Short communication 265
A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab Giuliana Carlosa,d, Rachael Anfortha,d, Shaun Choub, Arthur Clementsc,d and Pablo Fernandez-Peñasa,d The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed cell death-1, is pioneering the treatment for advanced melanoma. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immune-related nature. Reported dermatological side effects mostly comprise nonspecific rash and pruritus. This is a report of a 75-year-old man with metastatic melanoma who was initially administered pembrolizumab at 10 mg/kg every 3 weeks. He developed spongiotic dermatitis that was partially treated with topical steroids after cycle 3. Pembrolizumab cycles were stopped because of disease progression after cycle 6. On the 30-day follow-up, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows. Both punch skin biopsies (haematoxylin and eosin and direct immunofluorescence studies) confirmed a bullous
Introduction Our immune system possesses checkpoints that are able to protect healthy cells from attack by immune-related cells. Cancers cells are able to use these checkpoints in their favour to avoid attack by the immune system and proliferate. The blockade of immune checkpoints has revolutionized cancer treatments. The use of monoclonal antibodies targeting and modulating the immune system is showing good results in the treatment of solid tumours. The side effects of these drugs are most likely to be mild and immune-related. The mechanisms of dermatological toxicities are still under investigation. Dermatological assessments are necessary during the use of these treatments.
Case In March 2012, a 75-year-old man was diagnosed with metastatic melanoma after investigation for recurrent bronchitis revealed multiple lung lesions on a chest radiograph. A subsequent computed tomography (CT) scan of the chest, abdomen and pelvis revealed multiple pulmonary nodules, one of which was biopsied, confirming metastatic melanoma on histopathological examination. Mutation testing of the tumour sample excluded the presence of any BRAF mutation. 0960-8931 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
pemphigoid diagnosis. He was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment, which was switched to dexamethasone following the diagnosis of new brain metastases. Melanoma Res 25:265–268 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Melanoma Research 2015, 25:265–268 Keywords: adverse events, bullous pemphigoid, immune-related, metastatic melanoma, pembrolizumab a Department of Dermatology, bAnatomical Pathology, Institute of Clinical Pathology and Medical Research, cWestmead Institute for Cancer Research, Westmead Hospital, NSW and dSydney Medical School, The University of Sydney, Sydney, Australia
Correspondence to Giuliana Carlos, MBBS, Department of Dermatology (D5a), Westmead Hospital, Darcy Rd, Westmead, NSW 2145, Sydney, Australia Tel: + 61 02 9845 5686; fax: + 61 02 9845 9673; e-mail: [email protected] Received 25 November 2014 Accepted 27 February 2015
This was based on a background of developing a 0.25-mm-thick lentigo maligna lesion, which was subsequently excised from the right side of the face in November 2005. In May 2012, the patient received a single dose of dacarbazine chemotherapy, before commencing the phase 3 trial of 3 versus 10 mg/kg ipilimumab (CA184169). From July to September 2012, he received four cycles of ipilimumab, achieving an initial response to treatment. Dacarbazine chemotherapy was subsequently recommenced in December 2012, completing three cycles of treatment by January 2013. Unfortunately, progress CT imaging confirmed progressive disease, requiring a switch to fotemustine chemotherapy in February 2013, before a quick change to the PD-1 inhibitor pembrolizumab in the MK3475-001 study in March 2013, which was commenced at 10 mg/kg every 3 weeks. The patient was referred to the Department of Dermatology before commencing pembrolizumab. Full skin examination and baseline full-body photography were performed. At the end of April 2013, after the third cycle of pembrolizumab, the patient developed a moderate-to-severe itching reaction around the hips and presented to our department 2 weeks later. On examination, the patient DOI: 10.1097/CMR.0000000000000155
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
266 Melanoma Research
2015, Vol 25 No 3
had ill-defined desquamative erythematous plaques over both hips. A punch skin biopsy was performed on the left hip, revealing an epidermis with mild spongiosis, irregular acanthosis and focal exocytosis of lymphocytes and eosinophils, whereas in the dermis there was mild to moderate superficial perivascular chronic inflammation with eosinophilic infiltration.
