Background

This is a rare vasculitis that classically presents with plaque-like violaceous lesions on the extensor surfaces of the extremities and the trunk. Recently, interesting histopathological variants have been described in AIDS patients.

OUTLINE

Epidemiology
Disease Associations	Acro-osteolysis Celiac disease Crohn's disease HIV-1 Hyperimmunoglobulinemia D IgA paraproteinemia Lymphoma Myelodysplasia POEMS syndrome Pyoderma gangrenosum Relapsing polychondritis Rheumatoid arthritis Wegener's granulomatosis
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	EED
INCIDENCE	Uncommon

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
ACRO-OSTEOLYSIS
Erythema elevatum diutinum with extensive acro-osteolysis. Ellabban A, Schumacher HR Jr. Division of Rheumatology, University of Pennsylvania School of Medicine, Philadelphia, USA.	J Rheumatol 1997 Jun;24(6):1203-5 Abstract quote Erythema elevatum diutinum (EED) is a rare chronic skin disease with cutaneous vasculitis, characterized by the absence of systemic vasculopathy. We describe a 79-year-old white woman who has been followed with the diagnosis of EED for 27 years. Our patient has a previously unreported combination of EED and acro-osteolysis. After reviewing possible reasons for the association, her vasculitis seems the most likely factor.
CELIAC DISEASE
Erythema elevatum diutinum associated with celiac disease: response to a gluten-free diet. Rodriguez-Serna M, Fortea JM, Perez A, Febrer I, Ribes C, Aliaga A. Department of Dermatology, Hospital General, Valencia, Spain.	Pediatr Dermatol 1993 Jun;10(2):125-8 Abstract quote An 11-year-old girl with a history of insulin-dependent diabetes mellitus had erythema elevatum diutinum (EED) associated with a celiac disease related to a possible kidney disease. Dapsone did not improve the skin manifestations. However, the lesions disappeared after a gluten-free diet was begun. To our knowledge, this report describes the first case of EED in a patient with celiac disease.
Erythema elevatum diutinum in association with coeliac disease. Tasanen K, Raudasoja R, Kallioinen M, Ranki A. Department of Dermatology, Oulu University Hospital, Finland.	Br J Dermatol 1997 Apr;136(4):624-7 Abstract quote Erythema elevatum diutinum (EED) has been described in association with several immunological or infectious diseases. We describe a female patient who presented with clinically and histologically typical EED in whom previously undiagnosed coeliac disease was found. Appearance of EED lesions was preceded by widespread joint pains. In extensive laboratory tests, the only abnormal findings were an elevated erythrocyte sedimentation rate (ESR) and decreased haemoglobin and folic acid levels. Later, IgA and IgG type antireticulin and antigliadin antibodies were detected. Serum total IgA was elevated but no paraproteinaemia was found. In lesional skin, granular deposits of IgA and C3 were seen at the dermo-epidermal junction. A duodenal biopsy revealed total villous atrophy. Dapsone treatment was partly effective but complete healing of the EED lesions was achieved only after the introduction of a strict gluten-free diet. The patient has now remained symptom-free on the diet for 1.5 years.
CROHN'S DISEASE
Erythema elevatum diutinum in a patient with Crohn's disease. Walker KD, Badame AJ. Department of Dermatology, Tulane University Medical School, New Orleans, LA 70112.	J Am Acad Dermatol 1990 May;22(5 Pt 2):948-52 Abstract quote A possible association between erythema elevatum diutinum and Crohn's disease is described. To our knowledge, erythema elevation diutinum has never been reported in a patient with Crohn's disease, nor has the disorder been considered one of the cutaneous manifestations of inflammatory bowel disease. Erythema elevatum diutinum is believed to be mediated by the deposition of circulating immune complexes in the dermal perivascular spaces. Our patient showed clinical and histopathologic findings typical of both erythema elevatum diutinum and Crohn's disease. The patient also had a positive Raji cell assay, which demonstrates the presence of a circulating immune complex. Increased levels of circulating immune complexes have been found in patients with inflammatory bowel disease, and the gastrointestinal inflammation in Crohn's disease could lead to enhanced antigenic exposure and increased formation of immune complexes. We contend that inflammatory bowel disease may have contributed to the development of erythema elevatum diutinum in our patient.
