Erythema elevatum diutinum: clinical, histopathologic, and immunohistochemical characteristics of six patients

Erythema elevatum diutinum (EED) is a chronic cutaneous vasculitis occurring in association with a variety of conditions including autoimmunity, infectious disease, and hematological abnormalities. The role of associated medical problems is controversial, and the exact pathogenesis of EED is unknown. A series of six cases is reported. The typical clinical presentation was that of erythematous papules and plaques involving the extensor surfaces of the extremities. Histologically, a spectrum from leukocytoclastic vasculitis to vessel occlusion and dermal fibrosis was seen. The lesions of EED have many mimics clinically and histologically. Establishing the diagnosis of EED is important so appropriate screening for associated conditions can ensue. The vascular endothelium of EED stains positive for CD31, CD34, VEGF, and factor VIIIa and negative for factor XIIIa, TGFB, and LANA, a reaction pattern that does not distinguish it from similar appearing lesions. Thus, the chronic and recurrent nature of EED is the primary means of distinguishing it from entities that are clinically and histologically similar.     

持久性隆起性红斑伴再生障碍性贫血一例并文献复习

持久性隆起性红斑(erythema elevatum diutinum, EED)是一种罕见的皮肤白细胞破碎性血管炎,其病因不明确,认为与感染、血液系统疾病、自身免疫性疾病感染的循环免疫复合物在血管壁沉积有关,因此除单纯的皮肤表现外,既往报道39.4%的EED伴发HIV、病毒性肝炎、链球菌感染、副蛋白血症、骨髓增生异常综合征、系统性红斑狼疮和类风湿性关节炎等疾病。现报道我院诊治的持久性隆起性红斑伴再生障碍性贫血一例,并通过文献检索,分析伴发其他系统性疾病的EED的临床特征,初步探讨EED与血液系统疾病及恶性肿瘤的关联性。     

Nodular Erythema Elevatum Diutinum Mimicking Kaposi's Sarcoma in a Human Immunodeficiency Virus Infected Patient

Erythema elevatum diutinum (EED) has been emerging as a specific Human Immunodeficiency Virus (HIV) associated dermatosis in recent times. It is an extremely rare chronic disease of unknown origin and part of the spectrum of leukocytoclastic vasculitis. We describe a case of EED simulating Kaposi''s sarcoma in a 52-year-old HIV infected female patient with no previous opportunistic infections and CD4+ count of 164/mm³. Therapy with oral dapsone (100 mg/day) for two weeks resulted in resolution of some lesions.     

The evolution of lesions in erythema elevatum diutinum

We obtained biopsies from early, fully developed, and late lesions of erythema elevatum diutinum (EED) in a 49-year-old man. The histologic and electron-microscopic findings were compared with those reported in the literature and three other cases from our files. Early lesions show leukocytoclastic vasculitis with capillary proliferation. Later lesions show vasculitis, dermal aggregates of neutrophils, fibrosis, and areas of granulation tissue. Newly formed vessels in granulation tissue may be more susceptible to damage by immune complexes, and the early formation of granulation tissue in EED may prevent an early resolution of vasculitis. Damage to dermal connective tissue in EED incites either scarring or, rarely, a fibrohistiocytic proliferation. Ultrastructural examination of one case showed histiocytes with myelin figures and intracellular lipid and cholesterol.     

Factor XIIIa+ dermal dendrocytes in erythema elevatum diutinum and ordinary cutaneous leukocytoclastic vasculitis lesions

Factor XIIIa+ dermal dendrocytes belong to the dermal microvascular unit and are related to wound healing, angiogenic and fibrogenic processes. Erythema elevatum diutinum (EED) is a leukocytoclastic vasculitis followed by repair and fibrosis. In order to verify the involvement of fXIIIa+DD in the pathogenesis of EED and ordinary leukocytoclastic vasculitis (OLV) these cells were immune labeled with anti-factor XIIIa antibody and quantified in 15 biopsies of EED, 18 of OLV and compared with 11 fragments of normal skin (NS). The number of vessels was evaluated by endothelial cell staining with anti CD34 antibody. FXIIIa+DD appeared in both groups of vasculitis with hyperthophic dendrites, with no difference in their number at any level of the dermis. The number of fXIIIa+DD in the superficial dermis was higher in OLV than in NS (p<0.001). The number of dermal vessels in the EED group was higher at all dermis depths evaluated when compared with NS (p<0.05) and in the middle and deep dermis when compared with OLV (p<0.05). The results suggest the participation of fXIIIa+DD in the immunopathological mechanisms of both groups of vasculitis studied. However, there was no correlation between the number of fXIIIa+DD and angiogenesis and fibrogenesis in the EED lesions.     

