Caffeine in the Treatment of Atopic Dermatitis and Psoriasis: A Review

Main Article Content

Mais Bassam Alashqar

Keywords

Caffeine, atopic dermatitis, psoriasis, cyclic adenosine monophosphate, phosphodiesterase, ataxia-telangiectasia mutated kinase, ataxia-telangiectasia mutated and Rad3-Related kinase, apoptosis, necrosis, antioxidant, reactive oxygen species

Abstract

   Atopic dermatitis (AD) and psoriasis are inflammatory skin diseases. AD is characterized by immune dysregulation and barrier impairment, while psoriasis is by immune dysfunction and resultant keratinocyte hyper-proliferation.
   Caffeine has shown effective in ameliorating the symptoms of both diseases, but it is not conclusive through which pathways. The aim of this study was to provide a detailed discussion of available work on this topic, as well as known modes of action of caffeine that are relevant to these two conditions.
   After an extensive review of the literature, we found that both diseases have decreased intracellular cyclic adenosine monophosphate (cAMP) levels in cutaneous leukocytes, so it is very likely that being a methylxanthine, and hence a phosphodiesterase (PDE) inhibitor, caffeine raises intracellular cAMP levels, which suppresses inflammatory pathways and potentiates anti-inflammatory ones. Moreover, caffeine is known to be an ATR (ataxia-telangiectasia mutated) kinase and an ATM (ATM- and Rad3-Related) kinase inhibitor, which promotes prompt apoptosis of damaged cells. It was also found to have anti-necrotic effects in reactive oxygen species (ROS)-damaged cells. These pro-apoptotic and anti-necrotic properties may also be reducing the inflammation. Finally, caffeine's metabolites have shown antioxidising effects against ROS, which certainly would reduce inflammation caused by lipid peroxidation, DNA damage and organelle destruction.
   We find that caffeine acts in a number of ways to improve symptoms of inflammation and that it is an effective adjunct to therapy in AD and psoriasis.

References

1- Rudikoff, D., Cohen, S. R., & Scheinfeld, N. (2014). Atopic dermatitis and eczematous disorders. Boca Raton: CRC Press, Taylor & Francis Group.

2- Margolis, J. S., Abuabara, K., Bilker, W., Hoffstad, O., & Margolis, D. J. (2014). Persistence of mild to moderate atopic dermatitis. JAMA dermatology, 150(6), 593-600.

3- Abd, E., Namjoshi, S., Mohammed, Y. H., Roberts, M. S., & Grice, J. E. (2015). Synergistic skin penetration enhancer and nanoemulsion formulations promote the human epidermal permeation of caffeine and naproxen. Journal of pharmaceutical sciences.

4- Otberg, N., Patzelt, A., Rasulev, U., Hagemeister, T., Linscheid, M., Sinkgraven, R., ... & Lademann, J. (2008). The role of hair follicles in the percutaneous absorption of caffeine. British journal of clinical pharmacology, 65(4), 488-492.

5- Abd, E., Namjoshi, S., Mohammed, Y. H., Roberts, M. S., & Grice, J. E. (2015). Synergistic skin penetration enhancer and nanoemulsion formulations promote the human epidermal permeation of caffeine and naproxen. Journal of pharmaceutical sciences.

6- Wilkinson, S. C., Maas, W. J., Nielsen, J. B., Greaves, L. C., van de Sandt, J. J., & Williams, F. M. (2006). Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies. International archives of occupational and environmental health, 79(5), 405-413.