HIV-1
Erythema elevatum diutinum in a patient with acquired immunodeficiency syndrome. Another clinical simulator of Kaposi's sarcoma. Requena L, Sanchez Yus E, Martin L, Barat A, Arias D. Department of Dermatology, Jimenez Diaz Foundation, Nuestra Senora de la Concepcion Clinic, Universidad Autonoma, Madrid, Spain.	Arch Dermatol 1991 Dec;127(12):1819-22 Abstract quote 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.
Erythema elevatum diutinum and HIV infection: a report of five cases. Muratori S, Carrera C, Gorani A, Alessi E. Institute of Dermatological Sciences, University of Milan, IRCCS Ospedale Maggiore, Via Pace 9, 20122 Milan, Italy.	Br J Dermatol 1999 Aug;141(2):335-8 Abstract quote 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.
HYPERIMMUNO-GLOBULINEMIA D
Association of hyperimmunoglobulinaemia D syndrome with erythema elevatum diutinum. Miyagawa S, Kitamura W, Morita K, Saishin M, Shirai T. Department of Dermatology, Nara Medical University, Japan.	Br J Dermatol 1993 May;128(5):572-4 Abstract quote Hyperimmunoglobulinaemia D and periodic fever syndrome was observed in a female patient with erythema elevatum diutinum. The association of this skin disease with hyperimmunoglobulinaemia D may indicate a pathogenetic relationship. The skin lesions responded to dapsone therapy.
IgA PARAPROTEINEMIA
Erythema elevatum diutinum associated with IgA paraproteinemia successfully controlled with intermittent plasma exchange. Chow RK, Benny WB, Coupe RL, Dodd WA, Ongley RC. Division of Dermatology, University of British Columbia, Vancouver.	Arch Dermatol 1996 Nov;132(11):1360-4 Abstract quote BACKGROUND: We review the literature and report a case of refractory erythema elevatum diutinum associated with IgA paraproteinemia that was successfully controlled with intermittent plasma exchange (PLEX). OBSERVATIONS: Typical lesions of erythema elevatum diutinum developed in a 72-year-old patient with IgA paraproteinemia; the condition predictably flared whenever IgA levels reached a threshold of 8 g/L. After 8 years of unsuccessful treatment with various agents, we instituted a trial of PLEX during an acute flare. Following 6 exchanges over a period of 2 weeks, the IgA level decreased from 8 to 2 g/L and the skin lesions cleared. Three weeks later, new skin lesions developed and the IgA level had rebounded from 2 to just over 8 g/L. A second course of PLEX was administered, with excellent results, and a 3-month course of oral chlorambucil (2 mg/d) was initiated. The patient's condition remained in clinical remission for 10 months. Over the ensuing 9 years, she suffered 11 further flares, each of which was associated with IgA levels of 8 to 10 g/L and each responding dramatically to 3 to 5 PLEXs followed by a consolidative dose of intravenous cyclophosphamide (250-500 mg). CONCLUSION: We believe that PLEX may have an important role in the management of severe erythema elevatum diutinum associated with monoclonal paraproteinemia refractory to other therapy.
LYMPHOMA
A case of erythema elevatum diutinum associated with B-cell lymphoma: a rare distribution involving palms, soles and nails. Futei Y, Konohana I. Department of Dermatology, Hiratsuka City Hospital, Kanagawa 254-0065, Japan.	Br J Dermatol 2000 Jan;142(1):116-9 Abstract quote We report a case of erythema elevatum diutinum (EED) in association with malignant B-cell lymphoma. A 62-year-old man developed EED with an unusual distribution involving the palms, soles and nails. Treatment with dapsone was effective for his skin and nails until he developed generalized lymphadenopathy which turned out to be malignant lymphoma. Many haematological diseases, e.g. IgA paraproteinaemia and myeloma, have been reported in association with EED, but not malignant lymphoma. Even though it may just be a coincidence, we would like to add malignant lymphoma as one of the diseases associated with EED because the activity of EED and malignant lymphoma fluctuated in parallel.
