Letters to the Editor
transplant patients.10 Accordingly, we found the presence of HPV 52 in our patient’s oral lesions. Hence, Vemurafenib administration in an immunosuppressed patient may have triggered the onset of HPV associated lesions that completely regressed after drug discontinuation. A. Pileri,1,2,* M. Cricca,3 L. Gandolfi,4 C. Misciali,1 B. Casadei,4 P.L. Zinzani,4 A. Patrizi1 1
Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 2Division Dermatology, Departement of Surgery and Translational Medicine, University of Florence, Florence, 3Microbiology Unit, Department Of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 4Haematogy Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy *Correspondence: A. Pileri. E-mail: [email protected] The content of this manuscript has never been published or presented elsewhere.
References 1 Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol 2013; 27: 11–18. 2 Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819. 3 Haroche J, Cohen-Aubart F, Emile JF et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013; 121: 1495–1500. 4 Boussemart L, Routier E, Mateus C et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2013; 24: 1691–1697. 5 Fava P, Marra E, Astrua C et al. Dermatological approach to vemurafenib skin toxicity: a single centre experience. G Ital Dermatol Venereol 2014; [Epub ahead of print]. 6 Samuel J, Macip S, Dyer MJ. Efficacy of vemurafenib in hairy-cell leukemia. N Engl J Med 2014; 370: 286–288. 7 Dalle S, Poulalhon N, Debarbieux S et al. Tracking of second primary melanomas in vemurafenib-treated patients. JAMA Dermatol 2013; 149: 488–490. 8 Sinha R, Edmonds K, Newton-Bishop JA, Gore ME, Larkin J, Fearfield L. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br J Dermatol 2012; 167: 987–994. 9 Bouda M, Gorgoulis VG, Kastrinakis NG et al. High risk HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal oral mucosa. Mod Pathol 2000; 13: 644–653. 10 Katz J, Islam MN, Bhattacharyya I, Sandow P, Moreb JS. Oral squamous cell carcinoma positive for p16/human papilloma virus in post allogeneic stem cell transplantation: 2 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 118: e74–e78. DOI: 10.1111/jdv.13105
JEADV 2016, 30, 1025–1067
1055
Successful treatment of Wilson disease-associated IgA pemphigus with IVIG IgA pemphigus (IgAP) is a rarely seen autoimmune bullous disease. Corticosteroids (CS) are the mainstays for the treatment of IgAP, owing to the inflammatory nature of the disease.1 Due to its neutrophilic nature, dapson and colchicine also are an effective treatment option in IgAP.2 Oral retinoids like isotretinoin and acitretin were found to be effective in the treatment of IgAP.3,4 Mycophenolate mofetil and adalimumab are also reported to be useful in treating IgAP.5 Azathioprine, a commonly used immunosuppressant in pemphigus, does not seem to be effective in treating IgAP.2 Aggressive therapy with prednisone, cyclophosphamide and plasmapheresis has also been used for a recurrence after initial treatment with dapsone and prednisone.6 To our knowledge, up to now intravenous immunoglobulin (IVIG) never used against IgAP. Furthermore, there are no reports regarding Wilson disease (WD)-associated IgAP in the literature. Here we report a recalcitrant WD-associated IgAP case, which was successfully treated with IVIG. A twenty-year-old male patient was hospitalized in the dermatology department due to a massive vesiculopustular skin lesion on the scalp and axilla. On dermatologic evaluation, diffuse, superinfected, purulent, vesiculopustular skin lesions were found on the scalp and the unilateral axillar region which were secondarily vegetated (Fig. 1). Lesions were very itchy and painfull. Oral mucosa involvement was absent. A skin sample was taken from the vesiculopustular lesion that revealed intraepidermal fishnet like deposition of IgA autoantibodies in IF examination. On microscopic evaluation, perifollicular neutrophil accumulation and significant acantholysis was found (Fig. 1). Two-time desmoglein (DSGL) levels were measured in the blood sample and a negative result was obtained. Liver enzymes were highly elevated in this patient so possible liver pathologies were considered. Copper level in blood and 24 h urine was higly elevated. The Kayser–Fleischer ring was positive on eye examination. Liver biopsy revealed cirrhosis. In conclusion WD was diagnosed in this patient. CS treatment at the dosage 0.5–1 mg/ kg was initiated and patient responded to it very quickly. However, disease relapsed following the CS tapering. Due to increase of relapse frequencies, IVIG administration was started. As a result, long-term remission was obtained and frequency of relapses decreased during 1 year of follow-up. IgAP shows a moderate clinical course compared to IgG pemphigus.7 WD is an autosomal recessive liver disease due to abnormal deposition of copper in hepatocytes. This patient was diagnosed with IgAP and WD simultaneously in the dermatology department. Development of autosomal recessive
© 2015 European Academy of Dermatology and Venereology
Letters to the Editor
1056
(a)
(b)
(c)
(d)
Figure 1 Non-infected untouched vesiculopustular lesions on scalp (a). Vegetative skin lesions on axillar region (b). Healed scalp and axilla following the steroid and IVIG treatment (c). Suprabasal acantholysis, including follicular epidermis and superficial polymorphnuclear cell infiltration (H&E 9100) (d).
