Clinical and Experimental Dermatology 1992; 17: 60-62.
Disseminated granuloma annulare as a presentation of acquired immunodeficiency syndrome (AIDS) J.M.MCGREGOR
AND D.H.MCGIBBON
St John's Dcrmatoloii)' Centre, St Thomas' Hospital, London SEI
7EH, UK Accepted for publtcation 27 April 1991
Summary Localized granuloma annulare is rhe commonest form of a granulomatous dermatosis characterized b\ flesh coloured or violaceous papules often arranged in rings. Se\eral rarer atypical variants are also reported including disseminated or generalized, subcutaneous and perforating types. There is a predilection for females and a documented association with diabetes mellitus in some cases. Recently it has been suggested that atypical variants of granuloma annulare might be associated with the acquired immunodeficiency syndrome (AIDS). We describe a patient presenting with extensive generalized granuloma annulare in whom an underlying diagnosis of Human Immunodeficiency Virus (HIV) disease was confirmed.
Case report A 43-year-old homosexual, Caucasian male presented with a 2-ycar history of a generalized pruritic eruption, beginning on his face and slowl\ spreading to involve the trunk, limbs, hands and feet. His past medical bistory was unremarkable and his general health was good although he had noticed some weight loss over the preceding year. On examination a widespread violaceous papulonodular eruption (Fig. 1) was present on the face, trunk, limbs and dorsum of hands and feet. There were scaly erythematous plaques around the nasolabial folds, eyebrows and glabella compatible with seborrhoeic dermatitis. He had inguinal lymphadenopathy but no cervical or axillary lymphadenopathy. Serological tests for antibody to human immunodeficiency virus (HIV) were found to be positive by enzyme linked immunoabsorbant assay and T-lymphocytc subsets revealed T-helper cells 12/mm' and T-suppressor Correspondence: Or J.M.McGregor, Department of Dermatology, Guy's Hospital, St Thomas' Street, London SKI 9RT, U.K. 60
Figure I. Violaceous papulonodular eruption seen on the dorsum of the hands which extended ()\er the trunk, limbs and face.
cells 120/mm\ a ratio of helper to suppressor cells of 01 (normal ratio 3-0). A chest radiograph was normal anti induced sputum for Pncitmocystis carinil was negative on three occasions. Serum haematological and biocbemical profiles were normal. Tbree skin biopsy specimens were taken and submitted for bistopathoiogical examination. All biopsy specimens showed similar changes by light microscopy of widespread collagen degeneration v\ith necrobiosis and a surrounding infiltrate of inflammatory cells, including
DISSEMINATED GRANULOMA ANNULARE AND AIDS
61
Figure 2. Disseminated gninuloma annulare: widespread collagen dcjjL-ncration with surrounding histiocytic inliltrate and occasional giant cells. (Ilacmatowlin-cosin stain; x 2,S).
histi()c\tes and occasional giant cells, consistent with a diagnosis of diffuse granuloma annulare (Fig. 2). Treatment witb emollients and potent topical steroids improved the pruritic seborrhoeic component of the eruption but the papulonodular granuloma annulare remained unchanged. Two months after diagnosis of HIV disease, the patient was started on oral zidovudine (AZT) at a dose of 250 mg daily. The eruption resolved completely within 4 weeks and has not returned over a follow up period of 12 montbs on treatment. The patient remains otherwise well. Discussion (iranuloma annulare (G.^) in association with AIDS was first mentioned in the British literature in 1985.' Since then, although no causal relationship between GA and I IIX has been established, numbers of reported cases linking the two conditions have increased with a notable predominance of atypical types of GA described, suggesting that the disease process may be modified by immunodeficiency syndromes. The real incidence of GA in HI\' disease may be underestimated as a wide differential diagnosis of a cutaneous papular eruption exists in patients with AIDS. In particular Kaposi's sarcoma, cutaneous lymphoma and a papular eruption of HIV disease- have all been described as resembling GA, emphasizing the importance of skin biopsy as a prerequisite to diagnosis. In addition, common forms of GA and HIV disease may remain unreported. There are currently 10 reported cases of GA and HIV disease: seven of disseminated type' '' and one perforating type;' the remaining two are described as extensive localized GA.' A subcutaneous variant of GA which occurs mainly in children'* has not yet been described in patients with HIV disease.
