- Email: [email protected]
Decrease of ultraviolet A light–induced “common deletion” in healthy volunteers after oral Polypodium leucotomos extract supplement in a randomized clinical trial
Letters 511
J AM ACAD DERMATOL VOLUME 62, NUMBER 3
molecules in some nontoxic cereals may share epitopes with gliadin protein, resulting in cross-reactivity and thus provocation of DH. In celiac disease, increased levels of IgG class antibodies to corn as well as to ‘‘toxic’’ cereals such as wheat and barley have been documented,3 and in an in vivo challenge test, some patients with celiac disease had an inflammatory response after rectal corn challenge.5 Thus both animal model and human challenge experiments support the concept that corn (maize) may cause relevant antibodies and inflammation of gut mucosa in celiac disease; however, we are not aware of previous reports of DH provoked by corn and proven by rechallenge. Firas Al-Niaimi,a Neil H. Cox,a and Susan LewisJonesb Departments of Dermatology, Cumberland Infirmary, Carlisle,a and Ninewells Hospital, Dundee,b United Kingdom Funding sources: None. Conflicts of interest: None declared. Correspondence to: Firas Al-Niaimi, Specialist registrar, Department of Dermatology, Salford Royal Hospital, Stott Lane, Manchester, UK E-mail: [email protected] REFERENCES 1. Vainio E, Varjonen E. Antibody response against wheat, rye, barley, oats and corn: comparison between gluten-sensitive patients and monoclonal antigliadin antibodies. Int Arch Allergy Immunol 1995;106:134-8. 2. Ellis HJ, Freedman AR, Ciclitira PJ. The production and characterisation of monoclonal antibodies to wheat gliadin peptides. J Immunol Methods 1998;120:17-22. 3. Troncone R, Auricchio S, De Vincenzi M, Donatiello A, Farris E, Silano V. An analysis of cereals that react with serum antibodies in patients with coeliac disease. J Paediatr Gastroenterol Nutr 1987;6:346-50. 4. Coombs RRA, Kieffer M, Fraser DR, Frazier PJ. Naturally developing antibodies to wheat gliadin fractions and to other cereal antigens in rabbits, rats and guinea pigs on normal laboratory diets. Int Arch Allergy Appl Immunol 1983;70:200-4. 5. Kristjansson G, Hogman M, Venge P, Hallgren R. Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn. Gut 2005;54:769-74. doi:10.1016/j.jaad.2009.06.002
Decrease of ultraviolet A lighteinduced ‘‘common deletion’’ in healthy volunteers after oral Polypodium leucotomos extract supplement in a randomized clinical trial To the Editor: Ultraviolet (UV) radiation causes sunburn, immunosuppression, pigmentary changes,
photoaging, and skin cancer in a wavelengthdependent fashion. More than 95% of the incident UV radiation is ultraviolet A (UVA; 320-400 nm), which penetrates into the dermis. It induces DNA damage through the formation of reactive oxygen species (ROS), which are involved in oxidative base damage. ROS also induce matrix metalloproteinase (MMP) upregulation, which is partially responsible for skin photoaging.1 The common deletion (CD) is a 4977 base pairelong mitochondrial DNA whose deletion is induced by, and is a marker of, chronic UVA radiation in fibroblasts and keratinocytes.2,3 Polypodium leucotomos is an extract of a fern species marketed for the management of psoriasis, vitiligo, autoimmune diseases, and the prevention of photodamage/aging. P leucotomos contains polyphenols, which are potent ROS inhibitors with antiinflammatory, antioxidant, and photoprotective properties both in vitro and in vivo.4 At low concentrations, P leucotomos inhibits MMP-1 photoinduced membrane damage and reduces psoralen/UVA-induced phototoxicity.1,5 This randomized, investigator-blinded, controlled, institutional review boardeapproved study was designed to detect and quantify P leucotomos’ UVA-induced photoaging marker, the CD, in P leucotomosetreated and nontreated subjects after UVA irradiation. Ten healthy volunteers between 29 and 54 years of age with Fitzpatrick skin types II and III were enrolled in a study (Fig 1). Exclusion criteria included subjects with a history of current or planned pregnancy, skin cancer, photosensitivity, radiation (other than sunlight) or asbestos exposure, smoking during the previous 6 months, subjects taking any drug that might alter skin responses to UV radiation, and subjects who were unable to undergo skin biopsies. Subjects were instructed not to change their normal photoprotection practices during the study. Each subject underwent a pretreatment 3-mm punch biopsy from the proximal right volar forearm skin that was bisected for CD determination by semiquantitative real-time polymerase chain reaction and stained with hematoxylineeosin to obtain a baseline histology. Each subject’s left volar forearm was covered with a UVA opaque fenestrated adhesive patch (DV Die Cutting Inc, Danvers, MA). UVA was then administered to the left volar forearm for UVA minimal erythema dose (MED-A) determination using an Ultralite Hand/Foot Unit (Model HA 1200 12 UVA, FA 1200, AC voltage 115, amp 12, frg 50/60 Hz, with light bulbs model: F36T12-BL emitting wavelengths of 320-400 nm with a peak in 350 nm as a light source [Ultralite Enterprises Inc, Lawrenceville, GA]). The windows were exposed to
512 Letters
J AM ACAD DERMATOL MARCH 2010
Fig 1. Flow diagram summarizing participant flow, numbers and timing of randomization assignment, interventions, and measurements for each randomized group.