Fig. 1
The patient was treated with topical betamethasone twice daily, but was unfortunately noncompliant with the treatment. On assessment before cycle 6, the patient had developed persistent eczematous plaques extending over the back, chest, hips, thighs and lower legs, associated with a severe itching, significantly affecting his quality of life. At the time, steroids were recommended, but the patient refused to proceed with the treatment. Unfortunately, due to disease progression, the patient was taken off the MK-3475-001 trial on 8 July 2013. At the 30-day follow-up visit, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows (Fig. 1). Two punch skin biopsies were subsequently taken from the left thigh, for haematoxylin and eosin staining and direct immunofluorescence studies. Both biopsies confirmed subepidermal blisters with eosinophilic infiltration. The overlying epidermis showed early degenerative changes and parakeratosis. There was moderate inflammation in the papillary dermis, consistent with the presence of multiple lymphocytes and eosinophils (Fig. 2). Immunofluorescence microscopy showed noncontinuous linear deposition of IgG at the dermoepidermal junction (+) (Fig. 3) and continuous linear deposition of C3 at the dermoepidermal junction (+ + ). The diagnosis was thus consistent with bullous pemphigoid (BP). Accordingly, the patient was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment. This was subsequently switched to dexamethasone after 3 weeks of treatment, following the diagnosis of new brain metastases. Unfortunately, the patient was referred to palliative care and passed away in October 2013.
Discussion The innovative blockade of immune checkpoints with targeted immunotherapies, such us monoclonal antibodies against the programmed cell death-1 (PD-1) receptor and its ligands (PDL1 and PDL2), is pioneering the treatment for advanced melanoma. The PD-1 receptor is an inhibitory receptor and a negative regulator of T-cell effector mechanisms that limits immune responses against cancer [1]. PD-1 was discovered in 1992 by Okazaki and Honjo [2], who were studying the mechanisms of T-cell death.
Left elbow: clinical picture of extensive erythematous plaques and papules with multiple intact and ruptured bullae.
Pembrolizumab (MK-3475) is a highly selective, humanized monoclonal immunoglobulin G4-kappa isotype antibody against PD-1 that is designed to block the negative immune-regulatory signalling of the PD-1 receptor expressed by T cells, B cells and macrophages [1]. Of note, there is increasing evidence of promising and durable responses after immunotherapy in patients with metastatic melanoma [1]. In a phase 1 study, 104 patients with metastatic melanoma received treatment with MK-3475 at a dose of 0.1–10 mg/kg every 2 weeks. The objective response rate in all dose categories was reported to be 28% (19–38%), with a progression-free survival rate at 24 weeks of 41% (30–51%) [3]. This was also confirmed by Hamid and colleagues, who compared the use of MK-3475 in patients with metastatic melanoma who had and who had not previously been treated with ipilimumab. Response
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Bullous pemphigoid in a patient treated with pembrolizumab Carlos et al. 267
Fig. 2
Haematoxylin and eosin stains showing the presence of a subepidermal blister with epidermal eosinophil infiltration and moderate dermal inflammation.
Fig. 3
associated with pembrolizumab (MK-3475) were fatigue, diarrhoea and skin disorders. Dermatological side effects mostly comprised nonspecific rash and pruritus (21% patients) [1]. BP is an autoimmune blistering disease that commonly, but not exclusively, affects the elderly population [5]. Subepidermal blistering results after the adhesion and structure of the basement membrane zone are attacked by autoantibodies (most of them of the IgG type) [6]. These autoantigens target two main proteins, a cytoplasmatic protein, BP230, and a transmembrane protein, P180 [7]. The cutaneous manifestations of BP are extremely polymorphic, are variable and are sometimes nonspecific. The clinical symptoms mimic almost the entire spectrum of cutaneous inflammatory conditions [7]. Symptoms such as pruritus and eczematous plaques can be present alone or in association with erythema, and they may precede the formation of bullae by weeks or months, or may not even become clinically apparent [6]. There are associations that may play a role in the aetiology of BP, such as medications, age, and its unknown associations with other endocrine or neurologic conditions and neoplasia. Although there is no proven increased risk for the development of other autoimmune diseases, BP has been associated with other autoimmune disorders [5]. The activation of tissue factor, an initiator of the intrinsic coagulation pathway, may be involved in the pathogenesis of inflammation, tissue damage and blister formation in BP. Eosinophils are a major intravascular source of tissue factor, and this is correlated with their presence in early cutaneous inflammation [5].