7- Leung, D. Y., & Bieber, T. (2003). Atopic dermatitis. The Lancet,361(9352), 151-160. doi:10.1016/s0140-6736(03)12193-9

8- Andoh, T., & Kuraishi, Y. (2014). Antipruritic mechanisms of topical E6005, a phosphodiesterase 4 inhibitor: Inhibition of responses to proteinase-activated receptor 2 stimulation mediated by increase in intracellular cyclic AMP. Journal of Dermatological Science,76(3), 206-213. doi:10.1016/j.jdermsci.2014.10.005

9- Gooderham, M., & Papp, K. (2015). Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast. BioDrugs,29(5), 327-339. doi:10.1007/s40259-015-0144-3

10- Wakita, H., Ohkuro, M., Ishii, N., Hishinuma, I., & Shirato, M. (2015). A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fibre nerves. Experimental Dermatology,24(3), 215-216. doi:10.1111/exd.12606

11- Dong, C., Virtucio, C., Zemska, O., Baltazar, G., Zhou, Y., Baia, D., . . . Jarnagin, K. (2016). Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes. Journal of Pharmacology and Experimental Therapeutics,358(3), 413-422. doi:10.1124/jpet.116.232819

12- Andoh, T., Yoshida, T., & Kuraishi, Y. (2014). Topical E6005, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch-related responses in mice with chronic atopy-like dermatitis. Experimental Dermatology,23(5), 359-361. doi:10.1111/exd.12377

13- Qi, X. F., Kim, D. H., Yoon, Y. S., Li, J. H., Song, S. B., Jin, D., ... & Lee, K. J. (2009). The adenylyl cyclase-cAMP system suppresses TARC/CCL17 and MDC/CCL22 production through p38 MAPK and NF-κB in HaCaT keratinocytes. Molecular immunology, 46(10), 1925-1934.

14- Rubio, L., Alonso, C., López, O., Rodríguez, G., Coderch, L., Notario, J., ... & Parra, J. L. (2011). Barrier function of intact and impaired skin: percutaneous penetration of caffeine and salicylic acid. International journal of dermatology, 50(7), 881-889.

15- Salpietro, D. C., Naccari, F., Polimeni, I., & Pellegrino, C. (1998). Reduced plasma c-AMP levels in children with atopic dermatitis. Pediatric Allergy and Immunology : Official Publication of the European Society of Pediatric Allergy and Immunology, 9(3), 130-132. doi:10.1111/j.1399-3038.1998.tb00358.x

16- Voorhees, J. J., Duell, E. A., Bass, L. J., Powell, J. A., & Harrell, E. R. (1972). Decreased cyclic AMP in the epidermis of lesions of psoriasis. Archives of Dermatology, 105(5), 695-701.

17- Voorhees, J. J., Stawiski, M., Duell, E. A., Haddox, M. K., & Goldberg, N. D. (1973). Increased cyclic GMP and decreased cyclic AMP levels in the hyperplastic, abnormally differentiated epidermis of psoriasis. Life Sciences,13(6), 639-653. doi:10.1016/0024-3205(73)90281-6

18- Adachi, K., Iizuka, H., Halprin, K. M., & Levine, V. (1980). Epidermal cyclic AMP is not decreased in psoriasis lesions. The Journal of investigative dermatology, 74(2), 74-76.

19- Herlin, T., & Kragballe, K. (1981). Enhanced monocyte and neutrophil cytotoxicity and normal cyclic nucleotide levels in severe psoriasis. British Journal of Dermatology, 105(4), 405-414.

20- Iizuka, H., & Ohkawara, A. (1986). “Ischemic” rise of epidermal cyclic AMP is a beta-adrenergic adenylate cyclase-dependent process. Journal of investigative dermatology, 86(3), 271-274.

21- Hanifin, J. M., Chan, S. C., Cheng, J. B., Tofte, S. J., Henderson, W. R., Kirby, D. S., & Weiner, E. S. (1996). Type 4 Phosphodiesterase Inhibitors Have Clinical and In Vitro Anti-inflammatory Effects in Atopic Dermatitis. Journal of Investigative Dermatology,107(1), 51-56. doi:10.1111/1523-1747.ep12297888

22- Butler, J. M., Chan, S. C., Stevens, S., & Hanifin, J. M. (1983). Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. Journal of Allergy and Clinical Immunology, 71(5), 490-497.

