Urticarial Vasculitis with Papular Lesions in a Patient with Type C Hepatitis and Cryoglobulinemia

We describe a case of urticarial vasculitis accompanied by erythematous wheals, palpable pupura, and subsequent necrotic ulcerated papular lesions in a patient with type C chronic hepatitis and type II cryoglobulinemia (IgM-kappa and polyclonal IgG). A 56-year-old man developed recurrent urticarial lesions on his lower extremities and trunk. The histology revealed leukocytoclastic vasculitis with perivascular immunoglobulin deposits. Subsequently, multiple reddish papular lesions with necrotic ulcerations appeared on the extensor aspect of his extremities and buttocks. Histology of these lesions showed cryoglobulinemic vasculitis with prominent fibrinoid necrosis of the vascular walls and cryoprecipitate within the vasculature as well as increased hyalinized collagen bundles. These papular lesions have not previously been described as cutaneous necrotizing venulitis to the best of our knowledge. It is suggested that the immune response to hepatitis C virus infection and cryoglobulins may be responsible for severe necrotizing venulitis, resulting in unusual cutaneous lesions.     

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.     

Erythema elevatum diutinum in a patient with acquired immunodeficiency syndrome. Another clinical simulator of Kaposi's sarcoma.

Several types of vasculitis have been described in patients with human immunodeficiency virus infection. Erythema elevatum diutinum is a rare variant of cutaneous leukocytoclastic vasculitis which, with the exception of the case reported herein, has been described only once in human immunodeficiency virus-infected patients. Our male patient, a longtime intravenous drug abuser, had cutaneous lesions, closely resembling Kaposi's sarcoma, on the extensor surfaces of the lower extremities. Cutaneous biopsy specimens, however, demonstrated leukocytoclastic vasculitis with fibrinoid necrosis of the vessel walls and areas of basophilic degeneration of collagen bundles in early lesions, whereas late lesions showed dense diffuse fibrosis with proliferation of dermal spindle cells and some foci of residual leukocytoclastic vasculitis. Oral therapy with dapsone resulted in marked clearing of the cutaneous lesions within few days. This case raises the necessity of histologic confirmation for all cases of suspected Kaposi's sarcoma in patients with acquired immunodeficiency syndrome. We discuss the possible pathogenesis of leukocytoclastic vasculitis in human immunodeficiency virus-infected patients.     

Dermatologic perivascular hemophagocytosis: a report of two cases

Hemophagocytic syndrome includes fever, hepatosplenomegaly, cytopenias, coagulopathy, and abnormal liver function tests, with some patients developing lymphadenopathy and cutaneous eruptions. Herein we report two cases of dermal perivascular hemophagocytosis identified in skin biopsies of two patients with no additional symptoms attributable to hemophagocytic syndrome. Biopsies showed capillary ectasia with dermal perivascular infiltrates. The overlying epidermis and adjacent subcutaneous fat was unremarkable. The infiltrate consisted of perivascular neutrophils and benign histiocytes with predominately phagocytized erythrocytes and occasional engulfed karyorrhectic debris. Perivascular nuclear dust (leukocytoclasia) and extravasated erythrocytes were present, but other factors typically found in leukocytoclastic vasculitis were absent, namely fibrin deposition and endothelial hypertrophy and/or necrosis. This appears to be hemophagocytosis, possibly associated with late lesions of leukocytoclastic vasculitis. Both hemophagocytosis and leukocytoclastic vasculitis are associated with activated immunity with increased cytokines and/or immune complexes. It is important to consider this uncommon finding in the evaluation of indeterminate cutaneous eruptions.     

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.     

Acute hemorrhagic edema of infancy: a case report

A 12-month-old male presented with edematous purpuric plaques on the extremities (including the palms and soles), and violaceous targetoid macules on the hard palate and earlobes. The patient had an upper respiratory infection and conjunctivitis 10 days prior to the development of the skin lesions, and was vaccinated 3 weeks before this presentation. He was found to have increased IgA levels and increased ESR. Skin biopsies demonstrated leukocytoclastic vasculitis and IgA granular deposition on superficial dermal vessels. These findings are characteristic of acute hemorrhagic edema of infancy, an entity that must be distinguished from other leukocytoclastic vasculitis, especially Henoch-Sch?nlein purpura.     