Immunofluorescence showing noncontinuous linear deposition of IgG at the dermoepidermal junction.
rates were similar (rates of 38 and 37%, respectively) and the overall median progression-free survival was greater than 7 months [1]. PD-1 inhibition has fewer side effects and greater antitumour activity than other immunotherapies due to its increased selectivity for immune-suppressive signals, predominantly through the regulation of the effector phase of T-cell responses [4]. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immunerelated nature. The most frequent adverse events
Over the years, several anti-inflammatory, immunosuppressive and immunomodulatory treatments have been postulated to treat BP. A class A strength of recommendation and a very high level of evidence was given to topical, oral and intravenous steroids, which through their immunosuppressive and anti-inflammatory effects can achieve medical improvement quite rapidly [5,6]. Other treatments with a lower level of evidence include azathioprine, methotrexate, dapsone, sulphonamides, mycophenolate mofetil, anti-inflammatory antibiotics and nicotinamide [6]. As far as we know, this is the first report of BP in a patient treated with the PD-1 inhibitor, pembrolizumab. On the basis of its mechanism of action, pembrolizumab can be hypothesized to induce immune-related conditions, and such patients should be closely monitored. It is impossible to determine for sure whether this patient was at a higher risk of developing immune-related disorders as a result of two different immunotherapy regimens (i.e. ipilimumab and pembrolizumab), although these two drugs were administered months apart, given the potentially long biological half-lives of these agents.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
268 Melanoma Research
2015, Vol 25 No 3
The study by Wolchok et al. [8] revealed increased toxicity, particularly in the liver. In this case, the patient developed spongiotic dermatitis with eosinophilic infiltration, which progressed to BP within a month following cessation of pembrolizumab, supporting the concept that the immune system may remain activated long after the medication is ceased. The rapid clinical improvement after only a short course of treatment tends to support the drug-induced mechanism. With the introduction and increasing use of newer, more effective immunotherapies like pembrolizumab for various malignancies including metastatic melanoma, there is a need for increased emphasis on early recognition, diagnosis and effective management of these immunerelated adverse events, including skin disorders.
Acknowledgements The authors wish to acknowledge the support and input of Merck Sharp & Dohme – Oncology Clinical Research in the review of this report and also the Department of Immunology at the Institute for Clinical Pathology and Medical Research – Westmead Hospital, Sydney, Australia for the immunofluorescence image.
Conflicts of interest
Pablo Fernandez-Peñas has a consultant or advisory role in Roche (C). Rachael Anforth received a scholarship from the University of Sydney. For the remaining authors there are no conflicts of interest.
