Two
selective phosphodiesterase-4 (PDE4) inhibitors—viz., crisaborole (Eucrisa®,
Pfizer) and apremilast (Otezla®, Celgene)—have recently received approval by the United
States Food and Drug Administration for the treatment of related but different
dermatologic skin conditions (viz., atopic dermatitis and plaque psoriasis,
respectively). The purpose of this review is to summarize the underlying
biochemistry and pathophysiology associated with these dermatologic conditions,
review the chemistry, pharmacology and safety of each of these products, and
present preclinical and clinical evidence that may help explain why these two
PDE4 inhibitors offer new treatment options for these skin conditions.
References
[1]
Liu, Y., Wu, E.Q., Bensimon, A.G., et al. (2012) Cost per Responder Associated with Biologic Therapies for Crohn’s Disease, Psoriasis, and Rheumatoid Arthritis. Advances in Therapy, 29, 620-634. https://doi.org/10.1007/s12325-012-0035-7
[2]
Pfizer (2017) Eucrisa Prescribing Information.
[3]
Celgene (2017) Otezla Prescribing Information.
[4]
Rall, T.W. and Sutherland, E.W. (1958) Formation of a Cyclic Adenine Ribonucleotide by Tissue Particles. Journal of Biological Chemistry, 232, 1065-1076.
[5]
Butcher, R.W. and Sutherland, E.W. (1962) Adenosine 3',5'-Phosphate in Biological Materials. I. Purification and Properties of Cyclic 3',5'-Nucleotide Phosphodiesterase and Use of This Enzyme to Characterize Adenosine 3',5'-Phosphate in Human Urine. Journal of Biological Chemistry, 237, 1244-1250.
[6]
Sutherland, E.W. and Rall, T.W. (1958) Fractionation and Characterization of a Cyclic Adenine Ribonucleotide Formed by Tissue Particles. Journal of Biological Chemistry, 232, 1077-1091.
[7]
Bender, A.T. and Beavo, J.A. (2006) Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use. Pharmacological Reviews, 58, 488-520.
https://doi.org/10.1124/pr.58.3.5
[8]
Moustafa, F. and Feldman, S.R. (2014) A Review of Phosphodiesterase-Inhibition and the Potential Role for Phosphodiesterase 4-Inhibitors in Clinical Dermatology. Dermatology Online Journal, 20, 1-10.
[9]
Beavo, J.A. (1995) Cyclic Nucleotide Phosphodiesterases: Functional Implications of Multiple Isoforms. Physiological Reviews, 75, 725-748.
https://doi.org/10.1152/physrev.1995.75.4.725
[10]
Fertig, B.A. and Baillie, G.S. (2018) PDE4-Mediated cAMP Signalling. Journal of Cardiovascular Development and Disease, 5, E8.
[11]
Dong, C., Virtucio, C., Zemska, O., et al. (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, 413-422.
https://doi.org/10.1124/jpet.116.232819
[12]
Fischmeister, R., Castro, L.R., Abi-Gerges, A., et al. (2006) Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases. Circulation Research, 99, 816-828.
https://doi.org/10.1161/01.RES.0000246118.98832.04
[13]
Zhao, C.Y., Greenstein, J.L. and Winslow. R.L. (2015) Interaction between Phosphodiesterases in the Regulation of the Cardiac Beta-Adrenergic Pathway. Journal of Molecular and Cellular Cardiology, 88, 29-38.
https://doi.org/10.1016/j.yjmcc.2015.09.011
[14]
Serezani, C.H., Ballinger, M.N., Aronoff, D.M. and Peters-Golden, M. (2008) Cyclic AMP: Master Regulator of Innate Immune Cell Function. American Journal of Respiratory Cell and Molecular Biology, 39, 127-132.
https://doi.org/10.1165/rcmb.2008-0091TR
[15]
Dessauer, C.W., Watts, V.J., Ostrom, R.S., Conti, M., Dove, S. and Seifert, R. (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. Pharmacological Reviews, 69, 93-139. https://doi.org/10.1124/pr.116.013078
[16]
Levy, J., Zhou, D. and Zippin, J. (2016) Cyclic Adenosine Monophosphate Signaling in Inflammatory Skin Disease. Journal of Clinical & Experimental Dermatology Research, 7, 326.