Generalized GA as described in our case has a 2 5:1 female predominance in the general population, characteristically occurs in the age group 40-70 and is often chronic of 1-4 years duration.'' Tn contrast, patients reported with generalized GA and HIV disease have been males, predominantly in the age group 20-40 and often with a history of transient eruptions.'*' In addition to our patient, disseminated GA was reported to clear rapidly after starting treatment with AZT in the one other case where it was used.'' The pathogenesis of GA remains controversial, although much evidence supports a cell mediated mechanism.'"" Immunophenotyping of T-lymphocyte populations in the inflammatory infiltrate of GA demonstrate a predominance ofthe heiper/inducer subset.'' In contrast, in one patient with GA and I4IV disease where immunophenotyping ofthe lymphoeytic infiltrate was performed, a predominance ofthe cytotoxic/suppressor subtype was demonstrated. If this represents a cell mediated reaction it would suggest that the dominant role ofthe T-helper lymphocyte was not critical in the pathogenesis of this eruption. In support of this observation, delayed type hypersensitivity reactions mediated by cytotoxic/suppressor T-cells acting in the absence of the helper/ inducer T-cell subset have been sbown tooccur in mice.'^ The mechanisms involved in the pathogenesis of HIV infection are intimately coupled with the functioning of the hosts' cellular immune system. In particular, selective depletion ofthe CD4 + ve heiper/inducer T-cell population and disruption of antigen presentation in the HIVinfected patient'' is thought to account for the inability of patients' lymphocytes to respond appropriately to protein antigens hence explaining the atypical clinical presentations of common diseases that are well recognised in AIDS. HIV antigens are unlikel\ to be causal in the appear-
62
J.M.MCGREGOR AND D.H.MCGIBBON ance of GA but tbe course and presentation of this cutaneous eruption might be modified by disruption of h. both antigen presentation and effector cell mechanisms in the HIV-infected patient. The appearance of an atypical variant of GA in a patient at risk should alert the clinician 7. to the possibility of an underlying immunodeficiency syndrome. References 1. Smith NP. AIDS, Kaposi's sarcoma and the dermatologist. Journal of the Royal Society of Medicine 198.S; 78: 97-99. 2. James WD, Rcdficld RR, I.iipton GP. A papular eruption associated with human T l cell lymphotrophic virus t\pe III disease. Journat of the .-Imerican .-Icademy of Dernuitology 1985; 13: 563-6. 3. Uhadially R, Sibbald G, Walter j , i laberman II. Granuloma annulare in patients with human immunodeficJcncv wrus. Journat ofthe .tinerican Academy of Dermatology 1989; 20: 232-5. 4. Penneys N S , Hicks B. Unusual cutaneous lesions associated with acquired immunodeficientv \\nilritmt:. Journal of the American .-icademy of Dermalology 1985; 13: 845-52. 5. Bakos I,, I Iampe S, de Rocha J, Pires AS, Weisbluth M, Zampese M, Generalised granuloma annularc In a patient with acquired
immunodc(icicnc\ syndrome (AIDS). Journal oJ the Aineriemi Academy of Dermatology 1987; 17: 844-845. Jones SK, llarman R R M Atypical granuloma annulare in patients with the acquired immunodeficiency s.\T\iiritmc. Journal of the American Academy of Dermalology 1989; 20: 299 301). I leurier C;, HassJ, Hergleld V, Ravmond R, Tubbs D. Perforating granuloma annulare in a patieni with acquired inmnodeficiency syndrome. Archives of Dermatology 1987; 123: 1217-122(1. 8. Victor J, Selmanowitz M. Atypical granuloma annularc. .In hues of Dermatology I9W); 93: 454-456. 9. Friedman-Birnbaum R. Generalised and localised granuloma annulare. International Journal of Dermatology 1986; 115: 3293.13. 10. Lmbert P, Winkelmann R. Histologic, ultrastructural and histochemical studies of granuloma annularc. Archives of Dermatology 1977;113: 1681-1686. 1 i. Beuchner SA, Winkelmann R, Banks P. Identification
Disseminated granuloma annulare as a presentation of acquired immunodeficiency syndrome (AIDS) J.M.MCGREGOR
AND D.H.MCGIBBON
St John's Dcrmatoloii)' Centre, St Thomas' Hospital, London SEI
7EH, UK Accepted for publtcation 27 April 1991
Summary Localized granuloma annulare is rhe commonest form of a granulomatous dermatosis characterized b\ flesh coloured or violaceous papules often arranged in rings. Se\eral rarer atypical variants are also reported including disseminated or generalized, subcutaneous and perforating types. There is a predilection for females and a documented association with diabetes mellitus in some cases. Recently it has been suggested that atypical variants of granuloma annulare might be associated with the acquired immunodeficiency syndrome (AIDS). We describe a patient presenting with extensive generalized granuloma annulare in whom an underlying diagnosis of Human Immunodeficiency Virus (HIV) disease was confirmed.