References 1
2 3
4 5
6
7
8
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134–144. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007; 19:813–824. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443–2454. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012; 366:2517–2519. Ruocco E, Wolf R, Caccavale S, Brancaccio G, Ruocco V, Lo Schiavo A. Bullous pemphigoid: associations and management guidelines: facts and controversies. Clin Dermatol 2013; 31:400–412. Venning VA, Taghipour K, Mohd Mustapa MF, Highet AS, Kirtschig G. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol 2012; 167:1200–1214. Lo Schiavo A, Ruocco E, Brancaccio G, Caccavale S, Ruocco V, Wolf R. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. Clin Dermatol 2013; 31:391–399. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 3692:122–133.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab Giuliana Carlosa,d, Rachael Anfortha,d, Shaun Choub, Arthur Clementsc,d and Pablo Fernandez-Peñasa,d The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed cell death-1, is pioneering the treatment for advanced melanoma. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immune-related nature. Reported dermatological side effects mostly comprise nonspecific rash and pruritus. This is a report of a 75-year-old man with metastatic melanoma who was initially administered pembrolizumab at 10 mg/kg every 3 weeks. He developed spongiotic dermatitis that was partially treated with topical steroids after cycle 3. Pembrolizumab cycles were stopped because of disease progression after cycle 6. On the 30-day follow-up, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows. Both punch skin biopsies (haematoxylin and eosin and direct immunofluorescence studies) confirmed a bullous
Introduction Our immune system possesses checkpoints that are able to protect healthy cells from attack by immune-related cells. Cancers cells are able to use these checkpoints in their favour to avoid attack by the immune system and proliferate. The blockade of immune checkpoints has revolutionized cancer treatments. The use of monoclonal antibodies targeting and modulating the immune system is showing good results in the treatment of solid tumours. The side effects of these drugs are most likely to be mild and immune-related. The mechanisms of dermatological toxicities are still under investigation. Dermatological assessments are necessary during the use of these treatments.
Case In March 2012, a 75-year-old man was diagnosed with metastatic melanoma after investigation for recurrent bronchitis revealed multiple lung lesions on a chest radiograph. A subsequent computed tomography (CT) scan of the chest, abdomen and pelvis revealed multiple pulmonary nodules, one of which was biopsied, confirming metastatic melanoma on histopathological examination. Mutation testing of the tumour sample excluded the presence of any BRAF mutation. 0960-8931 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
pemphigoid diagnosis. He was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment, which was switched to dexamethasone following the diagnosis of new brain metastases. Melanoma Res 25:265–268 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Melanoma Research 2015, 25:265–268 Keywords: adverse events, bullous pemphigoid, immune-related, metastatic melanoma, pembrolizumab a Department of Dermatology, bAnatomical Pathology, Institute of Clinical Pathology and Medical Research, cWestmead Institute for Cancer Research, Westmead Hospital, NSW and dSydney Medical School, The University of Sydney, Sydney, Australia
Correspondence to Giuliana Carlos, MBBS, Department of Dermatology (D5a), Westmead Hospital, Darcy Rd, Westmead, NSW 2145, Sydney, Australia Tel: + 61 02 9845 5686; fax: + 61 02 9845 9673; e-mail: [email protected] Received 25 November 2014 Accepted 27 February 2015
This was based on a background of developing a 0.25-mm-thick lentigo maligna lesion, which was subsequently excised from the right side of the face in November 2005. In May 2012, the patient received a single dose of dacarbazine chemotherapy, before commencing the phase 3 trial of 3 versus 10 mg/kg ipilimumab (CA184169). From July to September 2012, he received four cycles of ipilimumab, achieving an initial response to treatment. Dacarbazine chemotherapy was subsequently recommenced in December 2012, completing three cycles of treatment by January 2013. Unfortunately, progress CT imaging confirmed progressive disease, requiring a switch to fotemustine chemotherapy in February 2013, before a quick change to the PD-1 inhibitor pembrolizumab in the MK3475-001 study in March 2013, which was commenced at 10 mg/kg every 3 weeks. The patient was referred to the Department of Dermatology before commencing pembrolizumab. Full skin examination and baseline full-body photography were performed. At the end of April 2013, after the third cycle of pembrolizumab, the patient developed a moderate-to-severe itching reaction around the hips and presented to our department 2 weeks later. On examination, the patient DOI: 10.1097/CMR.0000000000000155
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
266 Melanoma Research
2015, Vol 25 No 3
had ill-defined desquamative erythematous plaques over both hips. A punch skin biopsy was performed on the left hip, revealing an epidermis with mild spongiosis, irregular acanthosis and focal exocytosis of lymphocytes and eosinophils, whereas in the dermis there was mild to moderate superficial perivascular chronic inflammation with eosinophilic infiltration.
