236 Commentaries
species then have the capacity to damage these same biological molecules further, resulting in potential changes to a cell’s phenotype or to its signalling pathways. Hence, unavoidable interaction with UVA results in a local cutaneous environment that is constantly under threat from homeostatic imbalance. Melatonin is a multifunctional lipophilic hormone, produced primarily from the pineal gland. However, it has recently been shown that melatonin can be produced in a variety of extraneuronal tissues, including the skin.5 Its molecular structure suggests that it may act as a direct scavenger of ROS but, perhaps more importantly, it has been shown to influence the expression of enzymes key to the cell’s antioxidant defence system, inducing increased expression of catalase, glutathione peroxidase and Cu/Zn- and Mn-superoxide dismutases.6 Hence, expression of cutaneous melatonin may be one mechanism by which the skin exerts control over its oxidant/antioxidant status. In this issue, Rezzani et al.7 explore whether melatonin, applied exogenously in a well-defined in vitro model system, can protect against some of the deleterious effects of UVA irradiation. In this system, UVA irradiation induced cell death and expression of haem oxygenase (HO)-1 and cytochrome C, and reduced the expression of some extracellular matrix (ECM) proteins. Following treatment with melatonin, applied in millimolar concentrations, expression of HO-1 and cytochrome C was abrogated and there was a partial normalization of ECM protein expression. Taken together, these data suggest that cutaneous melatonin may well play a role in local antioxidant defence following UVA irradiation, offering an enticing possibility that melatonin biology may be useful in protecting the skin against oxidative damage. It will be very interesting to observe whether the modulation of oxidative pathways in vitro by melatonin can be recapitulated in a less reductionist experimental system or studied in more detail in vivo. Centre for Dermatology, Institute of Inflammation & Repair, The University of Manchester, 1.525 Stopford Building, Oxford Road, Manchester M13 9PT, U.K. E-mail: [email protected]
R.E.B. WATSON
References 1 Cadet J, Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol 2013; 5:a012559. 2 Pattison DI, Rahmanto AS, Davies MJ. Photo-oxidation of proteins. Photochem Photobiol Sci 2012; 11:38–53. 3 Watson REB, Gibbs NK, Griffiths CEM, Sherratt MJ. Damage to skin extracellular matrix induced by UV exposure. Antioxid Redox Signal 2013; (in press) 4 Valacchi G, Sticozzi C, Pecorelli A et al. Cutaneous responses to environmental stressors. Ann N Y Acad Sci 2012; 1271:75–81. 5 Slominski A, Tobin DJ, Zmijewski MA et al. Melatonin in the skin: synthesis, metabolism and functions. Trends Exp Dermatol 2007; 19:19–24. 6 Tan DX, Reiter RJ, Manchester LC et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum
British Journal of Dermatology (2014) 170, pp234–238
antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2:181–97. 7 Rezzani R, Rodella LF, Favero G et al. Attenuation of ultraviolet Ainduced alterations in NIH3T3 dermal fibroblasts by melatonin. Br J Dermatol 2014; 170:382–91.