MYELODYSPLASIA
Simultaneous occurrence of two rare cutaneous markers of poor prognosis in myelodysplastic syndrome: erythema elevatum diutinum and specific lesions. Aractingi S, Bachmeyer C, Dombret H, Vignon-Pennamen D, Degos L, Dubertret L. Department of Dermatology, H pital Saint-Louis, Paris, France.	Br J Dermatol 1994 Jul;131(1):112-7 Abstract quote We report the concomitant occurrence of erythema elevatum diutinum and specific skin lesions in a patient with a myelodysplastic syndrome (MDS). This patient's course, and review of other reported cases, support the opinion that neutrophilic dermatoses are associated with a poor prognosis of MDS. The simultaneous appearance of these manifestations could be the consequence of a particular chemotactism of myeloid cells, expressed after acute transformation.
POEMS SYNDROME
POEMS syndrome, steroid-dependent diabetes mellitus, erythema elevatum diutinum, and rheumatoid arthritis as extramedullary manifestations of plasma cell dyscrasia. Albitar S, Bourgeon B, Genin R, Jacquesson M, Riviere JP, Serveaux MO, Ribera A, Serveaux JP. Hemodialysis Center, AURAR, 6 Avenue Stanislas Gimart, F-97490 Ste Clotilde de La Reunion, France.	Am J Kidney Dis 1998 Apr;31(4):E3 Abstract quote POEMS syndrome is a rare synopsis of different multisystemic disorders (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy, and skin lesions) associated with plasma cell dyscrasia. We herein report the atypical case of a 44-year-old white man presenting with glomerulopathy, POEMS syndrome, and erythema elevatum diutinum with a few-year history of non-insulin-dependent diabetes mellitus (NIDDM) and seronegative rheumatoid arthritis (RA) as early manifestations of IgAlambda multiple myeloma. The prescription of 1 mg/kg/day prednisone improved the patient's features dramatically. Skin lesions improved by the association of glucocorticoids and plasma exchange, recurred when plasmapheresis ceased, and remitted when plasma exchange was reintroduced. NIDDM requiring insulinotherapy recurred when corticoids were discontinued and remitted when prednisone was reintroduced. However, prednisone and plasmapheresis had no effect on polyneuropathy, M-paraprotein, and plasma cell dyscrasia in our patient, who developed indolent multiple myeloma a few years later. We thus concluded that POEMS syndrome, steroid-dependent diabetes mellitus, rheumatoid arthritis, RA, and skin vasculitis in our patient were triggered by plasma cell dyscrasia.
PYODERMA GANGRENOSUM
Pyoderma gangrenosum in association with erythema elevatum diutinum: report of two cases. Planaguma M, Puig L, Alomar A, Matias-Guiu X, de Moragas JM. Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Spain.	Cutis 1992 Mar;49(3):201-6 Abstract quote We report on the appearance of centrifugally spreading ulcers with undermined borders in two patients with chronic recurrent erythema elevatum diutinum controlled with dapsone. The ulcerated lesions were consistent on clinical and pathologic examination with the diagnosis of pyoderma gangrenosum. They eventually responded to treatment with oral corticosteroids. The addition of cyclosporine was required in one case. No associated disease was found in any of the patients. The possible pathophysiological mechanisms of this uncommon association are reviewed.
RELAPSING POLYCHONDRITIS
Erythema elevatum diutinum in a patient with relapsing polychondritis. Bernard P, Bedane C, Delrous JL, Catanzano G, Bonnetblanc JM. Department of Dermatology, CHRU Dupuytren, Limoges, France.	J Am Acad Dermatol 1992 Feb;26(2 Pt 2):312-5 Abstract quote A 69-year-old man with a history of relapsing polychondritis developed a widespread cutaneous eruption that was clinically and histologically typical of erythema elevatum diutinum. This eruption was accompanied by a recurrence of arthralgias. The significance of this association between relapsing polychondritis and erythema elevatum diutinum, which has not been previously reported, is discussed.
RHEUMATOID ARTHRITIS
Erythema elevatum diutinum complicated by rheumatoid arthritis. Nakajima H, Ikeda M, Yamamoto Y, Kodama H. Department of Dermatology, Kochi Medical School, Japan.	J Dermatol 1999 Jul;26(7):452-6 Abstract quote 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 Sjogren's syndrome.
