Erythema elevatum diutinum

INTRODUCTION — Erythema elevatum diutinum (EED) is a chronic form of cutaneous small vessel vasculitis consisting of violaceous, red-brown, or yellowish papules, plaques, or nodules that favor the extensor surfaces (picture 1A-D) [1,2]. Histologic leukocytoclastic vasculitis is a key confirmatory diagnostic feature. EED may occur in association with infections, hematologic abnormalities, autoimmune diseases, or other conditions. Oral dapsone is the primary mode of treatment.

The clinical features, diagnosis, and management of EED will be reviewed here. Other manifestations of cutaneous small vessel vasculitis are reviewed separately. (See "Overview of cutaneous small vessel vasculitis" and "Evaluation of adults with cutaneous lesions of vasculitis".)

EPIDEMIOLOGY — EED is a rare disease that most frequently affects young and middle-aged adults between the ages of 30 and 60 years. There are rare reports of EED in children [3,4]. There is no known sex or racial predilection [5].

PATHOGENESIS — The pathogenesis of EED is not well understood. EED appears to be a form of immune complex-mediated vasculitis. The cutaneous findings may result from the deposition of immune complexes in small blood vessels in the skin, leading to complement activation, neutrophilic infiltration, and the release of destructive enzymes [6]. In support of this theory, direct immunofluorescence studies reveal perivascular deposition of complement, immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), and fibrin in EED [7].

In addition, the findings of an in vitro study suggest that activation of cytokines such as interleukin (IL) 8 contributes to selective recruitment of leukocytes to affected skin [8]. This exaggerated neutrophil recruitment may contribute to the development of subsequent tissue damage and fibrosis by inducing apoptosis in endothelial cells [9]. Furthermore, IL-8 may trigger endothelial-to-mesenchymal transition and increase endothelial-derived fibroblasts/myofibroblasts, resulting in fibrosis [10,11]. Antineutrophil cytoplasmic antibodies (ANCA) may also play a role in the pathogenesis of EED [12].

CLINICAL FEATURES — EED most commonly manifests as a bilateral eruption of violaceous, red-brown, or yellowish papules, plaques, or nodules (picture 1A-D). Early EED tends to be soft and erythematous. Older lesions are often more firm secondary to fibrosis.

EED is most frequently found on acral skin and periarticular skin. The extensor surfaces of the elbows, knees, ankles, hands, and fingers are common locations [1,2]. Less frequently involved sites include the face, retroauricular area, trunk, axillae, buttocks, genitalia, palms, and soles [13-16].

Nodular lesions progressing to bulky masses appear to be more common in patients with EED associated with human immunodeficiency virus (HIV) infection than in other patients with EED [17-20]. Additional reported presentations of EED include annular plaques with raised borders [13,21]; verrucous plaques on the soles [22-24]; vesicobullous presentations [25-28]; a keloid-like appearance [29]; and tender, red plaques limited to sites of old burn scars [30]. (See 'Associated disorders' below.)

The cutaneous manifestations of EED may be asymptomatic or associated with a burning or stinging sensation or pruritus [27,31,32]. These symptoms are more likely to be present early in the course of disease. Extracutaneous symptoms may include arthralgia, fever, or other constitutional symptoms [31]. Ocular abnormalities, such as peripheral keratitis, nodular scleritis, panuveitis, and blindness, have also been reported in patients with EED [33-35].

ASSOCIATED DISORDERS — EED may occur in association with a number of systemic diseases. Examples of disorders that have been linked to EED in the literature include infections, hematologic disorders, and autoimmune diseases. However, data are insufficient for definitive conclusions on a causative relationship between these diseases and EED:

●Infection – Infections reported to occur in association with EED have included HIV infection [36-46], beta-hemolytic streptococcal infections [47], hepatitis [48-50], and tuberculosis [51]. A literature review of published reports between 1977 and 2012 identified 19 reported cases of EED in association with HIV infection [20]. The relationship between EED and HIV infection is postulated to involve immune complex deposition in blood vessels triggered by the HIV infection itself or other infections acting as antigenic stimuli [44]. EED has occurred in HIV-positive patients with concomitant tuberculosis, hepatitis C, or hepatitis B [46,48,52].

●Hematologic disorders – Hematologic disorders reported to occur in conjunction with EED include plasma cell dyscrasias (particularly IgA monoclonal gammopathies), myelodysplasia, myeloproliferative disorders, B cell lymphoma, and hairy cell leukemia [1,27,53-58]. EED may appear years after the diagnosis of the hematologic disease [1].

●Autoimmune disease – EED has occurred in patients with a variety of autoimmune and inflammatory diseases. Examples include inflammatory bowel disease [59-61], rheumatoid arthritis [62-65], celiac disease [66-68], relapsing polychondritis [69,70], lupus erythematosus [71-73], granulomatous polyangiitis [74], and dermatomyositis [75].