Biologics in nail psoriasis DOI: 10.1111/bjd.12752 ORIGINAL ARTICLE, p 398 In this edition of the BJD, Rich et al.1 report the findings of a multicentre pharmaceutically sponsored randomized controlled trial (RCT) in which nail psoriasis is assessed. The article is titled ‘Ustekinumab improves nail disease in patients with moderate-to-severe psoriasis: results from PHOENIX 1’. In truth, the first and last words could be substituted with any of the major RCTs of biological psoriasis treatments, as they all are helpful in nail disease. The points of interest are: how well does it work, does it work on all aspects of psoriatic nail disease, how does it compare with other biologics in nail disease, and are we measuring the right thing? Scoring of severity of skin psoriasis is well established with the Psoriasis Area and Severity Index and the Dermatology Life Quality Index (DLQI). Nails have struggled as the poor relative. Rich has a substantial background in trials involving nail disease, and established the Nail Psoriasis Severity Index (NAPSI) with her collaborator Dick Scher in 2003.2 The NAPSI has strengths (it is simple and quick) and drawbacks (it is not always representative, and not good at measuring some aspects of nail disease). Being based usually on the measurement of a target nail, it is open to the variation that arises when there are 20 digits to choose from. Also, in most instances it will be applied only to the fingers, as toenail psoriasis differs from that of the fingers in many respects and is also often complicated by other factors, such as trauma. Efforts to overcome these drawbacks have resulted in the creation of several variants of NAPSI entailing an increased score per nail (to maximize statistical sensitivity) or an increase in the number of nails scored (to make it more representative). Currently, the simplicity of the NAPSI and its early adoption gives it ascendancy and explains its inclusion in the National Institute for Health and Care Excellence clinical guideline 153 for psoriasis.3 Global assessment of nail disease using the Nail Physician’s Global Assessment was used in the study of Rich et al., and might have been a counterbalance to the problems of statistics applied to a limited sample of one digit, if it had been applied as a ‘global’ score. However, it was applied only to the same target nail assessed through the NAPSI. A simple
© 2014 British Association of Dermatologists
Commentaries 237
measure of the number of fingernails affected was also used, but does not help to differentiate between mild and severe disease within digits. The final word in any global assessment is the patient’s account of their burden. The DLQI, EuroQoL and others meet this need, but at the same time, they do not define which aspect of the skin, joint, nail or scalp disease is affecting quality of life. With this in mind, Ortonne et al.4 refined a nail psoriasis quality-of-life index including questions specific to the handicap in minor and major daily social and practical activities relating to the nail disease. No quality-of-life measures were used in the current ustekinumab study. With the three measures of single-nail NAPSI, single-nail ‘Nail Physician’s Global Assessment’ (Nail PGA) and number of nails involved, Rich et al. are able to confirm that ustekinumab works by 12 weeks for some features of fingernail psoriasis and by 24 weeks to a greater extent, probably reflecting the delay in improvement in nail plate features in comparison with those of the nail bed. The results are expressed as both percentage change in NAPSI and absolute changes in the NAPSI score. Statistical significance is reported for the percentage values at 12 weeks. No other statistical significance is reported at other points or with other scoring scales. The other measures look to indicate improvement, but there are some details to note. Firstly, the Nail PGA is helpful as a global measure to document an improvement in most patients with moderate or severe nail disease after 24 weeks of treatment. For those with mild disease, fewer than a quarter will show improvement by this measure and a small number will get worse. This is clinically relevant and a common finding in nail psoriasis treatments – that it is possible to make bad disease better, but difficult to make mild disease go away completely. The other interesting finding from the Nail PGA is that the larger dose of 90 mg does not produce an obviously better result than the smaller dose of 45 mg, with a possible exception in those with the most severely affected nails. Where there is a cost–efficacy calculation, or possibly even a safety matter of minimizing medication, this dose factor might be considered. We can conclude that ustekinumab is a useful treatment for many patients with nail psoriasis as measured by the doctor. It is difficult to make direct comparisons with other studies reporting nail outcomes for different biologics, as there are variations in the methodology, measures and data presentations in spite of the common ground of using the NAPSI in many. A 2013 Cochrane report5 on interventions in nail psoriasis states, ‘It was not possible to pool and compare the results because the studies were all so different’. The outstanding methodological challenges in this area are the need to broaden the scoring to include all affected fingernails, to standardize the reporting of data and to agree on a patient-reported outcome. Overcoming the clinical challenge of providing an effective treatment is within sight, although some special disease groups, such as those with pustular nail disease, remain exceedingly difficult to treat.
© 2014 British Association of Dermatologists
Conflicts of interest None declared. Bristol Dermatology Centre, University Hospitals Bristol, Bristol BS2 8HW, U.K. E-mail: [email protected]
D.