Erythema elevatum diutinum: a case report and review of literature

Erythema elevatum diutinum (EED) is a rare cutaneous leukocytoclastic vasculitis thought to be related to increased levels of circulating antibodies. It has been shown to be associated with HIV infection, tuberculosis, as well as various autoimmune diseases. A retrospective review of all cases of EED indexed in PubMed between 1990 and 2014 was performed. Inclusion criteria for articles was availability of full text in English and a biopsy-confirmed diagnosis of EED. All other articles were excluded. Cases were stratified by age and anatomic location of the lesions. Treatment response was coded as “complete,” “partial,” and “none.” A total of 133 cases of EED with 381 lesions detailed in case reports and case series were included. Twenty-one cases were associated with HIV. Of 47 patients with reported paraproteinemias, IgA paraproteinemia was found in 57.45%, IgG paraproteinemia in 29.8%, IgM paraproteinemia in 10.6%, and IgD paraproteinemia in 2.1% of cases. Of 40 (30.1%) patients with reported comorbid autoimmune disease, rheumatoid arthritis was associated with 10 cases. Cancer was found to be associated with 9.77% of cases. Seventy-five patients were treated with dapsone, with 36 (48%) achieving complete treatment response, 24 (32%) achieving partial response, and seven (9.3%) achieving no response. Keeping the clinical associations of EED in mind, especially malignancy, is critical in management of the disease. More structured studies need to take place in order to fully define the mechanisms and strength of these associations.     

Late‐stage nodular erythema elevatum diutinum mimicking sclerotic fibroma

Erythema elevatum diutinum (EED) is a rare, cutaneous vasculitis of uncertain origin. EED can present clinically as chronic bilateral, symmetrical, periarticular papules, plaques and nodules. We report here an unusual case of EED presenting as multiple, densely fibrosing nodules on the feet of a 60‐year‐old human immunodeficiency virus positive woman. The initial evaluation of the patient was complicated by the strong histologic resemblance of multiple lesions to sclerotic fibroma, a cutaneous manifestation of Cowden disease. Our case highlights the important features that distinguish these 2 pathologic entities.     

Granuloma faciale with extrafacial lesions

Extrafacial involvement in granuloma faciale (GF) is rather exceptional. We report herein a patient with GF associated with lesions on the trunk and the forearm. Histological studies of facial and extrafacial lesions shared similar characteristics: a mixed inflammatory infiltrate with abundant eosinophils in the superficial and middle dermis with a narrow grenz zone of uninvolved dermis between the epidermis and the infiltrate. Evidence of vasculitis was clearly observed in both biopsy specimens. Treatment with dapsone did not alter the course of the disease. We review the 12 cases of extrafacial GF that have been reported in the English and Spanish literature. In these cases a diagnosis of erythema elevatum diutinum (EED) may be suggested. Although GF and EED may share some pathogenic mechanisms, there are several clinical and histological differences between them that make us consider EED and GF as distinct entities.     

Erythema elevatum diutinum complicated by rheumatoid arthritis.

A 53-year-old female developed erythema elevatum diutinum (EED) twelve years after the onset of rheumatoid arthritis. The arthritis had been well controlled for the last several years. Annular purpuric macules were characteristically complicated by common nodular and plaque lesions. Both leukocytoclastic vasculitis and fibrosis were observed in the macular lesions, indicating that the lesions were a manifestation of an early phase of EED. Both types of skin lesions disappeared with treatment with dapsone. They have not relapsed for two years after stopping the dapsone. The leukocytoclastic vasculitis was thought to have developed independently of the rheumatoid arthritis. She had noticed sicca symptoms two years before the appearance of EED, but she did not satisfy the diagnostic criteria for Sjögren's syndrome.     