IgD immune complex vasculitis in a patient with hyperimmunoglobulinemia D and periodic fever

We describe a 27-year-old Dutch woman with the hyperimmunoglobulinemia D and periodic fever syndrome. During febrile attacks she occasionally presented with skin lesions on the distal parts of her upper and lower extremities, with the histologic picture of a leukocytoclastic vasculitis. Clear perivascular deposits of IgD and C3 were presented in early lesional skin on immunofluorescence investigation. Circulating IgD immune complexes were demonstrated on several occasions, both during and in between clinical attacks. These findings are consistent with an IgD immune complex-mediated pathogenesis for the skin lesions. In 10 patients with other forms of immune complex vasculitis of the skin, minimal perivascular deposits of IgD were found in four cases. In these cases, however, IgD was never found as the solitary immunoglobulin class.     

Recurrent Cutaneous Vascuiitis in Cystic Fibrosis

We treated a patient with cystic fibrosis who experienced recurrent episodes of palpable purpura and arthralgias associated with exacerbations of her pulmonary disease. Skin biopsy demonstrated the classic findings of leukocytoclastic vasculitis, and C3 deposits were detected in the dermal blood vessels. Chronic bacterial infection and antibiotics are possible sources of antigen involved in immune complex formation in patients with chronic lung diseases.     

Lucio phenomenon mimicking antiphospholipid syndrome: The occurrence of antiphospholipid antibodies in a leprosy patient

Lucio phenomenon is an atypical reaction of leprosy, characterized by vasculitic lesions that can mimic antiphospholipid syndrome (APS) clinically. Distinguishing the two can be difficult as antiphospholipid autoantibodies may be present in patients with leprosy. We report on a 32‐year‐old female patient presenting with a sudden onset of fever, hemorrhagic bullae, and skin necrosis on her lower legs. She was treated for APS due to the presence of antiphospholipid antibodies but had an inadequate response. A skin biopsy revealed thrombotic vasculopathy and necrotizing vasculitis associated with aggregation of foam cells in the perivascular area and subcutis, with acid‐fast bacilli in the histiocytes and blood vessel walls. Direct immunofluorescence showed IgM, C3, and fibrinogen deposition in the superficial and deep dermal blood vessels. The pathology confirmed the diagnosis of Lucio phenomenon, and appropriate therapy was given. It is essential to evaluate the patient comprehensively, including clinical, serological, and pathological aspects, to obtain the correct diagnosis.     

Hypereosinophilic syndrome presenting as cutaneous necrotizing eosinophilic vasculitis and Raynaud's phenomenon complicated by digital gangrene

Cutaneous necrotizing eosinophilic vasculitis is a recently identified type of vasculitis that is characterized by an eosinophil-predominant necrotizing vasculitis affecting small dermal vessels. Clinically, it presents with pruritic erythematous and purpuric papules and plaques, peripheral eosinophilia and a good response to systemic steroid therapy. This vasculitis can be idiopathic or associated with connective tissue diseases. Although the pathogenic roles of eosinophil-derived granule proteins and interleukins have been documented in diseases associated with eosinophilia, a role of CD40 (a glycoprotein of the tumour necrosis factor receptor superfamily) has rarely been described. We describe two patients with idiopathic hypereosinophilic syndrome (HES) presenting with multiple erythematous patches and plaques on the lower extremities and Raynaud's phenomenon. They satisfied the criteria for the diagnosis of HES by clinical and laboratory investigations. Histopathology of the cutaneous lesions revealed prominent eosinophilic infiltration with local fibrinoid change in vessel walls in the dermis and subcutis. Immunohistochemical detection of CD3, CD4, CD8 and CD40 was performed. Infiltrating eosinophils were strongly stained by anti-CD40 monoclonal antibody. One patient improved with prednisolone, pentoxifylline and nifedipine, without recurrence. The other patient initially improved with steroids, but after self-withdrawal of steroid developed digital ischaemia that evolved to severe necrosis and required amputation. Cutaneous necrotizing eosinophilic vasculitis, Raynaud's phenomenon and digital gangrene may develop as cutaneous manifestations of HES. CD40 may play a part in the pathogenesis of eosinophilic vasculitis in HES.     

