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Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy
J AM ACAD DERMATOL
Letters 877
VOLUME 65, NUMBER 4
REFERENCES 1. Brandt O, Abeck D, Gianotti R, Burgdorf W. Gianotti-Crosti syndrome. J Am Acad Dermatol 2006;54:136-45. 2. Patrizi A, Di Lernia V, Neri I, Ricci G. An unusual case of recurrent Gianotti-Crosti syndrome. Pediatr Dermatol 1994;11:283-4. 3. Baleviciene G, Maciuleviciene R, Schwartz R. Papular acrodermatitis of childhood: the Gianotti-Crosti syndrome. Cutis 2001;67:291-4. 4. Baldari U, Monti A, Righini M. An epidemic of infantile papular acrodermatitis (Gianotti-Crosti syndrome) due to Epstein-Barr virus. Dermatology 1994;188:203-4. doi:10.1016/j.jaad.2010.08.008
Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy To the Editor: We describe a 41-year-old HIV-positive woman on a regimen of lamivudine, tenofovir, atazanavir, and ritonavir who developed a diffuse, pruritic, nonspecific dermatitis that was unresponsive to medium-potency topical corticosteroids who was treated with a single intramuscular (IM) injection of 60 mg triamcinolone acetonide (TAC). After missing her follow-up appointment, the patient presented at 3 months with resolution of her eruption, weight gain of 7 kg, round facies, and increased density of coarse hairs on the face. She had lower than baseline blood pressure of 92/50 mm Hg, adrenocorticotropic hormone level less than 5 pg/mL (normal 7-50 pg/mL), and endogenous cortisol level 2.2 g/dL (normal 5-23 g/mL), with normal testosterone, dehydroepiandrosterone, and thyroid-stimulating hormone levels. The patient’s treatment with IM TAC and subsequent physical and laboratory findings supported a diagnosis of iatrogenic Cushing syndrome (ICS) with secondary adrenal insufficiency (SAI). Within 6 months of the initial injection, cortisol levels normalized and the physical effects of cortisol excess also waned. The IM corticosteroid injection is an important therapeutic option in the treatment of steroidresponsive dermatologic disease, especially when topical or oral corticosteroid treatment is ineffective or impractical, or when patient adherence to therapy is a concern. While the side effects of topical and oral corticosteroids for dermatologic diseases are well described,1 adverse events from corticosteroid injections are underappreciated in the dermatology literature.2 Absorption of corticosteroid via IM administration is dependent on muscle-to-fat ratio at the site of injection, which renders this treatment approach less predictable and potentially more toxic.1 In our patient, however, increased absorption of corticosteroid via a single IM administration alone is
unlikely to have accounted for the occurrence of ICS and SAI. Concurrent use of ritonavir and atazanavir, both of which are cytochrome P450 (CYP 450) 3A4 inhibitors, likely resulted in the prolonged catabolism of triamcinolone acetonide and subsequent increased blood concentration of the glucocorticoid. Inhibition of cytochrome activity by protease inhibitors, specifically ritonavir, not only affects the magnitude and duration of corticosteroid activity, but also alters physiologic, pharmacologic, and toxicologic effects of corticosteroids on relevant organs.3 This case demonstrates that increased exposure to glucocorticoids due to prolonged catabolism may lead to ICS, hypothalamic-pituitary-adrenal suppression with subsequent risk for SAI once effects of excess exogenous steroids wear off. Although ICS has been documented in patients treated with oral,4 intra-articular,5 and inhaled3 corticosteroids in the presence of CYP 450 inhibitors, to our knowledge this syndrome has not been documented for patients treated with IM corticosteroids in a dermatologic case. Dermatologists should be aware of ICS and