AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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. EED was first described in 1888 by Hutchinson and in 1889 by Bury. However, the name EED was first used by Radcliff-Crocker and Williams 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. The difference lies in the patient population and possibly the cause of onset.

Pathophysiology

The pathophysiology of EED is not well understood. According to Gibson and Su, 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), and fibrin around the damaged vessels. The findings from Grabbe et al support the idea that the initiation of EED may occur via activation of cytokines such as interleukin 8, which causes selective recruitment of leukocytes to tissue sites.

Frequency

United States

EED is a rare disease. Although first described in 1888, the largest study of EED was published in 1992 and included 13 patients.

International

This condition is rare.

Mortality/Morbidity

No mortality due to EED has been reported. EED 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.

Race

No racial predilection is reported for EED.

Sex

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

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

• Patients 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 2). However, on rare occasions, blisters and ulcers may also appear.
• 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.
• 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 EED.

Physical

• On physical examination, the lesions are generally found symmetrically on the extensor surfaces of the skin, especially over the joints.
• • 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 1).
  • The buttocks, the face, and the ears as well as the palms, the soles, the legs, the forearms, and the genitals may be involved; 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.
• 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 EED with ocular abnormalities, including nodular scleritis, panuveitis, autoimmune keratolysis, and peripheral keratitis. Therefore, attention should be given to ocular symptoms and eye examination findings.

Causes

The cause of EED has not yet been definitively established.

• Disorders that have been associated with EED include recurrent bacterial infections (especially streptococcal), viral infections (including hepatitis B or HIV), rheumatologic disease (in the Bury type), lupus erythematosus, and B-cell lymphoma.
• In recent years, several reports, including the 2 largest clinical studies completed on EED, have suggested hematologic disease as the most common factor associated with EED.
• Monoclonal gammopathies, especially IgA monoclonal gammopathy, have been found in a significant number of patients in several studies.
• EED has also been reported after the administration of erythropoietin.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Multicentric reticulohistiocytosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• Electron microscopy is not routinely necessary 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 EED. The use of this technique is supported by the growing number of studies showing that monoclonal gammopathies might play a causal role in EED.
• 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 EED is often elevated.
• Antineutrophil cytoplasmic antibodies of IgA class may become a helpful paraclinical marker of disease.

Procedures

• A skin biopsy is the most useful study for the diagnosis of EED. The histologic findings are discussed below.

Histologic Findings

EED is a type of necrotizing vasculitis. No specific histologic finding can be used to differentiate EED from other leukocytoclastic diseases. However, the simultaneous presence of several histologic findings can help distinguish the disease from others.

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, can be detected perivascularly. The epidermis can be affected by the changes in the dermis; edema, acanthosis, and even necrosis can be observed.

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. This was termed extracellular cholesterosis (EC) and was thought at first to have a different etiology than EED. Today, EC is known to be a manifestation of EED. 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

• Dapsone (diaminodiphenylsulfone) revolutionized the treatment of patients with EED. Several studies and clinical experience have shown a good response to dapsone, therefore making it the treatment of choice. The dosage depends on each patient. Sulfones have a suppressive effect on EED, as shown by the recurrence of the disease 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 EED.
• Intermittent plasma exchange (PLEX) was shown to control IgA paraproteinemia associated with EED. The IgA levels responded to PLEX treatment, followed by consolidative doses of cyclophosphamide. This treatment might be promising for the control of severe EED that is not controlled by dapsone.

Surgical Care

Surgical excision of the lesions is sometimes performed to provide symptomatic relief.

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.

MEDICATION

Section 7 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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

Drug Category: Sulfones

These agents have been demonstrated to effectively suppress the manifestations of EED.

Drug Category: Vitamins

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Prognosis

• EED is a chronic disease that usually evolves over a 5- to 10-year period, at which point it may resolve.
• EED lesions tend to not leave scars, but areas of hyperpigmentation or hypopigmentation can be visible.
• Dapsone and other therapies can be successful in limiting the progression of the disease.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Plaques and papular lesions on the wrists and the dorsum of the hands and the digits of a patient with erythema elevatum diutinum.
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Media file 2:  Nodular lesions on the knees of a patient with erythema elevatum diutinum.
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Media type:  Photo

Media file 3:  Fibrinoid changes in dermal blood vessels with polymorphonuclear neutrophil infiltration.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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• Bury JS. A case of erythema with remarkable nodular thickening and induration of the skin associated with intermittent albuminuria. Illus Med News. 1889;3:145.
• Casanova FH, Meirelles RL, Tojar M, et al. Autoimmune keratolysis in a patient with leukocytoclastic vasculitis: unusual erythema elevatum diutinum with granulomatous pattern. Cornea. Apr 2001;20(3):329-32. [Medline].
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• Gubinelli E, Cocuroccia B, Fazio M, et al. Papular neutrophilic dermatosis and erythema elevatum diutinum following erythropoietin therapy in a patient with myelodysplastic syndrome. Acta Derm Venereol. 2003;83(5):358-61. [Medline].
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• Kohler IK, Lorincz AL. Erythema elevatum diutinum treated with niacinamide and tetracycline. Arch Dermatol. Jun 1980;116(6):693-5. [Medline].
• Laymon CW. Erythema elevatum diutinum. A type of allergic vasulitis. Arch Dermatol. Jan 1962;85:22-8. [Medline].
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• Mitamura Y, Fujiwara O, Miyanishi K, et al. Nodular scleritis and panuveitis with erythema elevatum diutinum. Am J Ophthalmol. Feb 2004;137(2):368-70. [Medline].
• Mraz JP, Newcomer VD. Erythema elevatum diutinum. Presentation of a case and evaluation of laboratory and immunological status. Arch Dermatol. Sep 1967;96(3):235-46. [Medline].
• Radcliffe-Crocker H, Williams C. Erythema elevatum diutinum. Br J Dermatol. 1894;6:1-9.
• Tasanen K, Raudasoja R, Kallioinen M, Ranki A. Erythema elevatum diutinum in association with coeliac disease. Br J Dermatol. Apr 1997;136(4):624-7. [Medline].
• Weidman FD, Besancon JH. Erythema elevatum diutinum: role of streptococci, and relationship to other rheumatic dermatoses. Arch Dermatol Syphilol. 1929;20:593.
• Wilkinson SM, English JS, Smith NP, et al. Erythema elevatum diutinum: a clinicopathological study. Clin Exp Dermatol. Mar 1992;17(2):87-93. [Medline].
• Wolff HH, Maciejewski W, Scherer R. [Erythema elevatum diutinum. I. Electron microscopy of a case with extracellular cholesterosis (author''s transl)]. Arch Dermatol Res. Feb 15 1978;261(1):7-16. [Medline].
• Yiannias JA, el-Azhary RA, Gibson LE. Erythema elevatum diutinum: a clinical and histopathologic study of 13 patients. J Am Acad Dermatol. Jan 1992;26(1):38-44. [Medline].

Article Last Updated: Feb 21, 2007