WEGENER'S GRANULOMATOSIS
Erythema elevatum diutinum associated with Wegener's granulomatosis and IgA paraproteinemia. Kavanagh GM, Colaco CB, Bradfield JW, Archer CB. Department of Dermatology, Bristol Royal Infirmary, University of Bristol, United Kingdom.	J Am Acad Dermatol 1993 May;28(5 Pt 2):846-9 Abstract quote A 69-year-old man had erythema elevatum diutinum for several years before he developed IgA paraproteinemia and a limited form of Wegener's granulomatosis. This is the first report of an association between erythema elevatum diutinum and Wegener's granulomatosis. IgA paraproteinemia has been reported in association with erythema elevatum diutinum but not with Wegener's granulomatosis.

 

PATHOGENESIS	CHARACTERIZATION
CYTOKINES
Erythema elevatum diutinum--evidence for disease-dependent leucocyte alterations and response to dapsone. Grabbe J, Haas N, Moller A, Henz BM. Department of Dermatology, Medical University of Luebeck, Ratzenburger Allee 160, D-23538 Luebeck, Germany.	Br J Dermatol 2000 Aug;143(2):415-20 Abstract quote 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.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
ANCA
Antineutrophil cytoplasmic antibodies of IgA class in neutrophilic dermatoses with emphasis on erythema elevatum diutinum. Ayoub N, Charuel JL, Diemert MC, Barete S, Andre M, Fermand JP, Piette JC, Frances C. Dermatology- Internal Medicine Department.	Arch Dermatol. 2004 Aug;140(8):931-6. Abstract quote   OBJECTIVE: To evaluate the prevalence of IgA and IgG antineutrophil cytoplasmic antibodies (ANCAs) in erythema elevatum diutinum in comparison with 2 other groups of neutrophilic dermatoses: Sweet syndrome and pyoderma gangrenosum. DESIGN: Detection of IgA and IgG ANCAs in the serum of patients with neutrophilic dermatoses and characterization of the previously known antigenic targets. SETTING: All serum was analyzed without knowledge of diagnosis in the Immunology Department, Pitie-Salpetriere Hospital, Paris, France.Patients Ten patients with erythema elevatum diutinum, 10 with Sweet syndrome, 10 with pyoderma gangrenosum, and 10 healthy volunteers. MAIN OUTCOME MEASURES: IgA and IgG ANCAs were sought by indirect immunofluorescence with ethanol and formaldehyde-fixed human neutrophil preparations as the substrate. Enzyme-linked immunosorbent assays were further performed for antigen characterization. RESULTS: IgA ANCAs were observed in 60% and IgG ANCAs in 10 (33%) of the patients. All patients with erythema elevatum diutinum had IgA ANCAs. IgA fluorescence in formaldehyde-fixed neutrophils was restricted to those from patients with erythema elevatum diutinum. Enzyme-linked immunosorbent assays disclosed no single predominant target, and antigens remained largely undetermined in erythema elevatum diutinum. CONCLUSIONS: The ANCAs, particularly of IgA class, may prove to be a helpful paraclinical marker in erythema elevatum diutinum and an interesting perspective for understanding the pathophysiology of the disease. The nature of the unidentified targets and the pathogenicity of ANCAs, however, remain to be assessed.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Erythema elevatum diutinum: a clinical and histopathologic study of 13 patients. Yiannias JA, el-Azhary RA, Gibson LE. Department of Dermatology, Mayo Clinic, Rochester, MN 55905	J Am Acad Dermatol 1992 Jan;26(1):38-44 Abstract quote BACKGROUND: Erythema elevatum diutinum is a rare condition representing a chronic leukocytoclastic vasculitis. OBJECTIVE: Clinical and laboratory features of the disease were reviewed to better understand the disease. METHODS: The medical records and histopathologic slides of 13 patients with erythema elevatum diutinum were studied. RESULTS: The lesions were violaceous, deep red, or brown and typically were papules or plaques. Lesions were most often located on the extensor surfaces of the extremities. Associated medical problems included hematologic abnormalities in six patients: IgA clonal gammopathies (four), multiple myeloma (one), and myelodysplasia (one). Erythema elevatum diutinum preceded the myeloproliferative disorders by an average of 7.8 years. All patients showed vasculitis. Leukocytoclasia was present in 27 of 35 specimens. The predominant cell type in the inflammatory infiltrate was polymorphonuclear leukocytes or a mixture of polymorphonuclear leukocytes and lymphocytes. CONCLUSION: The most significant finding of this study is the association of erythema elevatum diutinum with hematologic disease, most frequently an IgA monoclonal gammopathy.
