Letters to the Editor
978
necrosis after rituximab could be responsible for an acute recruitment of mast cells, eosinophils and neutrophils. As already suggested by other authors, a cytokine-release phenomenom limited to the skin could also be hypothesized.4 Usually, the resolution of the phenomenom is fast with H1 antihistamine and rituximab may be continued. More cases should be collected to precise histological features and pathophysiological significance of these urticarial reactions. S. Ingen-Housz-Oro,1,* N. Ortonne,2,3 O. Chosidow1,3,4 teil, Department of Dermatology, AP-HP, Henri Mondor Hospital,Cre France, 2Department of Pathology, AP-HP, Henri Mondor Hospital, Paris-Est Creteil Val de Marne UPEC, Cre teil, teil, France, 3Universite Cre teil, France France, 4INSERM, Centre d’Investigation Clinique 006, Cre *Correspondence: S. Ingen-Housz-Oro. E-mail: [email protected] 1
References 1 Heinzerling LM, Urbanek M, Funk JO et al. Reduction of tumor burden and stabilization of disease by systemic therapy with anti-CD20 antibody (rituximab) in patients with primary cutaneous B-cell lymphoma. Cancer 2000; 89: 1835–1844. 2 Errante D, Bernardi D, Bianco A et al. Rituximab-related urticarial reaction in a patient treated for primary cutaneous B-cell lymphoma. Ann Oncol 2006; 17: 1720–1721. 3 Perez-Gala S, Delgado-Jimenez Y, Goiriz R et al. Cytokine-release syndrome related to rituximab limited to lesions and excision scars of lesions of primary cutaneous lymphoma. Arch Dermatol 2006; 142: 1516–1517. 4 Brunet-Possenti F, Franck N, Tamburini J et al. Focal rituximab-induced edematous reaction at primary cutaneous follicle center lymphoma lesions: case report and literature review. Dermatology 2011; 223: 200–202. 5 Willemze R, Swerdlow SH, Harris NL et al. Primary cutaneous follicle centre lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid tissues, 4th edn. International Agency for Research on Cancer, Lyon, France, 2008: 227. 6 Weiner GJ. Rituximab: mechanism of action. Semin Hematol 2010; 47: 115–123. 7 van der Kolk LE, Grillo-L opez AJ, Baars JW et al. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol 2001; 115: 807–811.
effect on kidney function has been reported. We report on a significant reduction in glomerular filtration rate (GFR) in a retrospective analysis of 16 patients treated with VMF for melanoma (maximal follow-up: 8 months). As part of normal surveillance measures, patients treated with VMF were monitored (at baseline, 1 and 3 months) for glomerular filtration rate, urine analysis for erythrocytes, leucocytes and nitrites, proteinuria and albuminuria. In case of proteinuria, microalbuminuria and b2-microglobulinuria were assessed. Among these 16 patients [10 men, six women; median age 59.4 years (range: 36–78)] treated with VMF, 12 were classified as stage IV and four classified as stage IIIc according to the AJCC 2009 classification.3 For eight patients, VMF was the first line treatment for melanoma, it was the second line for seven patients and the third for only one patient. A total of 15 patients experienced a significant decrease in GFR after 1 month (mean reduction 29 mL/min; 95%CI:[15.4; 43.2]; Fig. 1), and this persisted after 3 months (mean reduction 29 mL/min;95%CI:[16.9; 41.7]; Fig. 1). For patients with maximum follow-up (8 months), the decrease in GFR persisted at 8 months. A total of five patients presented with a significant proteinuria (median shot-proteinuria: 0.56 g/L [range 0.36 to 1.68]) including two patients with microalbuminuria, and two patients with both microalbuminuria and b2-microglobulinuria. Blood pressure measurements remained within normal limits for all patients.
