Vasculitis and Related Disorders

Vasculitis and Related Disorders

Erythema Elevatum Diutinum: A Clinicopathological Study of Eight Cases

Introduction.—A rare chronic skin disease characterized by persistent red-purple to yellow papules, plaques, and nodules, erythema elevatum diutinum affects the acral surfaces of the body, especially the extensor surfaces of the hands. Typical histopathologic characteristics include leukocytoclatic vasculitis with polymorphonuclear neutrophils, nuclear dust, extravasated red cells, and fibrin deposits in the walls of the small arterioles. Also, other histologic features resembling dermatofibroma, dermatitis herpetiformis, granuloma faciale, and granuloma annulare are occasionally seen.

Vasculitis and Related Disorders

Methods.—The clinical records as well as 13 skin biopsy specimens of 8 patients with erythema elevatum diutinum were reviewed.

Results.—Concurrent pityriasis rubra pilaris was seen in 1 of the patients. Another patient had erythema elevatum diutinum after and at the sites of mosquito bites. These associations have not been reported previously. Two unusual patterns were found besides the typical histopathologic features of diffuse dermal involvement by eosinophils, neutrophils, and leukocytoclastic vasculitis: (1) palisaded necrotizing granulomas associated with Churg-Strauss granuloma, and (2) pyogenic granuloma-like lesions.

Conclusions.—With time, the most prominent finding is fibrosis. Diseases that have been associated with erythema elevatum diutinum include recurrent bacterial infections, polycythemia vera, collagen vascular diseases, hairy cell leukemia, myelodysplastic syndrome, mixed cryoglobulins, IgA gammopathy, and HIV infection.

► This description of 8 cases of erythema elevatum diutinum with a review of the literature is accompanied by some well-done photomicrographs. The authors also describe unusual histopathologic features found in several patients. This article is worth keeping in your files to reference the next time you think a patient might have this condition.

The Role of Cytokines in Henoch Schonlein Purpura

Introduction.—Acute inflammation in patients with Henoch Schonlein purpura (HSP) manifests as a leukocytoclastic vasculitis on light microscopy. The proinflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-a) are probably involved in the pathogenesis of the disease. Potential correlations between disease activity and serum TNF-α and IL-1 levels were assessed in 20 children with a clinical diagnosis of HSP.

Methods.—Skin biopsies of cutaneous vasculitis lesions and healthy skin were taken during the acute disease phase and after remission. Biopsy specimens were immunostained for TNF, IL-1, and IL-6. Also measured were erythrocyte sedimentation rate (ESR), C-reactive protein, immunoglobulins, complement (C) 3 and 4 levels, TNF-α, and IL-1. Urinalysis was done in all patients. For patients with renal involvement, renal function tests, quantitative proteinuria, and creatinine clearance were performed.

Results.—Mean patient age was 9.8 years. The mean serum TNF level during the acute phase was 14.0 pg/mL. In the acute phase, it was 6.8 pg/mL. The serum TNF levels in patients with renal involvement were significantly higher compared to those of patients without renal involvement . Serum IL-1 levels were undectable during the acute phase and remission. Leukocytoclastic vasculitis was observed in all biopsy specimens. Immunohistochemical studies showed TNF and less intense IL-1 and IL-6 staining in the nucleated epidermal layer, with a granular, intracellular pattern. The affected skin during the acute phase showed significantly increased staining.

Conclusion.—Significant increases for TNF-α and IL-1 β were observed in skin biopsy specimens taken from patients with HSP. These findings were similar in patients with and without renal involvement. Staining was significantly different during the remission and acute phases.

► Besbas et al. studied the levels of TNF-α , IL-1, and IL-6 in the serum and skin of patients with HSP, and demonstrated that levels of TNF in the serum and skin correlated with disease activity. They also demonstrated a direct correlation between elevated serum TNF levels and renal disease. The cutaneous expression of IL-1 and IL-6 was increased within lesional skin during the acute phase of HSP. Presumably, TNF-α and IL-1 could mediate disease by altering the expression of cell adhesion molecules such as endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, eventuating in the clinical picture of vasculitis.

