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Erythema Elevatum Diutinum
LAWRENCE E. GIBSON, MD
ROKEA A. EL-AZHARY, MD, PhD
E
rythema elevatum diutinum (EED) is a distinctive form of chronic cutaneous vasculitis. Described over 100 years ago, the early descriptions
are still an excellent source for information regarding
the symptoms and signs of this unusual disease. Early
writings separated EED into the Bury type, occurring in
young women with a history of rheumatic disease, as
well as the Hutchinson type, occurring in elderly men.
The disease now is considered one entity regardless of
the underlying cause.1– 4
Most often, EED presents as persistent, symmetrical,
firm, tender, red to reddish brown or purple papules
and nodules that then may coalesce to form larger
nodules or plaques. The extensor aspects of the extremities are the preferred location for skin lesions, although
truncal and retroauricular lesions have also been described. These lesions are usually located near joints
such as the fingers, hands, elbows, ankles, and knees,
although palmar and plantar lesions are also seen (Fig
1). At times the lesions may resemble vesicles, hemorrhagic nodules, ulcerations, or other vascular processes.
Partial resolution may give a yellowish or brown hue to
the lesions, resembling xanthomata (Fig 2).5,6 Recent
reports of HIV-associated EED emphasize nodular lesions as well as palmar/plantar involvement.7–13
Although asymptomatic in some cases, the onset of
new lesions may be associated with pruritus or a burning or stinging sensation in the skin. Established lesions
may be tender to the touch. Patients may have arthralgias as well as fever and other systemic symptoms. As
a general rule, EED is seen more often in patients in the
fourth through the six decade and with a slight male
predominance. Cases associated with HIV infection
more often have onset at an earlier age.
The cause of EED is unknown, but it is presumed to
be related to vascular immune complex deposition. The
classic papers cite streptococcal infection and/or rheumatoid disease as possible causes for immune-complex
formation; however, EED may also be associated with
several autoimmune disorders including seropositive
rheumatoid arthritis, ulcerative colitis, Crohn’s disease,
relapsing polychondritis, pyoderma gangrenosum,
type I diabetes mellitus, and gluten-sensitive enteropaFrom the Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.
Address correspondence to Lawrence E. Gibson, MD, Mayo Clinic, 200
First St., Rochester, MN 55905, USA.
© 2000 by Elsevier Science Inc. All rights reserved.
655 Avenue of the Americas, New York, NY 10010
thy. Associated infections have included bacterial, viral,
tuberculous, hepatitis, as well as syphilis.14 –23 Several
case reports over the past decade have detailed the
association of EED with HIV infection.7–13 Many of
these HIV patients are also infected with hepatitis B, C,
or cytomegalovirus (CMV) in addition to other opportunistic organisms.
The histopathologic changes in EED have been thoroughly reviewed.10,24 –27 Early lesions begin with leukocytoclastic vasculitis (LCV) with a wedge-shaped polymorphonuclear cell infiltrate and fibrin deposition in
the superficial and mid-dermis. Polymorphonuclear
cells, leukocytoclastic debris and macrophages as well
as histiocytes and, rarely, eosinophils may surround the
blood vessels in early stages (Figs 3 and 4). Early on,
papillary edema may be present to such a degree as to
correlate clinically with pseudovesiculation. Superficial
resemblance to Sweet’s syndrome may be seen, although the latter by definition must lack significant
leukocytoclasis and/or vasculitis.
As the process continues, histiocytes make up a
larger proportion of the infiltrate, and one may see
phagocytosed leukocytoclastic debris. Later lesions
demonstrate a combination of granulation response or
healing skin together with a proliferation of dermal
spindle cells with or without multinucleate giant cells
(Fig 5). At this stage the histopathology may resemble
sclerosing hemangioma, various types of fibrous histiocytoma or, in the extreme, dermatofibrosarcoma protuberans. Ongoing vessel damage is documented by the
presence of dilated blood vessels with hypertrophic
endothelial cells projecting into the lumen, simulating a
granulation response.28 At times this response can be
confused with Kaposi’s sarcoma or bacillary angiomatosis.29 The latter two possibilities become more problematic in the cases associated with HIV infection. Xanthomatized histiocytes may be seen in more chronic
lesions (Fig 6). Several studies30 –32 have documented
that the lipid is actually intracellular as opposed to the
older nomenclature, which refers to EED as extracellular cholesterolosis.
Recent reviews of the histopathologic changes in
EED have documented the presence of spindle cells
comprised of histiocytes, fibroblasts, and myofibroblasts, with positive staining with markers such as Mac387, CD34, and focal, alpha-smooth muscle actin (␣0738-081X/00/$–see front matter
PII S0738-081X(99)00120-0
296 GIBSON AND EL-AZHARY
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2000;18:295–299
Figure 3. Photomicrograph demonstrating leukocytoclastic
vasculitis with a diffuse dermal mixed cellular infiltrate in EED.