Fig. 1
The patient was treated with topical betamethasone twice daily, but was unfortunately noncompliant with the treatment. On assessment before cycle 6, the patient had developed persistent eczematous plaques extending over the back, chest, hips, thighs and lower legs, associated with a severe itching, significantly affecting his quality of life. At the time, steroids were recommended, but the patient refused to proceed with the treatment. Unfortunately, due to disease progression, the patient was taken off the MK-3475-001 trial on 8 July 2013. At the 30-day follow-up visit, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows (Fig. 1). Two punch skin biopsies were subsequently taken from the left thigh, for haematoxylin and eosin staining and direct immunofluorescence studies. Both biopsies confirmed subepidermal blisters with eosinophilic infiltration. The overlying epidermis showed early degenerative changes and parakeratosis. There was moderate inflammation in the papillary dermis, consistent with the presence of multiple lymphocytes and eosinophils (Fig. 2). Immunofluorescence microscopy showed noncontinuous linear deposition of IgG at the dermoepidermal junction (+) (Fig. 3) and continuous linear deposition of C3 at the dermoepidermal junction (+ + ). The diagnosis was thus consistent with bullous pemphigoid (BP). Accordingly, the patient was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment. This was subsequently switched to dexamethasone after 3 weeks of treatment, following the diagnosis of new brain metastases. Unfortunately, the patient was referred to palliative care and passed away in October 2013.
Discussion The innovative blockade of immune checkpoints with targeted immunotherapies, such us monoclonal antibodies against the programmed cell death-1 (PD-1) receptor and its ligands (PDL1 and PDL2), is pioneering the treatment for advanced melanoma. The PD-1 receptor is an inhibitory receptor and a negative regulator of T-cell effector mechanisms that limits immune responses against cancer [1]. PD-1 was discovered in 1992 by Okazaki and Honjo [2], who were studying the mechanisms of T-cell death.
Left elbow: clinical picture of extensive erythematous plaques and papules with multiple intact and ruptured bullae.
Pembrolizumab (MK-3475) is a highly selective, humanized monoclonal immunoglobulin G4-kappa isotype antibody against PD-1 that is designed to block the negative immune-regulatory signalling of the PD-1 receptor expressed by T cells, B cells and macrophages [1]. Of note, there is increasing evidence of promising and durable responses after immunotherapy in patients with metastatic melanoma [1]. In a phase 1 study, 104 patients with metastatic melanoma received treatment with MK-3475 at a dose of 0.1–10 mg/kg every 2 weeks. The objective response rate in all dose categories was reported to be 28% (19–38%), with a progression-free survival rate at 24 weeks of 41% (30–51%) [3]. This was also confirmed by Hamid and colleagues, who compared the use of MK-3475 in patients with metastatic melanoma who had and who had not previously been treated with ipilimumab. Response
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Bullous pemphigoid in a patient treated with pembrolizumab Carlos et al. 267
Fig. 2
Haematoxylin and eosin stains showing the presence of a subepidermal blister with epidermal eosinophil infiltration and moderate dermal inflammation.
Fig. 3
associated with pembrolizumab (MK-3475) were fatigue, diarrhoea and skin disorders. Dermatological side effects mostly comprised nonspecific rash and pruritus (21% patients) [1]. BP is an autoimmune blistering disease that commonly, but not exclusively, affects the elderly population [5]. Subepidermal blistering results after the adhesion and structure of the basement membrane zone are attacked by autoantibodies (most of them of the IgG type) [6]. These autoantigens target two main proteins, a cytoplasmatic protein, BP230, and a transmembrane protein, P180 [7]. The cutaneous manifestations of BP are extremely polymorphic, are variable and are sometimes nonspecific. The clinical symptoms mimic almost the entire spectrum of cutaneous inflammatory conditions [7]. Symptoms such as pruritus and eczematous plaques can be present alone or in association with erythema, and they may precede the formation of bullae by weeks or months, or may not even become clinically apparent [6]. There are associations that may play a role in the aetiology of BP, such as medications, age, and its unknown associations with other endocrine or neurologic conditions and neoplasia. Although there is no proven increased risk for the development of other autoimmune diseases, BP has been associated with other autoimmune disorders [5]. The activation of tissue factor, an initiator of the intrinsic coagulation pathway, may be involved in the pathogenesis of inflammation, tissue damage and blister formation in BP. Eosinophils are a major intravascular source of tissue factor, and this is correlated with their presence in early cutaneous inflammation [5].