VARIANTS
CORNEA
Peripheral ulcerative keratitis associated with erythema elevatum diutinum and a positive rheumatoid factor: a report of three cases. Takiwaki H, Kubo Y, Tsuda H, Arase S, Shiota H. Department of Dermatology, School of Medicine, University of Tokushima, Japan.	Br J Dermatol 1998 May;138(5):893-7 Abstract quote Peripheral ulcerative keratitis (PUK) is a complication of collagen-vascular diseases such as rheumatoid arthritis (RA) and other systemic vasculitides. We report three cases of erythema elevatum diutinum with PUK. These patients presented with nodules and plaques consistent with erythema elevatum diutinum on the extremities and crusted or ulcerated purpuric lesions on the soles. Histopathological examination of these lesions revealed a dense neutrophilic infiltrate with nuclear dust and fibrin around blood vessels. All the patients developed PUK concomitant with the development of the skin lesions. The rheumatoid factor was positive at high titre in all three patients; this was associated with probable RA in one. Cutaneous lesions were dramatically improved by administration of dapsone in all cases. Dapsone was also effective in treating the ocular lesions in two patients.
Autoimmune keratolysis in a patient with leukocytoclastic vasculitis: unusual erythema elevatum diutinum with granulomatous pattern. Casanova FH, Meirelles RL, Tojar M, Martins MC, Rigueiro MP, de Freitas D. Department of Ophthalmology, Federal University of Sao Paulo, Paulista School of Medicine, Brazil.	Cornea 2001 Apr;20(3):329-32 Abstract quote PURPOSE: Leukocytoclastic vasculitis (LCCV) is an immune complex-mediated, small vessel disease that is clinically characterized by the presence of palpable purpuric lesions, most often in association with rheumatic diseases. Ocular manifestations of LCCV are rare. METHODS: We describe a patient with an unusual granulomatous pattern of erythema elevatum diutinum (EED) associated with autoimmune keratolysis. RESULTS: We studied a 64-year-old man with decreased visual acuity and nodular lesions in both hands. Ocular examination revealed bilateral superior corneal melting with perforation in the left eye and conjunctival thickening in both eyes, in association with a severe inflammatory reaction. Histopathologic examination of the conjunctiva revealed granulomatous vasculitis with neutrophilic infiltrate, giant cells, and fibroblastic proliferation. A punch biopsy taken from his skin showed similar characteristics that suggested EED; however, there were no giant cells. CONCLUSION: To our knowledge, autoimmune keratolysis secondary to cutaneous LCCV (EED) has not been described previously, and there has been no description of granulomatous reaction (in the conjunctiva) in EED.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Erythema elevatum diutinum: clinical, histopathologic, and immunohistochemical characteristics of six patients. Wahl CE, Bouldin MB, Gibson LE. University of California-San Diego, San Diego, California, USA.	Am J Dermatopathol. 2005 Oct;27(5):397-400. Abstract quote   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.
The evolution of lesions in erythema elevatum diutinum. LeBoit PE, Yen TS, Wintroub B.	Am J Dermatopathol 1986 Oct;8(5):392-402 Abstract quote 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.
Erythema elevatum diutinum: a clinicopathological study of eight cases. Sangueza OP, Pilcher B, Martin Sangueza J. Department of Pathology, Medical College of Georgia, Augusta 30912, USA.	Am J Dermatopathol 1997 Jun;19(3):214-22 Abstract quote Erythema elevatum diutinum (EED) is a rare cutaneous condition that initially presents as leukocytoclastic vasculitis (LCCV) of the skin and later resolves with fibrosis. In addition to the LCCV, EED may show features reminiscent of other entities. For example, it may mimic lesions of dermatofibroma, granuloma annulare, granuloma faciale, or dermatitis herpetiformis. For this study, we reviewed the clinical records and 13 skin biopsies in eight patients with EED. One of the patients had concurrent pityriasis rubra pilaris, and another developed lesions of EED following and at the sites of mosquito bites; these associations have not been noted previously. In addition to such typical histopathological features as diffuse dermal involvement by neutrophils, eosinophils, and leukocytoclastic vasculitis, we also found two unusual patterns. The first was characterized by palisaded necrotizing granulomas, as previously described and associated with Churg-Strauss granuloma; the second condition simulated a pyogenicgranuloma--like lesion.
