Erythema Elevatum Diutinum 

Updated: Mar 22, 2019
Author: Firas G Hougeir, MD; Chief Editor: William D James, MD 

Overview

Background

Erythema elevatum diutinum (EED) is a rare type of leukocytoclastic vasculitis characterized by red, purple, brown, or yellow papules, plaques, or nodules. These lesions are usually distributed on the extensor surfaces of the body.[1] Erythema elevatum diutinum was first described in 1888 by Hutchinson[2] and in 1889 by Bury.[3] However, the name erythema elevatum diutinum was first used by Radcliff-Crocker and Williams[4] who found similarities between the cases of Hutchinson and Bury and their own. No clinical examination difference is apparent between the Hutchinson type and the Bury type of erythema elevatum diutinum. The difference lies in the patient population and possibly the cause of onset.

Pathophysiology

The pathophysiology of erythema elevatum diutinum is not well understood. According to Gibson and Su,[5] the lesions are thought to be caused by the deposition of immune complexes in small blood vessels. This induces an inflammatory cascade, which damages the vessels. This repetitive damage causes fibrosis and the appearance of cholesterol crystals and myelin figures in the vessels. Direct immunofluorescence shows deposits of complement as well as immunoglobulin G (IgG), immunoglobulin (IgM), immunoglobulin A (IgA),[6] and fibrin around the damaged vessels. The findings from Grabbe et al[7] support the idea that the initiation of erythema elevatum diutinum may occur via activation of cytokines such as interleukin 8, which causes selective recruitment of leukocytes to tissue sites.[8]

Etiology

The cause of erythema elevatum diutinum (EED) has not yet been definitively established.

Disorders that have been associated with erythema elevatum diutinum include recurrent bacterial infections (especially streptococcal), viral infections (including hepatitis B or HIV),[9] rheumatologic disease (in the Bury type), lupus erythematosus, and B-cell lymphoma.[10, 11, 12, 13]

In recent years, several reports, including the 2 largest clinical studies completed on erythema elevatum diutinum, have suggested hematologic disease as the most common factor associated with erythema elevatum diutinum.

Monoclonal gammopathies, especially IgA monoclonal gammopathy, have been found in a significant number of patients in several studies.

Erythema elevatum diutinum has also been reported after the administration of erythropoietin.[14]

Epidemiology

Frequency

Erythema elevatum diutinum is a rare disease. Although first described in 1888, the largest study of erythema elevatum diutinum was published in 1992 and included 13 patients.[15]

Race

No racial predilection is reported for erythema elevatum diutinum.

Sex

Erythema elevatum diutinum is found in both males and females. The Hutchinson type of erythema elevatum diutinum is predominant in men. The Bury type of erythema elevatum diutinum is found in women with a history of rheumatologic disease.

Age

Erythema elevatum diutinum can occur at any age. However, erythema elevatum diutinum is mostly an adult disease that occurs from the third to sixth decade of life. Men with erythema elevatum diutinum are usually older (Hutchinson type), and women are usually younger (Bury type).

Prognosis

Erythema elevatum diutinum is a chronic disease that usually evolves over a 5- to 10-year period, at which point it may resolve. Erythema elevatum diutinum lesions tend to not leave scars, but areas of hyperpigmentation or hypopigmentation can be visible.

No mortality due to erythema elevatum diutinum has been reported. Erythema elevatum diutinum lesions can be completely asymptomatic, but they may be cosmetically disturbing. In other cases, the lesions can be associated with pain, itching, and/or a burning sensation. The most common systemic symptom is joint pain.

Dapsone and other therapies can be successful in limiting the progression of the disease.

 

Presentation

History

Patients with erythema elevatum diutinum (EED) usually present with persistent, firm lesions on the extensor surfaces of their skin, especially over the joints. These lesions are most often nodules and round or oval plaques (see image below). However, on rare occasions, blisters and ulcers may also appear.

Nodular lesions on the knees of a patient with ery Nodular lesions on the knees of a patient with erythema elevatum diutinum.

The color of the lesions progresses over time from yellow or pinkish to red, purple, or brown. In addition to the color changes, patients may describe the lesions as increasing in number and size over time. They may also note that the lesions enlarge during the day and return to their previous size overnight.[16]

The lesions can be completely asymptomatic, painful, or cause a sensation of burning or itching. These symptoms can be exacerbated by cold.

The general health of the patient may be otherwise excellent, although a history of arthralgia is found relatively often with erythema elevatum diutinum.

Physical Examination

Upon physical examination, erythema elevatum diutinum lesions are generally found symmetrically on the extensor surfaces of the skin, especially over the joints.[17]

Clinical studies show a preference for the extensor surfaces of the hands, the wrists, the elbows, the ankles, the Achilles tendons, the fingers, and the toes (see image below).

Plaques and papular lesions on the wrists and the Plaques and papular lesions on the wrists and the dorsum of the hands and the digits of a patient with erythema elevatum diutinum.

The buttocks, the face, and the ears as well as the palms, the soles, the legs, the forearms, and the genitals may be involved[18] ; however, the trunk is usually spared.

The lesions usually feel firm and are freely movable over the underlying tissue, except when on the palms and the soles.[18]

Their surface is generally smooth and sometimes slightly scaly.

Crusting and/or bleeding, although uncommon, have been noted.

