Commentaries
A peptide from a gastric pathogen for the treatment of acne DOI: 10.1111/bjd.13458 ORIGINAL ARTICLE, p 1358 Acne vulgaris is an extremely common skin condition that can be divided into different subtypes according to the clinical phenotype present.1 The most common subtype is acne comedonica, which is characterized by comedones followed by acne that is dominated by papules and pustules. Acne conglobata is the most severe form, which additionally shows nodules and, when healed, can leave disfiguring scars. The distribution of acne corresponds to the highest density of pilosebaceous units (face, neck, upper chest, shoulders and back).2 Other forms of acne are steroid-induced acne or acne excoriee des jeunes filles.1 The pathomechanisms of acne vulgaris are not yet fully understood. Seborrhoea, follicular hyperkeratosis and bacterial infection seem to play major roles in the pathogenesis of acne vulgaris.1,2 The role of Propionibacterium acnes in the pathogenesis of acne remains somewhat unclear as clinically effective, topically applied antibiotics have direct antimicrobial, as well as anti-inflammatory, effects.3 However, many studies support a direct role of P. acnes in the pathogenesis of acne vulgaris.1 Nevertheless, at present, we have only started to begin to understand the role of the microbiome in inflammatory conditions of the skin.4 Currently, several efficient drugs to treat acne are available.2 Topical retinoids, for example, affect follicular hyperkeratosis,2 whereas benzoylperoxide has an additional effect on bacterial colonization and seborrhoea.2 Topical antibiotics are used to reduce the bacterial load and inflammation.2,3 As an example, systemic tetracyclines have both an antimicrobial and antiinflammatory effect.2,3 Systemic retinoids are very potent in reducing seborrhoea and hyperkeratosis.2 As the understanding of the cutaneous microbiome and the role of commensal bacteria in driving skin inflammation increases, therapeutic targeting of P. acnes in the treatment of acne vulgaris is an area of active research.5 However, as microbial resistance towards antibiotics is increasing, a more targeted and specific therapy against P. acnes might be beneficial.6,7 In a current study, Ryu et al.8 describe a new therapeutic agent that selectively reduces cutaneous colonization with P. acnes. They used the antimicrobial peptide protein HPA3NT3, derived from Helicobacter pylori, and created a synthetic a-helical cationic variant with antibacterial and anti-inflammatory activity. Treatment with HPA3NT3 in vitro induced morphological disruptions in P. acnes cells, suggestive of a bactericidal effect, whereas the minimal inhibitory concentration of HPA3NT3 against P. acnes was low (04 lmol L 1).8 Furthermore, HPA3NT3 decreased the P. acnes-induced expression of interleukin-8 and intracellular calcium mobilization in HK cells by inhibiting P. acnes-activated Toll-like receptor 2-medi© 2014 British Association of Dermatologists
1291
ated nuclear factor kappa B signalling pathways.8 Finally, this antimicrobial peptide significantly reduced P. acnes-induced skin inflammation in a murine model.8 One point that might remain difficult for topical antimicrobial peptides is the penetration of the molecule to the deeper hair follicle where it should exert its effects.8 As the authors discussed, methods of application other than the topical route might be needed. In summary, this research represents a new approach to treating bacteria-induced inflammatory skin conditions like, such as acne vulgaris. Further thorough investigations are needed to confirm the role of the new drug in inflammatory skin diseases in human studies. Conflicts of interest None declared. Department of Dermatology and Allergy, Ludwig-Maximilian University, Frauenlobstr. 9-11, 80337 Munich, Germany E-mail: [email protected]
M. REINHOLZ
References 1 Mourelatos K, Eady EA, Cunliffe WJ et al. Temporal changes in sebum excretion and propionibacterial colonization in preadolescent children with and without acne. Br J Dermatol 2007; 156:22–31. 2 Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet 2012; 379:361–72. 3 Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol 2013; 168:474–85. 4 Grice EA, Kong HH, Conlan S et al. Topographical and temporal diversity of the human skin microbiome. Science 2009; 324:1190–2. 5 Fitz-Gibbon S, Tomida S, Chiu BH et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol 2013; 133:2152–60. 6 Gollnick HP, Krautheim A. Topical treatment in acne: current status and future aspects. Dermatology 2003; 206:29–36. 7 Thiboutot DM. Inflammasome activation by Propionibacterium acnes: the story of IL-1 in acne continues to unfold. J Invest Dermatol 2014; 134:595–7. 8 Ryu S, Park Y, Kim B et al. Inhibitory and anti-inflammatory effects of the Helicobacter pylori-derived antimicrobial peptide HPA3NT3 against Propionibacterium acnes in the skin. Br J Dermatol 2014; 171:1358–67.