10, 15, 20, 25, 30, or 35 J/cm2 doses of UVA light. One week later, those subjects randomized not to receive any oral treatment were exposed to 2 and 3 times their MED-A to their right volar forearm, through a UVA opaque fenestrated adhesive patch, while those subjects randomized to receive oral
P leucotomos were administered PL 240 mg 8 and 2 hours before exposure to two to three times their MED-A in the same areas. Each subject had a second and a third 3-mm punch biopsy specimen taken 24 hours later from the two irradiated areas and a fourth biopsy specimen taken from an
Letters 513
J AM ACAD DERMATOL VOLUME 62, NUMBER 3
adjacent nonirradiated (ie, shielded) site. These specimens were bisected for CD determination and hematoxylin-eosin staining. A histologic examination showed mild superficial perivascular inflammatory lymphocytic infiltrates in the majority of the control group’s irradiated sites. Baseline CD could not be quantified in two subjects in the nonP leucotomosetreated group; they were excluded from the subsequent analysis. At two times the MED, average CD values in the non-P leucotomosetreated group increased by 217% over baseline, while values in the P leucotomosetreated decreased by 84% (P ¼ .06). At three times the MED, those values increased 760% and 61%, respectively (P ¼ .07). No interaction significance was found (P ¼ .08). Pretreatment with P leucotomos showed a strong trend but failed to achieve statistical significance in preventing the increase of CD levels 24 hours after UVA irradiation. Although chronic UVA exposure has been associated with CD elevation,2,3 our findings showed increments in CD expression after acute UVA exposure. According to our interaction analysis, P leucotomos’ effect exhibited a trend towards preventing the increase of CD levels as the UVA dose increased. Except for the expected erythema after UVA irradiation, no treatment-related adverse events were recorded in any of the subjects. Although pretreatment with P leucotomos did not prevent the development of mild superficial perivascular inflammatory lymphocytic infiltrate in subjects irradiated with UVA, more biopsies in the control group (those not receiving P leucotomos; n ¼ 6) reported the development of the infiltrate after UVA irradiation compared with biopsy reports in the PL group (n ¼ 5) after irradiation with UVA. In addition, all biopsies from adjacent nonirradiated (ie, shielded) sites reported normal skin (ie, no infiltrates). Although larger studies are needed to characterize P leucotomos’ role in photoaging, this pilot study’s findings suggest that P leucotomos may prevent UVAinduced skin photodamage possibly by preventing UVA-dependent mitochondrial DNA damage. Adriana Villa, MD,a Martha H. Viera, MD,a Sadegh Amini, MD,a Ran Huo, MD,a Oliver Perez, MD,b Phillip Ruiz, MD, PhD,a Alexandra Amador, PhD,a George Elgart, MD,a and Brian Berman, MD, PhDa Department of Dermatology and Cutaneous Surgery,a University of Miami, Miller School of Medicine, Miami, Florida, and the Department of Dermatology,b University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Supported by a 2008 Women’s Dermatologic Society Academic Research Grant awarded to Adriana Villa, MD. Conflicts of interest: None declared. Correspondence to: Brian Berman, MD, PhD, Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, 1600 NW 10th Ave, RSMB, Rm 2023A, Miami, FL 33136. E-mail: [email protected]