Cutaneous Vasculitis in Behcet’s Disease: A Clinical and Histopathologic Study of 20 Patients

Background.—Although small vessel vasculitis is frequent in skin lesions of Behcet’s disease (BD), BD is considered a neutrophilic dermatosis. Whether the various cutaneous manifestations of BD are secondary to cutaneous vasculitis was determined.

Methods.—Forty-eight skin biopsy specimens collected between 1980 and 1995 from 42 patients with BD were reviewed. Twenty-three specimens with histologically proven necrotizing vasculitis from 20 of these patients were further examined.

Findings.—The cutaneous vasculitic manifestations appeared as erythema nodosum-like eruptions, palpable purpura, hemorrhagic blisters, infiltrated erythema, Sweet’s syndrome-like eruptions, papulopustular lesions, and extragenital ulcerations. It was common for a patient to have combinations of various skin lesions. Venous vessels were affected in the entire dermis to the subcutis, but there was sparing of arterial vessels from the middermis to the subcutis. Histologically, leukocytoclastic vasculitis was seen in 7 patients, and lymphocytic vasculitis was seen in 13; extensive to focally localized fibrinoid necrosis of vessel walls was present.

Conclusions.—Cutaneous vasculitis associated with BD is mainly venulitis or phlebitis. In the current series, 48% of patients with BD and cutaneous lesions had lymphocytic or leukocytoclastic vasculitis. Behcet’s disease should be considered a vasculitis-associated disease separate from the neutrophilic dermatoses.

► Chen et al. provide additional data to justify the inclusion of BD in the category of vasculitis. In evaluating a number of different lesions from patients with BD, they are able to show evidence of leukocytoclastic or lymphocytic vasculitis in almost half of the lesions. Unfortunately, the heterogeneity of the clinical lesions, and the findings of what some believe are different immunologically based types of vasculitis reinforces our lack of understanding of this disease. This article, like many others that describe BD, highlights the findings but does not help clarify its etiology.

Cutaneous Manifestations of Churg-Strauss Syndrome: A Clinicopathologic Correlation

Background.—Churg-Strauss syndrome, a multisystem vasculitis seen in patients with asthma and eosinophilia, is a distinct clinical entity. The clinical and histologic features of the cutaneous findings in affected patients were reported.

Methods and Findings.—All 90 patients diagnosed as having Churg- Strauss syndrome at the Mayo Clinic between 1976 and 1995 were included in the review. Forty percent had cutaneous findings. Six percent had skin lesions as the initial manifestation. Cutaneous findings most often documented were purpura and petechiae on the lower extremities and cutaneous nodules and papules on the elbows. The most common findings in 37 biopsy specimens from 29 patients were extravascular necrotizing granulomata and leukocytoclastic vasculitis.

Conclusions.—Cutaneous lesions are common in patients with Churg- Strauss syndrome. These lesions have a characteristic clinical and histologic pattern that may help establish the diagnosis.

► This study describes the cutaneous manifestations in a cohort of 90 patients with Churg-Strauss syndrome. Skin problems occurred in 40%; biopsy specimens most commonly demonstrated leukocytoclastic vasculitis and extravascular necrotizing granulomas. The authors emphasize the overlap in clinical and histologic features between Wegener’s granulomatosis and Churg-Strauss syndrome.

Idiopathic Perniosis and Its Mimics: A Clinical and Histological Study of 38 Cases

Background.—The histopathology of perniosis is described as a lymphocytic vascular reaction with variable papillary dermal edema. It has been suggested that it originates as an abnormal response to cold, with resulting ischemia of vessel walls. Systemic lupus erythematosus, Behcet’s disease, and other connective tissue diseases may cause acral perniotic lesions that mimic perniosis.