(H&E X100)
Figure 1. (a) Papular and nodular lesions located over or near
the joints of the fingers, hand and wrist in a patient with EED.
(b) Nodules and plaques located over the knees and thigh in the
same patient.
SMA). None of these stains are specific for EED, but
they typify the chronic fibrous response.10,26
Although the pathogenesis of EED is unclear, it is
presumed to represent an immune-complex disease
Figure 2. Erythematous to brownish slightly raised plaques over
the Achilles area and heel somewhat resembling xanthomata.
characterized by repeated immune-complex deposition
followed by inflammation and partial healing. Classically, these lesions were produced by streptococcal infection or autoimmune disease. Typical lesions have
been reproduced by the intradermal injection of streptococcal antigen in patients with EED.33–36 Recent case
reports illustrate the course of EED in patients with HIV
infection. The response of EED to antiretroviral agents
and to dapsone in HIV patients lends support to an
infectious cause for EED in this subset of patients.7–13
In addition, EED has been associated with hypergammaglobulinemia and with IgA monoclonal gammopathies. Duperrat and Rappaport37 reported a case
that preceded the onset of multiple myeloma by 4 years.
Subsequent to this initial report, several studies have
Figure 4. A higher power view of EED demonstrating blood
vessel wall damage with transmural polymorphonuclear cell
infiltrate. (H&E X200)
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2000;18:295–299
Figure 5. A later lesion in EED demonstrating spindle cell
proliferation in the dermis. (H&E X100)
documented the association of EED with either hypergammaglobulinemia or paraproteinemia, especially
with IgA paraprotein. Cryoglobulins have also been
reported.24,25,27,31,36 – 41 At times the paraprotein may be
small and special techniques such as immunoelectrophoresis may be required to separate the paraprotein
from the polyclonal immune globulins.
The diagnosis of erythema elevatum diutinum is
based upon the characteristic clinical lesions in combination with histopathological findings supported by
appropriate laboratory investigations. Screening of patients suspected to have EED for infections, including
streptococcal, hepatitis, treponemal diseases, and HIV,
is essential. Serum protein electrophoresis is also essential. Other tests that may be appropriate include endomysial antibody testing, systemic evaluation for glu-
ERYTHEMA ELEVATUM DIUTINUM
297
ten-sensitive enteropathy, rheumatoid factor, or
evaluations to rule out autoimmune disorders.
The differential diagnosis of EED is quite broad and
includes Sweet’s syndrome, pyoderma gangrenosum,
granuloma faciale, fixed drug reaction, erythema multiforme, lichen planus, bullous pemphigoid, porphyria
cutanea tarda, fibrous histiocytoma or dermatofibroma,
bacillary angiomatosis, Kaposi’s sarcoma, xanthoma,
and necrobiotic xanthogranuloma. Careful clinical and
histopathologic evaluation and pertinent laboratory investigations should confirm the diagnosis.
Treatment of EED is difficult because this disorder
runs a chronic and recurrent course. Treatment of an
underlying cause or infection should result in improvement of EED. In most cases, dapsone or sulfonamides
are considered first-line treatment for EED.6,24,25,36 Unfortunately, with cessation of dapsone therapy, the skin
lesions tend to recur. As mentioned earlier in patients
with associated HIV infection, treatment with antiretroviral agents may be effective when combined with
dapsone or sulfonamide treatment. Dapsone may be
less effective in lesions that have progressed to the
fibrotic stage. Other therapies employed for EED have
included niacinamide and tetracycline,42 colchicine,43
intralesional, potent topical, or oral corticosteroids,24
and chloroquine.44 Intermittent plasma exchange in an
EED patient with IgA paraproteinemia has been reported to be effective.45 The long-term outlook for EED
patients depends upon the underlying disorder. These
patients are not prone to develop systemic vasculitis.
Osteolysis has recently been reported in one patient
with over 20 years’ follow-up.46
Conclusions
Finally, EED is a chronic recurring form of cutaneous
leukocytoclastic vasculitis thought to be due to immune-complex disease. It may be associated with various inflammatory and infectious diseases, including
HIV. Diagnosis is based upon the characteristic clinical
pattern, together with confirmatory histopathologic
and laboratory findings. The prescribed therapy for this
condition depends upon the associated disorders. Successful therapy requires the combination of treatment of
both the underlying disorder and the anti-inflammatory agents directed at the lesions themselves.
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Figure 6. High power view of EED case showing nuclear dust,
dermal edema and xanthomatized histiocytes. (H&E X400)
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