eMedicine Specialties > Dermatology > Diseases of the Vessels

Erythema Elevatum Diutinum

Firas G Hougeir, MD, Staff Physician, Department of Dermatology, Mayo Clinic Scottsdale
James A Yiannias, MD, Associate Professor of Dermatology; Associate Dean, Mayo School of Graduate Medical Education, Mayo Foundation for Medical Education and Research; Vice Chair, Medical Division, Department of Dermatology, Mayo Clinic Scottsdale

Updated: Jun 30, 2009

Introduction

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. Erythema elevatum diutinum was first described in 1888 by Hutchinson¹ and in 1889 by Bury.² However, the name erythema elevatum diutinum was first used by Radcliff-Crocker and Williams³ 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,⁴ 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),⁵ and fibrin around the damaged vessels. The findings from Grabbe et al⁶ 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.⁷

Frequency

United States

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.⁸

International

Erythema elevatum diutinum is rare.

Mortality/Morbidity

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.

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).

Clinical

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 Media File 2). However, on rare occasions, blisters and ulcers may also appear.

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.⁹

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

Upon physical examination, erythema elevatum diutinum lesions are generally found symmetrically on the extensor surfaces of the skin, especially over the joints.¹⁰

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 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.

The buttocks, the face, and the ears as well as the palms, the soles, the legs, the forearms, and the genitals may be involved¹¹ ; 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.¹¹

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.^12,13 Therefore, attention should be given to ocular symptoms and eye examination findings.

Causes

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), rheumatologic disease (in the Bury type), lupus erythematosus, and B-cell lymphoma.^14,15,16,17
• 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.¹⁸

Differential Diagnoses

Other Problems to Be Considered

Multicentric reticulohistiocytosis

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.¹⁹

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,²⁰ can be detected perivascularly. The epidermis can be affected by the changes in the dermis; edema, acanthosis, and even necrosis can be observed.

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.²¹ 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.²² 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.²³
• Intermittent plasma exchange (PLEX) was shown to control IgA paraproteinemia associated with erythema elevatum diutinum.²⁴ 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.

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.²⁵

Medication

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

Sulfones

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

Dapsone (Avlosulfon)

DOC in patients with EED. Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.
Dose depends on patient. Optimal dose should be determined by physician. Available for oral intake in 25 mg and 100 mg scored tablets. Not considered to have an effect on growth and development of the child.

Dosing

Adult

50-300 mg/d PO

Pediatric

Not established

Interactions

May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during the second and third month of therapy); probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both drugs; because of increases in renal clearance, levels may significantly decrease when administered concurrently with rifampin

Contraindications

Documented hypersensitivity; known G-6-PD deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution patients regarding adverse effects (eg, weakness, fever, pallor, purpura, jaundice, paresthesias); fatal cases of agranulocytosis, aplastic anemia, and other blood anomalies have been reported; CBC counts are recommended weekly for the first month, monthly for the first 6 mo, and then semiannually; has been demonstrated to be carcinogenic in female rats; no adequate studies have been performed on the safety of dapsone during pregnancy; excreted in large amounts in breast milk and can cause hemolytic reactions in neonates

Vitamins

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

Niacinamide (Vitamin B-3)

A 1980 study showed niacinamide to be helpful in suppressing clinical manifestations of EED. Has also been used for management of many disorders, including livedoid vasculitis and leprosy. Presumed mechanism of action is as an anti-inflammatory agent and as a vasodilator. Mainly used for treatment and prevention of pellagra and niacin or tryptophan deficiency. Available for oral intake in 50-, 100-, and 500-mg tab.