Case report A 43-year-old homosexual, Caucasian male presented with a 2-ycar history of a generalized pruritic eruption, beginning on his face and slowl\ spreading to involve the trunk, limbs, hands and feet. His past medical bistory was unremarkable and his general health was good although he had noticed some weight loss over the preceding year. On examination a widespread violaceous papulonodular eruption (Fig. 1) was present on the face, trunk, limbs and dorsum of hands and feet. There were scaly erythematous plaques around the nasolabial folds, eyebrows and glabella compatible with seborrhoeic dermatitis. He had inguinal lymphadenopathy but no cervical or axillary lymphadenopathy. Serological tests for antibody to human immunodeficiency virus (HIV) were found to be positive by enzyme linked immunoabsorbant assay and T-lymphocytc subsets revealed T-helper cells 12/mm' and T-suppressor Correspondence: Or J.M.McGregor, Department of Dermatology, Guy's Hospital, St Thomas' Street, London SKI 9RT, U.K. 60
Figure I. Violaceous papulonodular eruption seen on the dorsum of the hands which extended ()\er the trunk, limbs and face.
cells 120/mm\ a ratio of helper to suppressor cells of 01 (normal ratio 3-0). A chest radiograph was normal anti induced sputum for Pncitmocystis carinil was negative on three occasions. Serum haematological and biocbemical profiles were normal. Tbree skin biopsy specimens were taken and submitted for bistopathoiogical examination. All biopsy specimens showed similar changes by light microscopy of widespread collagen degeneration v\ith necrobiosis and a surrounding infiltrate of inflammatory cells, including
DISSEMINATED GRANULOMA ANNULARE AND AIDS
61
Figure 2. Disseminated gninuloma annulare: widespread collagen dcjjL-ncration with surrounding histiocytic inliltrate and occasional giant cells. (Ilacmatowlin-cosin stain; x 2,S).
histi()c\tes and occasional giant cells, consistent with a diagnosis of diffuse granuloma annulare (Fig. 2). Treatment witb emollients and potent topical steroids improved the pruritic seborrhoeic component of the eruption but the papulonodular granuloma annulare remained unchanged. Two months after diagnosis of HIV disease, the patient was started on oral zidovudine (AZT) at a dose of 250 mg daily. The eruption resolved completely within 4 weeks and has not returned over a follow up period of 12 montbs on treatment. The patient remains otherwise well. Discussion (iranuloma annulare (G.^) in association with AIDS was first mentioned in the British literature in 1985.' Since then, although no causal relationship between GA and I IIX has been established, numbers of reported cases linking the two conditions have increased with a notable predominance of atypical types of GA described, suggesting that the disease process may be modified by immunodeficiency syndromes. The real incidence of GA in HI\' disease may be underestimated as a wide differential diagnosis of a cutaneous papular eruption exists in patients with AIDS. In particular Kaposi's sarcoma, cutaneous lymphoma and a papular eruption of HIV disease- have all been described as resembling GA, emphasizing the importance of skin biopsy as a prerequisite to diagnosis. In addition, common forms of GA and HIV disease may remain unreported. There are currently 10 reported cases of GA and HIV disease: seven of disseminated type' '' and one perforating type;' the remaining two are described as extensive localized GA.' A subcutaneous variant of GA which occurs mainly in children'* has not yet been described in patients with HIV disease.