Other sporadic reports of disease associations include breast carcinoma [76], dermatitis herpetiformis [77], diffuse neuropathy [78], and elevated cryoglobulin levels [79]. One report describes a patient with simultaneous EED; pyoderma gangrenosum; and chronic, recurrent, annular dermatosis [80].

HISTOPATHOLOGY — The histopathologic features of EED vary over time. Early EED exhibits leukocytoclastic vasculitis, demonstrating perivascular neutrophilic infiltrates in the upper and mid-dermis and fibrin deposition within or around the walls of small blood vessels [20]. Lymphocytes, histiocytes, and (occasionally) a few eosinophils are also present (picture 2A-B). As the lesions mature, histiocytes and granulation tissue become more prevalent [20].

Later-stage EED may exhibit dermal fibrosis with spindle cells and fibrinoid necrosis or fibrosis of capillary walls. Vertically oriented capillaries may be evident. In some cases, vasculitis is difficult to appreciate. Intracellular lipidosis manifesting as cholesterol clefts may be present [81].

DIAGNOSIS — The diagnosis of EED is made based upon correlation of the clinical and histologic findings. There are no serologic studies that confirm a diagnosis of EED.

Clinical evaluation — A full dermatologic examination should be performed in patients with suspected EED. Clinical findings that strongly support a diagnosis of EED are persistent violaceous, red-brown, or yellowish papules, plaques, or nodules that are symmetrically distributed on acral or periarticular sites (particularly the extensor surfaces of the elbows, knees, ankles, hands, and fingers (picture 1A-D)). However, atypical distributions may also occur [82]. Ulceration and vesiculation are rare findings. Patients may report an associated stinging or burning sensation or pruritus. (See 'Clinical features' above.)

Skin biopsy — A skin biopsy is necessary to confirm the diagnosis. The biopsy specimen should contain the full thickness of the skin. We typically perform a punch biopsy that extends into the superficial subcutaneous fat.

Biopsy of a soft, early lesion is preferable to a biopsy of older, fibrotic lesions. Leukocytoclastic vasculitis is the key histologic finding of early EED. Granulation tissue, spindle cells, and fibrosis are common findings in later-stage EED. (See 'Histopathology' above.)

Direct immunofluorescence studies are usually not necessary for the evaluation of EED. If performed, perivascular deposits of fibrin, complement, and immunoglobulins may be seen [20].

EVALUATION — Once the diagnosis of EED is made, the possibility of an associated disease should be considered. Appropriate initial tests to evaluate for underlying disease include:

●Complete blood count

●Comprehensive metabolic panel

●HIV test

●Immunofixation electrophoresis

●Antistreptolysin O or antideoxyribonuclease B titer

●Hepatitis B and C serology

●Antinuclear antibody (ANA)

●Antineutrophil cytoplasmic antibodies

●Antiphospholipid antibodies [83]

●Chest radiograph

●Urinalysis

Specific testing for other infections or autoimmune diseases should be based upon the presence of suggestive signs, symptoms, or patient history. Performance of a complete review of systems and physical examination is optimal.

Because ocular abnormalities may occur in patients with EED, referral for ophthalmologic evaluation is appropriate for patients with ocular symptoms. (See 'Clinical features' above.)

DIFFERENTIAL DIAGNOSIS — Multiple disorders share clinical features with early or late-stage EED. Skin biopsy typically helps to distinguish between EED and other diseases.

The soft papules or plaques often representative of early EED may resemble extrafacial granuloma faciale, Sweet syndrome, rheumatoid neutrophilic dermatosis, or palisaded neutrophilic and granulomatous dermatosis:

●Granuloma faciale – Granuloma faciale is an uncommon disorder of unknown etiology characterized by one or more persistent, asymptomatic, smooth, red-brown or violaceous papules, plaques, or nodules, often with follicular prominence (picture 3). The face is the most common location. Histologic similarities between granuloma faciale and EED include inflammatory infiltrates containing neutrophils and eosinophils, as well as vasculitis and fibrosis on histopathologic examination. However, granuloma faciale may be more likely to exhibit a dense inflammatory infiltrate, plasma cells, and a predominance of eosinophils [84]. In addition, the presence of granulomas may be more likely in EED. (See "Granuloma faciale".)