Melanoma excision: how deep must we go? DOI: 10.1111/bjd.13459 ORIGINAL ARTICLE, p 1391 Several randomized trials, recently summarized in a systematic review,1 have been conducted to optimize the extent of surgiBritish Journal of Dermatology (2014) 171, pp1285–1299
1292 Commentaries
cal resection in primary melanoma. Quite surprisingly, excision criteria have been mostly limited to the width of peripheral margins, with no standardization of the depth of excision in relation, in particular, to the muscular fascia. In some studies, excision of the muscular fascia was optional while in others it was not mentioned at all. With the lack of strong evidence, attitudes may diverge. A survey, at the Mayo Clinic, of surgical practice for intermediate thickness melanoma disclosed an even split between surgeons resecting the muscular fascia as a routine procedure, and those resecting down to, but not including, the muscular fascia.2 A paper from Hunger et al.3 in this issue of the BJD shows similar heterogeneity at the University Hospital of Bern. Taking advantage of the diversity of surgical approaches, the authors compared 103 patients with melanoma thicker than 2 mm treated by preserving the muscular fascia and 110 similar patients treated by exciding it. No significant difference was documented between the two groups in terms of local recurrences, locoregional or distant metastases, and death attributable to the tumour after a median follow-up of about 4 years. The study had a limited statistical power, and the lack of significant differences should not be taken as treatment equivalence. Moreover, the study was an observational one. Even if the analysed groups were well balanced for all the potential confounding variables but tumour location, it is still possible that some unmeasured factor, unevenly distributed between the groups, influenced the measured outcomes. In spite of the above concerns, it is reassuring that all the observational studies published up to now on the same topics, reviewed by Hunger et al.,3 and involving a total of about 1300 patients, uniformly showed negative results or even an advantage from preserving the muscular fascia. The study of Hunger et al.3 prompts some general reflections on the role of case series when assessing benefits and risks of specific interventions. Randomized clinical trials remain the reference standard to assess efficacy.4 However, when a new treatment entails a dramatic change in disease outcome compared with a reference standard, and it is supported by a clear understanding of biological mechanisms, as, for example, in the case of pulse dye laser treatment of Port Wine stains, well-built cohort studies may represent an acceptable option. When the treatment advantages are small and influenced by complex variables as in the case of different surgical procedures for treating melanoma, reliance on observational studies is debatable. As randomized trials could be difficult to conduct when strong preferences are already established, a trial should be, ideally, considered as soon as a new treatment option has been envisaged. Controversial issues, such as the one concerning melanoma, could be best addressed in the context of large-scale international trials. Initiatives, such as the International Federation of Dermatology Clinical Trials Networks may help in this respect.5
British Journal of Dermatology (2014) 171, pp1285–1299
Conflicts of interest None declared.