Kutane Vaskulitiden

Vasculitis is characterized by an inflammatory reaction of vessel walls with damage to the dependent tissues. Forms of vasculitis which frequently have skin changes include leukocytoclastic angiitis (LcV), Henoch-Schönlein purpura (HSP), cutaneous polyarteriitis nodosum (cPAN), erythema elevatum et diutinum (EED) and urticarial vasculitis (UV). In other forms of vasculitis, systemic manifestations predominate but there are a variety of skin changes. Kawasaki disease (MK), cryoglobulinemic vasculitis (kV), Wegener granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangitis (MPA) belong to this group. The causes of vasculitis are heterogeneous. Triggers include infections, drugs, collagen vascular diseases, autoimmune diseases and lymphoproliferative disorders. Idiopathic vasculitis, particularly LcV and EED, occur only once and have a self-limited course. The diagnostic work up depends on the clinical picture and includes inflammatory markers, circulating immune complexes, different types of cryoglobulins and anti-neutrophilic cytoplasmic antibodies, collagen vascular disease specific autoantibodies and additional hematological studies. Vasculitis can manifest in many organs and requires a thorough work up specifically in cases where WG, MPA, CSS and PAN are under consideration.     

Erythema elevatum diutinum--evidence for disease-dependent leucocyte alterations and response to dapsone

Erythema elevatum diutinum (EED) is a type of leucocytoclastic vasculitis of unknown aetiology. We report a patient with unusually widespread and disabling EED that had been unresponsive to corticosteroids and antibiotics, but resolved on dapsone. Biopsies of fresh lesions showed typical features of leucocytoclastic vasculitis, with prominent neutrophil infiltration, marked expression of the beta(2)-integrins CR3 and LFA-1, and increased mast cell numbers. Older lesions exhibited granulation tissue and fibrosis, macrophages were more dominant, beta(2)-integrins were expressed less markedly, and mast cell numbers were lower. In vitro chemotaxis of the patient's peripheral blood neutrophils prior to treatment showed increased random migration and directed migration towards interleukin-8 (by 424%), but a profoundly decreased responsiveness towards the bacterial peptide analogue N-formyl-methionyl-leucyl-phenylalanine (fMLP) (by 98%). These values returned to normal after dapsone treatment and clinical improvement 5 months later. These findings support the concept that in EED, activation via cytokines such as interleukin-8 allows a selective recruitment of leucocytes to tissue sites, while immune complexes and bacterial peptides sustain the persistent local inflammatory infiltrate and the leucocytoclastic vasculitis.     

Late-stage nodular erythema elevatum diutinum

Erythema elevatum diutinum (EED) is a rare chronic vasculitic process of unknown etiology that presents as bilateral, symmetrical, periarticular, red-brown papules and plaques, often over dorsa of joints. Early histologic changes are characterized by leukocytoclastic vasculitis. With chronicity, the lesions develop dense neutrophilic infiltrate and fibrosis. We describe an unusual case of late-stage nodular EED present for 35 years in a seronegative 75-year-old man. Asymptomatic papules and plaques measuring from 0.7 to 9.0 cm were seen over the interphalangeal joints, elbows, knees, and ankles. The histologic findings were characterized by predominant concentric fibrosis that formed well-circumscribed dermal and subcutaneous nodules. Awareness of this unusual presentation of EED helps to avoid misdiagnosis as cutaneous neoplasms.     

Erythema elevatum diutinum and HIV infection: a report of five cases

Erythema elevatum diutinum (EED) is emerging as a specific HIV-associated dermatosis, 11 cases having so far been reported in the medical literature and five patients with the disease having been seen by us during the last 4 years. As the disease is poorly known, it is easily confused with Kaposi's sarcoma or bacillary angiomatosis, but the histopathological features are diagnostic. EED is considered to be an immune complex-mediated vasculitis. A streptococcal infection seemed to be the trigger factor in four of our patients. Partial control of the cutaneous lesions was achieved by the use of antibiotics.     

Erythema elevatum et diutinum

Erythema elevatum et diutinum (EED) is a rare, chronic, cutaneous, leukocytoclastic vasculitis. It is characterized by symmetric, plaques, papules and nodules occurring preferentially on the extensor aspects of the arms. An association with chronic infections, neoplasms, especially myeloproliferative diseases and paraproteinemia, as well as autoimmune disorders (rheumatoid arthritis, Crohn disease) has been described. An 83-year-old woman with EED presented with symmetric, skin colored, firm nodules on the extensor surfaces of her fingers for two years. This case report summarizes the central clinical aspects and differential diagnosis of EED as well as its therapeutic options.     