●Sweet syndrome – Sweet syndrome is an acute neutrophilic dermatosis characterized by multiple tender, erythematous plaques or pustules on the face, neck, upper trunk, and extremities (picture 4A-B). Associated fever, leukocytosis, arthralgias, myalgias, headaches, and general malaise are common. On histopathology, there is a diffuse neutrophilic infiltrate in the upper dermis. Unlike EED, leukocytoclastic vasculitis usually is absent. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

●Rheumatoid neutrophilic dermatosis – Rheumatoid neutrophilic dermatosis (RND) classically presents as asymptomatic papulonodules or plaques distributed on the extensor surfaces of extremities (particularly the hands and forearms) as well as the neck and trunk (picture 5). RND usually occurs in association with rheumatoid arthritis, but can also develop in patients with seronegative arthritis. Histologic findings include a dense neutrophilic dermal infiltrate without vasculitis. (See "Neutrophilic dermatoses", section on 'Rheumatoid neutrophilic dermatitis'.)

●Palisaded neutrophilic and granulomatous dermatosis – Palisaded neutrophilic granulomatous dermatosis (PNGD) is a rare neutrophilic dermatosis with varied clinical presentations. The most common clinical presentation is erythematous papules symmetrically distributed on extensor surfaces of the upper extremities, especially the fingers and elbows. PNGD usually presents in patients with an underlying systemic condition such as rheumatoid arthritis and other autoimmune diseases, lymphoproliferative disorders, or infection. (See "Neutrophilic dermatoses", section on 'Palisaded neutrophilic granulomatous dermatitis and interstitial granulomatous dermatitis'.)

Disorders in the differential diagnosis of late-stage EED primarily include disorders that may present with firm papules, plaques, or nodules on extensor surfaces, such as tuberous xanthomas, rheumatoid nodules, and multicentric reticulohistiocytosis:

●Tuberous xanthomas – Tuberous xanthomas present as pink-yellow papules or nodules on extensor surfaces, especially the elbows and knees (picture 6). Tuberous xanthomas occur in association with disorders of lipid or cholesterol metabolism. A biopsy reveals foamy cells and cholesterol clefts. (See "Cutaneous xanthomas".)

●Rheumatoid nodules – Rheumatoid nodules are common in patients with rheumatoid arthritis. Affected patients develop firm, semi-mobile nodules that are several millimeters to a few centimeters in diameter (picture 7). Rheumatoid nodules are usually found in periarticular locations over extensor surfaces and in areas subject to pressure or trauma. The nodules are often asymptomatic, but may be tender or painful, particularly if there is associated trauma or ulceration. Histologic findings include a central zone of brightly eosinophilic fibrin surrounded by a palisaded layer of histiocytes and granulation tissue. Acute or early lesions may show leukocytoclastic vasculitis or an interstitial neutrophilic infiltrate. (See "Rheumatoid nodules".)

●Multicentric reticulohistiocytosis – Multicentric reticulohistiocytosis is a disease characterized by cutaneous and mucous membrane reticulohistiocytomas and severe arthropathy. The cutaneous manifestations are skin-colored, pink, red-brown, or yellow papules or nodules that range from a few millimeters to 2 cm in diameter (picture 8). Favored sites include the head, hands, fingers, ears, and articular regions of the limbs. Small papules aligned along the periungual regions result in a characteristic "coral bead" appearance. Numerous multinucleated giant cells with eosinophilic, granular cytoplasm is the key histologic finding. (See "Cutaneous manifestations of internal malignancy", section on 'Multicentric reticulohistiocytosis'.)

Other granulomatous disorders (eg, granuloma annulare, sarcoidosis, leprosy, necrobiotic xanthogranuloma) may be considered in the differential diagnosis of EED. In addition, an isolated fibrotic papule, plaque or nodule of EED may resemble a dermatofibroma, dermatofibrosarcoma protuberans, or keloid. Occasionally, EED with a prominent vascular component, especially in an HIV-infected patient, might be mistaken for Kaposi sarcoma or bacillary angiomatosis [19,52].

TREATMENT — Although EED is a benign and usually asymptomatic disorder, the chronic and disfiguring course drives most patients to seek treatment.

First-line therapy — Due to the rarity of EED, there are limited data on the treatment of this disease. First-line treatment consists of dapsone therapy based upon multiple reports of improvement in EED following use of this therapy. Treatment of an associated underlying disorder (if present) is also recommended [20]. Improvement in EED has been reported after treatment of associated IgA paraproteinemia [53,85], B cell lymphoma [57], ulcerative colitis [60], pulmonary lymphoepithelioma-like carcinoma [86], and multiple myeloma [87].

Dapsone — Dapsone is the medical treatment of choice for EED:

●Efficacy – Use of dapsone for EED is primarily supported by multiple case reports and small case series [8,11,16,18,20,27,33,38,40,42,46,47,52,55,57,61,62,73,88-92]. A review of the literature published from 1990 to 2014 identified 75 reported cases of EED treated with dapsone. Thirty-six had full response, 24 had partial response, and 7 had no response. Eight patients had to discontinue therapy due to adverse events [50]. No randomized trials have evaluated dapsone for EED.