Immunofluorescence showing noncontinuous linear deposition of IgG at the dermoepidermal junction.
rates were similar (rates of 38 and 37%, respectively) and the overall median progression-free survival was greater than 7 months [1]. PD-1 inhibition has fewer side effects and greater antitumour activity than other immunotherapies due to its increased selectivity for immune-suppressive signals, predominantly through the regulation of the effector phase of T-cell responses [4]. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immunerelated nature. The most frequent adverse events
Over the years, several anti-inflammatory, immunosuppressive and immunomodulatory treatments have been postulated to treat BP. A class A strength of recommendation and a very high level of evidence was given to topical, oral and intravenous steroids, which through their immunosuppressive and anti-inflammatory effects can achieve medical improvement quite rapidly [5,6]. Other treatments with a lower level of evidence include azathioprine, methotrexate, dapsone, sulphonamides, mycophenolate mofetil, anti-inflammatory antibiotics and nicotinamide [6]. As far as we know, this is the first report of BP in a patient treated with the PD-1 inhibitor, pembrolizumab. On the basis of its mechanism of action, pembrolizumab can be hypothesized to induce immune-related conditions, and such patients should be closely monitored. It is impossible to determine for sure whether this patient was at a higher risk of developing immune-related disorders as a result of two different immunotherapy regimens (i.e. ipilimumab and pembrolizumab), although these two drugs were administered months apart, given the potentially long biological half-lives of these agents.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
268 Melanoma Research
2015, Vol 25 No 3
The study by Wolchok et al. [8] revealed increased toxicity, particularly in the liver. In this case, the patient developed spongiotic dermatitis with eosinophilic infiltration, which progressed to BP within a month following cessation of pembrolizumab, supporting the concept that the immune system may remain activated long after the medication is ceased. The rapid clinical improvement after only a short course of treatment tends to support the drug-induced mechanism. With the introduction and increasing use of newer, more effective immunotherapies like pembrolizumab for various malignancies including metastatic melanoma, there is a need for increased emphasis on early recognition, diagnosis and effective management of these immunerelated adverse events, including skin disorders.
Acknowledgements The authors wish to acknowledge the support and input of Merck Sharp & Dohme – Oncology Clinical Research in the review of this report and also the Department of Immunology at the Institute for Clinical Pathology and Medical Research – Westmead Hospital, Sydney, Australia for the immunofluorescence image.
Conflicts of interest
Pablo Fernandez-Peñas has a consultant or advisory role in Roche (C). Rachael Anforth received a scholarship from the University of Sydney. For the remaining authors there are no conflicts of interest.
References 1
2 3
4 5
6
7
8
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134–144. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007; 19:813–824. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443–2454. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012; 366:2517–2519. Ruocco E, Wolf R, Caccavale S, Brancaccio G, Ruocco V, Lo Schiavo A. Bullous pemphigoid: associations and management guidelines: facts and controversies. Clin Dermatol 2013; 31:400–412. Venning VA, Taghipour K, Mohd Mustapa MF, Highet AS, Kirtschig G. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol 2012; 167:1200–1214. Lo Schiavo A, Ruocco E, Brancaccio G, Caccavale S, Ruocco V, Wolf R. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. Clin Dermatol 2013; 31:391–399. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 3692:122–133.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