Department of Dermatology, Azienda Ospedaliera Papa Giovanni XXIII, Centro Studi GISED, Bergamo, 24100, Italy E-mail: [email protected]
L. NALDI
References 1 Sladden MJ, Balch C, Barzilai DA et al. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev 2009: CD004835. 2 Grotz TE, Markovic SN, Erickson LE et al. Mayo Clinic consensus recommendations for the depth of excision in primary cutaneous melanoma. Mayo Clin Proc 2011; 86:522–8. 3 Hunger RE, Seyed Jafari SM, Angermeier S, Shafighi M. Excision of fascia in melanoma thicker than 2 mm: no evidence for improved clinical outcome. Br J Dermatol 2014; 171:1391–6. 4 Lavori PW, Louis TA, Bailar JC 3rd, Polansky M. Designs for experiments. Parallel comparisons of treatment. N Engl J Med 1983; 309:1291–8. 5 The International Federation of Dermatology Clinical Trials Networks. Global collaboration in dermatology research. Available at: http:// www.nottingham.ac.uk/ifdctn/ (last accessed 31 August 2014).
Hand eczema – a chronic condition with farreaching consequences DOI: 10.1111/bjd.13454 ORIGINAL ARTICLE, p 1428 Hand eczema is known to be a long-lasting disease, yet very few published studies have examined the long-term prognosis. This issue of the BJD presents new and interesting data emanating from a 7-year follow-up of 536 patients with hand eczema, who had been examined and treated by dermatologists at nine different dermatological clinics all over Denmark.1 The participation rate at follow-up was as high as 70%. Clinical status was evaluated using a validated self-administered photographic guide, while occupational consequences and health-related quality of life were assessed by questionnaire. The study confirms the obvious tendency of hand eczema to become chronic. ‘Current’ hand eczema is often defined as hand eczema at any time during the previous year, thus corresponding to the occurrence measure of 1-year period prevalence. Sixty-eight per cent of the patients reported eczema during the previous year, in agreement with earlier follow-up studies. Encouragingly, 73% of the patients reported amelioration of their condition. Many probably learn from experience how to manage their hand eczema, and find ways to reduce detrimental exposure. Notably, however, 20% of the patients still had moderate to severe hand eczema after 7 years. © 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
A peptide from a gastric pathogen for the treatment of acne DOI: 10.1111/bjd.13458 ORIGINAL ARTICLE, p 1358 Acne vulgaris is an extremely common skin condition that can be divided into different subtypes according to the clinical phenotype present.1 The most common subtype is acne comedonica, which is characterized by comedones followed by acne that is dominated by papules and pustules. Acne conglobata is the most severe form, which additionally shows nodules and, when healed, can leave disfiguring scars. The distribution of acne corresponds to the highest density of pilosebaceous units (face, neck, upper chest, shoulders and back).2 Other forms of acne are steroid-induced acne or acne excoriee des jeunes filles.1 The pathomechanisms of acne vulgaris are not yet fully understood. Seborrhoea, follicular hyperkeratosis and bacterial infection seem to play major roles in the pathogenesis of acne vulgaris.1,2 The role of Propionibacterium acnes in the pathogenesis of acne remains somewhat unclear as clinically effective, topically applied antibiotics have direct antimicrobial, as well as anti-inflammatory, effects.3 However, many studies support a direct role of P. acnes in the pathogenesis of acne vulgaris.1 Nevertheless, at present, we have only started to begin to