DE
BERKER
References 1 Rich P, Bourcier M, Sofen H et al. Ustekinumab improves nail disease in patients with moderate-to-severe psoriasis: results from PHOENIX 1. Br J Dermatol 2014; 170:398–407. 2 Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad Dermatol 2003; 49:206–12. 3 National Institute for Health and Care Excellence. Psoriasis: The Assessment and Management of Psoriasis. NICE clinical guideline 153. Available at: http://www.nice.org.uk/nicemedia/live/13938/61190/61190. pdf (last accessed 20 November 2013). 4 Ortonne JP, Baran R, Corvest M et al. Development and validation of nail psoriasis quality of life scale (NPQ10). J Eur Acad Dermatol Venereol 2010; 24:22–7. 5 de Vries AC, Bogaards NA, Hooft L et al. Interventions for nail psoriasis. Cochrane Database Syst Rev 2013; 2013:CD007633.
Dissolving unwanted submental fat DOI: 10.1111/bjd.12762 ORIGINAL ARTICLE, p 445 In this issue of BJD, Rzany et al.1 present a paper that extends research into lipolysis of submental fat pads with an injectable formula of deoxycholic acid, a synthetic derivative of a bile salt. Submental fat pads are perceived by some as ageing and aesthetically unattractive. There are several options for their reduction, including surgery and liposuction. Lipolytic injections have been available for at least the last decade. Initially, these injections combined phosphatidylcholine and deoxycholic acid in a mixture called lipodissolve.2 However, there were concerns about the lack of controlled clinical trials and manufacturing uncertainties that led lipodissolve to be discontinued and disapproved of by medical regulators in several countries.3 In 2010 the U.S. Food and Drug Administration issued warning letters to six U.S.A.-based medical spas and a Brazilian company using and promoting lipodissolve for fat removal.3 Rotunda and Kolodney developed the concept of using deoxycholic acid as the sole lipolytic agent, and investigated localized fat reduction and lipoma treatment. This proved effective for localized fat reduction, but less so for lipomas, possibly because of their fibrous and lobulated pathology.4
British Journal of Dermatology (2014) 170, pp234–238
species then have the capacity to damage these same biological molecules further, resulting in potential changes to a cell’s phenotype or to its signalling pathways. Hence, unavoidable interaction with UVA results in a local cutaneous environment that is constantly under threat from homeostatic imbalance. Melatonin is a multifunctional lipophilic hormone, produced primarily from the pineal gland. However, it has recently been shown that melatonin can be produced in a variety of extraneuronal tissues, including the skin.5 Its molecular structure suggests that it may act as a direct scavenger of ROS but, perhaps more importantly, it has been shown to influence the expression of enzymes key to the cell’s antioxidant defence system, inducing increased expression of catalase, glutathione peroxidase and Cu/Zn- and Mn-superoxide dismutases.6 Hence, expression of cutaneous melatonin may be one mechanism by which the skin exerts control over its oxidant/antioxidant status. In this issue, Rezzani et al.7 explore whether melatonin, applied exogenously in a well-defined in vitro model system, can protect against some of the deleterious effects of UVA irradiation. In this system, UVA irradiation induced cell death and expression of haem oxygenase (HO)-1 and cytochrome C, and reduced the expression of some extracellular matrix (ECM) proteins. Following treatment with melatonin, applied in millimolar concentrations, expression of HO-1 and cytochrome C was abrogated and there was a partial normalization of ECM protein expression. Taken together, these data suggest that cutaneous melatonin may well play a role in local antioxidant defence following UVA irradiation, offering an enticing possibility that melatonin biology may be useful in protecting the skin against oxidative damage. It will be very interesting to observe whether the modulation of oxidative pathways in vitro by melatonin can be recapitulated in a less reductionist experimental system or studied in more detail in vivo. Centre for Dermatology, Institute of Inflammation & Repair, The University of Manchester, 1.525 Stopford Building, Oxford Road, Manchester M13 9PT, U.K. E-mail: [email protected]
R.E.B. WATSON
References 1 Cadet J, Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol 2013; 5:a012559. 2 Pattison DI, Rahmanto AS, Davies MJ. Photo-oxidation of proteins. Photochem Photobiol Sci 2012; 11:38–53. 3 Watson REB, Gibbs NK, Griffiths CEM, Sherratt MJ. Damage to skin extracellular matrix induced by UV exposure. Antioxid Redox Signal 2013; (in press) 4 Valacchi G, Sticozzi C, Pecorelli A et al. Cutaneous responses to environmental stressors. Ann N Y Acad Sci 2012; 1271:75–81. 5 Slominski A, Tobin DJ, Zmijewski MA et al. Melatonin in the skin: synthesis, metabolism and functions. Trends Exp Dermatol 2007; 19:19–24. 6 Tan DX, Reiter RJ, Manchester LC et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum
British Journal of Dermatology (2014) 170, pp234–238
antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2:181–97. 7 Rezzani R, Rodella LF, Favero G et al. Attenuation of ultraviolet Ainduced alterations in NIH3T3 dermal fibroblasts by melatonin. Br J Dermatol 2014; 170:382–91.