[17]
Slominski, A., Zbytek, B., Zmijewski, M., et al. (2006) Corticotropin Releasing Hormone and the Skin. Frontiers in Bioscience, 11, 2230-2248.
https://doi.org/10.2741/1966
[18]
Teng, M.W., Bowman, E.P., McElwee, J.J., et al. (2015) IL-12 and IL-23 Cytokines: from Discovery to Targeted Therapies for Immune-Mediated Inflammatory Diseases. Nature Medicine, 21, 719-729. https://doi.org/10.1038/nm.3895
[19]
Grewe, M., Bruijnzeel-Koomen, C.A., Schopf, E., et al. (1998) A Role for Th1 and Th2 Cells in the Immunopathogenesis of Atopic Dermatitis. Immunology Today, 19, 359-361. https://doi.org/10.1016/S0167-5699(98)01285-7
[20]
Eichenfield, L., Tom, W., Chamlin, S.L., Feldman, S.R., Hanifin, J.M., Simpson, E.L. et al. (2014) Guidelines of Care for the Management of Atopic Dermatitis: Section 1. Diagnosis and Assessment of Atopic Dermatitis. Journal of the American Academy of Dermatology, 70, 338-351. https://doi.org/10.1016/j.jaad.2013.10.010
[21]
Hanifin, J.M., Lloyd, R., Okubo, K., Guerin, L.L., Fancher, L. and Chan, S.C. (1992) Relationship between Increased Cyclic AMP-Phosphodiesterase Activity and Abnormal Adenylyl Cyclase Regulation in Leukocytes from Patients with Atopic Dermatitis. Journal of Investigative Dermatology, 98, 100S-105S.
https://doi.org/10.1111/1523-1747.ep12462340
[22]
Salpietro, D.C., Naccari, F., Polimeni, I. and Pellegrino, C. (1998) Reduced Plasma c-AMP Levels in Children with Atopic Dermatitis. Pediatric Allergy and Immunology, 9, 130-132. https://doi.org/10.1111/j.1399-3038.1998.tb00358.x
[23]
Anon (2018) Atopic Dermatitis. Vol. 2018, National Institutes of Health, Bethesda.
[24]
Griffiths, C.E.M., van de Kerkof, P. and Czarnecka-Operacz, M. (2017) Psoriasis and Atopic Dermatitis. Dermatologic Therapy, 7, S31-S41.
https://doi.org/10.1007/s13555-016-0167-9
[25]
Kim, B.E. and Leung. D.Y.M. (2018) Significance of Skin Barrier Dysfunction in Atopic Dermatitis. Allergy, Asthma & Immunology Research, 10, 207-215.
https://doi.org/10.4168/aair.2018.10.3.207
[26]
Kim, B.S. (2017) Atopic Dermatitis.
https://emedicine.medscape.com/article/1049085-overview
[27]
Piliang, M. (2009) Atopic Dermatitis. Vol. 2018, Cleveland Clinic, Cleveland.
[28]
Leung, D.Y. and Guttman-Yassky, E. (2014) Deciphering the Complexities of Atopic Dermatitis: Shifting Paradigms in Treatment Approaches. Journal of Allergy and Clinical Immunology, 134, 769-779. https://doi.org/10.1016/j.jaci.2014.08.008
[29]
Buys, L.M. (2007) Treatment Options for Atopic Dermatitis. American Family Physician, 75, 523-528.
[30]
Ference, J.D. and Last, A.R. (2009) Choosing Topical Corticosteroids. American Family Physician, 79, 135-140.