SAI as a consequence of even short-term IM corticosteroid and concomitant CYP 450 inhibitor therapy. When corticosteroid therapy in patients using ritonavir is unavoidable, management may include supplanting ritonavir with non-nucleoside reverse transcriptase inhibitors to avoid concurrent use of CYP 450 inhibitors.4 Danielle Levine, MD,a Sonia Ananthakrishnan, MD,b and Amit Garg, MDa Department of Dermatologya and Division of Endocrinology,b Boston University School of Medicine, Boston, Massachusetts Funding sources: None. Conflicts of interest: None declared. Correspondence to: Amit Garg, MD, Department of Dermatology, 609 Albany St, J207, Boston, MA 02118 E-mail: [email protected] REFERENCES 1. Wolverton SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders; 2001. pp. 109-26. 2. Heymann WR. Intramuscular triamcinolone. J Am Acad Dermatol 2006;54:866-7. 3. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9:389-96. Epub 2008 May 4. 4. Busse KH, Formentini E, Alfaro RM, Kovacs JA, Penzack SR. Influence of antiretroviral drugs on the pharmacokinetics of
J AM ACAD DERMATOL
878 Letters
OCTOBER 2011
prednisolone in HIV-infected individuals. J Acquir Immune Defic Syndr 2008;48:561-6. 5. Dort K, Padia S, Wispelwey B, Moore CC. Adrenal suppression due to an interaction between ritonavir and injected triamcinolone: a case report. AIDS Res Ther 2009;6:10. doi:10.1016/j.jaad.2010.09.014
Subepidermal blistering disease with 3 distinct autoantibodies: Anti-BP230, anti-laminin gamma-1, and anti-laminin-332 To the Editor: A 25-year-old Japanese woman presented with pruritic tense blisters involving the lips, forearms, fingers, and soles (Fig 1, A-C ). No mucosal involvement was observed. A skin biopsy specimen taken from a bulla on her left forearm demonstrated subepidermal separation with eosinophilic inflammatory infiltrate in the dermis (Fig 2, A). Direct immunofluorescence (IF) microscopy of the lesion showed linear deposition of C3 and IgG at the dermoepidermal junction (Fig 2, B and C ). Indirect IF on sodium-split skin revealed linear IgG deposition on both the epidermal and the dermal sides (titer 1:20; Fig 2, D). Enzyme-linked immunosorbent assay (ELISA) using bacterial recombinant protein of the NC16a domain of COL17 (MBL, Nagoya, Japan) was negative. ELISA using bacterial recombinant proteins of the N- and C-terminal domains of BP230 (MBL, Nagoya, Japan) was also negative. Immunoblot analysis with epidermal and dermal extracts derived from normal human skin and purified laminin-332 was performed. The results showed the presence of circulating IgG autoantibodies against BP230, laminin g1, and the g 2 chain of laminin-332 (Fig 2, E, F, and G). Oral prednisolone, 40 mg per day (PSL), failed to alleviate the symptoms. With the addition of 75 mg per day of oral diaphenylsulfone (DDS), the cutaneous lesions rapidly healed with postinflammatory hyperpigmentation. PSL and DDS were tapered without relapse of skin lesions. At 10 months after referral, she discontinued PSL and was taking DDS at 25 mg daily. Previously, antibodies against laminin-332 were detected in about 10% to 20% of mucous membrane pemphigoid (MMP) patients. The majority of the patients have antibodies reactive with the a3 subunit of the protein. However, our case showed reactivity only with the g2 subunit. The mucosal involvement that is typically seen in MMP was not observed in our case. Circulating antibodies against BP230 were detected in the serum of a patient by immunoblot analysis but not by BP230 ELISA (MBL, Nagoya, Japan). This ELISA system utilizes the N- and Cterminal domains of BP230, but not the central-rod domain.1 Therefore the autoantibodies against BP230
Fig 1. Clinical presentation of the patient. Tense blisters involve the fingers (A), forearms (B), and lips (C).