A Case of Cutaneous Leukocytoclastic Vasculitis Associated with Granulocyte Colony-Stimulating Factor: An Unusual Presentation

Drug-induced vasculitis is an inflammation of small-sized blood vessel caused by the use of drugs. It accounts for approximately 10% of acute cutaneous vasculitis. Propylthiouracil, hydralazine, and allopurinol have been widely known as causative agents. The most common clinical feature of drug-induced vasculitis is palpable purpura on lower extremities. A 66-year-old Korean female presented with erythematous nodules on upper chest and back. She had been on medication for multiple myeloma. Laboratory results showed neutropenia. After a single injection of filgrastim (recombinant granulocyte colony-stimulating factor), she developed cutaneous lesions with concurrent increase in absolute neutrophil count. A skin biopsy revealed leukocytoclastic vasculitis. After discontinuation of filgrastim injection, her skin lesions disappeared spontaneously.     

Annular lesions of cutaneous sarcoidosis with granulomatous vasculitis

Sarcoidosis is known to be involved in diseases with vasculitis as sarcoid vasculitis. However, vasculitis in cutaneous sarcoidal lesions is extremely rare. Here we describe a case of sarcoidosis with multiple annular skin lesions with granulomatous vasculitis. A 62‐year‐old female was diagnosed with sarcoidosis by chest‐abdominal computed tomographic examination and laboratory tests. The skin lesions had appeared on her lower limbs 2 years before. Physical examination showed multiple infiltrated annular eruptions on the lower extremities. A skin biopsy of an area of erythema showed multiple non‐caseating epithelioid cell granulomas in the dermis and subcutaneous fat and granulomatous vasculitis with fibrinoid degeneration in the subcutaneous fat. There are two types of vasculitis in sarcoidosis: leukocytoclastic and granulomatous vasculitis. Ulcers and livedo were more common in granulomatous vasculitis than in leukocytoclastic vasculitis. The present case had unique annular skin lesions of sarcoidosis with granulomatous vasculitis.     

Eritema elevatum et diutinum con afectación palmar y asociación con p-ANCA

—Erythema elevatum et diutinum is a distinctive benign chronic localized form of cutaneous leukocytoclastic vasculitis which results in patterned concentric fibrosis and secondary deposition of lipid material. Its cause is unknown but it is presumed to be related to vascular immune complex deposition. Associated medical problems include hematologic diseases, most frequently IgA monoclonal gammopathy.A 24 year-old female presented with multiple symmetrically distributed reddish brown papules and plaques located predominantly over the extensor aspects of the extremities, specially near the joints. Examination revealed also multiple elastic-hard raised plaques involving thoroughly her palms. A biopsy taken from a recent lesion revealed a neutrophilic infiltrate and nuclear dust around the dermal vessels, with leucocytoclastic vasculitis. Screening for internal disease showed no abnormal findings except for p-ANCA positive test (anti-MPO). Treatment with dapsone 100 mg daily led to a dramatic clinical response.We describe an example of erythema elevatum et diutinum which had an unusual distribution involving the palms, a circumstance scarcely reported so far. We discuss also the possible significance of the associated p-ANCA positive test.     

