Erythema Elevatum Diutinum


Article Author:
Jessica Newburger


Article Editor:
George Schmieder


Editors In Chief:
Amanda Oakley
Jules Lipoff
Shyam Verma


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Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Anoosh Zafar Gondal
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Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/4/2019 8:17:57 PM

Introduction

Erythema elevatum diutinum (EED) is a rare, chronic dermatosis that is characterized by red–violet to red–brown papules, plaques, and nodules that favor the extensor surfaces. Lesions often are asymptomatic, though patients may experience pain or a burning sensation. Extracutaneous symptoms include arthralgia, fever, or other constitutional symptoms. The condition is benign in nature but may be associated with infections, hematologic abnormalities, autoimmune diseases, or other conditions. Spontaneous resolution often occurs after 5 to 10 years.[1][2]

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]

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]

Enhancing Healthcare Team Outcomes

 EED is a skin disorder that is best managed by a multidisciplinary team that includes nurses and pharmacists. The diagnosis usually required a biopsy. However, treatment of EED is not adequate once it is established. The triggers or the primary cause must be treated; with all treatment recurrences are common. It often takes years for the skin disorder to resolve.


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Erythema Elevatum Diutinum - Questions

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A 50-year-old White male presents with red-brown papules, plaques, and nodules on his elbows and knees for approximately two years. The lesions are asymptomatic, though he has developed some arthralgias in those joints. You diagnose this patient with erythema elevatum diutinum. Which systemic disease is most likely associated with this condition?



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Which area is least likely to have lesions of erythema elevatum diutinum?



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Which of the following immunoglobulins is NOT typically seen under direct immunofluorescence in a biopsy of erythema elevatum diutinum?



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A patient is diagnosed with erythema elevatum diutinum and started on dapsone. Unfortunately, he does not respond to treatment. Which of the following is an appropriate alternative therapy for EED?



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Erythema Elevatum Diutinum - References

References

JAAD Grand Rounds quiz. Adult with red-brown nodules and plaques., Khan F,Chan CS,LeLeux TM,Diwan AH,Hsu S,, Journal of the American Academy of Dermatology, 2011 Aug     [PubMed]
Erythema elevatum diutinum: a clinicopathological study., Wilkinson SM,English JS,Smith NP,Wilson-Jones E,Winkelmann RK,, Clinical and experimental dermatology, 1992 Mar     [PubMed]
Erythema elevatum diutinum: a clinical and histopathologic study of 13 patients., Yiannias JA,el-Azhary RA,Gibson LE,, Journal of the American Academy of Dermatology, 1992 Jan     [PubMed]
Erythema elevatum diutinum: skin and systemic manifestations, immunologic studies, and successful treatment with dapsone., Katz SI,Gallin JI,Hertz KC,Fauci AS,Lawley TJ,, Medicine, 1977 Sep     [PubMed]
Erythema Elevatum Diutinum., Bansal R,Aron J,Rajnish I,, The American journal of the medical sciences, 2017 Feb     [PubMed]
Erythema elevatum diutinum., Dowd PM,Munro DD,, Journal of the Royal Society of Medicine, 1983 Apr     [PubMed]
Erythema elevatum diutinum and IgA myeloma: an interesting association., Archimandritis AJ,Fertakis A,Alegakis G,Bartsokas S,Melissinos K,, British medical journal, 1977 Sep 3     [PubMed]
Late-stage nodular erythema elevatum diutinum., High WA,Hoang MP,Stevens K,Cockerell CJ,, Journal of the American Academy of Dermatology, 2003 Oct     [PubMed]
Erythema elevatum diutinum., Gibson LE,el-Azhary RA,, Clinics in dermatology, 2000 May-Jun     [PubMed]
Erythema elevatum diutinum associated with IgA paraproteinemia successfully controlled with intermittent plasma exchange., Chow RK,Benny WB,Coupe RL,Dodd WA,Ongley RC,, Archives of dermatology, 1996 Nov     [PubMed]
Wahl CE,Bouldin MB,Gibson LE, Erythema elevatum diutinum: clinical, histopathologic, and immunohistochemical characteristics of six patients. The American Journal of dermatopathology. 2005 Oct;     [PubMed]
Mraz JP,Newcomer VD, Erythema elevatum diutinum. Presentation of a case and evaluation of laboratory and immunological status. Archives of dermatology. 1967 Sep;     [PubMed]
Ramsey ML,Gibson B,Tschen JA,Wolf JE Jr, Erythema elevatum diutinum. Cutis. 1984 Jul;     [PubMed]
Jose SK,Marfatia YS, Erythema elevatum diutinum in acquired immune deficiency syndrome: Can it be an immune reconstitution inflammatory syndrome? Indian journal of sexually transmitted diseases and AIDS. 2016 Jan-Jun;     [PubMed]

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