23- Grewe, S. R., Chan, S. C., & Hanifin, J. M. (1982). Elevated leukocyte cyclic AMP—phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP—agonist hyporesponsiveness. Journal of Allergy and Clinical Immunology, 70(6), 452-457.

24- Chan, S. C., Reifsnyder, D., Beavo, J. A., & Hanifin, J. M. (1993). Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. Journal of allergy and clinical immunology, 91(6), 1179-1188.

25- Paller, A. S., Tom, W. L., Lebwohl, M. G., Blumenthal, R. L., Boguniewicz, M., Call, R. S., ... & Spellman, M. C. (2016). Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology, 75(3), 494-503.

26- Ahluwalia, J., Udkoff, J., Waldman, A., Borok, J., & Eichenfield, L. F. (2017). Phosphodiesterase 4 Inhibitor Therapies for Atopic Dermatitis: Progress and Outlook. Drugs. doi:10.1007/s40265-017-0784-3

27- Felding, J., Sørensen, M. D., Poulsen, T. D., Larsen, J., Andersson, C., Refer, P., ... & Hegardt, P. (2014). Discovery and early clinical development of 2-{6-[2-(3, 5-dichloro-4-pyridyl) acetyl]-2, 3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis. Journal of Medicinal Chemistry, 57(14), 5893–5903.

28- Hanifin, J. M., Chan, S. C., Cheng, J. B., Tofte, S. J., Henderson, W. R., Kirby, D. S., & Weiner, E. S. (1996). Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. Journal of Investigative Dermatology, 107(1), 51-56.

29- Samrao, A., Berry, T. M., Goreshi, R., & Simpson, E. L. (2012). A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Archives of dermatology, 148(8), 890-897.

30- Wittmann, M., & Helliwell, P. S. (2013). Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. Dermatology and therapy, 3(1), 1-15.

31- Kaplan, R. J., Daman, L., Shereff, R., Rosenberg, E. W., & Robinson, H. (1976). Treatment of atopic dermatitis with topically applied caffeine. Archives of dermatology, 112(6), 880-881.

32- Kaplan, R. J., Daman, L., Rosenberg, E. W., & Feigenbaum, S. (1977). Treatment of atopic dermatitis with topically applied caffeine—a follow-up report. Archives of dermatology, 113(1), 107-107.

33- Griffiths, C. E. M., Van Leent, E. J. M., Gilbert, M., & Traulsen, J. (2002). Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17‐butyrate cream for the treatment of atopic dermatitis. British Journal of Dermatology, 147(2), 299-307.

34- Menter, A., Ryan, C., & Menter, A. (2017). Psoriasis. Boca Raton, FL: CRC Press, Taylor & Francis Group.

35- Grewal, I. S. (2009). Emerging protein biotherapeutics. Boca Raton: CRC Press.

36- Morris, A., Rogers, M., Fischer, G., & Williams, K. (2001). Childhood psoriasis: a clinical review of 1262 cases. Pediatric dermatology, 18(3), 188-198.

37- Frateschi, S., Camerer, E., Crisante, G., Rieser, S., Membrez, M., Charles, R. P., ... & Rotman, S. (2011). PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. Nature communications, 2, 161.

38- Tsuji, F., Aono, H., Tsuboi, T., Murakami, T., Enomoto, H., Mizutani, K., & Inagaki, N. (2010). Role of leukotriene B4 in 5-lipoxygenase metabolite-and allergy-induced itch-associated responses in mice. Biological and Pharmaceutical Bulletin, 33(6), 1050-1053.

39- Khanna, K. K., & Jackson, S. P. (2001). DNA double-strand breaks: signaling, repair and the cancer connection. Nature genetics, 27(3), 247.

40- Silverberg, J. I., Patel, M., Brody, N., & Jagdeo, J. (2012). Caffeine protects human skin fibroblasts from acute reactive oxygen species-induced necrosis. Journal of drugs in dermatology: JDD, 11(11), 1342-1346.