DOI: 10.1111/jdv.12313
Vemurafenib significantly decreases glomerular filtration rate Editor, Vemurafenib (VMF), a BRAF inhibitor, has been approved as first line treatment for stage IIIC-IV melanoma.1 This treatment is new and so far, side-effects and tolerance are not depicted. The most frequent adverse events are arthralgia, rash, QTc interval prolongation, fatigue, alopecia, squamous-cell carcinoma, photosensitivity, nausea and diarrhoea.2 No evidence of any
JEADV 2014, 28, 976–983
Figure 1 Glomerular filtration rate at baseline, after 1 month of treatment with Vemurafenib and after 3 months of treatment with Vemurafenib (Mann–Whitney test, n = 16, presented as median, interquartile range, 10th and 90th percentile).
© 2013 European Academy of Dermatology and Venereology
Letters to the Editor
We report an almost constant reduction in the GFR in patients treated with VMF. Decrease in GFR was observed early after introduction of the treatment with VMF, which was moderate and persisted all along the treatment. Although this reduction was not leading to impairment in renal function, it was significant. The mechanism of this decrease in GFR remains unknown and seems variable. As the decrease in GFR was moderate, renal biopsy was not performed. Vemurafenib is part of the class of Kinase inhibitors (KI), the decrease in the GFR may be related to a class side-effect.4,5 Some side-effects of VMF (prolonged QTc, hand foot syndrome) are also observed with Tyrosine KI. Nephrotoxicity of Tyrosine KI is known, often related to structural damages of the nephron and characterized by hypertension, mild or moderate proteinuria (usually reversible) and in some rare cases nephritic syndrome, acute renal dysfunction, proliferative or collapsing glomerulonephritis, interstitial nephritis and thrombotic microangiopathy. In the present evaluation, none of the patients displayed such symptoms. Antiproliferative effects of VMF may also have induced a specific tubular toxicity resulting in an increase in microalbuminuria and b2-microglobulinuria. This was observed in only two cases. We report an almost constant alteration in the GFR in patients treated with VMF for metastatic melanoma. Clinicians should be aware of such side-effect, to adapt the follow-up and avoid nephrotoxic drugs for these patients. C. Uthurriague,1 S. Thellier,1 D. Ribes,2 L. Rostaing,2 C. Paul,1 N. Meyer1,3,* 1
Department of Dermatology, Paul Sabatier–Toulouse IlI University, Larrey hospital, Toulouse, France 2 Department of Nephrology, Paul Sabatier–Toulouse III University, Rangueil hospital, Toulouse, France, 3 Inserm UMR 1037-CRCT, Claudius-Regaud Institute, Toulouse, France *Correspondence: N. Meyer. E-mail: [email protected]
References 1 Drugs@FDA: FDA Approved Drug Products [Internet]. [citated 18 sep 2013]. available on: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist 2 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–2516. 3 Balch CM, Gershenwald JE, Soong S-J et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199–6206. 4 Jhaveri KD, Flombaum CD, Kroog G, Glezerman IG. Nephrotoxicities associated with the use of tyrosine kinase inhibitors: a single-center experience and review of the literature. Nephron Clin Pract 2011; 117: c312–c319. 5 Halimi J-M, Azizi M, Bobrie G et al. Vascular and renal effects of antiangiogenic therapy. Nephrol Ther 2008; 4: 602–615. DOI: 10.1111/jdv.12322
JEADV 2014, 28, 976–983
979
Multiple eruptive dermatofibromas related to imatinib treatment Editor Solitary dermatofibroma (DF) is a very common lesion that usually arises on the lower legs of young women. ‘Multiple eruptive dermatofibromas’ (MEDF) is a rare clinical variant that consists of 5–8 DFs appearing in a period of time shorter than 4 months.1 We present two patients with MEDF associated to the oral intake of imatinib. First patient was a 47-year-old woman with chronic myeloid leukaemia (CML) treated with imatinib for 1 year. For the last 5 months of this treatment, she referred progressive appearance of asymptomatic brown nodules, first on the right arm and later on both legs. She presented eight brown plaques with size ranging between 0.6 and 0.9 cm (Fig. 1a). CML showed complete clinical and molecular response along