|Year : 2016 | Volume
| Issue : 1 | Page : 81-84
Erythema elevatum diutinum in acquired immune deficiency syndrome: Can it be an immune reconstitution inflammatory syndrome?
Sheethal K Jose, Yogesh S Marfatia
Department of Skin-VD, SSG Hospital, Vadodara, Gujarat, India
|Date of Web Publication||14-Apr-2016|
Sheethal K Jose
Department of Skin-VD, SSG Hospital, Vadodara, Gujarat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
A 47-year-old male with acquired immune deficiency syndrome (AIDS) presented with multiple hyperpigmented papules and nodules on both ankles, dorsum of bilateral feet and soles. It was associated with mild itching and pain. The patient was diagnosed with human immunodeficiency virus (HIV) in 2007. First-line antiretroviral therapy (ART) was started in 2009 to which he responded initially. He was shifted to second-line ART 11 months ago in March 2015 due to treatment failure as suggested by CD4 count of 50 cells/mm3. The present skin lesions started 2 months after the initiation of second-line ART. Differential diagnoses considered were Kaposi's sarcoma and immune reconstitution inflammatory syndrome (IRIS) related infections, but biopsy was suggestive of erythema elevatum diutinum (EED). Patient was started on oral dapsone 100 mg/day and increased to 200 mg/day to which he is responding gradually. In the present case, appearance of the lesions after initiation of second-line ART coupled with increase in CD4 count and decrease of viral load below undetectable level suggest that EED could be an IRIS.
Keywords: EED, HIV/AIDS, IRIS
|How to cite this article:|
Jose SK, Marfatia YS. Erythema elevatum diutinum in acquired immune deficiency syndrome: Can it be an immune reconstitution inflammatory syndrome?. Indian J Sex Transm Dis 2016;37:81-4
|How to cite this URL:|
Jose SK, Marfatia YS. Erythema elevatum diutinum in acquired immune deficiency syndrome: Can it be an immune reconstitution inflammatory syndrome?. Indian J Sex Transm Dis [serial online] 2016 [cited 2020 May 27];37:81-4. Available from: http://www.ijstd.org/text.asp?2016/37/1/81/180287
| Introduction|| |
Erythema elevatum diutinum (EED) is a rare, chronic, and treatable skin condition that often manifests as red-brown nodules, papules, or plaques commonly distributed acrally and symmetrically on extensor surfaces. Lesions are often asymptomatic; nevertheless, pain or burning sensation may occur. It has many clinical and histological mimics and is often associated with a variety of underlying systemic diseases. It has been emerging as a specific human immunodeficiency virus (HIV) associated dermatosis in recent times.
| Case Report|| |
A 47-year-old married male with acquired immune deficiency syndrome (AIDS) who was a shopkeeper by profession presented with skin lesions on both lower limbs for past 9 months. It was associated with mild itching and pain. There were no complaints of joint pain or redness of eyes. The patient was diagnosed with HIV in 2007 and first-line antiretroviral therapy (ART) (tenofovir, lamivudine, efavirenz) was started in 2009. He developed severe fatigue, weight loss, cough, and dyspnea, and CD4 count dropped to 50 cells/mm 3 with plasma viral load of 157 copies/ml, 11 months ago in March 2015. Due to treatment failure, he was then put on second-line ART (abacavir, lamivudine, atazanavir, and ritonavir) and his CD4 count increased to 204 cells/mm 3 with plasma viral load of 38 copies/ml in September 2015. The present skin lesions started 2 months after initiation of second-line ART. Patient also had history of pulmonary tuberculosis (TB) in 2007 when his CD4 count was 213 cells/mm 3, and Herpes Zoster in 2012 when CD4 count was 78 for which treatment was taken.
