Correspondence 997
(a)
(b)
Fig 1. (a) Foil attenuator with 10 apertures, (b) temperature probe.
Irradiance vs. temperature Mean output mWcm–2
7·5 7·0 6·5 6·0 5·5 5·0 4·5
59
57
55
51 53
49
45 47
43
41
39
37
33 35
31
29
27
25
4·0 Temperature ºC Fig 2. Output vs. temperature.
this range with our unit to be 29–40 °C. Using the device over this range gives acceptably accurate results due to its use at the same tube temperatures as those calibrated, yet with a more rapid turnaround. Additionally it ensures that the surface temperature is comfortable for the patient. These factors taken in conjunction with the attractive pricing and ease of use of this procedure compared with other methods should facilitate its introduction to centres still not performing MED tests, and provide the basis of a standardized MED methodology. Leeds Teaching Hospitals Trust, Leeds, U.K. E-mail: [email protected]
D. TURNER V. GOULDEN
Reference 1 Otman SGH, Edwards C, Brambles B, Anstey AV. Validation of a semiautomated method of minimal erythema dose testing for narrowband ultraviolet B phototherapy. Br J Dermatol 2006; 155:416–21. Funding sources: none. Conflicts of interest: none declared.
© 2013 British Association of Dermatologists
Toxic epidermal necrolysis in a patient receiving vemurafenib for treatment of metastatic malignant melanoma DOI: 10.1111/bjd.12796 DEAR EDITOR, Vemurafenib is a specific inhibitor of V600mutant BRAF and is indicated as monotherapy for the treatment of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma. In the short time that it has been available, it has developed a well-recorded adverse event profile, specifically of cutaneous toxic effects.1,2 Toxic epidermal necrolysis (TEN) is a dermatological emergency with a predicted mortality rate of 3–90% dependent on a well-documented illness severity score (SCORTEN).3 We describe the first case report in the literature of TEN associated with vemurafenib, and its management. A 73-year-old woman was diagnosed with metastatic melanoma (Breslow thickness 76 mm) of the plantar aspect of her left foot in June 2011. She underwent primary surgical excision and left inguinal lymphadenectomy (one of seven lymph nodes involved). Mutation analysis (cobasâ 4800; Roche Diagnostics Limited, Burgess Hill, U.K.) showed a British Journal of Dermatology (2014) 170, pp970–1001
998 Correspondence
(a)
(b)
(c)
Fig 1. (a) Separation of epidermis from dermis; (b) interface colloid bodies; (c) moderate upper dermal chronic inflammatory infiltrate with loose fibrosis and some scattered neutrophils interfacing colloid bodies. All haematoxylin and eosin stain; original magnification (a) 910, (b) 920, (c) 940.
(a)
(b)
(c)
Fig 2. (a, b) Widespread erythema with blistering and epidermal loss visible on the chest, upper abdomen and arm. (c) Target lesions seen to be present within and independent of erythematous areas.
V600E mutation in BRAF, and the patient was started on vemurafenib at the standard dose of 960 mg twice daily. In addition to vemurafenib the patient was taking sodium valproate (200 mg daily) for a previous seizure unrelated to her melanoma. Two weeks after starting vemurafenib, she developed a grade 1 rash (Common Terminology Criteria for Adverse Events version 4.0 of the National Cancer Institute), which was treated conservatively. During the following 3 weeks the rash progressed and she was noted to have blisters affecting the head, torso and upper limbs. Histological examination of the skin revealed areas of full-thickness degenerative necrosis of the epidermis with separation from the dermis (Fig. 1a). There were interface colloid bodies (Fig. 1b) and a moderate upper dermal chronic inflammatory infiltrate with loose fibrosis and some scattered neutrophils (Fig. 1c). The histological appearances together with the clinical findings were consistent with TEN of the skin. Supportive treatment was commenced and she was transferred to the burns unit of a tertiary care centre 6 days later, where specialists in the management of TEN were available. Clinical examination showed that she was febrile, hypotensive and tachycardic. Her upper limbs, upper chest and back were erythematous with some erosions (Fig. 2a,b). Target lesions were present (Fig. 2c) and 65% of the patient’s body surface area demonstrated detachable epidermis. There was conjunctival involvement, oral mucositis and superficial erosions in the British Journal of Dermatology (2014) 170, pp970–1001
vulval area. Mucosal sloughing in the upper airway was also observed. Laboratory investigations of note showed no eosinophilia and normal liver function. On clinical assessment, the patient had a SCORTEN of 4 out of a possible 7, predicting a mortality rate of > 50%. The patient required multiorgan support and was electively intubated and ventilated. Intravenous immunoglobulin (IVIg) was commenced at 15 g kg 1 over 3 days. The skincare regime involved 2-hourly application of liquid paraffin 50% and white soft paraffin 50%, clobetasol propionate ointment for the body twice daily and Trimovateâ cream (clobetasone butyrate, oxytetracycline and nystatin; GlaxoSmithKline, Brentford, U.K.) twice daily for the groin and vulval area. Re-epithelialization was slow, and therefore a further 2 days of IVIg at the same dose was prescribed 4 days later. Ciclosporin was not administered for the treatment of TEN owing to coexisting renal failure. The skin began to improve and the patient was transferred back to the referring hospital. In the subsequent days she developed a ventilatoracquired pneumonia and melaena, and died of multiorgan failure. TEN is rare, and its clinicopathological profile complex.4 Aetiologically, one may argue that the association of antiepileptics with TEN favours sodium valproate as the causative drug in this case. However, the long duration of therapy of sodium valproate and the recent introduction of vemurafenib argue strongly for the latter to be the causative agent, either directly or in concert with sodium valproate. © 2013 British Association of Dermatologists