Classification of urticaria and the reactive inflammatory vascular dermatoses

The common feature of all the conditions discussed in this article is that they are inflammatory vascular dermatoses that may occur as reactive processes in association with other diseases. The histopathologic characteristics of the lesions range from mild, perivascular dermal infiltration with inflammatory cells and vasodilation to various degrees of vessel damage (endothelial swelling to fibrinoid necrosis). The vessel damage is reflected in varying degrees of secondary changes including extravasation of edema fluid, extravasation of erythrocytes, epidermal necrosis, separation of the dermal-epidermal junction zone, and widespread tissue necrosis. The etiology of most of these conditions is still unknown, although strong evidence indicates that type III (circulating immune-complex-mediated) pathogenesis may be responsible for necrotizing venulitis (leukocytoclastic vasculitis) and that a type I (IgE-mediated) pathogenesis may be involved in some types of urticaria. For many of the reactions described, the patients have serum sickness-like systemic signs and symptoms in addition to cutaneous lesions, and a circulating immune-complex-mediated pathogenesis has been considered. Future investigations must address the types of antigens and antibodies present in the circulating immune complexes, the detection of specific antigen in cutaneous blood vessels, the reproduction of lesions in experimental animals, and the mechanisms responsible for the spectrum of clinicopathologic lesions produced, with special attention to the possibility that vessel damage results from circulating immune complex-induced lymphocytic rather than only leukocytoclastic vasculitis.     

A case of exemestane induced pseudocellulitis

Exemestane is an aromatase inhibitor increasingly incorporated into the treatment of hormone sensitive breast cancer. Pseudocellulitis describes an uncomplicated inflammation of the dermis and hypodermis from a noninfectious etiology. It presents with erythema, swelling, warmth and tenderness of the affected skin. We report a case of a 47‐year‐old Indian woman who presented with 2‐day history of redness and swelling of her left lower limb. There were no other symptoms. She was recently switched from tamoxifen to aromasin as adjuvant treatment for her breast cancer. Examination revealed erythema, edema, and warmth over the left lower limb. Laboratory investigations and doppler ultrasound scan were unremarkable. Skin punch biopsy showed dermal inflammatory infiltrate composed of lymphocytes, histiocytes and scattered eosinophils and neutrophils, concentrated in the superficial and deep perivascular regions suggestive of a leukocytoclastic vasculitis. The diagnosis of exemestane induced leukocytoclastic vasculitis presenting as pseudocellulitis was made. She was given a course of systemic and topical steroids with completere solution of lesion within 2 weeks. This is the first reported case of exemestane induced pseudocellulitis to our knowledge. Dermatologists and clinicians should be aware of this peculiar adverse drug reaction to avoid misdiagnosis and prevent unnecessary treatment.     

Immunoglobulin A-associated lymphocytic vasculopathy: a clinicopathologic study of eight patients

Introduction: Cutaneous IgA‐associated vasculitis can be a clue to Henoch–Schönlein purpura (HSP), which typically comprises renal and gastrointestinal tract disease and arthritis, whereby prominent and predominant IgA deposits within the cutaneous vasculature provoke a pustular leukocytoclastic vasculitis. Design: We describe eight patients with a novel expression of a cutaneous IgA vascular injury syndrome, namely a lymphoid vasculopathy which clinically and light microscopically resembled a pigmentary purpura (PP) in six, and correlate direct immunofluorescence (DIF) and clinical features to light microscopy. Results: Among associated diseases were prior viral infection, an HSP symptom complex, an undifferentiated connective tissue disease syndrome, lupus erythematosus profundus (LEP), Degos' disease and Berger's disease. Skin lesions comprised non‐palpable petechial lesions involving lower extremities in all cases and also the upper extremities in two. A superficial perivascular lymphocytic infiltrate unaccompanied by vascular fibrin deposits was associated with prominent erythrocyte extravasation including into the epidermis. Mural and extravascular fibrin deposition was seen in one biopsy from a PP‐like lesion and mural fibrinoid necrosis was seen in the cases of LEP and Degos' disease; in biopsies from these three cases, the presence of fibrin deposition warranted use of the appellation ‘lymphocytic vasculitis’. In all patients, DIF showed prominent and predominant IgA deposits. Conclusions: A non‐necrotizing lymphocytic purpuric vascular reaction is one manifestation of vascular IgA deposition in the skin. A subpopulation of human lymphocytes bear surface Fc receptor and/or C3 receptors (‘complement receptor lymphocytes’) which can bind circulating immune complexes (ICs) or C3 generated via activation of the alternative complement cascade. Thus, circulating ICs are a potential pathogenic basis of this eruption, the histologic differential diagnosis of which is idiopathic PP and PP of drug or viral etiology.     