all the follow-up. Second patient was a 48-yearold man with CML. He complained about the rapid appearance of numerous brown nodules while he was taking imatinib, 4 years ago. Their appearance was concomitant with the loss of response to imatinib treatment. Then, he started a new treatment with nilotinib without appearance of additional skin lesions and with sustained complete molecular response. Clinical examination revealed 24, well-circumscribed, firm, round nodules involving mostly both legs, with only a few lesions scattered on the trunk (Fig. 1b). Excisional biopsy specimens of both patients showed acanthosis and hyperpigmented elongated rete ridges over a fibrohistiocytic proliferation of spindle cells between the collagen fibres. An increased number of Melan A, c-kit and microphthalmia-associated transcription factor-1 positive melanocytes were found in the epidermis overlying DF in both cases (Fig. 2). C-kit also highlighted numerous mast cells within both lesions, especially in the first case. We did not find differences with Masson Fontana staining between the epidermis covering the DFs and the surrounding normal skin. Multiple eruptive dermatofibromas is an uncommon variant of DF frequently associated with autoimmune diseases, neoplasms or human immunodeficiency virus infection.2 MEDF associated to drugs is rarer, but it has been described in relationship with immunosuppressive drugs such as efalizumab and methotrexate.3,4 It is also associated with highly active antiretroviral drugs in HIV-infected patients within a syndrome of immune restoration. These cases of MEDF in HIV-infected patients are also considered as a reactive process, and in some of the reported cases, leishmanias or mycobacteria were found within the proliferating cells of DF.5 Natural occurring T-regulatory cells are upregulated in CML, resulting in a diminished immune response and in disease progression.6 Imatinib is supposed to regulate Treg cell number, thus improving immune system although its global effects on immunity are controversial.6
© 2013 European Academy of Dermatology and Venereology
978
necrosis after rituximab could be responsible for an acute recruitment of mast cells, eosinophils and neutrophils. As already suggested by other authors, a cytokine-release phenomenom limited to the skin could also be hypothesized.4 Usually, the resolution of the phenomenom is fast with H1 antihistamine and rituximab may be continued. More cases should be collected to precise histological features and pathophysiological significance of these urticarial reactions. S. Ingen-Housz-Oro,1,* N. Ortonne,2,3 O. Chosidow1,3,4 teil, Department of Dermatology, AP-HP, Henri Mondor Hospital,Cre France, 2Department of Pathology, AP-HP, Henri Mondor Hospital, Paris-Est Creteil Val de Marne UPEC, Cre teil, teil, France, 3Universite Cre teil, France France, 4INSERM, Centre d’Investigation Clinique 006, Cre *Correspondence: S. Ingen-Housz-Oro. E-mail: [email protected] 1
References 1 Heinzerling LM, Urbanek M, Funk JO et al. Reduction of tumor burden and stabilization of disease by systemic therapy with anti-CD20 antibody (rituximab) in patients with primary cutaneous B-cell lymphoma. Cancer 2000; 89: 1835–1844. 2 Errante D, Bernardi D, Bianco A et al. Rituximab-related urticarial reaction in a patient treated for primary cutaneous B-cell lymphoma. Ann Oncol 2006; 17: 1720–1721. 3 Perez-Gala S, Delgado-Jimenez Y, Goiriz R et al. Cytokine-release syndrome related to rituximab limited to lesions and excision scars of lesions of primary cutaneous lymphoma. Arch Dermatol 2006; 142: 1516–1517. 4 Brunet-Possenti F, Franck N, Tamburini J et al. Focal rituximab-induced edematous reaction at primary cutaneous follicle center lymphoma lesions: case report and literature review. Dermatology 2011; 223: 200–202. 5 Willemze R, Swerdlow SH, Harris NL et al. Primary cutaneous follicle centre lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid tissues, 4th edn. International Agency for Research on Cancer, Lyon, France, 2008: 227. 6 Weiner GJ. Rituximab: mechanism of action. Semin Hematol 2010; 47: 115–123. 7 van der Kolk LE, Grillo-L opez AJ, Baars JW et al. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol 2001; 115: 807–811.
