Chapter 165. Erythema Elevatum Diutinum

Erythema elevatum diutinum (EED) is a chronic leukocytoclastic vasculitis (LCV) that was initially described by Hutchinson in 1888 and subsequently by Bury in 1889. The name EED was first used by Radcliff-Crocker and Williams who separated it into two groups.1–3 The Bury type tended to occur more commonly in younger women with a history of underlying rheumatologic disease, and the Hutchinson type tended to occur in elderly males.

The incidence of EED is unknown; however, it appears to be a rare disease. There is no significant mortality associated with EED. It presents predominantly in males, in the fourth to sixth decade of life.

The pathogenesis of EED is not entirely clear; however, the prevailing and traditional theories are based on immune complex deposition within vessel walls, complement fixation, inflammation, and subsequent vascular destruction.1 The various disease associations seen in EED (see Section “Associated Diseases”) have provided further understanding of the underlying pathomechanism of EED.

Antineutrophil cytoplasmic antibodies (ANCA) of the immunoglobulin G (IgG) type have proven useful for the diagnosis and monitoring of disease activity in various systemic vasculitides, including granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis (MPO), polyarteritis nodosa, and Churg–Strauss syndrome.4

There are reports in the literature documenting the occurrence of IgA ANCAs in patients with neutrophil-driven dermatoses such as Henoch–Schönlein purpura, inflammatory bowel disease, and various cutaneous vasculitides, including EED.5,6 It seems likely that abnormal functioning or activation of the neutrophil, which is the primary inflammatory cell in EED, may represent the central event. Most importantly, some of the neutrophilic dermatoses, including EED, have been associated with underlying paraproteinemias (monoclonal and polyclonal IgA gammopathies)7 and hematologic malignancies. The severity of EED does not, however, appear to be dependent on the total paraprotein levels. Nevertheless, immunoelectrophoresis screening for monoclonal gammopathies as a marker of EED has been recommended.8 Hence, IgA ANCAs against yet unidentified neutrophilic antigenic targets may prove to be useful clinical markers in EED.9

In a recent analysis of the clinical, histopathologic, and immunohistochemical features in six patients with EED by Wahl et al,8 the vascular endothelium of EED was immunoreactive for CD31, CD34, vascular endothelial growth factor, and factor VIIIa but nonimmunoreactive for factor XIIIa, transforming growth factor-β, and latency-associated nuclear antigen of human herpesvirus 8. The staining properties of the endothelium in EED were compared to endothelial staining in similar lesions, including LCV, urticarial vasculitis, dermatofibromas, and capillary hemangiomas. No significant differences in the immunohistochemical staining properties were observed. The authors concluded that the chronic and recurrent nature of EED is the primary means of distinguishing it from other entities that are similar clinically and histologically.8

EED typically presents as multiple, persistent, symmetric, and erythematous to violaceous papules/nodules/plaques on the extensor surfaces of the hands (Fig. 165-1), elbows (Fig. 165-2), wrists, knees (Fig. 165-3), ankles, Achilles tendons, fingers (Fig. 165-4) and toes, buttocks (see eFig. 165-4.1), face, ears, legs, forearms, and genitals.1 The trunk, however, is usually spared, but may be involved rarely.10 Other atypical sites of involvement include the retroauricular and palmoplantar regions.1,2,10 Overlying epidermal changes, such as vesicles, bullae or ulcers, may be present. Lesions may be exacerbated by cold exposure and may become more raised, erythematous, and firm in the evening.11–13

With time, the lesions may become firmer and develop a yellowish-brown coloration, resembling xanthomata (see Fig. 165-2). These eventually heal with dyspigmentation. The onset of new lesions may be associated with symptoms of pruritus, burning, stinging sensations, paresthesias, or may be completely asymptomatic. Constitutional symptoms, including fever and arthralgias, are seen commonly.1,14

The clinical presentation of EED in human immunodeficiency virus-infected (HIV-infected) individuals is somewhat different and can mimic lesions of Kaposi sarcoma and bacillary angiomatosis usually seen in immunosuppressive states.15 Nodular lesions have been reported in HIV-infected patients.

For histopathology see Figure 165-5.

Histopathology

Histopathologic findings are predominantly those of a chronic LCV, with thickening of blood vessel walls, mural and luminal neutrophilia, vascular occlusion, fibrinoid necrosis of vessel walls, endothelial cell swelling, leukocytoclasia, and dermal neutrophilia with lymphocytes (Fig. 165-5). Epidermal changes of hyperkeratosis, acanthosis, ulceration, subepidermal edema, and bulla formation may also be observed.1,3,16

The histopathologic features characteristic for EED are not usually all present within the same lesion. There is an evolution of the pathologic features that can be seen with progression from the early stages into the later stages of disease.