and autoimmune disease in the same patient probably is coincidental. However, abnormally deposition of copper in the epidermis could negatively influence IgAP by unknown mechanisms and make IgAP recalcitrant to the traditional treatment. Because of the recalcitrant nature of IgAP, malignancy association also was considered in this patient. IgA gammopathy is the most common malignancy associated with IgAP. In this patient, IgA gammopathy is also ruled out. D-penicillamine prescribed against WD was thought to be a possible aggravating factor of IgAP, that is why d-penicillamine was replaced with trientine hydrochloride for the treatment of WD. It was troublesome to choose safe treatment for IgAP in patients with chronic liver failure. Dapson and oral retinoids were abandoned due to their well-known hepatotoxic side effects. As a result, IVIG administration was planned for this patient. IVIG is an effective treatment options for the classic IgG pemphiguses, however in the literature, reports regarding IVIG in the treatment of IgAP are limited. Patients with chronic liver disease were treated with IVIG at the 1 g/kg/per cycle dosages. Low dosage CS and IVIG combination brought patients to the long-term remission and the frequency of relapses was decreased during the 1-year follow-up. This case was admitted as a refractory IgAP probably due to abnormal copper metabolism. Chronic liver failure limited to the use of firstline drugs against IgAP in this patient. However, IVIG was found to be effective and safe for the treatment of recalcitrant IgAP in this case.
JEADV 2016, 30, 1025–1067
M. Iskandarli,1,* B. Gerceker Turk,1 I. Ertam,1 B. Yaman,2 G. Ozturk1 1 Department of Dermatology and Venereology, Ege University Faculty of Medicine, 2Department of Pathology, Ege University Faculty of Medicine, Izmir, Turkey *Correspondence: M. Iskandarli. E-mail: [email protected]
References 1 Camisa C, Warner M. Treatment of pemphigus. Dermatol Nurs 1998; 10: 115–118, 123-31. 2 Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol 1992; 27: 993–1000. 3 Gruss C, Zillikens D, Hashimoto T et al. Rapid response of IgA pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin. J Am Acad Dermatol 2000; 43: 923–926. ~ez A, Hashimoto T, Amagai M, Fernan4 Ruiz-Genao DP, Hernandez-N un dez-Herrera J, Garcıa-Dıez A. A case of IgA pemphigus successfully treated with acitretin. Br J Dermatol 2002; 147: 1040–1042. 5 Howell SM, Bessinger GT, Altman CE, Belnap CM. Rapid response of IgA pemphigus of the subcorneal pustular dermatosis subtype to treatment with adalimumab and mycophenolate mofetil. J Am Acad Dermatol 2005; 53: 541–543. 6 Chorzelski TP, Beutner EH, Kowalewski C et al. IgA pemphigus foliaceus with a clinical presentation of pemphigus herpetiformis. J Am Acad Dermatol 1991; 24: 839–844. 7 Tsuruta D, Ishii N, Hamada T et al. IgA pemphigus. Clin Dermatol 2011; 29: 437–442. DOI: 10.1111/jdv.13106
© 2015 European Academy of Dermatology and Venereology
transplant patients.10 Accordingly, we found the presence of HPV 52 in our patient’s oral lesions. Hence, Vemurafenib administration in an immunosuppressed patient may have triggered the onset of HPV associated lesions that completely regressed after drug discontinuation. A. Pileri,1,2,* M. Cricca,3 L. Gandolfi,4 C. Misciali,1 B. Casadei,4 P.L. Zinzani,4 A. Patrizi1 1
Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 2Division Dermatology, Departement of Surgery and Translational Medicine, University of Florence, Florence, 3Microbiology Unit, Department Of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 4Haematogy Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy *Correspondence: A. Pileri. E-mail: [email protected] The content of this manuscript has never been published or presented elsewhere.
