), chronic signs (endarteritis obliterans), or past signs (acellular scar of healed arteritis) must be recognized and presence of extravascular findings such as patterned fibrosis or collagenolytic granulomas noted. Although vasculitis can be classified by etiology, many cases have no identifiable cause, and a single etiologic agent can elicit several distinct clinicopathologic expressions of vasculitis. Therefore, the classification of cutaneous vasculitis is best approached morphologically by determining vessel size and principal inflammatory response. These histologic patterns roughly correlate with pathogenic mechanisms that, when coupled with direct immunofluorescent examination, anti-neutrophil cytoplasmic antibody (ANCA) status, and findings from work-up for systemic disease, allow for specific diagnosis, and ultimately, more effective therapy. Herein, we review cutaneous vasculitis focusing on diagnostic criteria, classification, epidemiology, etiology, pathogenesis, and evaluation of the cutaneous vasculitis patient.     

Cutaneous manifestations in patients with microscopic polyangiitis: two case reports and a minireview

Microscopic polyangiitis is a systemic small vessel vasculitis, which often has cutaneous and musculoskeletal features. Microscopic polyangiitis is a member of the family of anti-neutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitides and is strongly associated with anti-myeloperoxidase (MPO)-ANCA. Titres of MPO-ANCA may reflect disease activity and play a pathogenic role. Patients with microscopic polyangiitis usually present with erythematous macules on the extremities as the first cutaneous manifestation. Skin biopsy specimens from the erythema reveal small-sized vessels that are infiltrated with neutrophils, consistent with leukocytoclastic vasculitis, in the deep dermis to the subcutaneous fat tissue. The cutaneous involvement is present at an early stage of microscopic polyangiitis with other non-specific symptoms, such as arthralgias and myalgias. The initial cutaneous manifestations are important in early diagnosis of possible ANCA-associated vasculitides with elevated ANCA titres.     

Life-threatening purpura and vasculitis

Palpable purpura, the inflammation of blood vessels is the hallmark of vasculitis. It can be observed in a variety of settings, where vessels can be affected primarily or as a secondary event. Every patient with vasculitis should be considered to have a systemic disease unless proven otherwise. One or more systemic symptoms occur in at least 50% of patients and there is no way to predict systemic involvement. Patients may demonstrate mild systemic involvement like arthralgia and arthritis, fever and malaise or more severe symptoms such as massive proteinuria and raised creatinine leading to chronic renal failure, severe intestinal bleeding or perforation with a fatal outcome. In this article we will review the life-threatening aspects of purpura and vasculitis.     

Necrotizing vasculitis within cutaneous lesions of mycosis fungoides

Mycosis fungoides is a T cell lymphoma with a predilection for cutaneous involvement. This paper describes the clinical manifestations and histopathologic features of a case of mycosis fungoides with necrotizing vasculitis localized to the lesions of cutaneous lymphoma. Elevated levels of circulating immune complexes were found in this patient. The large numbers of perivascular malignant helper T lymphocytes may have induced immunoglobulin synthesis, resulting in the formation of these complexes followed by deposition in vessel walls and subsequent necrotizing vasculitis. Possible alternative mechanisms include the presence of anti-T cell antibodies, or cytotoxic effector cells.     

The severity of histopathological changes of leukocytoclastic vasculitis is not predictive of extracutaneous involvement

Leukocytoclastic vasculitis is defined by histologic features and can be observed in a wide range of entities. Independent of the causative disease, extracutaneous complications are frequent, mainly in the kidneys and gastrointestinal tract. It has been suggested that the severity of histological changes could correlate with the clinical course of the disease. We have therefore compared the severity of histological changes of leukocytoclastic vasculitis to clinical and laboratory findings indicative of extracutaneous involvement in a large group of patients. Among 289 patients followed for cutaneous vasculitis, we included 184 patients with purpuric papules and proven leukocytoclastic vasculitis who all had standardized investigations. A cutaneous biopsy was performed early and standardized laboratory investigations were carried out. The slides were retrospectively randomized and the depth of vasculitis and severity of vascular necrosis were determined according to a semiquantitative scale. These data were compared to the renal, gastrointestinal and articular symptoms using Fischer's exact test, Chi-square test and variance analysis. The intensity of vascular necrosis and the depth of vasculitis were no more severe in patients having renal changes, gastrointestinal involvement or articular symptoms. Both variance analysis and Chi-square tests failed to show a significant increase in the severity score in patients having extracutaneous complications. In this study, the severity of histopathological changes was not predictive of extracutaneous involvement. Thus it appears that the degree of involvement of the cutaneous vessels probably does not correlate with that of vessels in visceral organs.     