Biologics in nail psoriasis DOI: 10.1111/bjd.12752 ORIGINAL ARTICLE, p 398 In this edition of the BJD, Rich et al.1 report the findings of a multicentre pharmaceutically sponsored randomized controlled trial (RCT) in which nail psoriasis is assessed. The article is titled ‘Ustekinumab improves nail disease in patients with moderate-to-severe psoriasis: results from PHOENIX 1’. In truth, the first and last words could be substituted with any of the major RCTs of biological psoriasis treatments, as they all are helpful in nail disease. The points of interest are: how well does it work, does it work on all aspects of psoriatic nail disease, how does it compare with other biologics in nail disease, and are we measuring the right thing? Scoring of severity of skin psoriasis is well established with the Psoriasis Area and Severity Index and the Dermatology Life Quality Index (DLQI). Nails have struggled as the poor relative. Rich has a substantial background in trials involving nail disease, and established the Nail Psoriasis Severity Index (NAPSI) with her collaborator Dick Scher in 2003.2 The NAPSI has strengths (it is simple and quick) and drawbacks (it is not always representative, and not good at measuring some aspects of nail disease). Being based usually on the measurement of a target nail, it is open to the variation that arises when there are 20 digits to choose from. Also, in most instances it will be applied only to the fingers, as toenail psoriasis differs from that of the fingers in many respects and is also often complicated by other factors, such as trauma. Efforts to overcome these drawbacks have resulted in the creation of several variants of NAPSI entailing an increased score per nail (to maximize statistical sensitivity) or an increase in the number of nails scored (to make it more representative). Currently, the simplicity of the NAPSI and its early adoption gives it ascendancy and explains its inclusion in the National Institute for Health and Care Excellence clinical guideline 153 for psoriasis.3 Global assessment of nail disease using the Nail Physician’s Global Assessment was used in the study of Rich et al., and might have been a counterbalance to the problems of statistics applied to a limited sample of one digit, if it had been applied as a ‘global’ score. However, it was applied only to the same target nail assessed through the NAPSI. A simple
© 2014 British Association of Dermatologists
Commentaries 237
measure of the number of fingernails affected was also used, but does not help to differentiate between mild and severe disease within digits. The final word in any global assessment is the patient’s account of their burden. The DLQI, EuroQoL and others meet this need, but at the same time, they do not define which aspect of the skin, joint, nail or scalp disease is affecting quality of life. With this in mind, Ortonne et al.4 refined a nail psoriasis quality-of-life index including questions specific to the handicap in minor and major daily social and practical activities relating to the nail disease. No quality-of-life measures were used in the current ustekinumab study. With the three measures of single-nail NAPSI, single-nail ‘Nail Physician’s Global Assessment’ (Nail PGA) and number of nails involved, Rich et al. are able to confirm that ustekinumab works by 12 weeks for some features of fingernail psoriasis and by 24 weeks to a greater extent, probably reflecting the delay in improvement in nail plate features in comparison with those of the nail bed. The results are expressed as both percentage change in NAPSI and absolute changes in the NAPSI score. Statistical significance is reported for the percentage values at 12 weeks. No other statistical significance is reported at other points or with other scoring scales. The other measures look to indicate improvement, but there are some details to note. Firstly, the Nail PGA is helpful as a global measure to document an improvement in most patients with moderate or severe nail disease after 24 weeks