Sj?gren's syndrome. Association of cutaneous vasculitis with central nervous system disease

We describe a group of patients with Sj?gren's syndrome, who commonly present to dermatologists with cutaneous manifestations of vasculitis. Two specific clinically recognizable forms of cutaneous vasculitis predominate: palpable purpura of the lower extremities (Waldenstr?m's benign hypergammaglobulinemic purpura) and urticarialike vasculitis. Two pathologic types of cutaneous vasculopathy are demonstrated, one leukocytoclastic and the other mononuclear. The leukocytoclastic vasculopathy is associated with high titers of Ro(SS-A) and La(SS-B) autoantibodies (detected by gel double-diffusion techniques) and general serohyperreactivity. In marked contrast, the mononuclear vasculopathy is associated with low titers of Ro(SS-A) and La(SS-B) autoantibodies (detected by enzyme-linked immunosorbent assay but not gel double-diffusion techniques) and general serohyporeactivity. Approximately 70% of patients with Sj?gren's syndrome and cutaneous vasculitis have also developed peripheral and/or central nervous system disease. The pathogenesis of the nervous system disease is unknown, but preliminary data suggest a vasculopathy.     

Nodular vasculitis in systemic lupus erythematosus

A 42-year-old man presented with fever, photosensitivity, headaches, myalgia, hyperhidrosis, muscle weakness, alopecia, nasal crustae, weight loss, painful nails, arthritis, oral ulcers, erythema, discoid cutaneous lesions, and painful subcutaneous nodes. We made a diagnosis of systemic lupus erythematosus (SLE), type II cryoglobulinemia, and nodular vasculitis. In the skin, different types of vasculitis may be observed. Typically, histology shows leukocytoclastic vasculitis of superficial vessels both in SLE and mixed cryoglobulinemia, which clinically results in palpable purpura. In our patient, however, histopathological examination of the subcutaneous nodes not only revealed leukocytoclastic vasculitis of the superficial vasculature but also showed even more extensive involvement of dermal and subdermal small and medium sized vessels, giving rise to a nodular vasculitis.     

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 macroglobulinosis: a case series

Cutaneous macroglobulinosis is a rare skin manifestation of Waldenstrom macroglobulinemia. It is characterized by the deposition of eosinophilic, immunoglobulin-derived material in the dermis. It typically presents as pink or skin-colored papules favoring the extensor surfaces of the extremities. There are 11 reported cases of cutaneous macroglobulinosis in the literature. In our consultative dermatopathology practice we encountered three additional cases. In Case 1, a 41-year-old female with a monoclonal immunoglobulin M (IgM)-kappa gammopathy developed skin-colored papules on her extensor extremities, forehead and back. Histopathologic and immunohistochemical analyses revealed periodic acid-Schiff (PAS)-positive pink material in the dermis that stained with IgM. In Case 2, an 83-year-old female with a monoclonal IgM-lambda paraproteinemia developed non-blanching papules and plaques on the lower extremities and cheeks. Skin biopsies showed a striking occlusion of the vessels with a PAS-positive eosinophilic precipitate, which was also found in the extravascular spaces and stained with IgM using direct immunofluorescence (DIF) and immunohistochemical stains. In Case 3, an 80-year-old male with Waldenstrom macroglobulinemia developed ulcerated papules and nodules on the lower extremities. The biopsy findings were similar to those of Case 2. We present a series of three patients with cutaneous macroglobulinosis and explore variations in the clinical and histopathological findings of this uncommon entity.