References 1 Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol 2013; 27: 11–18. 2 Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819. 3 Haroche J, Cohen-Aubart F, Emile JF et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013; 121: 1495–1500. 4 Boussemart L, Routier E, Mateus C et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2013; 24: 1691–1697. 5 Fava P, Marra E, Astrua C et al. Dermatological approach to vemurafenib skin toxicity: a single centre experience. G Ital Dermatol Venereol 2014; [Epub ahead of print]. 6 Samuel J, Macip S, Dyer MJ. Efficacy of vemurafenib in hairy-cell leukemia. N Engl J Med 2014; 370: 286–288. 7 Dalle S, Poulalhon N, Debarbieux S et al. Tracking of second primary melanomas in vemurafenib-treated patients. JAMA Dermatol 2013; 149: 488–490. 8 Sinha R, Edmonds K, Newton-Bishop JA, Gore ME, Larkin J, Fearfield L. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br J Dermatol 2012; 167: 987–994. 9 Bouda M, Gorgoulis VG, Kastrinakis NG et al. High risk HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal oral mucosa. Mod Pathol 2000; 13: 644–653. 10 Katz J, Islam MN, Bhattacharyya I, Sandow P, Moreb JS. Oral squamous cell carcinoma positive for p16/human papilloma virus in post allogeneic stem cell transplantation: 2 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 118: e74–e78. DOI: 10.1111/jdv.13105
JEADV 2016, 30, 1025–1067
1055
Successful treatment of Wilson disease-associated IgA pemphigus with IVIG IgA pemphigus (IgAP) is a rarely seen autoimmune bullous disease. Corticosteroids (CS) are the mainstays for the treatment of IgAP, owing to the inflammatory nature of the disease.1 Due to its neutrophilic nature, dapson and colchicine also are an effective treatment option in IgAP.2 Oral retinoids like isotretinoin and acitretin were found to be effective in the treatment of IgAP.3,4 Mycophenolate mofetil and adalimumab are also reported to be useful in treating IgAP.5 Azathioprine, a commonly used immunosuppressant in pemphigus, does not seem to be effective in treating IgAP.2 Aggressive therapy with prednisone, cyclophosphamide and plasmapheresis has also been used for a recurrence after initial treatment with dapsone and prednisone.6 To our knowledge, up to now intravenous immunoglobulin (IVIG) never used against IgAP. Furthermore, there are no reports regarding Wilson disease (WD)-associated IgAP in the literature. Here we report a recalcitrant WD-associated IgAP case, which was successfully treated with IVIG. A twenty-year-old male patient was hospitalized in the dermatology department due to a massive vesiculopustular skin lesion on the scalp and axilla. On dermatologic evaluation, diffuse, superinfected, purulent, vesiculopustular skin lesions were found on the scalp and the unilateral axillar region which were secondarily vegetated (Fig. 1). Lesions were very itchy and painfull. Oral mucosa involvement was absent. A skin sample was taken from the vesiculopustular lesion that revealed intraepidermal fishnet like deposition of IgA autoantibodies in IF examination. On microscopic evaluation, perifollicular neutrophil accumulation and significant acantholysis was found (Fig. 1). Two-time desmoglein (DSGL) levels were measured in the blood sample and a negative result was obtained. Liver enzymes were highly elevated in this patient so possible liver pathologies were considered. Copper level in blood and 24 h urine was higly elevated. The Kayser–Fleischer ring was positive on eye examination. Liver biopsy revealed cirrhosis. In conclusion WD was diagnosed in this patient. CS treatment at the dosage 0.5–1 mg/ kg was initiated and patient responded to it very quickly. However, disease relapsed following the CS tapering. Due to increase of relapse frequencies, IVIG administration was started. As a result, long-term remission was obtained and frequency of relapses decreased during 1 year of follow-up. IgAP shows a moderate clinical course compared to IgG pemphigus.7 WD is an autosomal recessive liver disease due to abnormal deposition of copper in hepatocytes. This patient was diagnosed with IgAP and WD simultaneously in the dermatology department. Development of autosomal recessive
© 2015 European Academy of Dermatology and Venereology
Letters to the Editor
1056
(a)
(b)
(c)
(d)
Figure 1 Non-infected untouched vesiculopustular lesions on scalp (a). Vegetative skin lesions on axillar region (b). Healed scalp and axilla following the steroid and IVIG treatment (c). Suprabasal acantholysis, including follicular epidermis and superficial polymorphnuclear cell infiltration (H&E 9100) (d).