Early stage lesions are characterized by leukocytoclastic vasculitis with a moderately dense perivascular inflammatory infiltrate consisting of neutrophils, leukocytoclastic debris, macrophages, and histiocytes (see eFig. 165-5.1). Fibrin deposition is also evident within the vascular walls. At this stage, the histologic differential diagnosis is broad and includes all the potential causes of LCV. However, the histologic features of EED at this early stage may mimic those of dermatitis herpetiformis. The distinguishing feature for dermatitis herpetiformis includes a limitation of the neutrophilic infiltrate to the papillary dermis, whereas in EED the infiltrate tends to be more diffuse. Other entities to consider in the differential diagnosis include the neutrophilic dermatoses, such as Sweet syndrome, bowel bypass syndrome, and rheumatoid neutrophilic dermatitis, none of which has LCV as a predominant feature.17 Clinicopathologic correlation is necessary to establish the diagnosis in the early stages of disease.

With progression of disease, a granulation tissue-like response with fibroplasia and capillary proliferation becomes the predominant feature1,3 (see eFigs. 165-5.1 and 165-5.2). The infiltrate is increasingly composed mostly of histiocytes, some with phagocytosed nuclear debris. At this stage, the histopathologic features (see eFig. 165-5.3) may be indistinguishable from other fibrosing lesions, such as a solitary sclerotic fibroma, fibrous histiocytomas, and dermatofibrosarcoma protuberans, or vascular lesions such as pyogenic granuloma, Kaposi sarcoma, and bacillary angiomatosis.1,17,18 In the later stages of disease, xanthomatization is occasionally observed. This is characterized by the presence of both intra- and extracellular cholesterol deposits within infiltrating histiocytes and the dermis as demonstrated by ultrastructural studies.1,19

Direct immunofluorescence findings of lesional skin are generally nondiagnostic and range from few to many blood vessels within the superficial to middermis, with variable staining with various conjugates, including IgG, IgM, C3, and fibrinogen.14,20

Other Laboratory Findings

(See Section “Associated Diseases” and Table 165-1)

EED has been reported in association with a wide range of disease processes (see Table 165-1). Notable associations include chronic bacterial infections, especially streptococcal infections; HIV infection; underlying monoclonal and polyclonal gammopathies; and connective tissue diseases. Some of these disease associations have provided further insight into the pathogenesis of EED.

The most frequent disease association with EED is IgA paraproteinemia. Lesions of EED have been noted to flare with increased IgA levels. Hence, IgA paraprotein levels have been proposed to be a useful clinical marker in EED.23 Other notable associations have included chronic bacterial, viral, and parasitic infections. Bacterial infections, especially streptococcal infections, have been associated with EED, and typical skin lesions have been reproduced or exacerbated by the intradermal injection of streptococcal antigens.1,3,23 Juxta-articular nodules of EED have been observed in patients with HIV infection. The histopathology of these nodules usually reveals a predominance of fibrosis rather than a neutrophilic infiltrate, probably secondary to the advanced/chronic stage of such lesions.15,24,25 The role of infectious agents in the etiopathogenesis of EED is still unclear, but evidence suggests that perhaps these agents serve as antigenic triggers of a hypersensitivity response that manifests as EED.

Connective tissue diseases and autoimmune diseases have also been seen in association with EED.

As is the case with cutaneous vasculitis, treatment is aimed at alleviating discomfort associated with the lesions, diminishing damage to the skin, and eradication/minimization of underlying/associated conditions. Reports in the literature on treatment options are primarily anecdotal or based on experience in small case series. Management of EED remains challenging due to the chronic and recurrent nature of the disease. In general, treatment of the underlying cause or infectious process may result in resolution of lesions.1 Dapsone- and sulfone-based therapies are considered first-line treatment choices for EED.1,3,14,26 Dramatic and rapid response is usually seen within 48 hours of initiation of therapy, with near complete resolution of lesions within weeks to months.26 However, lesions may recur with discontinuation of therapy.1,23 The responsiveness of EED and other neutrophil-driven dermatoses to dapsone and sulfonamides is not completely known but is thought to be secondary to its inhibitory effects on neutrophil chemotaxis and function.13 In patients with HIV infection, treatment with a combination of antiretroviral agents and dapsone or sulfonamides may be beneficial.1 Other reported treatments with variable success in EED include niacinamide and tetracycline,27 colchicine,28 intralesional, potent topical or oral corticosteroids,3 phenformin,29,30 clofazimine,12 and cyclophosphamide.31

EED is a distinctive form of cutaneous vasculitis. It is the clinical pattern combined with the chronicity of this process that is unique to EED. Repeated antigenic stimulation or infection appears to play a key role in the pathogenesis. Although microscopic features of early lesions are shared with other cutaneous vasculitides, in the chronic phase of the disease, the microscopic pattern may resemble various other entities characterized by granulation response and healing skin. It is important to search for an underlying disease and to evaluate patients carefully for infection. Otherwise, treatment recommendations are anecdotal and similar to those used for other cutaneous vasculitides.