VARIANTS
FIBROHISTIOCYTIC AND NODULAR
Nodular erythema elevatum diutinum mimicking cutaneous neoplasms. Shanks JH, Banerjee SS, Bishop PW, Pearson JM, Eyden BP. Department of Histopathology, Christie Hospital NHS Trust, UK.	Histopathology 1997 Jul;31(1):91-6 Abstract quote AIMS: We describe the cutaneous pseudoneoplastic lesions in two patients with nodular erythema elevatum diutinum, a rare chronic disorder in which polymorph nuclear fragmentation (leukocytoclasis) is present within dermal nodules showing spindle cells and fibrosis. In both cases diagnostic difficulty was encountered clinically and pathologically and various benign and malignant neoplasms were considered in the differential diagnosis. METHODS AND RESULTS: Immunohistochemically the spindle cells were negative for CAM5.2, AE1/3, S100 protein and desmin (D33). They were positive for vimentin and focally positive for CD34 and alpha-smooth muscle actin. Some of the spindle cells were positive for Mac 387 and KP1(CD68). By electron microscopy, the lesions were shown to consist of fibroblasts/myofibroblasts and fusiform macrophages. CONCLUSIONS: Increased awareness of the features described will help to avoid misdiagnosis as a neoplastic process.
Nodular lesions of erythema elevatum diutinum in patients infected with the human immunodeficiency virus. LeBoit PE, Cockerell CJ. Department of Pathology, School of Medicine, University of California, San Francisco 94143-0506.	J Am Acad Dermatol 1993 Jun;28(6):919-22 Abstract quote BACKGROUND: Erythema elevatum diutinum (EED) is a rare, chronic form of cutaneous vasculitis that can result in fibrosis. Four patients infected with the human immunodeficiency virus (HIV) had unusual nodular lesions of EED. OBJECTIVE: Our purpose was to document the occurrence of these lesions in HIV-infected patients and to characterize the histopathologic and immunophenotypic features of nodular EED. METHODS: Clinicopathologic studies were supplemented by special stains of biopsy specimens. RESULTS: EED may be a complication of HIV infection. Nodules of EED are composed of small aggregates of Mac-387+ spindled cells. Within the aggregates can be seen neutrophils, nuclear dust, and fibrin. The marked fibrosis of the lesions may account for the lack of response to dapsone. CONCLUSION: EED should be considered in the differential diagnosis of juxta-articular nodules in HIV-infected patients; its diagnosis can be confirmed by biopsy.
Unusual erythema elevatum diutinum with fibrohistiocytic proliferation. Porneuf M, Duterque M, Sotto A, Jourdan J. Department of Internal Medicine, University of Nimes, France.	Br J Dermatol 1996 Jun;134(6):1131-4 Abstract quote 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.

 

SPECIAL STAINS/ IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
FACTOR XIIIa
Factor XIIIa+ dermal dendrocytes in erythema elevatum diutinum and ordinary cutaneous leukocytoclastic vasculitis lesions. Pacheco LS, Sotto MN. University of Sao Paulo School of Medicine, Department of Pathology and Dermatology, Brazil.	J Cutan Pathol 2000 Mar;27(3):136-40 Abstract quote 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.
ELECTRON MICROSCOPY
Ultrastructural study of chronic lesions of erythema elevatum diutinum: "extracellular cholesterosis" is a misnomer. Kanitakis J, Cozzani E, Lyonnet S, Thivolet J. Department of Dermatology, Ed. Herriot Hospital, Lyon, France.	J Am Acad Dermatol 1993 Aug;29(2 Pt 2):363-7 Abstract quote Erythema elevatum diutinum (EED) is a rare disease of unknown origin that belongs to the spectrum of leukocytoclastic vasculitis. Chronic lesions of EED contain lipid deposits, for which the term extracellular cholesterosis has been coined. We studied a typical case of EED with long-standing lesions. Findings of electron microscopic examination revealed a heavy, exclusively intracellular lipid deposition that consisted of lipid droplets, myelin figures, and rare cholesterol clefts within histiocytes but also within epidermal keratinocytes, mast cells, pericytes, and lymphocytes. These findings are in keeping with the results of previous ultrastructural studies and suggest that the term extracellular cholesterosis is a misnomer; intracellular lipidosis would more accurately describe the lipid deposition.
