1216 Commentaries
Mycosis fungoides: promoter hypermethylation predicts disease progression DOI: 10.1111/bjd.12870 ORIGINAL ARTICLE, p 1266 The development and progression of malignant diseases is driven by the acquisition of not only genetic, but also epigenetic alterations. The term epigenetics has been used to describe heritable changes in gene expression resulting from changes in chromatin structure without alterations in the primary DNA sequence. DNA methylation is the most studied epigenetic mechanism and refers to the addition of a methyl group to a cytosine nucleotide occurring in a CG dinucleotide. Approximately half of human gene promoters contain so-called CpG islands, genomic regions with high CG dinucleotide density, which are usually unmethylated. However, in cancer cells dozens to hundreds of promoter CpG islands become aberrantly methylated, which is often associated with transcriptional silencing of affected genes. Promoter CpG island hypermethylation demonstrates tumour-type-specific patterns and can contribute to the malignant phenotype of cells by inactivating tumour suppressor genes. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and is known to have a highly variable disease course. Whereas most patients who present with erythematous plaques have stable disease for years, a subset of patients experiences rapid disease progression with development of skin tumours and extracutaneous dissemination of tumour cells. Several tumour suppressor genes have previously been found to be silenced through promoter hypermethylation in MF, including CDKN2A, BCL7A and MLH1, pointing to the relevance of epigenetic mechanisms in its pathogenesis.1–3 In a study published in this issue of BJD, Gerardo Ferrara and colleagues examined the occurrence of promoter hypermethylation of 12 selected genes in early-stage MF skin lesions.4 Frequent hypermethylation of several genes such as CDKN1B and IGF2 was noted. Remarkably, the frequency of promoter hypermethylation of this gene panel was observed to be higher in patients with early-stage lesions who would go on to experience disease progression than in patients with a stable disease course. The authors found that in particular promoter hypermethylation of the peroxisome proliferatoractivated receptor-c gene (PPARG) in early-stage MF skin lesions was predictive of disease progression. The PPARG gene encodes a nuclear receptor regulating lipid metabolism that is normally expressed by T lymphocytes.5 Promoter hypermethylation of this potential tumour suppressor gene was associated with transcriptional repression. This study demonstrates that the frequency and pattern of promoter hypermethylation is associated with the propensity of MF to progress. The prognostic significance of promoter hypermethylation of PPARG and other genes might be applied British Journal of Dermatology (2014) 170, pp1214–1218
in the clinic. In addition, this study supports the notion that epigenetic deregulation acts as a driving force in MF, which is in line with the efficacy of epigenetic drugs such as the histone deacetylase inhibitor vorinostat in this T-cell malignancy. If epigenetic inactivation of PPARG might have a causal role in disease progression, then pharmacological agonists of the protein might have a therapeutic effect by limiting MF aggressiveness.6 This study clearly shows the clinical potential of detecting epigenetic alterations in MF. We can expect that future genome-wide analysis of DNA methylation in MF will reveal more diagnostic and prognostic biomarkers, which should be confirmed in large patient cohorts. Conflicts of interest None declared.
Department of Dermatology, Leiden University Medical Center, Albinusdreef 2, 2300, RC Leiden, the Netherlands E-mail: [email protected]
R.
VAN
DOORN
References 1 Navas IC, Ortiz-Romero PL, Villuendas R et al. p16(INK4a) gene alterations are frequent in lesions of mycosis fungoides. Am J Pathol 2000; 156:1565–72. 2 Scarisbrick JJ, Mitchell TJ, Calonje E et al. Microsatellite instability is associated with hypermethylation of the hMLH1 gene and reduced gene expression in mycosis fungoides. J Invest Dermatol 2003; 121:894–901. 3 van Doorn R, Zoutman WH, Dijkman R et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 2005; 23:3886–96. 4 Ferrara G, Pancione M, Votine C et al. A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert–Bazin type) mycosis fungoides. Br J Dermatol 2014 170:1266–75. 5 Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2:748–59. 6 Zhang C, Ni X, Konopleva M et al. The novel synthetic oleanane triterpenoid CDDO (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) induces apoptosis in mycosis fungoides/Sezary syndrome cells. J Invest Dermatol 2004; 123:380–7.