On general examination, patient was moderately built and nourished, and his vitals were within normal limits. Cutaneous examination revealed multiple well-defined nontender hyperpigmented papules and nodules on both ankles, dorsum of bilateral feet and soles [Figure 1]a,[Figure 1]b,[Figure 1]c. Inguinal lymph nodes were not palpable. There were no lesions elsewhere in the body. Hair, nail, and oral mucosa were normal. No ocular or systemic abnormality was noted.
|Figure 1: Multiple well-defined hyperpigmented papules and nodules on the following: (a) Medial aspect of left foot and ankle, (b) Lateral aspect of left foot, (c) Bilateral feet|
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Differential diagnoses considered were Kaposi's sarcoma and immune reconstitution inflammatory syndrome (IRIS) related infection including cutaneous TB. His routine blood investigations showed hemoglobin 11.5 g%, total leukocyte count 4300/mm 3; and differential count neutrophil 70%, lymphocytes 28%, eosinophils 1% and monocytes 1%, and platelets 287,000/mm 3. Liver function tests and renal function tests were normal. Mantoux test, serological tests for syphilis (VDRL, TPHA), hepatitis B and C, and anti-nuclear antibodies were negative. Chest radiography and abdominal ultrasonography were normal. Biopsy taken from the nodular lesion on dorsum of left foot showed a diffused dense infiltrate in reticular dermis with mild fibroplasia. The infiltrate consisted of neutrophils and histiocytes with scattering of lymphocytes and plasma cells. The infiltrate surrounded small thickened vessels and extended extensively into the interstitium. Small amount of neutrophilic nuclear dust was also present within the infiltrate [Figure 2]. Overlying epidermis and dermoepidermal junction were largely spared. These features were suggestive of EED. Patient was started on oral dapsone 100 mg/day and then increased to 200 mg/day to which he is responding gradually.
|Figure 2: Photomicrograph showing diffuse dense infiltrate of neutrophils, histiocytes with scattering of lymphocytes and plasma cells, and small amount of neutrophilic nuclear dust in reticular dermis (H and E, ×400)|
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| Discussion|| |
EED is an uncommon, chronic leukocytoclastic vasculitis (LCV) of unknown etiology that promotes tissue fibrosis. It was first described in men in 1888 by Hutchinson and women in 1889 by Bury. Radcliff-Crocker and Williams in 1894 concluded that the two types should be described as one entity, and so gave the name EED.
The disease could be the expression of an immune complex-mediated vasculitis (arthus type reaction) induced by situations involving either chronic antigenic exposure or occurrence of high antibody levels. Immune complex is deposited in small vessel walls which induces inflammatory cascade, activation of cytokines like interleukin 8, which causes selective recruitment of leukocytes to blood vessels, leading to repetitive damage to blood vessels resulting in fibrosis and appearance of cholesterol crystals and myelin figures.,
Joint disease is the most common association of EED though there are isolated reports of ocular abnormalities such as nodular scleritis, panuveitis, autoimmune keratolysis, and peripheral keratitis. Immunocomplexes may induce uveitis in EED. Prabhu et al. reported a case of EED in a 45-year-old healthy man associated with severe arthritis and scleritis, with dramatic response to oral dapsone. Other than HIV, EED has also been associated with infectious processes, commonly recurrent streptococcal bacterial infections, hematological diseases, hepatitis B and rheumatological disease, collagen vascular diseases, monoclonal gammopathies, and lymphomas.
It is histologically characterized by early changes of LCV with an infiltrate of polymorphonuclear cells and fibrin deposition in superficial and mid-dermis. Polymorphonuclear cells, macrophages, histiocytes, and occasionally eosinophils may surround blood vessels. Blood vessel dilatation with continual damage and hypertrophic endothelial cells may protrude into vessel lumen which may then stimulate granulation. In such a condition, lesions may be mistaken for Kaposi's sarcoma or bacillary angiomatosis. Polymorphonuclear leukocytes are always present, and their absence should prompt consideration of alternative diagnoses. Nodular lesions are composed of small aggregates of Mac-387 + spindle cells. Lesions may clinically mimic cutaneous malignancies (especially Kaposi's sarcoma or xanthomatous lesions), thus a biopsy must be obtained to confirm the correct diagnosis of EED and to exclude other entities in the differential diagnoses.