[31]
Ashcroft, D.M., Dimmock, P., Garside, R., Stein, K. and Williams, H.C. (2005) Efficacy and Tolerability of Topical Pimecrolimus and Tacrolimus in the Treatment of Atopic Dermatitis: Meta-Analysis of Randomised Controlled Trials. BMJ, 330, 516.
https://doi.org/10.1136/bmj.38376.439653.D3
[32]
Del Rosso, J.Q. and Plattner, J.J. (2014) From the Test Tube to the Treatment Room: Fundamentals of Boron-Containing Compounds and their Relevance to Dermatology. Journal of Clinical and Aesthetic Dermatology, 7, 13-21.
[33]
Hanifin, J.M., Chan, S.C., Cheng, J.B., et al. (1996) Type 4 Phosphodiesterase Inhibitors Have Clinical and in Vitro Anti-Inflammatory Effects in Atopic Dermatitis. Journal of Investigative Dermatology, 107, 51-56.
https://doi.org/10.1111/1523-1747.ep12297888
[34]
Paller, A.S., Tom, W.L., Lebwohl, M.G., et al. (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, 494-503.
https://doi.org/10.1016/j.jaad.2016.05.046
[35]
Butler, J.M., Chan, S.C., Stevens, S. and Hanifin, J.M. (1983) Increased Leukocyte Histamine Release with Elevated Cyclic AMP-Phosphodiesterase Activity in Atopic Dermatitis. Journal of Allergy and Clinical Immunology, 71, 490-497.
https://doi.org/10.1016/0091-6749(83)90467-0
[36]
Gladman, D.D. (2015) Clinical Features and Diagnostic Considerations in Psoriatic Arthritis. Rheumatic Diseases Clinics of North America, 41, 569-579.
https://doi.org/10.1016/j.rdc.2015.07.003
[37]
Foundation, N.P. (2018) About Psoriasis. https://www.psoriasis.org/about-psoriasis
[38]
WebMD (2018) The Signs and Symptoms of Psoriasis.
https://www.webmd.com/skin-problems-and-treatments/psoriasis/psoriasis-signs-symptoms
[39]
Dalgard, F.J., Gieler, U., Tomas-Aragones, L., et al. (2015) The Psychological Burden of Skin Diseases: A Cross-Sectional Multicenter Study among Dermatological Out-Patients in 13 European Countries. Journal of Investigative Dermatology, 135, 984-991. https://doi.org/10.1038/jid.2014.530
[40]
Yeung, H., Takeshita, J., Mehta, N.N., et al. (2013) Psoriasis Severity and the Prevalence of Major Medical Comorbidity: A Population-Based Study. JAMA Dermatology, 149, 1173-1179. https://doi.org/10.1001/jamadermatol.2013.5015
[41]
Ahlehoff, O., Gislason, G.H., Charlot, M., et al. (2011) Psoriasis Is Associated with Clinically Significant Cardiovascular Risk: A Danish Nationwide Cohort Study. Journal of Internal Medicine, 270, 147-157.
https://doi.org/10.1111/j.1365-2796.2010.02310.x
[42]
Gelfand, J.M., Neimann, A.L., Shin, D.B., Wang, X., Margolis, D.J. and Troxel, A.B. (2006) Risk of Myocardial Infarction in Patients with Psoriasis. JAMA, 296, 1735-1741. https://doi.org/10.1001/jama.296.14.1735
[43]
Parisi, R., Symmons, D.P., Griffiths, C.E., et al. (2013) Global Epidemiology of Psoriasis: A Systematic Review of Incidence and Prevalence. Journal of Investigative Dermatology, 133, 377-385. https://doi.org/10.1038/jid.2012.339
[44]
Rachakonda, T.D., Schupp, C.W. and Armstrong, A.W. (2014) Psoriasis Prevalence among Adults in the United States. Journal of the American Academy of Dermatology, 70, 512-516. https://doi.org/10.1016/j.jaad.2013.11.013
[45]
Rahman, P. and Elder, J.T. (2005) Genetic Epidemiology of Psoriasis and Psoriatic Arthritis. Annals of the Rheumatic Diseases, 64, ii37-ii39.