Mortality of bullous pemphigoid in Asia: the same as in Europe? DOI: 10.1111/bjd.13016 ORIGINAL ARTICLE, p 1319 Bullous pemphigoid (BP) is the most common autoimmune blistering disease of the skin, usually affecting the elderly. It is © 2014 British Association of Dermatologists
Commentaries
a chronic disease characterized by spontaneous exacerbations and remissions. Although the majority of patients finally go into clinical remission with treatment, the mortality is considerable among elderly patients. Indeed, the estimated 1-year mortality rate of BP varies between 11% and 41%, depending on the country, and the 1-year standardized mortality ratio (SMR) ranges from 2 to 15.1–7 In this issue of the BJD, Cai et al.8 explore the 3-year mortality rate, risk factors and causes of death in patients with BP in Singapore, compared with the general population in a retrospective cohort study of all newly diagnosed patients with BP seen at the National Skin Centre. From the 359 patients with BP included (the majority being Chinese patients), they found 1- and 3-year mortality rates of 267% and 457%, respectively, and a 274 times 3-year SMR for patients with BP compared with the age- and sex-matched general population. This study conducted in Asian patients essentially confirms the high mortality rate in patients with BP, which is in line with those previously reported in European series1–3,5–7 and from a large retrospective series of patients with BP from the U.S.4 Interestingly, the SMR was increased across all age groups but diminished with increasing age as previously reported.6 The lower mortality rate of patients with BP reported in some series may only be apparent and mainly related to a younger age of patients, especially in another recent study conducted in China where the mean age of patients with BP (643 years) was particularly low.9 Several studies have evaluated factors that may contribute to the poor prognosis of patients with BP, with varying results. Age and a Karnofsky score < 40 (range 0–100) have been shown to significantly affect prognosis.1,3 Besides, it is likely that comorbidities (neurological diseases, particularly dementia, Parkinson disease and stroke) and practice patterns (use of systemic corticosteroids and/or immunosuppressive drugs) also influence mortality at 1 year.1,5,6 In their study, Cai et al.8 evaluated in BP potential factors that may influence the 3-year mortality. In line with European studies, comorbidities (Parkinson disease, heart failure, chronic renal disease) but not older age were associated with an increased 3-year mortality rate. Besides, combination treatment with low to moderate dose corticosteroids and immunomodulatory agents (doxycycline and/or nicotinamide) was associated with a lower mortality rate.8 It is likely that the retrospective nature of the study, the absence of control of treatment modalities and the choice of a late endpoint (3-year) for mortality were responsible for these discrepancies. As, in general, most of the patients with BP died within the first year, especially within the first 6 months of treatment,1,3,7 large, controlled, prospective studies with 1-year follow-up still remain mandatory to attempt to define the precise prognostic factors, in order to compare BP mortality worldwide. Alongside comorbidities and practice patterns, biological features could also offer another signature to compare the vital outcome of patients with BP in both continents.10
© 2014 British Association of Dermatologists
1217
Funding sources No external funding. Conflicts of interest None declared.
Department of Dermatology, Reims University Hospital, Robert Debre Hospital, Marechal Koenig Avenue, 51092 Reims, France E-mail: [email protected]
P. BERNARD
References 1 Rzany B, Partscht K, Jung M et al. Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol 2002; 138:903–8. 2 Gudi VS, White MI, Cruickshank N et al. Annual incidence and mortality of bullous pemphigoid in the Grampian region of North-east Scotland. Br J Dermatol 2005; 153:424–7. 3 Joly P, Benichou J, Lok C et al. Prediction of survival for patients with bullous pemphigoid: a prospective study. Arch Dermatol 2005; 141:691–8. 4 Parker S, Dyson S, Brisman S et al. Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol 2008; 59:582–8. 5 Langan SM, Smeeth L, Hubbard R et al. Bullous pemphigoid and pemphigus vulgaris: incidence and mortality in the UK: population based cohort study. BMJ 2008; 337:a180. 6 Cortes B, Marazza G, Naldi L et al. Mortality of bullous pemphigoid in Switzerland: a prospective study. Br J Dermatol 2011; 165:368–74. 7 Joly P, Baricault S, Sparsa A et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 2012; 132:1998– 2004. 8 Cai SC, Allen JC, Lim YL et al. Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre. Br J Dermatol 2014; 170:1319–26. 9 Li J, Zuo YG, Zheng HY. Mortality of bullous pemphigoid in China. JAMA Dermatol 2013; 149:106–7. 10 Fichel F, Barbe C, Joly P. et al. Clinical and immunologic factors associated with bullous pemphigoid relapse during the first year of treatment: a multicenter, prospective study. JAMA Dermatol 2014; 150:25–33.