Dapsone is often ineffective for fibrotic nodular EED [5,13,19]. Therefore, dapsone may be most beneficial for early disease. (See 'Clinical features' above and 'Histopathology' above.)

In addition to cutaneous disease, dapsone may improve extracutaneous symptoms. Arthralgias and ocular symptoms have improved during dapsone treatment [20,35].

●Administration – Dapsone therapy for EED has been given in doses ranging from 50 to 300 mg per day [20]. A lower dose is typically administered (25 to 50 mg) at the start of treatment. The dose is then titrated upward dependent on patient tolerance and response to therapy. The usual adult dose for EED is 100 mg per day.

Benefit of dapsone for EED may be dose dependent [93]. Reductions in the size of EED lesions may be evident within the first few months of treatment [8,94].

●Adverse effects – Dapsone therapy is associated with risk for a variety of adverse effects, including hemolysis, agranulocytosis, methemoglobinemia, dapsone hypersensitivity syndrome, and peripheral neuropathy (table 1). Although hemolysis occurs to some degree in all patients, individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk for severe hemolytic anemia. Therefore, screening for G6PD deficiency should be performed prior to initiating dapsone therapy. Periodic laboratory monitoring for hematologic or liver abnormalities is also indicated during dapsone therapy. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia' and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Other therapies — Other local, surgical, and systemic therapies for EED have been reported to improve EED in small numbers of patients. Although these treatments may benefit some patients, there are fewer data on the efficacy of these therapies than for dapsone, precluding a recommendation for use as first-line therapy:

●Local treatment – Potent topical corticosteroids and intralesional corticosteroid injections have been administered for EED with variable results [31]. Potential benefit of topical dapsone is suggested by a case report in which application of dapsone 5% gel to EED for one week prior to the start of oral dapsone therapy was associated with improvement in erythema and flattening of lesions [95].

●Systemic treatment – Systemic therapies reported as effective in a few patients have included a variety of agents with antimicrobial, anti-inflammatory, or immunosuppressive properties. Improvement in EED has been reported after treatment with sulfasalazine, sulfapyridine, or sulfamethoxypyridazine [20,93,96] as well as tetracycline alone or combined with niacinamide [97,98]. In addition, individual patients have seemed to respond to regimens including colchicine [99], methotrexate [100], chloroquine [93], phenformin [101], mycophenolate mofetil [102], or cyclosporine combined with dapsone [103]. Antibiotics such as clarithromycin, erythromycin, and penicillin have also been administered for EED in combination with surgical excision or dapsone, with varying outcomes [19].

Oral glucocorticoids may improve EED when used alone or in conjunction with dapsone or other therapy [20,69,75]. However, oral glucocorticoids are rarely indicated due to the chronic nature of EED and, therefore, the risk for serious adverse effects with long-term glucocorticoid therapy. Rebound may occur upon discontinuation of systemic glucocorticoids. (See "Major adverse effects of systemic glucocorticoids".)

●Surgery – Fibrotic nodules often respond poorly to dapsone. Local surgical excision can be beneficial for localized fibrotic nodules of EED [29,104-106].

PROGNOSIS — EED usually has a prolonged course, characterized by fluctuating periods of exacerbation and stability. The disease may resolve spontaneously after 5 to 10 years; however, persistence up to 40 years has occurred [5,93]. EED does not progress to systemic vasculitis [31]. Recurrence is common after cessation of dapsone therapy [31].

SUMMARY AND RECOMMENDATIONS

●Overview – Erythema elevatum diutinum (EED) is a rare form of cutaneous small vessel vasculitis consisting of violaceous, red-brown, or yellowish papules, plaques, or nodules that favor the extensor surfaces (picture 1A-D). EED is most common in adults between the ages of 30 and 60 years. (See 'Clinical features' above and 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of EED is not well understood. EED may represent an immune complex-mediated vasculitis. The disorder may occur in association with infections, hematologic disorders, or autoimmune diseases. (See 'Pathogenesis' above and 'Associated disorders' above.)

●Diagnosis – The diagnosis of EED is made based upon correlation of the clinical and histologic findings. (See 'Diagnosis' above.)

●Treatment – Treatments for EED have included local medications, systemic medications, and surgery. We suggest oral dapsone as initial treatment based upon multiple case reports and small case series that suggest efficacy and the well-tolerated nature of this treatment (Grade 2C). In addition, the associated underlying disease (when present) should be treated. (See 'First-line therapy' above.)

●Prognosis – EED exhibits a prolonged course, characterized by fluctuating periods of exacerbation and stability. (See 'Prognosis' above.)