that were detected in our immunoblot study may have reacted with the central-rod domain of the BP230 antigen. Autoantibodies against BP230, an intracellular protein, are clearly associated with bullous pemphigoid (BP), but have not been shown to be involved in the initiation of the disease. A marked improvement with the administration of DDS and the absence of erythematous plaques in the patient were not typical of the BP clinical course and manifestations. Autoantibodies against laminin g1 are characteristic of anti-laminin g1 pemphigoid.2 Blisters involving the lips and therapeutic improvement with DDS are compatible with the clinical features of anti-laminin g1 pemphigoid. On the basis of these findings, the diagnosis of anti-laminin g1 pemphigoid may be appropriate. It is possible that the unusual autoimmune profile of the patient developed as a result of epitope
Letters 877
VOLUME 65, NUMBER 4
REFERENCES 1. Brandt O, Abeck D, Gianotti R, Burgdorf W. Gianotti-Crosti syndrome. J Am Acad Dermatol 2006;54:136-45. 2. Patrizi A, Di Lernia V, Neri I, Ricci G. An unusual case of recurrent Gianotti-Crosti syndrome. Pediatr Dermatol 1994;11:283-4. 3. Baleviciene G, Maciuleviciene R, Schwartz R. Papular acrodermatitis of childhood: the Gianotti-Crosti syndrome. Cutis 2001;67:291-4. 4. Baldari U, Monti A, Righini M. An epidemic of infantile papular acrodermatitis (Gianotti-Crosti syndrome) due to Epstein-Barr virus. Dermatology 1994;188:203-4. doi:10.1016/j.jaad.2010.08.008
Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy To the Editor: We describe a 41-year-old HIV-positive woman on a regimen of lamivudine, tenofovir, atazanavir, and ritonavir who developed a diffuse, pruritic, nonspecific dermatitis that was unresponsive to medium-potency topical corticosteroids who was treated with a single intramuscular (IM) injection of 60 mg triamcinolone acetonide (TAC). After missing her follow-up appointment, the patient presented at 3 months with resolution of her eruption, weight gain of 7 kg, round facies, and increased density of coarse hairs on the face. She had lower than baseline blood pressure of 92/50 mm Hg, adrenocorticotropic hormone level less than 5 pg/mL (normal 7-50 pg/mL), and endogenous cortisol level 2.2 g/dL (normal 5-23 g/mL), with normal testosterone, dehydroepiandrosterone, and thyroid-stimulating hormone levels. The patient’s treatment with IM TAC and subsequent physical and laboratory findings supported a diagnosis of iatrogenic Cushing syndrome (ICS) with secondary adrenal insufficiency (SAI). Within 6 months of the initial injection, cortisol levels normalized and the physical effects of cortisol excess also waned. The IM corticosteroid injection is an important therapeutic option in the treatment of steroidresponsive dermatologic disease, especially when topical or oral corticosteroid treatment is ineffective or impractical, or when patient adherence to therapy is a concern. While the side effects of topical and oral corticosteroids for dermatologic diseases are well described,1 adverse events from corticosteroid injections are underappreciated in the dermatology literature.2 Absorption of corticosteroid via IM administration is dependent on muscle-to-fat ratio at the site of injection, which renders this treatment approach less predictable and potentially more toxic.1 In our patient, however, increased absorption of corticosteroid via a single IM administration alone is
unlikely to have accounted for the occurrence of ICS and SAI. Concurrent use of ritonavir and atazanavir, both of which are cytochrome P450 (CYP 450) 3A4 inhibitors, likely resulted in the prolonged catabolism of triamcinolone acetonide and subsequent increased blood concentration of the glucocorticoid. Inhibition of cytochrome activity by protease inhibitors, specifically ritonavir, not only affects the magnitude and duration of corticosteroid activity, but also alters physiologic, pharmacologic, and toxicologic effects of corticosteroids on relevant organs.3 This case demonstrates that increased exposure to glucocorticoids due to prolonged catabolism may lead to ICS, hypothalamic-pituitary-adrenal suppression with subsequent risk for SAI once effects of excess exogenous steroids wear off. Although ICS has been documented in patients treated with oral,4 intra-articular,5 and inhaled3 corticosteroids in the presence of CYP 450 inhibitors, to our knowledge this syndrome has not been documented for patients treated with IM corticosteroids in a dermatologic case. Dermatologists should be aware of ICS and SAI as a consequence of even short-term IM corticosteroid and