41- Gaudin, D., & Yielding, K. L. (1969). Response of a “Resistant” Plasmacytoma to Alkylating Agents and X-Ray in Combination with the “Excision Repair Inhibitors Caffeine and Chloroquine∗. Proceedings of the Society for Experimental Biology and Medicine, 131(4), 1413-1416.

42- Rock, K. L., & Kono, H. (2008). The inflammatory response to cell death. Annual Review of Pathology, 3, 99–126. http://doi.org/10.1146/annurev.pathmechdis.3.121806.151456

43- Muralidharan, S., & Mandrekar, P. (2013). Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. Journal of leukocyte biology, 94(6), 1167-1184.

44- Nutten, S. (2015). Atopic dermatitis: global epidemiology and risk factors. Annals of Nutrition and Metabolism, 66(Suppl. 1), 8-16.

45- Lin, X., & Huang, T. (2016). Oxidative stress in psoriasis and potential therapeutic use of antioxidants. Free radical research, 50(6), 585-595.

46- Jagannath, S. S., Manohar, S. D., & Bhanudas, S. R. (2013). Chemical penetration enhancers—a review. World Journal of Pharmacy and Pharamceutical Sciences, 3(2), 1068-80.

47- Hanifin, J. M., & Chan, S. C. (1995). Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. Journal of investigative dermatology, 105(1), S84-S88.

48- Rachakonda, T. D., Schupp, C. W., & Armstrong, A. W. (2014). Psoriasis prevalence among adults in the United States. Journal of the American Academy of Dermatology, 70(3), 512-516.

49- Tenor, H., Hatzelmann, A., Church, M. K., Schudt, C., & Shute, J. K. (1996). Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects. British journal of pharmacology, 118(7), 1727-1735.

50- Levy, J., Zhou, D. M., & Zippin, J. H. (2016). Cyclic Adenosine Monophosphate Signaling in Inflammatory Skin Disease. Journal of Clinical and Experimental Dermatology Reseasrch, 7(326), 2.

51- Serezani, C. H., Ballinger, M. N., Aronoff, D. M., & Peters-Golden, M. (2008). Cyclic AMP: master regulator of innate immune cell function. American journal of respiratory cell and molecular biology, 39(2), 127-132.

52- Hanifin, J. M., & Chan, S. C. (1995). Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. Journal of investigative dermatology, 105(1), S84-S88.

53- Sawai, T., Ikai, K., & Uehara, M. (1995). Elevated cyclic adenosine monophosphate phosphodiesterase activity in peripheral blood mononuclear leucocytes from children with atopic dermatitis. British Journal of Dermatology, 132(1), 22-24.

54- Grewe, S. R., Chan, S. C., & Hanifin, J. M. (1982). Elevated leukocyte cyclic AMP—phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP—agonist hyporesponsiveness. Journal of Allergy and Clinical Immunology, 70(6), 452-457.

55- Samrao, A., Berry, T. M., Goreshi, R., & Simpson, E. L. (2012). A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Archives of dermatology, 148(8), 890-897.

56- Schafer, P. H., Parton, A., Gandhi, A. K., Capone, L., Adams, M., Wu, L., ... & Baillie, G. S. (2010). Apremilast, a cAMP phosphodiesterase‐4 inhibitor, demonstrates anti‐inflammatory activity in vitro and in a model of psoriasis. British journal of pharmacology, 159(4), 842-855.

57- Nazarian, R., & Weinberg, J. M. (2009). AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Current opinion in investigational drugs (London, England: 2000), 10(11), 1236-1242.

58- Rafael, A., & Torres, T. (2016). Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors. European Journal of Dermatology, 26(1), 3-8.

59- Furue, M., Terao, H., Rikihisa, W., Urabe, K., Kinukawa, N., Nose, Y., & Koga, T. (2003). Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis. British Journal of Dermatology, 148(1), 128-133.