REFERENCES 1. Philips N, Smith J, Keller T, Gonzalez S. Predominant effects of Polypodium leucotomos on membrane integrity, lipid peroxidation, and expression of elastin and matrixmetalloproteinase1 in ultraviolet radiation exposed fibroblasts, and keratinocytes. J Dermatol Sci 2003;32:1-9. 2. Berneburg M, Grether-Beck S, Ku¨rten V, Ruzicka T, Briviba K, Sies H, et al. Singlet oxygen mediates the UVA-induced generation of the photoaging-associated mitochondrial common deletion. J Biol Chem 1999;274:15345-9. 3. Berneburg M, Plettenberg H, Medve-Ko¨nig K, Pfahlberg A, GersBarlag H, Gefeller O, et al. Induction of the photoagingassociated mitochondrial common deletion in vivo in normal human skin. J Invest Dermatol 2004;122:1277-83. 4. Gombau L, Garcı´a F, Lahoz A, Fabre M, Roda-Navarro P, Majano P, et al. Polypodium leucotomos extract: antioxidant activity and disposition. Toxicol In Vitro 2006;20:464-71. 5. Capote R, Alonso-Lebrero JL, Garcı´a F, Brieva A, Pivel JP, Gonza´lez S. Polypodium leucotomos extract inhibits transurocanic acid photoisomerization and photodecomposition. J Photochem Photobiol B 2006;82:173-9. doi:10.1016/j.jaad.2009.05.045
Interobserver accuracy of store and forward teledermatology for skin neoplasms To the Editor: Few studies have compared diagnostic accuracy rates between teledermatologists (TDs) based on the gold standard of histopathology,1,2 and none have reported accuracy rates (histopathology as standard) between clinic dermatologists (CDs) viewing the same patients as TDs nor accuracy (histopathology as standard) of management plans. Methods of the larger study have been previously described.3,4 Briefly, each lesion was examined by a CD and, later, by a TD; both generated a primary diagnosis, up to two differential diagnoses, and a management plan. For interrater assessments, all study patients enrolled during Thursday afternoon clinics (when all three CDs were available) were seen by each CD independently; CDs were blinded to each other’s assessments. The three TDs viewed macro images of the lesions examined for these same patients.
J AM ACAD DERMATOL VOLUME 62, NUMBER 3
molecules in some nontoxic cereals may share epitopes with gliadin protein, resulting in cross-reactivity and thus provocation of DH. In celiac disease, increased levels of IgG class antibodies to corn as well as to ‘‘toxic’’ cereals such as wheat and barley have been documented,3 and in an in vivo challenge test, some patients with celiac disease had an inflammatory response after rectal corn challenge.5 Thus both animal model and human challenge experiments support the concept that corn (maize) may cause relevant antibodies and inflammation of gut mucosa in celiac disease; however, we are not aware of previous reports of DH provoked by corn and proven by rechallenge. Firas Al-Niaimi,a Neil H. Cox,a and Susan LewisJonesb Departments of Dermatology, Cumberland Infirmary, Carlisle,a and Ninewells Hospital, Dundee,b United Kingdom Funding sources: None. Conflicts of interest: None declared. Correspondence to: Firas Al-Niaimi, Specialist registrar, Department of Dermatology, Salford Royal Hospital, Stott Lane, Manchester, UK E-mail: [email protected] REFERENCES 1. Vainio E, Varjonen E. Antibody response against wheat, rye, barley, oats and corn: comparison between gluten-sensitive patients and monoclonal antigliadin antibodies. Int Arch Allergy Immunol 1995;106:134-8. 2. Ellis HJ, Freedman AR, Ciclitira PJ. The production and characterisation of monoclonal antibodies to wheat gliadin peptides. J Immunol Methods 1998;120:17-22. 3. Troncone R, Auricchio S, De Vincenzi M, Donatiello A, Farris E, Silano V. An analysis of cereals that react with serum antibodies in patients with coeliac disease. J Paediatr Gastroenterol Nutr 1987;6:346-50. 4. Coombs RRA, Kieffer M, Fraser DR, Frazier PJ. Naturally developing antibodies to wheat gliadin fractions and to other cereal antigens in rabbits, rats and guinea pigs on normal laboratory diets. Int Arch Allergy Appl Immunol 1983;70:200-4. 5. Kristjansson G, Hogman M, Venge P, Hallgren R. Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn. Gut 2005;54:769-74. doi:10.1016/j.jaad.2009.06.002