understand the role of the microbiome in inflammatory conditions of the skin.4 Currently, several efficient drugs to treat acne are available.2 Topical retinoids, for example, affect follicular hyperkeratosis,2 whereas benzoylperoxide has an additional effect on bacterial colonization and seborrhoea.2 Topical antibiotics are used to reduce the bacterial load and inflammation.2,3 As an example, systemic tetracyclines have both an antimicrobial and antiinflammatory effect.2,3 Systemic retinoids are very potent in reducing seborrhoea and hyperkeratosis.2 As the understanding of the cutaneous microbiome and the role of commensal bacteria in driving skin inflammation increases, therapeutic targeting of P. acnes in the treatment of acne vulgaris is an area of active research.5 However, as microbial resistance towards antibiotics is increasing, a more targeted and specific therapy against P. acnes might be beneficial.6,7 In a current study, Ryu et al.8 describe a new therapeutic agent that selectively reduces cutaneous colonization with P. acnes. They used the antimicrobial peptide protein HPA3NT3, derived from Helicobacter pylori, and created a synthetic a-helical cationic variant with antibacterial and anti-inflammatory activity. Treatment with HPA3NT3 in vitro induced morphological disruptions in P. acnes cells, suggestive of a bactericidal effect, whereas the minimal inhibitory concentration of HPA3NT3 against P. acnes was low (04 lmol L 1).8 Furthermore, HPA3NT3 decreased the P. acnes-induced expression of interleukin-8 and intracellular calcium mobilization in HK cells by inhibiting P. acnes-activated Toll-like receptor 2-medi© 2014 British Association of Dermatologists
1291
ated nuclear factor kappa B signalling pathways.8 Finally, this antimicrobial peptide significantly reduced P. acnes-induced skin inflammation in a murine model.8 One point that might remain difficult for topical antimicrobial peptides is the penetration of the molecule to the deeper hair follicle where it should exert its effects.8 As the authors discussed, methods of application other than the topical route might be needed. In summary, this research represents a new approach to treating bacteria-induced inflammatory skin conditions like, such as acne vulgaris. Further thorough investigations are needed to confirm the role of the new drug in inflammatory skin diseases in human studies. Conflicts of interest None declared. Department of Dermatology and Allergy, Ludwig-Maximilian University, Frauenlobstr. 9-11, 80337 Munich, Germany E-mail: [email protected]
M. REINHOLZ
References 1 Mourelatos K, Eady EA, Cunliffe WJ et al. Temporal changes in sebum excretion and propionibacterial colonization in preadolescent children with and without acne. Br J Dermatol 2007; 156:22–31. 2 Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet 2012; 379:361–72. 3 Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol 2013; 168:474–85. 4 Grice EA, Kong HH, Conlan S et al. Topographical and temporal diversity of the human skin microbiome. Science 2009; 324:1190–2. 5 Fitz-Gibbon S, Tomida S, Chiu BH et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol 2013; 133:2152–60. 6 Gollnick HP, Krautheim A. Topical treatment in acne: current status and future aspects. Dermatology 2003; 206:29–36. 7 Thiboutot DM. Inflammasome activation by Propionibacterium acnes: the story of IL-1 in acne continues to unfold. J Invest Dermatol 2014; 134:595–7. 8 Ryu S, Park Y, Kim B et al. Inhibitory and anti-inflammatory effects of the Helicobacter pylori-derived antimicrobial peptide HPA3NT3 against Propionibacterium acnes in the skin. Br J Dermatol 2014; 171:1358–67.