Laser-assisted drug delivery: beyond ablative devices DOI: 10.1111/bjd.13072 ORIGINAL ARTICLE, p 1336 Topical drug delivery is an area of ongoing research and development. The innate barrier function of the skin, in par-
British Journal of Dermatology (2014) 170, pp1214–1218
Mycosis fungoides: promoter hypermethylation predicts disease progression DOI: 10.1111/bjd.12870 ORIGINAL ARTICLE, p 1266 The development and progression of malignant diseases is driven by the acquisition of not only genetic, but also epigenetic alterations. The term epigenetics has been used to describe heritable changes in gene expression resulting from changes in chromatin structure without alterations in the primary DNA sequence. DNA methylation is the most studied epigenetic mechanism and refers to the addition of a methyl group to a cytosine nucleotide occurring in a CG dinucleotide. Approximately half of human gene promoters contain so-called CpG islands, genomic regions with high CG dinucleotide density, which are usually unmethylated. However, in cancer cells dozens to hundreds of promoter CpG islands become aberrantly methylated, which is often associated with transcriptional silencing of affected genes. Promoter CpG island hypermethylation demonstrates tumour-type-specific patterns and can contribute to the malignant phenotype of cells by inactivating tumour suppressor genes. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and is known to have a highly variable disease course. Whereas most patients who present with erythematous plaques have stable disease for years, a subset of patients experiences rapid disease progression with development of skin tumours and extracutaneous dissemination of tumour cells. Several tumour suppressor genes have previously been found to be silenced through promoter hypermethylation in MF, including CDKN2A, BCL7A and MLH1, pointing to the relevance of epigenetic mechanisms in its pathogenesis.1–3 In a study published in this issue of BJD, Gerardo Ferrara and colleagues examined the occurrence of promoter hypermethylation of 12 selected genes in early-stage MF skin lesions.4 Frequent hypermethylation of several genes such as CDKN1B and IGF2 was noted. Remarkably, the frequency of promoter hypermethylation of this gene panel was observed to be higher in patients with early-stage lesions who would go on to experience disease progression than in patients with a stable disease course. The authors found that in particular promoter hypermethylation of the peroxisome proliferatoractivated receptor-c gene (PPARG) in early-stage MF skin lesions was predictive of disease progression. The PPARG gene encodes a nuclear receptor regulating lipid metabolism that is normally expressed by T lymphocytes.5 Promoter hypermethylation of this potential tumour suppressor gene was associated with transcriptional repression. This study demonstrates that the frequency and pattern of promoter hypermethylation is associated with the propensity of MF to progress. The prognostic significance of promoter hypermethylation of PPARG and other genes might be applied British Journal of Dermatology (2014) 170, pp1214–1218
in the clinic. In addition, this study supports the notion that epigenetic deregulation acts as a driving force in MF, which is in line with the efficacy of epigenetic drugs such as the histone deacetylase inhibitor vorinostat in this T-cell malignancy. If epigenetic inactivation of PPARG might have a causal role in disease progression, then pharmacological agonists of the protein might have a therapeutic effect by limiting MF aggressiveness.6 This study clearly shows the clinical potential of detecting epigenetic alterations in MF. We can expect that future genome-wide analysis of DNA methylation in MF will reveal more diagnostic and prognostic biomarkers, which should be confirmed in large patient cohorts. Conflicts of interest None declared.
Department of Dermatology, Leiden University Medical Center, Albinusdreef 2, 2300, RC Leiden, the Netherlands E-mail: [email protected]
R.
VAN
DOORN
References 1 Navas IC, Ortiz-Romero PL, Villuendas R et al. p16(INK4a) gene alterations are frequent in lesions of mycosis fungoides. Am J Pathol 2000; 156:1565–72. 2 Scarisbrick JJ, Mitchell TJ, Calonje E et al. Microsatellite instability is associated with hypermethylation of the hMLH1 gene and reduced gene expression in mycosis fungoides. J Invest Dermatol 2003; 121:894–901. 3 van Doorn R, Zoutman WH, Dijkman R et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 2005; 23:3886–96. 4 Ferrara G, Pancione M, Votine C et al. A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert–Bazin type) mycosis fungoides. Br J Dermatol 2014 170:1266–75. 5 Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2:748–59. 6 Zhang C, Ni X, Konopleva M et al. The novel synthetic oleanane triterpenoid CDDO (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) induces apoptosis in mycosis fungoides/Sezary syndrome cells. J Invest Dermatol 2004; 123:380–7.