Generalized GA as described in our case has a 2 5:1 female predominance in the general population, characteristically occurs in the age group 40-70 and is often chronic of 1-4 years duration.'' Tn contrast, patients reported with generalized GA and HIV disease have been males, predominantly in the age group 20-40 and often with a history of transient eruptions.'*' In addition to our patient, disseminated GA was reported to clear rapidly after starting treatment with AZT in the one other case where it was used.'' The pathogenesis of GA remains controversial, although much evidence supports a cell mediated mechanism.'"" Immunophenotyping of T-lymphocyte populations in the inflammatory infiltrate of GA demonstrate a predominance ofthe heiper/inducer subset.'' In contrast, in one patient with GA and I4IV disease where immunophenotyping ofthe lymphoeytic infiltrate was performed, a predominance ofthe cytotoxic/suppressor subtype was demonstrated. If this represents a cell mediated reaction it would suggest that the dominant role ofthe T-helper lymphocyte was not critical in the pathogenesis of this eruption. In support of this observation, delayed type hypersensitivity reactions mediated by cytotoxic/suppressor T-cells acting in the absence of the helper/ inducer T-cell subset have been sbown tooccur in mice.'^ The mechanisms involved in the pathogenesis of HIV infection are intimately coupled with the functioning of the hosts' cellular immune system. In particular, selective depletion ofthe CD4 + ve heiper/inducer T-cell population and disruption of antigen presentation in the HIVinfected patient'' is thought to account for the inability of patients' lymphocytes to respond appropriately to protein antigens hence explaining the atypical clinical presentations of common diseases that are well recognised in AIDS. HIV antigens are unlikel\ to be causal in the appear-
62
J.M.MCGREGOR AND D.H.MCGIBBON ance of GA but tbe course and presentation of this cutaneous eruption might be modified by disruption of h. both antigen presentation and effector cell mechanisms in the HIV-infected patient. The appearance of an atypical variant of GA in a patient at risk should alert the clinician 7. to the possibility of an underlying immunodeficiency syndrome. References 1. Smith NP. AIDS, Kaposi's sarcoma and the dermatologist. Journal of the Royal Society of Medicine 198.S; 78: 97-99. 2. James WD, Rcdficld RR, I.iipton GP. A papular eruption associated with human T l cell lymphotrophic virus t\pe III disease. Journat of the .-Imerican .-Icademy of Dernuitology 1985; 13: 563-6. 3. Uhadially R, Sibbald G, Walter j , i laberman II. Granuloma annulare in patients with human immunodeficJcncv wrus. Journat ofthe .tinerican Academy of Dermatology 1989; 20: 232-5. 4. Penneys N S , Hicks B. Unusual cutaneous lesions associated with acquired immunodeficientv \\nilritmt:. Journal of the American .-icademy of Dermalology 1985; 13: 845-52. 5. Bakos I,, I Iampe S, de Rocha J, Pires AS, Weisbluth M, Zampese M, Generalised granuloma annularc In a patient with acquired
immunodc(icicnc\ syndrome (AIDS). Journal oJ the Aineriemi Academy of Dermatology 1987; 17: 844-845. Jones SK, llarman R R M Atypical granuloma annulare in patients with the acquired immunodeficiency s.\T\iiritmc. Journal of the American Academy of Dermalology 1989; 20: 299 301). I leurier C;, HassJ, Hergleld V, Ravmond R, Tubbs D. Perforating granuloma annulare in a patieni with acquired inmnodeficiency syndrome. Archives of Dermatology 1987; 123: 1217-122(1. 8. Victor J, Selmanowitz M. Atypical granuloma annularc. .In hues of Dermatology I9W); 93: 454-456. 9. Friedman-Birnbaum R. Generalised and localised granuloma annulare. International Journal of Dermatology 1986; 115: 3293.13. 10. Lmbert P, Winkelmann R. Histologic, ultrastructural and histochemical studies of granuloma annularc. Archives of Dermatology 1977;113: 1681-1686. 1 i. Beuchner SA, Winkelmann R, Banks P. Identification