60- Kharaeva, Z., Gostova, E., De Luca, C., Raskovic, D., & Korkina, L. (2009). Clinical and biochemical effects of coenzyme Q 10, vitamin E, and selenium supplementation to psoriasis patients. Nutrition, 25(3), 295-302.

61- Kaplan, R. J., Daman, L., Rosenberg, E. W., & Feigenbaum, S. (1978). Topical use of caffeine with hydrocortisone in the treatment of atopic dermatitis. Archives of dermatology, 114(1), 60-62.

62- Vali, A., Asilian, A., Khalesi, E., Khoddami, L., Shahtalebi, M., & Mohammady, M. (2005). Evaluation of the efficacy of topical caffeine in the treatment of psoriasis vulgaris. Journal of dermatological treatment, 16(4), 234-237.

63- Maréchal, A., & Zou, L. (2013). DNA damage sensing by the ATM and ATR kinases. Cold Spring Harbor perspectives in biology, 5(9), a012716.

64- Charrier, J. D., Durrant, S. J., Golec, J. M., Kay, D. P., Knegtel, R. M., MacCormick, S., ... & Rutherford, A. P. (2011). Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. Journal of medicinal chemistry, 54(7), 2320-2330.

65- Pires, I. M., Olcina, M. M., Anbalagan, S., Pollard, J. R., Reaper, P. M., Charlton, P. A., ... & Hammond, E. M. (2012). Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. British journal of cancer, 107(2), 291.

66- Fokas, E., Prevo, R., Pollard, J. R., Reaper, P. M., Charlton, P. A., Cornelissen, B., ... & Muschel, R. J. (2012). Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell death & disease, 3(12), e441.

67- Sarkaria, J. N., Busby, E. C., Tibbetts, R. S., Roos, P., Taya, Y., Karnitz, L. M., & Abraham, R. T. (1999). Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer research, 59(17), 4375-4382.

68- Tibbetts, R. S., Brumbaugh, K. M., Williams, J. M., Sarkaria, J. N., Cliby, W. A., Shieh, S. Y., ... & Abraham, R. T. (1999). A role for ATR in the DNA damage-induced phosphorylation of p53. Genes & development, 13(2), 152-157.

69- Lehmann, A. R. (1972). Effect of caffeine on DNA synthesis in mammalian cells. Biophysical journal, 12(10), 1316-1325.

70- Rauth, A. M. (1967). Evidence for dark-reactivation of ultraviolet light damage in mouse L cells. Radiation research, 31(1), 121-138.

71- Domon, M., & Rauth, A. M. (1969). Ultraviolet-light irradiation of mouse L cells: Effects on cells in the DNA synthesis phase. Radiation research, 40(2), 414-429.

72- M. Domon, B. Barton, A. Porte & A.M. Rauth (1970) The Interaction of Caffeine with Ultra-violet-light-irradiated DNA, International Journal of Radiation Biology and Related Studies in Physics, Chemistry and Medicine, 17:4, 395-399, DOI: 10.1080/09553007014550481

73- Rauth, A. M., Barton, B., & Lee, C. P. Y. (1970). Effects of caffeine on L-cells exposed to mitomycin C. Cancer research, 30(11), 2724-2729.

74- Roberts, J. J., Sturrock, J. E., & Ward, K. N. (1974). The enhancement by caffeine of alkylation-induced cell death, mutations and chromosomal aberrations in Chinese hamster cells, as a result of inhibition of post-replication DNA repair. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 26(2), 129-143.

75- Zajdela, F., & Latarjet, R. (1973). Inhibitory effect of caffeine on the induction of cutaneous cancers by ultraviolet rays in the mouse. Comptes rendus hebdomadaires des séances de l'Académie des sciences. Série D: Sciences naturelles, 277(12), 1073-1076.

76- Abd, E., Roberts, M. S., & Grice, J. E. (2016). A comparison of the penetration and permeation of caffeine into and through human epidermis after application in various vesicle formulations. Skin pharmacology and physiology, 29(1), 24-30.