Dosing

Adult

100 mg tab PO tid

Pediatric

Not established

Interactions

May increase hypotensive effects of ganglionic blocking drugs; long-term administration of isoniazid may call for increase in niacinamide dose for dietary purposes; cutaneous vasodilation may be a problem if high-dose used with peripheral vasodilators (eg, nitroglycerin); taking aspirin 30-60 min before first dose of the day may help alleviate prostaglandin-mediated adverse effects (eg, flushing, itching); clonidine may inhibit niacin-induced flushing

Contraindications

Documented hypersensitivity; active liver disease or unexplained, significant increases in AST and ALT levels; large doses of niacin, especially when administered in a sustained-release form (associated with severe hepatotoxicity); patients who have a definite and recent history of peptic ulcer disease (can reactivate ulcers)

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Caution in gallbladder disease or diabetes and patients predisposed to gout; monitor blood glucose level; may elevate uric acid levels; pregnancy category C when used at doses greater than RDA; caution when using in patients who have coronary artery disease (higher occurrence of cardiac arrhythmias have been reported)

Follow-up

Prognosis

• Erythema elevatum diutinum (EED) 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.
• Dapsone and other therapies can be successful in limiting the progression of the disease.

Multimedia

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.

Media file 2: Nodular lesions on the knees of a patient with erythema elevatum diutinum.

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

References

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2. 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.

3. Radcliffe-Crocker H, Williams C. Erythema elevatum diutinum. Br J Dermatol. 1894;6:1-9.

4. Gibson LE, Su WP. Cutaneous vasculitis. Rheum Dis Clin North Am. May 1990;16(2):309-24. [Medline].

5. Shimizu S, Nakamura Y, Togawa Y, Kamada N, Kambe N, Matsue H. Erythema elevatum diutinum with primary Sjögren syndrome associated with IgA antineutrophil cytoplasmic antibody. Br J Dermatol. Sep 2008;159(3):733-5. [Medline].

6. Grabbe J, Haas N, Moller A, Henz BM. Erythema elevatum diutinum--evidence for disease-dependent leucocyte alterations and response to dapsone. Br J Dermatol. Aug 2000;143(2):415-20. [Medline].

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8. 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].

9. Golmia A, Grinblat B, Finger E, Klieman C, Assir F, Scheinberg M. The development of erythema elevatum diutinum in a patient with juvenile idiopathic arthritis under treatment with abatacept. Clin Rheumatol. Jan 2008;27(1):105-6. [Medline].

10. Di Giacomo TB, Marinho RT, Nico MM. Erythema elevatum diutinum presenting with a giant annular pattern. Int J Dermatol. Mar 2009;48(3):290-2. [Medline].

11. Barzegar M, Davatchi CC, Akhyani M, Nikoo A, Daneshpazhooh M, Farsinejad K. An atypical presentation of erythema elevatum diutinum involving palms and soles. Int J Dermatol. Jan 2009;48(1):73-5. [Medline].

12. Aldave AJ, Shih JL, Jovkar S, McLeod SD. Peripheral keratitis associated with erythema elevatum diutinum. Am J Ophthalmol. Mar 2003;135(3):389-90. [Medline].

13. Casanova FH, Meirelles RL, Tojar M, Martins MC, Rigueiro MP, de Freitas D. Autoimmune keratolysis in a patient with leukocytoclastic vasculitis: unusual erythema elevatum diutinum with granulomatous pattern. Cornea. Apr 2001;20(3):329-32. [Medline].

14. Futei Y, Konohana I. A case of erythema elevatum diutinum associated with B-cell lymphoma: a rare distribution involving palms, soles and nails. Br J Dermatol. Jan 2000;142(1):116-9. [Medline].

15. Hancox JG, Wallace CA, Sangueza OP, Graham GF. Erythema elevatum diutinum associated with lupus panniculitis in a patient with discoid lesions of chronic cutaneous lupus erythematosus. J Am Acad Dermatol. Apr 2004;50(4):652-3. [Medline].

16. Mitamura Y, Fujiwara O, Miyanishi K, Sato H, Saga K, Ohtsuka K. Nodular scleritis and panuveitis with erythema elevatum diutinum. Am J Ophthalmol. Feb 2004;137(2):368-70. [Medline].