Methods.—Skin biopsy specimens from 38 patients with acral purpuric lesions were examined. The 39 lesions were diagnosed clinically or pathologically as perniosis.

Findings.—In 17 patients, a systemic or extracutaneous disease was established, including systemic lupus erythematosus, antiphospholipid antibodies, viral hepatitis, rheumatoid arthritis, cryofibrinogenemia, hyper-gammaglobulinemia, iritis, and Crohn’s disease. In 12 of the other 21 patients, further studies were done, and a positive antinuclear antibody was detected in 10. In those 21 patients, idiopathic perniosis was diagnosed on the basis of the absence of other serologic markers or signs of a specific systemic disease. Many of those patients had Raynaud’s phenomenon, small joint arthralgia, atopy, or a family history of connective tissue disease or Raynaud’s disease. Histopathology showed a superficial and deep angiocentric lymphocytic infiltrate with papillary dermal edema and lymphocytic exocytosis into the retia and acrosyringia.

In a few cases, a mild vacuolopathic or lichenoid interface dermatitis, adventitial dermal mucinosis, lymphocytic eccrine hidradenitis, vascular ectasia, and thrombosis of dermal papillary capillaries were seen. In patients with iritis, rheumatoid arthritis, or Crohn’s disease, biopsy specimens showed a granulomatous vasculitis and a granuloma annulare-like tissue reaction. In patients with systemic lupus erythematosus, cryofibrinogenemia, antiphospholipid antibodies, or hypergammaglobulinemia, biopsy specimens showed an interface dermatitis, superficial and deep angiocentric and eccrinotropic lymphocytic infiltrates, vascular ectasia, and dermal mucinosis with prominent involvement of the eccrine coil.

Discussion.—Many of these patients did not have features of idiopathic perniosis, for example, those with papillary dermal edema, thrombosis of dermal papillary capillaries, and lymphocytic exocytosis into the retia and acrosyringia. Vascular fibrin deposition involving reticular dermal vessels was seen; it was a significant discriminator of idiopathic perniosis and perniotic lesions with underlying systemic disease. Some of the latter cases were associated with cold exposure and were designated secondary perniosis; other cases were not associated with cold exposure and were designated perniotic mimics based on gross and microscopic morphologic characteristics of the lesions.

► Perniosis is common in the humid climate of northwest Europe and we have occasionally observed such patients during our cool, wet winters here in the southeastern part of the United States. Warming of the affected area often causes dramatic improvement. Lesions may include inflammatory red to purple macules, nodules, papules, or plaques, and may be accompanied by overlying blisters, erosions, or ulcers. An acral location is common. As indicated by Crowson and Magro, all affected patients should be investigated for the possibility of an underlying immune disorder.

Rheumatoid Neutrophilic Dermatitis

Objective.—Rheumatoid neutrophilic dermatitis is a rare skin manifestation of rheumatoid arthritis (RA) that usually appears as yellow papules and plaques on the neck and extremities. Two cases of rheumatoid neutrophilic dermatitis with dermal leukocytes and abundant leukocytosis without vasculitis were reported.

Case 1.—Man, 45, who had had RA for 2 years, had recurrent cutaneous lesions on his neck that appeared during flares of the articular disease and improved when his RA improved. A skin biopsy specimen showed a diffuse, dense neutrophilic dermal infiltrate. There was leukocytoclasia but no vasculitis.

Case 2.—Man, 60, who had had RA for 5 years, had extensive palpable purpura of the legs, arms, chest, buttocks, and thighs. A biopsy specimen showed extravasated erythrocytes and leucocytoclasia and an extensive neutrophilic dermal infiltrate. Purpuric lesions resolved with prednisone and dapsone. Papular and purpuric lesions resolved with cyclophosphamide therapy.

Comment.—Rheumatoid neutrophilic dermatitis occurs in patients with severe seropositive RA. Most previously reported patients have been female. Lesions generally last 1-3 weeks and resolve spontaneously without scarring or with treatment of the RA. Biopsy specimens show a neutrophil infiltrate of the dermis which may extend into the subcutaneous fat. There may be papillary microabscesses resembling those of a number of other diseases. A table of differential diagnoses is presented in the original article.