Decrease of ultraviolet A lighteinduced ‘‘common deletion’’ in healthy volunteers after oral Polypodium leucotomos extract supplement in a randomized clinical trial To the Editor: Ultraviolet (UV) radiation causes sunburn, immunosuppression, pigmentary changes,
photoaging, and skin cancer in a wavelengthdependent fashion. More than 95% of the incident UV radiation is ultraviolet A (UVA; 320-400 nm), which penetrates into the dermis. It induces DNA damage through the formation of reactive oxygen species (ROS), which are involved in oxidative base damage. ROS also induce matrix metalloproteinase (MMP) upregulation, which is partially responsible for skin photoaging.1 The common deletion (CD) is a 4977 base pairelong mitochondrial DNA whose deletion is induced by, and is a marker of, chronic UVA radiation in fibroblasts and keratinocytes.2,3 Polypodium leucotomos is an extract of a fern species marketed for the management of psoriasis, vitiligo, autoimmune diseases, and the prevention of photodamage/aging. P leucotomos contains polyphenols, which are potent ROS inhibitors with antiinflammatory, antioxidant, and photoprotective properties both in vitro and in vivo.4 At low concentrations, P leucotomos inhibits MMP-1 photoinduced membrane damage and reduces psoralen/UVA-induced phototoxicity.1,5 This randomized, investigator-blinded, controlled, institutional review boardeapproved study was designed to detect and quantify P leucotomos’ UVA-induced photoaging marker, the CD, in P leucotomosetreated and nontreated subjects after UVA irradiation. Ten healthy volunteers between 29 and 54 years of age with Fitzpatrick skin types II and III were enrolled in a study (Fig 1). Exclusion criteria included subjects with a history of current or planned pregnancy, skin cancer, photosensitivity, radiation (other than sunlight) or asbestos exposure, smoking during the previous 6 months, subjects taking any drug that might alter skin responses to UV radiation, and subjects who were unable to undergo skin biopsies. Subjects were instructed not to change their normal photoprotection practices during the study. Each subject underwent a pretreatment 3-mm punch biopsy from the proximal right volar forearm skin that was bisected for CD determination by semiquantitative real-time polymerase chain reaction and stained with hematoxylineeosin to obtain a baseline histology. Each subject’s left volar forearm was covered with a UVA opaque fenestrated adhesive patch (DV Die Cutting Inc, Danvers, MA). UVA was then administered to the left volar forearm for UVA minimal erythema dose (MED-A) determination using an Ultralite Hand/Foot Unit (Model HA 1200 12 UVA, FA 1200, AC voltage 115, amp 12, frg 50/60 Hz, with light bulbs model: F36T12-BL emitting wavelengths of 320-400 nm with a peak in 350 nm as a light source [Ultralite Enterprises Inc, Lawrenceville, GA]). The windows were exposed to
512 Letters
J AM ACAD DERMATOL MARCH 2010
Fig 1. Flow diagram summarizing participant flow, numbers and timing of randomization assignment, interventions, and measurements for each randomized group.