and autoimmune disease in the same patient probably is coincidental. However, abnormally deposition of copper in the epidermis could negatively influence IgAP by unknown mechanisms and make IgAP recalcitrant to the traditional treatment. Because of the recalcitrant nature of IgAP, malignancy association also was considered in this patient. IgA gammopathy is the most common malignancy associated with IgAP. In this patient, IgA gammopathy is also ruled out. D-penicillamine prescribed against WD was thought to be a possible aggravating factor of IgAP, that is why d-penicillamine was replaced with trientine hydrochloride for the treatment of WD. It was troublesome to choose safe treatment for IgAP in patients with chronic liver failure. Dapson and oral retinoids were abandoned due to their well-known hepatotoxic side effects. As a result, IVIG administration was planned for this patient. IVIG is an effective treatment options for the classic IgG pemphiguses, however in the literature, reports regarding IVIG in the treatment of IgAP are limited. Patients with chronic liver disease were treated with IVIG at the 1 g/kg/per cycle dosages. Low dosage CS and IVIG combination brought patients to the long-term remission and the frequency of relapses was decreased during the 1-year follow-up. This case was admitted as a refractory IgAP probably due to abnormal copper metabolism. Chronic liver failure limited to the use of firstline drugs against IgAP in this patient. However, IVIG was found to be effective and safe for the treatment of recalcitrant IgAP in this case.
JEADV 2016, 30, 1025–1067
M. Iskandarli,1,* B. Gerceker Turk,1 I. Ertam,1 B. Yaman,2 G. Ozturk1 1 Department of Dermatology and Venereology, Ege University Faculty of Medicine, 2Department of Pathology, Ege University Faculty of Medicine, Izmir, Turkey *Correspondence: M. Iskandarli. E-mail: [email protected]
References 1 Camisa C, Warner M. Treatment of pemphigus. Dermatol Nurs 1998; 10: 115–118, 123-31. 2 Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol 1992; 27: 993–1000. 3 Gruss C, Zillikens D, Hashimoto T et al. Rapid response of IgA pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin. J Am Acad Dermatol 2000; 43: 923–926. ~ez A, Hashimoto T, Amagai M, Fernan4 Ruiz-Genao DP, Hernandez-N un dez-Herrera J, Garcıa-Dıez A. A case of IgA pemphigus successfully treated with acitretin. Br J Dermatol 2002; 147: 1040–1042. 5 Howell SM, Bessinger GT, Altman CE, Belnap CM. Rapid response of IgA pemphigus of the subcorneal pustular dermatosis subtype to treatment with adalimumab and mycophenolate mofetil. J Am Acad Dermatol 2005; 53: 541–543. 6 Chorzelski TP, Beutner EH, Kowalewski C et al. IgA pemphigus foliaceus with a clinical presentation of pemphigus herpetiformis. J Am Acad Dermatol 1991; 24: 839–844. 7 Tsuruta D, Ishii N, Hamada T et al. IgA pemphigus. Clin Dermatol 2011; 29: 437–442. DOI: 10.1111/jdv.13106
© 2015 European Academy of Dermatology and Venereology