Conclusion.—Rheumatoid neutrophilic dermatitis is a rare neutrophilic vascular reaction that is found in patients with severe RA. It is characterized by leukocytoclasia.

► Rheumatoid neutrophilic dermatosis occurs in seropositive patients with RA. Lesions may be urticarial or annular and evolve into erythematous, subcutaneous papules, plaques, and nodules. There is a predilection for the trunk, shoulders, neck, and extremities. Biopsy specimens reveal a diffuse dermal infiltrate with numerous neutrophils which may be associated with the development of papillary dermal microabscesses. Thus, this entity is included in the histologic differential diagnosis of disorders associated with a neutrophilic infiltrate; these include Sweet’s syndrome, cellulitis, erythema elevation diutinum, pyoderma gangrenosum, and dermatitis herpetiformis.

Indomethacin Treatment of Eighteen Patients With Sweet’s Syndrome

Introduction.—Characterized by the acute onset of an eruption of painful erythematous or violaceous plaques or nodules on the limbs, face, and neck associated with fever, Sweet’s syndrome is known as acute febrile neutrophilic dermatosis. An effective treatment has been found with corticosteroid therapy, but relapses have occurred with a reduction in therapy. An alternative would be nonsteroidal anti-inflammatory drugs, but little is known regarding their efficacy in the treatment of Sweet’s syndrome. The therapeutic effect of the nonsteroidal anti-inflammation drug indomethacin for Sweet’s syndrome was investigated.

Methods.—Eighteen patients who had Sweet’s syndrome during a 4-year period were given indomethacin at 150 mg/day for the first week and 100 mg/day for 2 additional weeks. The patients were followed to determine the therapeutic response on days 4, 7, 14, 30, and 180.

Results.—A good initial response resulted in 17 of 18 cases. Within 48 hours, fever and arthralgia were markedly attenuated, and between 7 and 14 days, eruptions cleared. Around the third day of treatment, the skin began to flatten. Cutaneous lesions continued to develop on the remaining patient who had acute myeloid leukemia, but they were successfully treated with prednisone at 1/mg/kg/day. Two patients noted epigastric pain. At a mean follow-up of 20.1 months, no patient had a relapse after discontinuation of indomethacin.

Conclusion.—-For Sweet’s syndrome, indomethacin is a safe and effective treatment. Because of the open, nonrandomized character of this trial, these results should be interpreted cautiously. Indomethacin should be used as the initial treatment for elderly patients, in whom the side effects of corticosteroid therapy are frequent; for patients with cardiac failure or severe high blood pressure; for patients with diabetes mellitus; and for patients with osteoporosis.

► Indomethacin or other nonsteroidal anti-inflammatory drugs may be a worthwhile treatment alternative for patients with Sweet’s syndrome. My own experience with these patients is that they do not respond as readily as did the patients in this study.

Low-Dose Danazol in the Treatment of Livedoid Vasculitis

Objective.—Livedoid vasculitis is a chronic skin disorder that leaves ivory-white atrophic scars on the legs. Its etiology is unknown. The varied treatments that have been used with variable results include bed rest with leg elevation, saline soaking, elastic stockings, sympathetic blockers, immunosuppressants, vasodilators, sulfasalazine, fibrinolytic agents, dextran infusion, pentoxifylline, heparin, prostacyclin, and tissue plasminogen activator. Results of an open, prospective study of the efficacy of low-dose danazol for treatment of livedoid vasculitis and a search for predictive parameters of disease activity were presented, together with results of an investigation of the incidence of concurrent livedo reticularis and purpura-pigmentosa-chronica-like (PPC-like) lesions. Danazol was selected because of its effect on local thrombo-occlusive disease processes. It may enhance the activity of tissue plasminogen activator, which lyses microvascular thrombi, restores circulation, promotes wound healing, and enhances fibrinolysis.