Correspondence 999
It is important to note that most dermatological side-effects associated with vemurafenib treatment are manageable, and dose reduction and/or interruption can be useful in reducing these toxicities.2 This is the first case report associating vemurafenib with TEN. Physicians should be aware of the potential risk in order to initiate prompt specialist management. 1
Department of Dermatology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, U.K. 2 Department of Oncology, University of Oxford, Oxford, U.K. E-mail: [email protected]
R. SINHA1 K. LECAMWASAM1 K. PURSHOUSE2 J. REED2 M.R. MIDDLETON2 L. FEARFIELD1
2 Sinha R, Edmonds K, Newton-Bishop JA et al. 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; 167:987–94. 3 Bastuji-Garin S, Fouchard N, Bertocchi M et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115:149–53. 4 Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol 2013; 69:e1–13. Funding sources: none. Conflicts of interest: M.R.M. has received research funding and honoraria from Roche for consultancy and for speaking at sponsored meetings. L.F. has received honoraria to speak at a Roche-sponsored meeting.
References 1 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507–16.
© 2013 British Association of Dermatologists
Corrigenda DOI: 10.1111/bjd.12865 In the article by Piram et al.1 a unit dosage was listed incorrectly as oral MTX 15 mg kg appears below: oral MTX 15 mg m
2
1
on page 1266. The correct dosage
per week for 12 months
Reference 1 Piram M, McCuaig CC, Saint-Cyr C et al. Short- and long-term outcome of linear morphoea in children. Br J Dermatol 2013; 169:1265–71.
DOI: 10.1111/bjd.13022 In the article by Lowe et al.1 the first author’s name was published wrong. The correct name appears below. Garrett C. Lowe1
Reference 1 Lowe G, Henderson CL, Grau RH et al. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2011; 164:465–72.
© 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 170, pp970–1001
(a)
(b)
Fig 1. (a) Foil attenuator with 10 apertures, (b) temperature probe.
Irradiance vs. temperature Mean output mWcm–2
7·5 7·0 6·5 6·0 5·5 5·0 4·5
59
57
55
51 53
49
45 47
43
41
39
37
33 35
31
29
27
25
4·0 Temperature ºC Fig 2. Output vs. temperature.
this range with our unit to be 29–40 °C. Using the device over this range gives acceptably accurate results due to its use at the same tube temperatures as those calibrated, yet with a more rapid turnaround. Additionally it ensures that the surface temperature is comfortable for the patient. These factors taken in conjunction with the attractive pricing and ease of use of this procedure compared with other methods should facilitate its introduction to centres still not performing MED tests, and provide the basis of a standardized MED methodology. Leeds Teaching Hospitals Trust, Leeds, U.K. E-mail: [email protected]
D. TURNER V. GOULDEN
Reference 1 Otman SGH, Edwards C, Brambles B, Anstey AV. Validation of a semiautomated method of minimal erythema dose testing for narrowband ultraviolet B phototherapy. Br J Dermatol 2006; 155:416–21. Funding sources: none. Conflicts of interest: none declared.
© 2013 British Association of Dermatologists
Toxic epidermal necrolysis in a patient receiving vemurafenib for treatment of metastatic malignant melanoma DOI: 10.1111/bjd.12796 DEAR EDITOR, Vemurafenib is a specific inhibitor of V600mutant BRAF and is indicated as monotherapy for the treatment of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma. In the short time that it has been available, it has developed a well-recorded adverse event profile, specifically of cutaneous toxic effects.1,2 Toxic epidermal necrolysis (TEN) is a dermatological emergency with a predicted mortality rate of 3–90% dependent on a well-documented illness severity score (SCORTEN).3 We describe the first case report in the literature of TEN associated with vemurafenib, and its management. A 73-year-old woman was diagnosed with metastatic melanoma (Breslow thickness 76 mm) of the plantar aspect of her left foot in June 2011. She underwent primary surgical excision and left inguinal lymphadenectomy (one of seven lymph nodes involved). Mutation analysis (cobasâ 4800; Roche Diagnostics Limited, Burgess Hill, U.K.) showed a British Journal of Dermatology (2014) 170, pp970–1001
998 Correspondence
(a)
(b)
(c)
Fig 1. (a) Separation of epidermis from dermis; (b) interface colloid bodies; (c) moderate upper dermal chronic inflammatory infiltrate with loose fibrosis and some scattered neutrophils interfacing colloid bodies. All haematoxylin and eosin stain; original magnification (a) 910, (b) 920, (c) 940.