Melanoma excision: how deep must we go? DOI: 10.1111/bjd.13459 ORIGINAL ARTICLE, p 1391 Several randomized trials, recently summarized in a systematic review,1 have been conducted to optimize the extent of surgiBritish Journal of Dermatology (2014) 171, pp1285–1299
1292 Commentaries
cal resection in primary melanoma. Quite surprisingly, excision criteria have been mostly limited to the width of peripheral margins, with no standardization of the depth of excision in relation, in particular, to the muscular fascia. In some studies, excision of the muscular fascia was optional while in others it was not mentioned at all. With the lack of strong evidence, attitudes may diverge. A survey, at the Mayo Clinic, of surgical practice for intermediate thickness melanoma disclosed an even split between surgeons resecting the muscular fascia as a routine procedure, and those resecting down to, but not including, the muscular fascia.2 A paper from Hunger et al.3 in this issue of the BJD shows similar heterogeneity at the University Hospital of Bern. Taking advantage of the diversity of surgical approaches, the authors compared 103 patients with melanoma thicker than 2 mm treated by preserving the muscular fascia and 110 similar patients treated by exciding it. No significant difference was documented between the two groups in terms of local recurrences, locoregional or distant metastases, and death attributable to the tumour after a median follow-up of about 4 years. The study had a limited statistical power, and the lack of significant differences should not be taken as treatment equivalence. Moreover, the study was an observational one. Even if the analysed groups were well balanced for all the potential confounding variables but tumour location, it is still possible that some unmeasured factor, unevenly distributed between the groups, influenced the measured outcomes. In spite of the above concerns, it is reassuring that all the observational studies published up to now on the same topics, reviewed by Hunger et al.,3 and involving a total of about 1300 patients, uniformly showed negative results or even an advantage from preserving the muscular fascia. The study of Hunger et al.3 prompts some general reflections on the role of case series when assessing benefits and risks of specific interventions. Randomized clinical trials remain the reference standard to assess efficacy.4 However, when a new treatment entails a dramatic change in disease outcome compared with a reference standard, and it is supported by a clear understanding of biological mechanisms, as, for example, in the case of pulse dye laser treatment of Port Wine stains, well-built cohort studies may represent an acceptable option. When the treatment advantages are small and influenced by complex variables as in the case of different surgical procedures for treating melanoma, reliance on observational studies is debatable. As randomized trials could be difficult to conduct when strong preferences are already established, a trial should be, ideally, considered as soon as a new treatment option has been envisaged. Controversial issues, such as the one concerning melanoma, could be best addressed in the context of large-scale international trials. Initiatives, such as the International Federation of Dermatology Clinical Trials Networks may help in this respect.5
British Journal of Dermatology (2014) 171, pp1285–1299
Conflicts of interest None declared.
Department of Dermatology, Azienda Ospedaliera Papa Giovanni XXIII, Centro Studi GISED, Bergamo, 24100, Italy E-mail: [email protected]
L. NALDI
References 1 Sladden MJ, Balch C, Barzilai DA et al. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev 2009: CD004835. 2 Grotz TE, Markovic SN, Erickson LE et al. Mayo Clinic consensus recommendations for the depth of excision in primary cutaneous melanoma. Mayo Clin Proc 2011; 86:522–8. 3 Hunger RE, Seyed Jafari SM, Angermeier S, Shafighi M. Excision of fascia in melanoma thicker than 2 mm: no evidence for improved clinical outcome. Br J Dermatol 2014; 171:1391–6. 4 Lavori PW, Louis TA, Bailar JC 3rd, Polansky M. Designs for experiments. Parallel comparisons of treatment. N Engl J Med 1983; 309:1291–8. 5 The International Federation of Dermatology Clinical Trials Networks. Global collaboration in dermatology research. Available at: http:// www.nottingham.ac.uk/ifdctn/ (last accessed 31 August 2014).
Hand eczema – a chronic condition with farreaching consequences DOI: 10.1111/bjd.13454 ORIGINAL ARTICLE, p 1428 Hand eczema is known to be a long-lasting disease, yet very few published studies have examined the long-term prognosis. This issue of the BJD presents new and interesting data emanating from a 7-year follow-up of 536 patients with hand eczema, who had been examined and treated by dermatologists at nine different dermatological clinics all over Denmark.1 The participation rate at follow-up was as high as 70%. Clinical status was evaluated using a validated self-administered photographic guide, while occupational consequences and health-related quality of life were assessed by questionnaire. The study confirms the obvious tendency of hand eczema to become chronic. ‘Current’ hand eczema is often defined as hand eczema at any time during the previous year, thus corresponding to the occurrence measure of 1-year period prevalence. Sixty-eight per cent of the patients reported eczema during the previous year, in agreement with earlier follow-up studies. Encouragingly, 73% of the patients reported amelioration of their condition. Many probably learn from experience how to manage their hand eczema, and find ways to reduce detrimental exposure. Notably, however, 20% of the patients still had moderate to severe hand eczema after 7 years. © 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