17. Liu TC, Chen IS, Lin TK, Lee JY, Kirn D, Tsao CJ. Erythema elevatum diutinum as a paraneoplastic syndrome in a patient with pulmonary lymphoepithelioma-like carcinoma. Lung Cancer. Jan 2009;63(1):151-3. [Medline].

18. Gubinelli E, Cocuroccia B, Fazio M, Annessi G, Girolomoni G. 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].

19. Ayoub N, Charuel JL, Diemert MC, et al. Antineutrophil cytoplasmic antibodies of IgA class in neutrophilic dermatoses with emphasis on erythema elevatum diutinum. Arch Dermatol. Aug 2004;140(8):931-6. [Medline].

20. Weidman FD, Besancon JH. Erythema elevatum diutinum: role of streptococci, and relationship to other rheumatic dermatoses. Arch Dermatol Syphilol. 1929;20:593.

21. 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].

22. Katz SI, Gallin JI, Hertz KC, Fauci AS, Lawley TJ. Erythema elevatum diutinum: skin and systemic manifestations, immunologic studies, and successful treatment with dapsone. Medicine (Baltimore). Sep 1977;56(5):443-55. [Medline].

23. Kohler IK, Lorincz AL. Erythema elevatum diutinum treated with niacinamide and tetracycline. Arch Dermatol. Jun 1980;116(6):693-5. [Medline].

24. Chow RK, Benny WB, Coupe RL, Dodd WA, Ongley RC. Erythema elevatum diutinum associated with IgA paraproteinemia successfully controlled with intermittent plasma exchange. Arch Dermatol. Nov 1996;132(11):1360-4. [Medline].

25. 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].

26. Devillierre M, Verola O, Rybojad M, et al. [Pseudoneoplastic lesion of erythema elevatum diutinum]. Ann Dermatol Venereol. Aug-Sep 2008;135(8-9):575-9. [Medline].

27. Haber H. Erythema elevatum diutinum. Br J Dermatol. Apr 1955;67(4):121-45. [Medline].

28. Habif TP. Clinical Dermatology. 3^rd ed. St. Louis, Mo: Mosby-Year Book; 1996:589-96.

29. Hines HL. Erythema elevatum diutinum. Dermatol Int. Apr-Jun 1968;7(2):70-4. [Medline].

30. Laymon CW. Erythema elevatum diutinum. A type of allergic vasulitis. Arch Dermatol. Jan 1962;85:22-8. [Medline].

31. McEvoy GK, ed. AHFS Drug Information, 1999. Bethesda, Md: American Society of Health-System Pharmacists; 1999:731-5, 3182-4.

32. 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].

33. Wilkinson SM, English JS, Smith NP, Wilson-Jones E, Winkelmann RK. Erythema elevatum diutinum: a clinicopathological study. Clin Exp Dermatol. Mar 1992;17(2):87-93. [Medline].

Keywords

erythema elevatum diutinum, extracellular cholesterosis, EED, leukocytoclastic vasculitis

Contributor Information and Disclosures

Author

Firas G Hougeir, MD, Staff Physician, Department of Dermatology, Mayo Clinic Scottsdale
Firas G Hougeir, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

James A Yiannias, MD, Associate Professor of Dermatology; Associate Dean, Mayo School of Graduate Medical Education, Mayo Foundation for Medical Education and Research; Vice Chair, Medical Division, Department of Dermatology, Mayo Clinic Scottsdale
James A Yiannias, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Carrie L Kovarik, MD, Assistant Professor of Dermatology, Dermatopathology, and Infectious Diseases, University of Pennsylvania School of Medicine
Carrie L Kovarik, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Christen M Mowad, MD, Associate Professor, Department of Dermatology, Geisinger Medical Center
Christen M Mowad, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

Clinical guideline

Dermatologic manifestations.
New York State Department of Health - State/Local Government Agency [U.S.].  2004.  15 pages.  NGC:003931

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