Erythema Elevatum Diutinum

Etiology

The cause of EED is not well understood, but it is thought to be secondary to immune complex deposition in dermal blood vessels, which results in complement fixation and subsequent inflammation. The findings appreciated on examination of the skin may be seen due to deposition of immune complexes in small vessels, which leads to activation of complement, the influx of neutrophils, and the emission of destructive enzymes. Antineutrophil cytoplasmic antibodies may be pathogenic in EED. Furthermore, the initiation of EED may occur via activation of cytokines (interleukin-8), which causes selective recruitment of leukocytes to blood vessels. This leads to repetitive damage to the vessels and ultimately develops into fibrosis. [3][2][1]

Epidemiology

EED is rare, with descriptions of only several hundred cases in the literature. The disease can develop at any age but is more common in the fourth and sixth decades. An earlier onset occurs more often in the setting of HIV infection. The male-to-female ratio is approximately equal, and no racial predilection has been observed. [1]

Pathophysiology

Although the etiology of EED is unknown, circulating immune complexes, with repeated deposition, associated inflammation, and partial healing are thought to represent the underlying pathogenesis. Immune complex deposition results in complement activation, neutrophilic infiltration, and the release of destructive enzymes. This results in fibrin deposition in and around small dermal vessels during the later stages of the disease.[3]

EED has been described in association with a number of systemic diseases. It is frequently found with hematologic disorders, such as IgA monoclonal gammopathy, myelodysplasia, myeloproliferative disorders, paraproteinemia, and hairy cell leukemia. Infections from group B streptococci, HIV, syphilis, and viral hepatitis are commonly associated with EED as well as autoimmune conditions, such as celiac disease, Crohn disease, systemic lupus erythematosus and rheumatoid arthritis. In the study performed by Katz et al., two of five patients with EED demonstrated a prevalence of recurrent bacterial infections that were usually Streptococcal in nature. They also demonstrated increased C1q binding in three of five patients, a finding suggestive of the presence of circulating immune complexes. [4][1][5]

Histopathology

Histologically, EED is characterized by early changes of a leukocytoclastic vasculitis with a polymorphonuclear cell infiltrate and deposition of fibrin in the superficial and mid dermis. Polymorphonuclear cells, macrophages, histiocytes, and eosinophils may surround the blood vessels. These infiltrates may accumulate between collagen bundles. A papillary edema also may be seen in early lesions as a reflection of clinical pseudo vesiculation.[4][6]

Over time, the infiltrate contains more histiocytes and granulation tissue, and spindle cell proliferation may be seen. Extracellular cholesterol deposits may be observed in the fibrotic tissue. The fibrosis of late lesions is most likely a result of chronic dermal injury of leukocytoclastic vasculitis. Direct immunofluorescence may reveal changes consistent with vasculitis, such as fibrin deposits, intravascularly and perivascularly, complement, and immunoglobulins (IgG, IgA, IgM). [7][5][8]

History and Physical

On exam, lesions of EED present as red–brown, yellowish, or violaceous papules, plaques, or nodules. They typically are symmetrically distributed and favor acral and periarticular sites, specifically the extensor surfaces of the elbows, knees, ankles, hands, and fingers. Additional sites of involvement include the face, retro-auricular area, axillae, buttocks, and genitalia. The trunk is usually spared. The lesions usually feel firm and are mobile over the underlying tissue, except typically on the palms and the soles. [9][10]

Initially, the lesions are erythematous and soft but with time become red–brown or violaceous in color and firm to palpation secondary to fibrosis. Over the course of the disease process, the lesions can change in color as well as an increase in size and quantity. [2][11]

Typically, the lesions are asymptomatic, but there have been reports of patients who experienced pruritus and burning or tingling sensations, especially early in the disease course. EED in the setting of HIV infection is characterized by nodular lesions, used palmoplantar, that progress to form bulky masses. Arthralgias may develop in underlying joints, but extracutaneous involvement is extremely rare. The exception includes ocular abnormalities such as scleritis, uveitis, autoimmune keratolysis, and peripheral keratitis. [2][12]

The disease is chronic and has a relapsing and remitting course. The majority of cases resolve spontaneously over a period of 5 to 10 years, but the disease can last up to 40 years. EED lesions do not typically leave scars but can resolve with areas of hyperpigmentation or hypopigmentation. No mortality due to EED has been reported. [3][13]

Evaluation

A skin biopsy is the most useful study for the diagnosis of EED. Electron microscopy is not a necessary diagnostic tool but would show changes and features of leukocytoclastic vasculitis. The erythrocyte sedimentation rate in patients with EED is often elevated. Antineutrophil cytoplasmic antibodies of IgA class may be helpful as a marker of disease, and Immunoelectrophoresis can also be used to identify possible gammopathies.[14][5]

Treatment / Management

Treatment of EED is difficult because the disorder follows a chronic and recurrent course.

Dapsone, a sulfonamide antibiotic that impairs neutrophil chemotaxis and function, is the most effective treatment agent, but relapse is common upon discontinuation. It is also ineffective in nodular lesions, due to the fibrosis of the lesions. Other therapies include NSAIDs, niacinamide, tetracyclines, chloroquine, colchicine, and plasmapheresis. Topical and intralesional corticosteroids may be helpful for mild cases, but systemic corticosteroids are rarely indicated.[14](B3)

Antimicrobials, such as tetracyclines, are thought to alter neutrophil chemotaxis and phagocytosis, suppressing neutrophil chemotaxis and random migration in vivo. Niacinamide, an in vitro specific inhibitor of cyclic AMP, acts as a transfer factor needed for the suppression of antigen-induced lymphocyte transformation. It is relatively non-toxic and can be used in the treatment of neutrophil-driven disorders, with fewer side effects than dapsone. Local surgical excision can be beneficial for localized fibrotic nodules of EED. Regardless of treatment, the recurrence rate of EED is high if the underlying triggering factors are not controlled.[3][2][1](B3)

Differential Diagnosis

• Acute febrile neutrophilic dermatosis

• Dermatofibroma

• Erythema multiforme

• Granuloma annulare

• Granuloma faciale

• Multicentric reticulohistiocytosis

• Pyoderma gangrenosum

• Xanthomas