77- Abel, E. L., Hendrix, S. O., McNeeley, S. G., Johnson, K. C., Rosenberg, C. A., Mossavar-Rahmani, Y., ... & Kruger, M. (2007). Daily coffee consumption and prevalence of nonmelanoma skin cancer in Caucasian women. European Journal of Cancer Prevention, 16(5), 446-452.

78- Song, F., Qureshi, A. A., & Han, J. (2012). Increased caffeine intake is associated with reduced risk of basal cell carcinoma of the skin. Cancer research, 72(13), 3282-3289.

79- Loftfield, E., Freedman, N. D., Graubard, B. I., Hollenbeck, A. R., Shebl, F. M., Mayne, S. T., & Sinha, R. (2015). Coffee drinking and cutaneous melanoma risk in the NIH-AARP diet and health study. Journal of the National Cancer Institute, 107(2), dju421.

80- Chu, Y. F., Chen, Y., Brown, P. H., Lyle, B. J., Black, R. M., Cheng, I. H., ... & Prior, R. L. (2012). Bioactivities of crude caffeine: Antioxidant activity, cyclooxygenase-2 inhibition, and enhanced glucose uptake. Food Chemistry, 131(2), 564-568.

81- Devasagayam, T. P. A., Kamat, J. P., Mohan, H., & Kesavan, P. C. (1996). Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1282(1), 63-70.

82- Shi, X., Dalal, N. S., & Jain, A. C. (1991). Antioxidant behaviour of caffeine: efficient scavenging of hydroxyl radicals. Food and chemical toxicology, 29(1), 1-6.

83- Lee, C. (2000). Antioxidant ability of caffeine and its metabolites based on the study of oxygen radical absorbing capacity and inhibition of LDL peroxidation. Clinica Chimica Acta, 295(1), 141-154.

84- Scurachio, R. S., Mattiucci, F., Santos, W. G., Skibsted, L. H., & Cardoso, D. R. (2016). Caffeine metabolites not caffeine protect against riboflavin photosensitized oxidative damage related to skin and eye health. Journal of Photochemistry and Photobiology B: Biology, 163, 277-283.

85- Berthou, F. R. A. N. C. O. I. S., Flinois, J. P., Ratanasavanh, D., Beaune, P. H. I. L. L. I. P. E., Riche, C. H. R. I. S. T. I. A. N., & Guillouzo, A. N. D. R. E. (1991). Evidence for the involvement of several cytochromes P-450 in the first steps of caffeine metabolism by human liver microsomes. Drug metabolism and disposition, 19(3), 561-567.

86- Tsukahara, H., Shibata, R., Ohshima, Y., Todoroki, Y., Sato, S., Ohta, N., ... & Mayumi, M. (2003). Oxidative stress and altered antioxidant defenses in children with acute exacerbation of atopic dermatitis. Life sciences, 72(22), 2509-2516.

87- Ji, H., & Li, X. (2016). Oxidative stress in atopic dermatitis. Oxidative Medicine and Cellular Longevity, 2016, 1-8. doi:10.1155/2016/2721469

88- Zhou, Q., Mrowietz, U., & Rostami-Yazdi, M. (2009). Oxidative stress in the pathogenesis of psoriasis. Free Radical Biology and Medicine, 47(7), 891-905.

89- Gabr, S. A., & Al-Ghadir, A. H. (2012). Role of cellular oxidative stress and cytochrome c in the pathogenesis of psoriasis. Archives of dermatological research, 304(6), 451-457.

90- Yildirim, M., Inaloz, H. S., Baysal, V., & Delibas, N. (2003). The role of oxidants and antioxidants in psoriasis. Journal of the European Academy of Dermatology and Venereology, 17(1), 34-36.

91- Api, H., & Atik, U. (2003). Oxidant/antioxidant status in patients with psoriasis. Yonsei medical journal, 44(6), 987-990.

92- Dina Coronado, B. S., & Zane, L. T. (2016). Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis. J Drugs Dermatol, 15(4), 390-396.