of treatment. For those with mild disease, fewer than a quarter will show improvement by this measure and a small number will get worse. This is clinically relevant and a common finding in nail psoriasis treatments – that it is possible to make bad disease better, but difficult to make mild disease go away completely. The other interesting finding from the Nail PGA is that the larger dose of 90 mg does not produce an obviously better result than the smaller dose of 45 mg, with a possible exception in those with the most severely affected nails. Where there is a cost–efficacy calculation, or possibly even a safety matter of minimizing medication, this dose factor might be considered. We can conclude that ustekinumab is a useful treatment for many patients with nail psoriasis as measured by the doctor. It is difficult to make direct comparisons with other studies reporting nail outcomes for different biologics, as there are variations in the methodology, measures and data presentations in spite of the common ground of using the NAPSI in many. A 2013 Cochrane report5 on interventions in nail psoriasis states, ‘It was not possible to pool and compare the results because the studies were all so different’. The outstanding methodological challenges in this area are the need to broaden the scoring to include all affected fingernails, to standardize the reporting of data and to agree on a patient-reported outcome. Overcoming the clinical challenge of providing an effective treatment is within sight, although some special disease groups, such as those with pustular nail disease, remain exceedingly difficult to treat.
© 2014 British Association of Dermatologists
Conflicts of interest None declared. Bristol Dermatology Centre, University Hospitals Bristol, Bristol BS2 8HW, U.K. E-mail: [email protected]
D.
DE
BERKER
References 1 Rich P, Bourcier M, Sofen H et al. Ustekinumab improves nail disease in patients with moderate-to-severe psoriasis: results from PHOENIX 1. Br J Dermatol 2014; 170:398–407. 2 Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad Dermatol 2003; 49:206–12. 3 National Institute for Health and Care Excellence. Psoriasis: The Assessment and Management of Psoriasis. NICE clinical guideline 153. Available at: http://www.nice.org.uk/nicemedia/live/13938/61190/61190. pdf (last accessed 20 November 2013). 4 Ortonne JP, Baran R, Corvest M et al. Development and validation of nail psoriasis quality of life scale (NPQ10). J Eur Acad Dermatol Venereol 2010; 24:22–7. 5 de Vries AC, Bogaards NA, Hooft L et al. Interventions for nail psoriasis. Cochrane Database Syst Rev 2013; 2013:CD007633.
Dissolving unwanted submental fat DOI: 10.1111/bjd.12762 ORIGINAL ARTICLE, p 445 In this issue of BJD, Rzany et al.1 present a paper that extends research into lipolysis of submental fat pads with an injectable formula of deoxycholic acid, a synthetic derivative of a bile salt. Submental fat pads are perceived by some as ageing and aesthetically unattractive. There are several options for their reduction, including surgery and liposuction. Lipolytic injections have been available for at least the last decade. Initially, these injections combined phosphatidylcholine and deoxycholic acid in a mixture called lipodissolve.2 However, there were concerns about the lack of controlled clinical trials and manufacturing uncertainties that led lipodissolve to be discontinued and disapproved of by medical regulators in several countries.3 In 2010 the U.S. Food and Drug Administration issued warning letters to six U.S.A.-based medical spas and a Brazilian company using and promoting lipodissolve for fat removal.3 Rotunda and Kolodney developed the concept of using deoxycholic acid as the sole lipolytic agent, and investigated localized fat reduction and lipoma treatment. This proved effective for localized fat reduction, but less so for lipomas, possibly because of their fibrous and lobulated pathology.4
British Journal of Dermatology (2014) 170, pp234–238
![[Nail psoriasis].](/assets/img/hold.png)