Erythema elevatum diutinum: an ultrastructural case study. Lee AY, Nakagawa H, Nogita T, Ishibashi Y. Department of Dermatology, Faculty of Medicine, University of Tokyo, Japan.	J Cutan Pathol 1989 Aug;16(4):211-7 Abstract quote An electron microscopic study was made of a patient with erythema elevatum diutinum, a rare variant of cutaneous leukocytoclastic vasculitis. Biopsies were obtained from early evolving and late fibroproliferative lesions. Early lesions showed vasculitis and a massive dermal infiltrate composed mainly of neutrophils, histiocytes/macrophages and apparently increased Langerhans cells. Later lesions were characterized by a dense fibrosis with a proliferation of fibroblasts and myofibroblasts and a dermal infiltrate in which lymphocytes and histiocytes/macrophages predominated. Even in later lesions, dermal Langerhans cells were observed in great number. Langerhans cells may be involved in the evolution of this rare disease.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
GRANULOMA FACIALE
Granuloma faciale with extrafacial lesions. Roustan G, Sanchez Yus E, Salas C, Simon A. Department of Dermatology, Clinica Universitaria Puerta de Hierro, Madrid, Espana.	Dermatology 1999;198(1):79-82 Abstract quote 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.
LEUKOCYTOCLASTIC VASCULITIS
LOCALIZED CHRONIC FIBROSING VASCULITIS
Localized chronic fibrosing vasculitis of the skin: an inflammatory reaction that occurs in settings other than erythema elevatum diutinum and granuloma faciale. Carlson JA, LeBoit PE. Department of Pathology, Albany Medical College, New York, USA.	Am J Surg Pathol 1997 Jun;21(6):698-705 Abstract quote Erythema elevatum diutinum (EED) and granuloma faciale (GF) are chronic, localized forms of cutaneous leukocytoclastic vasculitis that result in patterned (storiform or concentric) fibrosis. EED often occurs in systemically ill patients as bilaterally symmetrical plaques, papules, or nodules, often over the dorsa of joints. GF occurs as one or a few plaques on the face. Eosinophils and plasma cells are prominent in GF, whereas neutrophils are plentiful in EED. Rarely, extrafacial lesions accompany facial ones in GF, and there are a few reports of upper respiratory tract masses with GF-like histologic features. We report on eight patients with solitary cutaneous lesions with histologic features similar to those of EED or GF, but whose clinical picture was not that of either disease. One, whose histology resembled GF, had a large multinodular dermal and subcutaneous mass that persisted despite attempted resection. Unusual histologic findings in other cases included storiform fibrosis with dense infiltrates of plasma cells, branching nerve fascicles admixed with EED-like changes, and EED-like areas adjacent to zones mimicking a sclerotic fibroma. Chronic fibrosing venulitis can be seen outside the stereotypic settings of GF and EED and is an inflammatory reaction pattern that does not signify a specific diagnosis. Because of transitions between EED or GF-like areas and those of patterned sclerosis with plasma cell-rich infiltrates, we believe that some "inflammatory pseudotumors" of the skin, and perhaps of other sites could be the result of localized vasculitis.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
TREATMENT	Dapsone Corticosteroids
DAPSONE
Erythema elevatum diutinum: skin and systemic manifestations, immunologic studies, and successful treatment with dapsone. Katz SI, Gallin JI, Hertz KC, Fauci AS, Lawley TJ.	Medicine (Baltimore) 1977 Sep;56(5):443-55 Abstract quote Erythema elevatum diutinum is a disease characterized by red, pink, purple and yellow cutaneous papules, nodules, and plaques distributed mainly over extensor surfaces. Histologically, there is leukocytoclastic vasculitis with fibrinoid necrosis of the upper and mid dermal vessel walls. Two of the five patients presented had moderately severe arthralgias and, unlike previously reported cases, three of them had a long history of bacterial infections and one had a coincident IgA monoclonal gammopathy. Each of the four patients treated with dapsone responded dramatically with rapid resolution of existing lesions and marked diminution of systemic symptoms. Skin lesions and systemic complaints recurred within 12 to 48 hours after discontinuing dapsone. Four of the patients had Arthus-like reactions to SKSD skin tests prior to therapy, with a marked decrease in the response after institution of therapy. Neutrophil chemotactic responsiveness of two patients was impaired. The sera of three patients had significant C1q binding activity suggesting that they might have circulating immune complexes.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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