10, 15, 20, 25, 30, or 35 J/cm2 doses of UVA light. One week later, those subjects randomized not to receive any oral treatment were exposed to 2 and 3 times their MED-A to their right volar forearm, through a UVA opaque fenestrated adhesive patch, while those subjects randomized to receive oral
P leucotomos were administered PL 240 mg 8 and 2 hours before exposure to two to three times their MED-A in the same areas. Each subject had a second and a third 3-mm punch biopsy specimen taken 24 hours later from the two irradiated areas and a fourth biopsy specimen taken from an
Letters 513
J AM ACAD DERMATOL VOLUME 62, NUMBER 3
adjacent nonirradiated (ie, shielded) site. These specimens were bisected for CD determination and hematoxylin-eosin staining. A histologic examination showed mild superficial perivascular inflammatory lymphocytic infiltrates in the majority of the control group’s irradiated sites. Baseline CD could not be quantified in two subjects in the nonP leucotomosetreated group; they were excluded from the subsequent analysis. At two times the MED, average CD values in the non-P leucotomosetreated group increased by 217% over baseline, while values in the P leucotomosetreated decreased by 84% (P ¼ .06). At three times the MED, those values increased 760% and 61%, respectively (P ¼ .07). No interaction significance was found (P ¼ .08). Pretreatment with P leucotomos showed a strong trend but failed to achieve statistical significance in preventing the increase of CD levels 24 hours after UVA irradiation. Although chronic UVA exposure has been associated with CD elevation,2,3 our findings showed increments in CD expression after acute UVA exposure. According to our interaction analysis, P leucotomos’ effect exhibited a trend towards preventing the increase of CD levels as the UVA dose increased. Except for the expected erythema after UVA irradiation, no treatment-related adverse events were recorded in any of the subjects. Although pretreatment with P leucotomos did not prevent the development of mild superficial perivascular inflammatory lymphocytic infiltrate in subjects irradiated with UVA, more biopsies in the control group (those not receiving P leucotomos; n ¼ 6) reported the development of the infiltrate after UVA irradiation compared with biopsy reports in the PL group (n ¼ 5) after irradiation with UVA. In addition, all biopsies from adjacent nonirradiated (ie, shielded) sites reported normal skin (ie, no infiltrates). Although larger studies are needed to characterize P leucotomos’ role in photoaging, this pilot study’s findings suggest that P leucotomos may prevent UVAinduced skin photodamage possibly by preventing UVA-dependent mitochondrial DNA damage. Adriana Villa, MD,a Martha H. Viera, MD,a Sadegh Amini, MD,a Ran Huo, MD,a Oliver Perez, MD,b Phillip Ruiz, MD, PhD,a Alexandra Amador, PhD,a George Elgart, MD,a and Brian Berman, MD, PhDa Department of Dermatology and Cutaneous Surgery,a University of Miami, Miller School of Medicine, Miami, Florida, and the Department of Dermatology,b University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Supported by a 2008 Women’s Dermatologic Society Academic Research Grant awarded to Adriana Villa, MD. Conflicts of interest: None declared. Correspondence to: Brian Berman, MD, PhD, Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, 1600 NW 10th Ave, RSMB, Rm 2023A, Miami, FL 33136. E-mail: [email protected]
REFERENCES 1. Philips N, Smith J, Keller T, Gonzalez S. Predominant effects of Polypodium leucotomos on membrane integrity, lipid peroxidation, and expression of elastin and matrixmetalloproteinase1 in ultraviolet radiation exposed fibroblasts, and keratinocytes. J Dermatol Sci 2003;32:1-9. 2. Berneburg M, Grether-Beck S, Ku¨rten V, Ruzicka T, Briviba K, Sies H, et al. Singlet oxygen mediates the UVA-induced generation of the photoaging-associated mitochondrial common deletion. J Biol Chem 1999;274:15345-9. 3. Berneburg M, Plettenberg H, Medve-Ko¨nig K, Pfahlberg A, GersBarlag H, Gefeller O, et al. Induction of the photoagingassociated mitochondrial common deletion in vivo in normal human skin. J Invest Dermatol 2004;122:1277-83. 4. Gombau L, Garcı´a F, Lahoz A, Fabre M, Roda-Navarro P, Majano P, et al. Polypodium leucotomos extract: antioxidant activity and disposition. Toxicol In Vitro 2006;20:464-71. 5. Capote R, Alonso-Lebrero JL, Garcı´a F, Brieva A, Pivel JP, Gonza´lez S. Polypodium leucotomos extract inhibits transurocanic acid photoisomerization and photodecomposition. J Photochem Photobiol B 2006;82:173-9. doi:10.1016/j.jaad.2009.05.045
Interobserver accuracy of store and forward teledermatology for skin neoplasms To the Editor: Few studies have compared diagnostic accuracy rates between teledermatologists (TDs) based on the gold standard of histopathology,1,2 and none have reported accuracy rates (histopathology as standard) between clinic dermatologists (CDs) viewing the same patients as TDs nor accuracy (histopathology as standard) of management plans. Methods of the larger study have been previously described.3,4 Briefly, each lesion was examined by a CD and, later, by a TD; both generated a primary diagnosis, up to two differential diagnoses, and a management plan. For interrater assessments, all study patients enrolled during Thursday afternoon clinics (when all three CDs were available) were seen by each CD independently; CDs were blinded to each other’s assessments. The three TDs viewed macro images of the lesions examined for these same patients.