effect on kidney function has been reported. We report on a significant reduction in glomerular filtration rate (GFR) in a retrospective analysis of 16 patients treated with VMF for melanoma (maximal follow-up: 8 months). As part of normal surveillance measures, patients treated with VMF were monitored (at baseline, 1 and 3 months) for glomerular filtration rate, urine analysis for erythrocytes, leucocytes and nitrites, proteinuria and albuminuria. In case of proteinuria, microalbuminuria and b2-microglobulinuria were assessed. Among these 16 patients [10 men, six women; median age 59.4 years (range: 36–78)] treated with VMF, 12 were classified as stage IV and four classified as stage IIIc according to the AJCC 2009 classification.3 For eight patients, VMF was the first line treatment for melanoma, it was the second line for seven patients and the third for only one patient. A total of 15 patients experienced a significant decrease in GFR after 1 month (mean reduction 29 mL/min; 95%CI:[15.4; 43.2]; Fig. 1), and this persisted after 3 months (mean reduction 29 mL/min;95%CI:[16.9; 41.7]; Fig. 1). For patients with maximum follow-up (8 months), the decrease in GFR persisted at 8 months. A total of five patients presented with a significant proteinuria (median shot-proteinuria: 0.56 g/L [range 0.36 to 1.68]) including two patients with microalbuminuria, and two patients with both microalbuminuria and b2-microglobulinuria. Blood pressure measurements remained within normal limits for all patients.
DOI: 10.1111/jdv.12313
Vemurafenib significantly decreases glomerular filtration rate Editor, Vemurafenib (VMF), a BRAF inhibitor, has been approved as first line treatment for stage IIIC-IV melanoma.1 This treatment is new and so far, side-effects and tolerance are not depicted. The most frequent adverse events are arthralgia, rash, QTc interval prolongation, fatigue, alopecia, squamous-cell carcinoma, photosensitivity, nausea and diarrhoea.2 No evidence of any
JEADV 2014, 28, 976–983
Figure 1 Glomerular filtration rate at baseline, after 1 month of treatment with Vemurafenib and after 3 months of treatment with Vemurafenib (Mann–Whitney test, n = 16, presented as median, interquartile range, 10th and 90th percentile).
© 2013 European Academy of Dermatology and Venereology
Letters to the Editor
We report an almost constant reduction in the GFR in patients treated with VMF. Decrease in GFR was observed early after introduction of the treatment with VMF, which was moderate and persisted all along the treatment. Although this reduction was not leading to impairment in renal function, it was significant. The mechanism of this decrease in GFR remains unknown and seems variable. As the decrease in GFR was moderate, renal biopsy was not performed. Vemurafenib is part of the class of Kinase inhibitors (KI), the decrease in the GFR may be related to a class side-effect.4,5 Some side-effects of VMF (prolonged QTc, hand foot syndrome) are also observed with Tyrosine KI. Nephrotoxicity of Tyrosine KI is known, often related to structural damages of the nephron and characterized by hypertension, mild or moderate proteinuria (usually reversible) and in some rare cases nephritic syndrome, acute renal dysfunction, proliferative or collapsing glomerulonephritis, interstitial nephritis and thrombotic microangiopathy. In the present evaluation, none of the patients displayed such symptoms. Antiproliferative effects of VMF may also have induced a specific tubular toxicity resulting in an increase in microalbuminuria and b2-microglobulinuria. This was observed in only two cases. We report an almost constant alteration in the GFR in patients treated with VMF for metastatic melanoma. Clinicians should be aware of such side-effect, to adapt the follow-up and avoid nephrotoxic drugs for these patients. C. Uthurriague,1 S. Thellier,1 D. Ribes,2 L. Rostaing,2 C. Paul,1 N. Meyer1,3,* 1