Cutaneous vasculitis update: small vessel neutrophilic vasculitis syndromes

A broad and diverse spectrum of vasculitic syndromes exists. These syndromes affect the skin with varying levels of associated systemic manifestations, running the gamut from a self-limited, localized, cutaneous phenomenon to rapidly progressive, multiorgan disease. The majority of cases of cutaneous vasculitis will show a neutrophilic small vessel vasculitis that can be either a primary (idiopathic) disorder (eg, cutaneous leukocytoclastic angiitis) or a secondary disorder that is associated with drugs, infection (eg, streptococcal infection, viral hepatitis), or underlying disease (eg, connective tissue disease, malignancy). Biopsy is the gold standard for the diagnosis of cutaneous vasculitis and also necessary for the detection of cutaneous vascular immune complexes by direct immunofluorescence. Based on the type of vessel disrupted by inflammation (small and/or muscular), the distribution of vasculitis in the dermis and subcutis, and predominate inflammatory cell-type mediating vessel wall damage, a list of relevant differential diagnoses can be generated. This histologic information coupled with extravascular findings such as tissue eosinophilia, tissue neutrophilia, and/or granulomas, plus pathophysiologic markers such as direct immunofluorescent examination for immune complexes and serologic evaluation for antineutrophil cytoplasmic antibodies allows for more accurate diagnosis of specific vasculitic entities. Herein, we review both primary and secondary vasculitic syndromes that affect the skin and show a small vessel neutrophilic mediated vasculitis.     

Cutaneous necrotizing venulitis.

The term vasculitis describes a variety of inflammatory changes in vessels. The most common type to affect the skin is a necrotizing venulitis associated with a neutrophilic polymorphonuclear leukocyte infiltrate. The most frequent presentation is palpable purpura on the lower extremities, but the lesions may include urticaria and ulcers. A diagnosis of cutaneous necrotizing venulitis obliges the physician to search for the cause, associated diseases, and the extent of the vascular involvement. Antigens, either in circulating immune complexes or as haptens bound to vessel proteins, are presumed to trigger immmune responses. The differentiation of large from small vessel disease and the prediction of systemic involvement may be difficult in a specific patient. Treatment, other than removal of the antigen, is theoretic or anecdotal.     

Cutaneous vasculitis

Vasculitis can range in severity from a self-limited single-organ disorder to a life-threatening disease with the prospect of multiple-organ failure. This condition presents many challenges to the physician, including classification and diagnosis, appropriate laboratory workup, treatment, and the need for careful follow-up. The physician must not only be able to recognize vasculitis but also be able to provide a specific diagnosis (if possible) as well as recognize and treat any underlying etiologic condition. Most diagnostic criteria are based on the size of vessel involvement, which often correlates with specific dermatologic findings. This may allow the dermatologist to provide an initial diagnosis and direct the medical evaluation. This article reviews the classification and diagnosis of cutaneous vasculitic syndromes and current treatment options; it also presents a comprehensive approach to diagnosing and treating the patient with suspected cutaneous vasculitis. (J Am Acad Dermatol 2003;48:311-40.) LEARNING OBJECTIVE: At the completion of this learning activity, participants should be familiar with the classification and clinical features of the various forms of cutaneous vasculitis. They should also have a rational approach to diagnosing and treating a patient with vasculitis.     

Cutaneous vasculitis and cutaneous vasculopathies

Cutaneous involvement may occur with virtually all syndromes of vasculitis. This can occur primarily as a dermatologic disorder or as a manifestation of a potentially life threatening systemic vasculitis. In this review article, classification, clinical manifestations, pathogenesis and therapy of cutaneous vasculitis will be discussed. Disorders which are primarily vascular in origin but lack a well defined inflammatory phase, referred to as ‘vasculopathies’ will also be discussed.     

Urticarial vasculitis

The vasculitides are a heterogeneous group of disorders characterized by inflammation and necrosis of blood vessels. They have been classified into several major groups on the basis of the size and type of vessels affected and the type of inflammation. Urticarial vasculitis is a recently recognized but relatively common presentation of cutaneous necrotizing vasculitis. This article discusses its clinical, pathologic, and immunologic features, its association with other disease states, and its differentiation from nonvasculitic urticaria.     