Mortality of bullous pemphigoid in Asia: the same as in Europe? DOI: 10.1111/bjd.13016 ORIGINAL ARTICLE, p 1319 Bullous pemphigoid (BP) is the most common autoimmune blistering disease of the skin, usually affecting the elderly. It is © 2014 British Association of Dermatologists
Commentaries
a chronic disease characterized by spontaneous exacerbations and remissions. Although the majority of patients finally go into clinical remission with treatment, the mortality is considerable among elderly patients. Indeed, the estimated 1-year mortality rate of BP varies between 11% and 41%, depending on the country, and the 1-year standardized mortality ratio (SMR) ranges from 2 to 15.1–7 In this issue of the BJD, Cai et al.8 explore the 3-year mortality rate, risk factors and causes of death in patients with BP in Singapore, compared with the general population in a retrospective cohort study of all newly diagnosed patients with BP seen at the National Skin Centre. From the 359 patients with BP included (the majority being Chinese patients), they found 1- and 3-year mortality rates of 267% and 457%, respectively, and a 274 times 3-year SMR for patients with BP compared with the age- and sex-matched general population. This study conducted in Asian patients essentially confirms the high mortality rate in patients with BP, which is in line with those previously reported in European series1–3,5–7 and from a large retrospective series of patients with BP from the U.S.4 Interestingly, the SMR was increased across all age groups but diminished with increasing age as previously reported.6 The lower mortality rate of patients with BP reported in some series may only be apparent and mainly related to a younger age of patients, especially in another recent study conducted in China where the mean age of patients with BP (643 years) was particularly low.9 Several studies have evaluated factors that may contribute to the poor prognosis of patients with BP, with varying results. Age and a Karnofsky score < 40 (range 0–100) have been shown to significantly affect prognosis.1,3 Besides, it is likely that comorbidities (neurological diseases, particularly dementia, Parkinson disease and stroke) and practice patterns (use of systemic corticosteroids and/or immunosuppressive drugs) also influence mortality at 1 year.1,5,6 In their study, Cai et al.8 evaluated in BP potential factors that may influence the 3-year mortality. In line with European studies, comorbidities (Parkinson disease, heart failure, chronic renal disease) but not older age were associated with an increased 3-year mortality rate. Besides, combination treatment with low to moderate dose corticosteroids and immunomodulatory agents (doxycycline and/or nicotinamide) was associated with a lower mortality rate.8 It is likely that the retrospective nature of the study, the absence of control of treatment modalities and the choice of a late endpoint (3-year) for mortality were responsible for these discrepancies. As, in general, most of the patients with BP died within the first year, especially within the first 6 months of treatment,1,3,7 large, controlled, prospective studies with 1-year follow-up still remain mandatory to attempt to define the precise prognostic factors, in order to compare BP mortality worldwide. Alongside comorbidities and practice patterns, biological features could also offer another signature to compare the vital outcome of patients with BP in both continents.10
© 2014 British Association of Dermatologists
1217
Funding sources No external funding. Conflicts of interest None declared.
Department of Dermatology, Reims University Hospital, Robert Debre Hospital, Marechal Koenig Avenue, 51092 Reims, France E-mail: [email protected]
P. BERNARD
References 1 Rzany B, Partscht K, Jung M et al. Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol 2002; 138:903–8. 2 Gudi VS, White MI, Cruickshank N et al. Annual incidence and mortality of bullous pemphigoid in the Grampian region of North-east Scotland. Br J Dermatol 2005; 153:424–7. 3 Joly P, Benichou J, Lok C et al. Prediction of survival for patients with bullous pemphigoid: a prospective study. Arch Dermatol 2005; 141:691–8. 4 Parker S, Dyson S, Brisman S et al. Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol 2008; 59:582–8. 5 Langan SM, Smeeth L, Hubbard R et al. Bullous pemphigoid and pemphigus vulgaris: incidence and mortality in the UK: population based cohort study. BMJ 2008; 337:a180. 6 Cortes B, Marazza G, Naldi L et al. Mortality of bullous pemphigoid in Switzerland: a prospective study. Br J Dermatol 2011; 165:368–74. 7 Joly P, Baricault S, Sparsa A et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 2012; 132:1998– 2004. 8 Cai SC, Allen JC, Lim YL et al. Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre. Br J Dermatol 2014; 170:1319–26. 9 Li J, Zuo YG, Zheng HY. Mortality of bullous pemphigoid in China. JAMA Dermatol 2013; 149:106–7. 10 Fichel F, Barbe C, Joly P. et al. Clinical and immunologic factors associated with bullous pemphigoid relapse during the first year of treatment: a multicenter, prospective study. JAMA Dermatol 2014; 150:25–33.
Laser-assisted drug delivery: beyond ablative devices DOI: 10.1111/bjd.13072 ORIGINAL ARTICLE, p 1336 Topical drug delivery is an area of ongoing research and development. The innate barrier function of the skin, in par-
British Journal of Dermatology (2014) 170, pp1214–1218