concomitant CYP 450 inhibitor therapy. When corticosteroid therapy in patients using ritonavir is unavoidable, management may include supplanting ritonavir with non-nucleoside reverse transcriptase inhibitors to avoid concurrent use of CYP 450 inhibitors.4 Danielle Levine, MD,a Sonia Ananthakrishnan, MD,b and Amit Garg, MDa Department of Dermatologya and Division of Endocrinology,b Boston University School of Medicine, Boston, Massachusetts Funding sources: None. Conflicts of interest: None declared. Correspondence to: Amit Garg, MD, Department of Dermatology, 609 Albany St, J207, Boston, MA 02118 E-mail: [email protected] REFERENCES 1. Wolverton SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders; 2001. pp. 109-26. 2. Heymann WR. Intramuscular triamcinolone. J Am Acad Dermatol 2006;54:866-7. 3. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9:389-96. Epub 2008 May 4. 4. Busse KH, Formentini E, Alfaro RM, Kovacs JA, Penzack SR. Influence of antiretroviral drugs on the pharmacokinetics of
J AM ACAD DERMATOL
878 Letters
OCTOBER 2011
prednisolone in HIV-infected individuals. J Acquir Immune Defic Syndr 2008;48:561-6. 5. Dort K, Padia S, Wispelwey B, Moore CC. Adrenal suppression due to an interaction between ritonavir and injected triamcinolone: a case report. AIDS Res Ther 2009;6:10. doi:10.1016/j.jaad.2010.09.014
Subepidermal blistering disease with 3 distinct autoantibodies: Anti-BP230, anti-laminin gamma-1, and anti-laminin-332 To the Editor: A 25-year-old Japanese woman presented with pruritic tense blisters involving the lips, forearms, fingers, and soles (Fig 1, A-C ). No mucosal involvement was observed. A skin biopsy specimen taken from a bulla on her left forearm demonstrated subepidermal separation with eosinophilic inflammatory infiltrate in the dermis (Fig 2, A). Direct immunofluorescence (IF) microscopy of the lesion showed linear deposition of C3 and IgG at the dermoepidermal junction (Fig 2, B and C ). Indirect IF on sodium-split skin revealed linear IgG deposition on both the epidermal and the dermal sides (titer 1:20; Fig 2, D). Enzyme-linked immunosorbent assay (ELISA) using bacterial recombinant protein of the NC16a domain of COL17 (MBL, Nagoya, Japan) was negative. ELISA using bacterial recombinant proteins of the N- and C-terminal domains of BP230 (MBL, Nagoya, Japan) was also negative. Immunoblot analysis with epidermal and dermal extracts derived from normal human skin and purified laminin-332 was performed. The results showed the presence of circulating IgG autoantibodies against BP230, laminin g1, and the g 2 chain of laminin-332 (Fig 2, E, F, and G). Oral prednisolone, 40 mg per day (PSL), failed to alleviate the symptoms. With the addition of 75 mg per day of oral diaphenylsulfone (DDS), the cutaneous lesions rapidly healed with postinflammatory hyperpigmentation. PSL and DDS were tapered without relapse of skin lesions. At 10 months after referral, she discontinued PSL and was taking DDS at 25 mg daily. Previously, antibodies against laminin-332 were detected in about 10% to 20% of mucous membrane pemphigoid (MMP) patients. The majority of the patients have antibodies reactive with the a3 subunit of the protein. However, our case showed reactivity only with the g2 subunit. The mucosal involvement that is typically seen in MMP was not observed in our case. Circulating antibodies against BP230 were detected in the serum of a patient by immunoblot analysis but not by BP230 ELISA (MBL, Nagoya, Japan). This ELISA system utilizes the N- and Cterminal domains of BP230, but not the central-rod domain.1 Therefore the autoantibodies against BP230
Fig 1. Clinical presentation of the patient. Tense blisters involve the fingers (A), forearms (B), and lips (C).
that were detected in our immunoblot study may have reacted with the central-rod domain of the BP230 antigen. Autoantibodies against BP230, an intracellular protein, are clearly associated with bullous pemphigoid (BP), but have not been shown to be involved in the initiation of the disease. A marked improvement with the administration of DDS and the absence of erythematous plaques in the patient were not typical of the BP clinical course and manifestations. Autoantibodies against laminin g1 are characteristic of anti-laminin g1 pemphigoid.2 Blisters involving the lips and therapeutic improvement with DDS are compatible with the clinical features of anti-laminin g1 pemphigoid. On the basis of these findings, the diagnosis of anti-laminin g1 pemphigoid may be appropriate. It is possible that the unusual autoimmune profile of the patient developed as a result of epitope