EED is now recognized as one of the defined reactive dermatoses associated with HIV. In majority of cases, it is seen in patients with low CD4+ counts (<200). However, in some cases, EED has been reported as the first clinical manifestation of HIV infection. Recently, a case of erosive and bullous EED in HIV-positive patient was also reported. It is believed that such an association results from HIV antigen-antibody interaction, which causes direct damage to vessel walls. It is also supposed that the immunosuppression caused by HIV predisposes towards infection by other agents trigger an antigenic stimulus for the development of EED. EED has also been associated with IgA hypergammopathy, which is also a common finding in HIV. There is another hypothesis suggesting that lesions are initially caused by an IgA-associated vasculitis. Because of the induced leakage of the vessel walls, lipid droplets (which are markedly elevated in the serum after ritonavir intake) pour into the perivascular tissue and became phagocytosed by histiocytes.,
Consequently, even though the association of EED with HIV infection is infrequent, laboratory investigation for this virus should be requested in conventional cases, and especially in cases of atypical and exacerbated clinical manifestations. EED lesions in HIV infection have been described as nodular with palmar/plantar involvement with greater numbers of lesions occurring at an earlier age and poor responsiveness to dapsone. In addition, ART should be introduced in these cases, in association with dapsone. Rao et al. reported a case of a 52-year-old HIV-infected female patient who presented with nodular EED mimicking Kaposi's Sarcoma. The patient was initially treated with oral dapsone but was switched to colchicine as she developed hypersensitivity to dapsone.
In present case, the lesions of EED developed 2 months after the initiation of second-line ART for treatment failure of first-line therapy. Hence, EED could be a part of noninfectious IRIS. This is further supported by the increase in CD4 from 50 to 204 cells/mm 3 and decrease in viral load to 38 copies/ml. In IRIS, there is paradoxical worsening of an existing infection or disease process or appearance of a new infection/disease process soon after initiation of therapy associated with immune recovery. Incidence of IRIS is higher at lower CD4 counts. The immunopathogenesis of the syndrome is unclear. There is a dysregulated immune response to a variety of antigenic stimuli and unbalanced reconstitution of effector and regulatory T-cells, leading to exuberant inflammatory response in patients receiving ART.
IRIS can result from infectious and noninfectious causes. Reported cases of noninfectious IRIS include Sweet's syndrome, Reiter's syndrome, systemic lupus erythematosus (SLE), urticaria, autoimmune thyroiditis, type B insulin resistance syndrome, myopathy, radiculopathy, porphyria, non-Hodgkin's lymphoma, Guillain–Barre syndrome, sarcoidosis, bullous disorders such as pemphigus. Certain minimum criteria should be fulfilled in order to diagnose IRIS. There must be a temporal association between initiation of ART and subsequent development of symptoms (usually within 3 months), with evidence of immune restoration (viral and immunological response demonstrated by a decrease in plasma HIV RNA level by more than 1 log10 copies/mL and an increase in CD4 T-cell count from baseline), and must exhibit clinical symptoms and signs consistent with an inflammatory process. The clinical course should neither be consistent with the usual course of a previously diagnosed opportunistic infection or a new infectious process nor should the symptoms and signs be explained by drug toxicity. A falling plasma viral load is a more important indicator than rising CD4 count.
Dapsone has been regarded as first-line therapy in EED although lesions often recur with cessation of therapy., However, dapsone may be less effective in HIV-infected and those lesions that have progressed to more fibrotic stage. As our patient had fibrosis, he responded slowly to dapsone therapy. Alternative treatments are surgical excision of larger nodules and especially the removal of possible antigenic stimulus. Other agents used include immunosuppressants like cyclophosphamide, especially if associated with hematological abnormalities, SLE, paraproteinemias or leukemias. Niacinamide may also help as it acts as an anti-inflammatory agent and vasodilator. Intralesional and topical steroids, colchicine, chloroquine, and tetracycline may also be tried. The course of EED is chronic and benign. Systemic complications are rare.
There is no test currently available to establish a diagnosis of IRIS. Its diagnosis requires a high index of suspicion. Therefore, in unusual lesions which develop after initiating or changing ART in a patient with low CD4 count and high viral load, IRIS should be considered. Infectious causes of IRIS are easily diagnosed, but the noninfectious causes are likely to be missed. The lesions should be thoroughly evaluated. In some cases like the present one, histopathology rules the roost.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]