Initial cutaneous manifestations associated with histopathological leukocytoclastic vasculitis in two patients with antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome (APS) is a multisystem disorder associated with a variety of circulating autoantibodies that target different phospholipid protein complexes. APS is sometimes lethal as a result of severe sequelae, which may be primary or secondary to the underlying disease. We report two women who presented histopathologically with leukocytoclastic vasculitis as the first cutaneous manifestation and were subsequently diagnosed with APS associated with systemic lupus erythematosus (SLE). Patient 1 presented with widespread cutaneous necrosis (WCN) with rapidly spreading pain down the lower extremities. Skin biopsy specimens from her leg purpura and WCN revealed perivascular infiltrates with neutrophils consistent with leukocytoclastic vasculitis and thromboses of small-sized dermal vessels. Patient 2 exhibited livedo reticularis, painful cutaneous nodules with necrosis, ulcer, and erythematous macules on her lower extremities, shoulder, and face. Skin biopsies of her right knee showed intravascular thrombosis of small dermal vessels and infiltration of perivascular tissues with necrotizing granulomatous vasculitis in the dermis. We found that these various cutaneous manifestations with leukocytoclastic vasculitis were present at an early stage of APS. Although progression to leukocytoclastic vasculitis in patients with APS is uncommon, our data suggest that the association between microvascular occlusions and cutaneous vessel vasculitis has a predictive value for the pathogenesis. It is important for dermatologists to recognize these cutaneous signs to permit early and accurate diagnosis and treatment.     

Clinical classification of vasculitis

Clinical classification of vasculitis is needed to facilitate diagnosis and management of the disease as well as to assign patients to defined groups for clinical studies. Caliber and size of the vessels predominantly involved strongly influence the clinical features of the different forms of vasculitis and therefore are one major criterion for classification. As such, panarteritis nodosa involves medium-sized vessels and presents on the skin with subcutaneous nodules and livedo racemosa, while it does not cause glomerulonephritis. Leukocytoclastic vasculitis (LcV) involves the small vessels, resulting in palpable purpura, and sometimes also in glomerulonephritis. The classification systems of the American College of Rheumatology (ACR) and of the Chapel Hill Consensus Conference (CHCC) have gained wide acceptance. Yet, they need to be updated, especially with regard to LcV, the most common vasculitis of the skin. Here distinctions must be made for prognostic, diagnostic and therapeutic reasons between IgG/IgM- and IgA-associated LcV (Henoch-Schoenlein purpura, HSP), as well as between HSP of children and HSP of adult age. The latter bears the highest, while IgG/IgM-associated LcV bears the lowest risk for complications. This update on the clinical classification of vaculitis is based on the ACR and CHCC system and focuses on those forms which regularly cause cutaneous symptoms. It provides a survey on the vasculitic syndromes and should help in deciding when i) extensive diagnostic procedures are needed in patients with LcV, ii) therapy should be less or more aggressive, e.g. in cutaneous versus systemic PAN, iii) therapy should be promptly initiated, e.g. when any form of severe, ANCA-associated vasculitis is suspected.     

A case of Churg-Strauss syndrome associated with antiphospholipid antibodies

Churg-Strauss syndrome (CSS) is a systemic vasculitis affecting both small- and medium-sized blood vessels, almost invariably affecting the lung, and frequently associated with cutaneous involvement. Microvascular vaso-occlusion leading to digital gangrene is not a feature of CSS. We report an unusual case of a patient with CSS with antiphospholipid antibodies who developed severe digital gangrene in addition to cutaneous vasculitis. The presence of antiphospholipid antibodies is not a feature usually seen in association with CSS. While the full clinical spectrum of CSS is still being defined, the identification of additional features associated with this syndrome might help to better understand the pathogenesis of the disease and to have an impact on both management and prognosis.     

A Practical Approach to the Diagnosis,Evaluation, and Management of Cutaneous Small-Vessel Vasculitis

Cutaneous small-vessel vasculitis (CSVV) is a disorder characterized by neutrophilic inflammation predominantly limited to the superficial cutaneous postcapillary venules. CSVV may be idiopathic or may have a defined cause such as infection, medication, connective tissue disease, or malignancy. CSVV may also be associated with extracutaneous disease or systemic vasculitis. The most common clinical presentation of CSVV consists of symmetrically distributed palpable purpura of the lower extremities. In general, lesional skin biopsy samples should be examined with light microscopy and direct immunofluorescence for adult patients with suspected CSVV. A complete history, review of systems, physical examination, and selected laboratory studies also should be performed to assess for inciting causes or extracutaneous involvement of CSVV. Treatment varies and depends on the chronicity of CSVV, the severity of cutaneous involvement, and the presence or absence of both an underlying cause and extracutaneous involvement of CSVV. An isolated episode of CSVV associated with a known inciting factor may be managed by removal or treatment of the trigger, along with symptomatic measures. First-line systemic treatments for chronic, idiopathic CSVV include colchicine or dapsone, used singly or in combination. Recurrent, chronic, or severely symptomatic CSVV that does not respond to the aforementioned therapies may require initiation of an immunosuppressive agent such as azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, or rituximab.