(a)
(b)
(c)
Fig 2. (a, b) Widespread erythema with blistering and epidermal loss visible on the chest, upper abdomen and arm. (c) Target lesions seen to be present within and independent of erythematous areas.
V600E mutation in BRAF, and the patient was started on vemurafenib at the standard dose of 960 mg twice daily. In addition to vemurafenib the patient was taking sodium valproate (200 mg daily) for a previous seizure unrelated to her melanoma. Two weeks after starting vemurafenib, she developed a grade 1 rash (Common Terminology Criteria for Adverse Events version 4.0 of the National Cancer Institute), which was treated conservatively. During the following 3 weeks the rash progressed and she was noted to have blisters affecting the head, torso and upper limbs. Histological examination of the skin revealed areas of full-thickness degenerative necrosis of the epidermis with separation from the dermis (Fig. 1a). There were interface colloid bodies (Fig. 1b) and a moderate upper dermal chronic inflammatory infiltrate with loose fibrosis and some scattered neutrophils (Fig. 1c). The histological appearances together with the clinical findings were consistent with TEN of the skin. Supportive treatment was commenced and she was transferred to the burns unit of a tertiary care centre 6 days later, where specialists in the management of TEN were available. Clinical examination showed that she was febrile, hypotensive and tachycardic. Her upper limbs, upper chest and back were erythematous with some erosions (Fig. 2a,b). Target lesions were present (Fig. 2c) and 65% of the patient’s body surface area demonstrated detachable epidermis. There was conjunctival involvement, oral mucositis and superficial erosions in the British Journal of Dermatology (2014) 170, pp970–1001
vulval area. Mucosal sloughing in the upper airway was also observed. Laboratory investigations of note showed no eosinophilia and normal liver function. On clinical assessment, the patient had a SCORTEN of 4 out of a possible 7, predicting a mortality rate of > 50%. The patient required multiorgan support and was electively intubated and ventilated. Intravenous immunoglobulin (IVIg) was commenced at 15 g kg 1 over 3 days. The skincare regime involved 2-hourly application of liquid paraffin 50% and white soft paraffin 50%, clobetasol propionate ointment for the body twice daily and Trimovateâ cream (clobetasone butyrate, oxytetracycline and nystatin; GlaxoSmithKline, Brentford, U.K.) twice daily for the groin and vulval area. Re-epithelialization was slow, and therefore a further 2 days of IVIg at the same dose was prescribed 4 days later. Ciclosporin was not administered for the treatment of TEN owing to coexisting renal failure. The skin began to improve and the patient was transferred back to the referring hospital. In the subsequent days she developed a ventilatoracquired pneumonia and melaena, and died of multiorgan failure. TEN is rare, and its clinicopathological profile complex.4 Aetiologically, one may argue that the association of antiepileptics with TEN favours sodium valproate as the causative drug in this case. However, the long duration of therapy of sodium valproate and the recent introduction of vemurafenib argue strongly for the latter to be the causative agent, either directly or in concert with sodium valproate. © 2013 British Association of Dermatologists
Correspondence 999
It is important to note that most dermatological side-effects associated with vemurafenib treatment are manageable, and dose reduction and/or interruption can be useful in reducing these toxicities.2 This is the first case report associating vemurafenib with TEN. Physicians should be aware of the potential risk in order to initiate prompt specialist management. 1
Department of Dermatology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, U.K. 2 Department of Oncology, University of Oxford, Oxford, U.K. E-mail: [email protected]
R. SINHA1 K. LECAMWASAM1 K. PURSHOUSE2 J. REED2 M.R. MIDDLETON2 L. FEARFIELD1
2 Sinha R, Edmonds K, Newton-Bishop JA et al. 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; 167:987–94. 3 Bastuji-Garin S, Fouchard N, Bertocchi M et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115:149–53. 4 Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol 2013; 69:e1–13. Funding sources: none. Conflicts of interest: M.R.M. has received research funding and honoraria from Roche for consultancy and for speaking at sponsored meetings. L.F. has received honoraria to speak at a Roche-sponsored meeting.
References 1 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507–16.
© 2013 British Association of Dermatologists
Corrigenda DOI: 10.1111/bjd.12865 In the article by Piram et al.1 a unit dosage was listed incorrectly as oral MTX 15 mg kg appears below: oral MTX 15 mg m
2
1
on page 1266. The correct dosage
per week for 12 months
Reference 1 Piram M, McCuaig CC, Saint-Cyr C et al. Short- and long-term outcome of linear morphoea in children. Br J Dermatol 2013; 169:1265–71.
DOI: 10.1111/bjd.13022 In the article by Lowe et al.1 the first author’s name was published wrong. The correct name appears below. Garrett C. Lowe1
Reference 1 Lowe G, Henderson CL, Grau RH et al. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2011; 164:465–72.
© 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 170, pp970–1001
![[Vemurafenib-induced toxic epidermal necrolysis].](/assets/img/hold.png)