Methods.—Oral danazol (200 mg) once daily was administered to 7 patients (2 males), age 21-40, with livedoid vasculitis. Adverse events were recorded, and parameters of coagulation, procoagulation, antifibrinolysis, and profibrinolysis were assessed.

Results.—Six patients completed treatment. One dropped out despite clinical improvement. Duration of therapy ranged from 4 to 12 weeks. Mean times for cessation of new lesion formation, significant pain relief, and complete remission were 1.6,3.2, and 10.8 weeks, respectively. Of the clinical variables measured, plasminogen levels were significantly elevated and fibrinogen levels significantly reduced by therapy in all 6 patients. Six of 7 patients had a summer exacerbation, and 2 had a winter exacerbation. Five patients had PPC-like lesions that appeared before (3 patients), during (1 patient), or after (1 patient) onset of livedoid vasculitis. Livedo reticularis was present concurrently with livedoid vasculitis in 1 patient and before in 3 patients, 2 of whom also had PPC-like lesions. The severity of PPC-like lesions and livedo reticularis was not correlated with the severity of livedoid vasculitis and neither patient responded to danazol treatment.

Conclusion.—Low-dose danazol was effective in treating livedoid vasculitis without causing major side effects.

► The authors treated 7 patients with livedoid vasculitis, a chronic, debilitating, and painful disease. A 90% response rate was achieved using oral danazol, 200 mg daily. Clinical improvement was mirrored by a significant elevation in plasminogen levels and corresponding decreases in fibrinogen levels within 1 month. Levels of other thrombolytics—antithrombin III, protein C, protein S, and α2-antiplasmin—also tended to increase with treatment. These authors achieved an excellent response rate with a reasonable safety profile.

Intravenous Cyclophosphamide Pulses in Pyoderma Gangrenosum: An Open Trial

Objective.—Pyoderma gangrenosum, an uncommon ulcerative skin condition, has no known cause. No treatment is consistently effective in all patients. Drugs used to treat pyoderma gangrenosum include prednisone, minocycline, topical cromoglycate, dapsone, and salazosulfapyridine. Success has also been reported with azathioprine, melphalan, pulse methyl-prednisolone, recombinant interferon-α2, nitrogen mustard, IV immunoglobulin, tracolimus, and cyclosporine. Because good results have been obtained in 5 patients with pyoderma gangrenosum treated with cyclophosphamide (CY), the efficacy of IV CY pulses was studied in an open trial of patients in Guadalajara.

Methods.—Nine patients. (3 males), aged 24-76 years, were given IV CY, 500 mg/mof body surface area, every 28-30 days for a maximum of 6 doses. Patients were assessed at baseline, at monthly intervals during treatment, and every 3 months thereafter. Safety and toxicity were assessed. Outcomes were complete remission (100% ulcer healing), partial remission (ulcer size decreased by 50% or more), and failure (ulcer size decreased by less than 50%).

Results.—Three patients had rheumatoid arthritis, 2 patients had systemic lupus erythematosus, and 7 were using prednisone. Fourteen previous therapeutic measures had failed. Seven patients had a complete response, 1 had a partial response, and 1 failed. Three patients had a recurrence; 2 were retreated and neither responded. Side effects included nausea and vomiting (1 patient) and thrombocytopenia (1 patient).

Conclusion.—Intravenous CY is effective in treating pyoderma gangrenosum in most patients and results in remission for a considerable time.

► The authors treated nine patients with pyoderma gangrenosum. All patients received IV CY, 500 mg/m2, monthly for up to 6 doses with an approximately 80% clinical remission rate. Pyoderma gangrenosum, although rarely fatal, carries a significant morbidity. The authors describe a very reasonable “therapeutic ladder” for patients with this disease, beginning with drugs with a very high safety profile—such as minocycline—and progressing to various other modalities. For refractory patients, IV CY would be a viable therapeutic option.