Erythema elevatum diutinum in human immunodeficiency virus-infected patients — report of a case and review of the literature

Erythema elevatum diutinum (EED) is a rare chronic disease of unknown origin, part of the spectrum of cutaneous leucocytoclastic vasculitis, A case of EED in a 32-year-old HIV-infected male patient, with no previous opportunistic infections and a CD4+ cell count of less than 200/mm³ is reported. Therapy with oral dapsone (100 mg/day for 15 days) resulted in clinical cure with no relapse after 6 months of follow-up. To our knowledge, only six cases of EED in HIV-positive patients have been reported to dale. A brief review of these seven cases is described.     

Erythema elevatum diutinum in a patient with human immunodeficiency virus

Erythema elevatum diutinum (EED) is a chronic cutaneous leukocytoclastic vasculitis. This rare disease is characterized by red, brownish-purple, and yellow papules, plaques, and nodules distributed symmetrically about the extremities. There have been recent reports of the disease in association with infection with the human immunodeficiency virus (HIV). We describe the case of a 51-year-old man with HIV who presented with EED, which was successfully treated with dapsone.     

Infantile erythema elevatum diutinum: report of a vesiculo-bullous case

Erythema elevatum diutinum (EED) is a localized, low-grade form of leukocytoclastic vasculitis mainly affecting adults, with only a few pediatric cases reported in the literature. The pathogenesis of this dermatosis is unknown, although an Arthus-type reaction to bacterial and viral antigens seems involved. We describe a case of EED in a 9 year-old child suffering from recurrent pharyngotonsillitis induced by Streptococcus pyogenes. Clinical presentation of the dermatosis was atypical, with vesicles and bullae intermingled with red-purple papules and plaques distributed mainly over the extensor aspects of the extremities. Histopathological examination of a vesiculo-bullous lesion revealed a subepidermal bulla containing neutrophils and nuclear dust suggesting dermatitis herpetiformis. Fibrin in vessel walls was observed throughout the dermis. Direct immunofluorescence was negative. A prompt and complete response to sulphone therapy was obtained in conjunction with tonsillectomy. Clinicians should be aware of atypical presentations of EED in children with vesicles and bullae mimicking During's disease.     

Erythema elevatum diutinum – a chronic leukocytoclastic vasculitis microscopically indistinguishable from granuloma faciale?

Background: As the sequential inflammatory changes are the same in erythema elevatum diutinum (EED) and granuloma faciale (GF), histopathologic distinction may be difficult. Methods: All available cases from 1998 to 2009 with the diagnosis of EED and GF were collected and reviewed, both clinically and histopathologically. Nine cases of EED and 41 cases of GF were reviewed in a blinded fashion using a checklist of 26 histopathologic criteria. Results: Only four of the evaluated criteria showed differences between GF and EED. High density of the infiltrate was noted in 97% of cases of GF but only in 56% of cases of EED. Eosinophils were the predominant cell type in 59% of cases of GF but in none of the cases of EED. Plasma cells were more frequent in GF (64%) than in EED (22%), and granulomas were never found in GF but in 22% of EED. A zone of perijunctional sparing (Grenz zone) was observed in about three quarters of the cases in both the groups. Conclusions: The histopathology of GF and EED is very similar and overlapping. The presence of a Grenz zone and patterned fibrosis does not distinguish the two diseases. However, granulomatous nodules are only seen in EED, and a predominance of eosinophils in the infiltrate favors a diagnosis of GF. Ziemer M, Koehler MJ, Weyers W. Erythema elevatum diutinum – a chronic leukocytoclastic vasculitis microscopically indistinguishable from granuloma faciale?     

Unusual erythema elevatum diutinum with fibrohistiocytic proliferation

A 78-year-old woman with a history of symmetrical erythematous plaques on the arms, and a monoclonal gammopathy. developed a strange striped reticulate papular dermatosis with central atrophy. Histological examination was compatible with a very late stage of erythema elevatum diutinum (EED). showing a fibrohistiocytic proliferation with areas of granulation tissue. This fibrosis may result from the chronic dermal injury of leucocytoclastic vasculitis and is sometimes the predominant histology of EED. Investigations for underlying haematological anomalies, such as paraproteinaemia and infection with human Immunodeficiency virus, must be performed. Dapsone is ineffective once the fibrous nodules have appeared.     

Erythema elevatum diutinum mimicking porphyria cutanea tarda

A case of erythema elevatum diutinum (EED) closely resembling porphyria cutanea tarda (PCT) is reported. The initial skin biopsies were suggestive for PCT but porphyrin levels in the urine, stool and plasma were normal. A further biopsy from an early cutaneous lesion showed a leucocytoclastic vasculitis with fibrinoid necrosis of the vessel walls.