Several studies have shown an association of erythema elevatum diutinum with ocular abnormalities, including nodular scleritis, panuveitis, autoimmune keratolysis, and peripheral keratitis.[19, 20] Therefore, attention should be given to ocular symptoms and eye examination findings.

 

DDx

 

Workup

Laboratory Studies

Electron microscopy is not routinely necessary for erythema elevatum diutinum (EED) but should show changes consistent with leukocytoclastic vasculitis.

Direct immunofluorescence study results show changes consistent with vasculitis, including deposits of complement, immunoglobulins (IgG, IgA, IgM), and fibrin intravascularly and perivascularly.

Immunoelectrophoresis (IEP) can be used to identify possible gammopathies. Yiannias et al advocate routine IEP testing for patients with erythema elevatum diutinum. The use of this technique is supported by the growing number of studies showing that monoclonal gammopathies might play a causal role in erythema elevatum diutinum.

A positive reaction to skin testing with streptokinase and streptodornase at 4 and 24 hours has been reported to help determine a causative association with bacterial infection.

The erythrocyte sedimentation rate in patients with erythema elevatum diutinum is often elevated.

Antineutrophil cytoplasmic antibodies of IgA class may become a helpful paraclinical marker of disease.[21]

Procedures

A skin biopsy is the most useful study for the diagnosis of erythema elevatum diutinum. The histologic findings are discussed below.

Histologic Findings

Erythema elevatum diutinum (EED) is a type of necrotizing vasculitis. No specific histologic finding can be used to differentiate erythema elevatum diutinum from other leukocytoclastic diseases. However, the simultaneous presence of several histologic findings can help distinguish erythema elevatum diutinum from other diseases.

Early lesions show vasculitis in the small vessels of the upper and mid dermis. Furthermore, a perivascular infiltrate consisting of mainly polymorphonuclear neutrophils; nuclear dust; and, to a lesser extent, macrophages, lymphocytes, and eosinophils is present throughout the dermis. The infiltrate may accumulate between collagen bundles. In addition, fibrinoid degeneration, first described as toxic hyaline deposits by Weidman and Besancon,[22] can be detected perivascularly. The epidermis can be affected by the changes in the dermis; edema, acanthosis, and even necrosis can be observed. See image below.

Fibrinoid changes in dermal blood vessels with pol Fibrinoid changes in dermal blood vessels with polymorphonuclear neutrophil infiltration.

Granulation tissue and fibrosis in the dermis characterize older lesions. Toxic hyaline is less apparent, but extracellular cholesterol deposits may be observed in the fibrotic tissue.[23] This was termed extracellular cholesterosis (EC) and was thought at first to have a different etiology than erythema elevatum diutinum. Today, EC is known to be a manifestation of erythema elevatum diutinum. Furthermore, the use of the term extracellular cholesterosis tends to be limited since it is now believed that the main lipid deposits are intracellular and that they are formed of cholesterol esters produced by damaged tissue.

 

Treatment

Medical Care

Dapsone (diaminodiphenylsulfone) revolutionized the treatment of patients with erythema elevatum diutinum (EED). Several studies and clinical experience have shown a good response to dapsone, therefore making it the treatment of choice.[24] The dosage depends on each patient. Sulfones have a suppressive effect on erythema elevatum diutinum, as shown by the recurrence of erythema elevatum diutinum after drug withdrawal. Systemic steroids generally have not been found to be effective.

Sulfapyridine has had similar effects as dapsone.

In one study, niacinamide was found to be helpful in suppressing erythema elevatum diutinum.[25]

Intermittent plasma exchange (PLEX) was shown to control IgA paraproteinemia associated with erythema elevatum diutinum.[26] The IgA levels responded to PLEX treatment, followed by consolidative doses of cyclophosphamide. This treatment might be promising for the control of severe erythema elevatum diutinum that is not controlled by dapsone.

Surgical Care

Surgical excision of the lesions is sometimes performed to provide symptomatic relief if medical therapy is not effective.[27]

Diet

A strict gluten-free diet was shown to help achieve full healing of a patient with celiac disease for whom dapsone therapy was not completely effective.[28]

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Sulfones

Class Summary

These agents have been demonstrated to effectively suppress the manifestations of erythema elevatum diutinum.

Dapsone (Avlosulfon)

Dapsone is the drug of choice. It is bactericidal and bacteriostatic against mycobacteria; its mechanism of action is similar to that of sulfonamides, where competitive antagonists of PABA prevent the formation of folic acid, inhibiting bacterial growth.

The dose depends on the patient. The optimal dose should be determined by the physician. Dapsone is available for oral intake in 25- and 100-mg scored tablets. It is not considered to have an effect on the growth and development of the child.

Vitamins

Class Summary

These agents may suppress erythema elevatum diutinum. They are essential for normal DNA synthesis and are used in tissue respiration, lipid metabolism, and glycogenolysis.

Niacin (Vitamin B-3)

A 1980 study showed niacinamide to be helpful in suppressing clinical manifestations of erythema elevatum diutinum. It has also been used for the management of many disorders, including livedoid vasculitis and leprosy. The presumed mechanism of action is as an anti-inflammatory agent and as a vasodilator. It is mainly used for the treatment and prevention of pellagra and niacin or tryptophan deficiency. It is available for oral intake in 50-, 100-, and 500-mg tablets.