Department of Dermatology, Paul Sabatier–Toulouse IlI University, Larrey hospital, Toulouse, France 2 Department of Nephrology, Paul Sabatier–Toulouse III University, Rangueil hospital, Toulouse, France, 3 Inserm UMR 1037-CRCT, Claudius-Regaud Institute, Toulouse, France *Correspondence: N. Meyer. E-mail: [email protected]
References 1 Drugs@FDA: FDA Approved Drug Products [Internet]. [citated 18 sep 2013]. available on: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist 2 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–2516. 3 Balch CM, Gershenwald JE, Soong S-J et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199–6206. 4 Jhaveri KD, Flombaum CD, Kroog G, Glezerman IG. Nephrotoxicities associated with the use of tyrosine kinase inhibitors: a single-center experience and review of the literature. Nephron Clin Pract 2011; 117: c312–c319. 5 Halimi J-M, Azizi M, Bobrie G et al. Vascular and renal effects of antiangiogenic therapy. Nephrol Ther 2008; 4: 602–615. DOI: 10.1111/jdv.12322
JEADV 2014, 28, 976–983
979
Multiple eruptive dermatofibromas related to imatinib treatment Editor Solitary dermatofibroma (DF) is a very common lesion that usually arises on the lower legs of young women. ‘Multiple eruptive dermatofibromas’ (MEDF) is a rare clinical variant that consists of 5–8 DFs appearing in a period of time shorter than 4 months.1 We present two patients with MEDF associated to the oral intake of imatinib. First patient was a 47-year-old woman with chronic myeloid leukaemia (CML) treated with imatinib for 1 year. For the last 5 months of this treatment, she referred progressive appearance of asymptomatic brown nodules, first on the right arm and later on both legs. She presented eight brown plaques with size ranging between 0.6 and 0.9 cm (Fig. 1a). CML showed complete clinical and molecular response along all the follow-up. Second patient was a 48-yearold man with CML. He complained about the rapid appearance of numerous brown nodules while he was taking imatinib, 4 years ago. Their appearance was concomitant with the loss of response to imatinib treatment. Then, he started a new treatment with nilotinib without appearance of additional skin lesions and with sustained complete molecular response. Clinical examination revealed 24, well-circumscribed, firm, round nodules involving mostly both legs, with only a few lesions scattered on the trunk (Fig. 1b). Excisional biopsy specimens of both patients showed acanthosis and hyperpigmented elongated rete ridges over a fibrohistiocytic proliferation of spindle cells between the collagen fibres. An increased number of Melan A, c-kit and microphthalmia-associated transcription factor-1 positive melanocytes were found in the epidermis overlying DF in both cases (Fig. 2). C-kit also highlighted numerous mast cells within both lesions, especially in the first case. We did not find differences with Masson Fontana staining between the epidermis covering the DFs and the surrounding normal skin. Multiple eruptive dermatofibromas is an uncommon variant of DF frequently associated with autoimmune diseases, neoplasms or human immunodeficiency virus infection.2 MEDF associated to drugs is rarer, but it has been described in relationship with immunosuppressive drugs such as efalizumab and methotrexate.3,4 It is also associated with highly active antiretroviral drugs in HIV-infected patients within a syndrome of immune restoration. These cases of MEDF in HIV-infected patients are also considered as a reactive process, and in some of the reported cases, leishmanias or mycobacteria were found within the proliferating cells of DF.5 Natural occurring T-regulatory cells are upregulated in CML, resulting in a diminished immune response and in disease progression.6 Imatinib is supposed to regulate Treg cell number, thus improving immune system although its global effects on immunity are controversial.6
© 2013 European Academy of Dermatology and Venereology