https://doi.org/10.1136/ard.2004.030775
[46]
Lonnberg, A.S., Skov, L., Skytthe, A., Kyvik, K.O., Pedersen, O.B. and Thomsen, S.F. (2013) Heritability of Psoriasis in a Large Twin Sample. British Journal of Dermatology, 169, 412-416. https://doi.org/10.1111/bjd.12375
[47]
Lonnberg, A.S., Skov, L., Duffy, D.L., et al. (2016) Genetic Factors Explain Variation in the Age at Onset of Psoriasis: A Population-Based Twin Study. Acta Dermato-Venereologica, 96, 35-38. https://doi.org/10.2340/00015555-2171
Li, J. and Yu, P. (2018) Genome-Wide Transcriptome Analysis Identifies Alternative Splicing Regulatory Network and Key Splicing Factors in Mouse and Human psoriasis. Scientific Reports, 8, Article No. 4124.
https://doi.org/10.1038/s41598-018-22284-y
[50]
Lui, H. (2018) Plaque Psoriasis.
https://emedicine.medscape.com/article/1108072-overview
[51]
Gladman, D.D. and Rosen, C.T. (2008) Psoriatic Arthritis. Oxford University Press, Oxford.
[52]
Clinic, M. Psoriatic Arthritis.
https://www.mayoclinic.org/diseases-conditions/psoriatic-arthritis/symptoms-causes/syc-20354076
[53]
Gladman, D.D., Antoni, C., Mease, P., Clegg, D.O. and Nash, P. (2005) Psoriatic Arthritis: Epidemiology, Clinical Features, Course, and Outcome. Annals of the Rheumatic Diseases, 64, ii14-ii17. https://doi.org/10.1136/ard.2004.032482
[54]
Moll, J.M. and Wright, V. (1973) Familial Occurrence of Psoriatic Arthritis. Annals of the Rheumatic Diseases, 32, 181-201. https://doi.org/10.1136/ard.32.3.181
[55]
Myers, A., Kay, L.J., Lynch, S.A. and Walker, D.J. (2005) Recurrence Risk for Psoriasis and Psoriatic Arthritis within Sibships. Rheumatology, 44, 773-776.
https://doi.org/10.1093/rheumatology/keh589
[56]
Chandran, V., Schentag, C.T., Brockbank, J.E., et al. (2009) Familial Aggregation of Psoriatic Arthritis. Annals of the Rheumatic Diseases, 68, 664-667.
https://doi.org/10.1136/ard.2008.089367
[57]
Karason, A., Love, T.J. and Gudbjornsson, B. (2009) A Strong Heritability of Psoriatic Arthritis over Four Generations—The Reykjavik Psoriatic Arthritis Study. Rheumatology, 48, 1424-1428. https://doi.org/10.1093/rheumatology/kep243
[58]
Haroon, M., Gallagher, P. and FitzGerald, O. (2015) Diagnostic Delay of More Than 6 Months Contributes to Poor Radiographic and Functional Outcome in Psoriatic Arthritis. Annals of the Rheumatic Diseases, 74, 1045-1050.
https://doi.org/10.1136/annrheumdis-2013-204858
[59]
Pfizer (2017) AN2728 Topical Ointment to Treat Mild-to-Moderate Plaque-Type Psoriasis (NCT01300052). Vol. 2018, ClinTrials.gov, Phase 2 Clinical Trial, A Multicenter, Randomized, Double-Blind, 12-Week Study of the Safety and Efficacy of AN2728 versus AN2728 Vehicle in the Treatment of Patients with Mild-to-Moderate Plaque-Type Psoriasis.
[60]
Zane, L.T., Chanda, S., Jarnagin, K., Nelson, D.B., Spelman, L. and Gold, L.S. (2016) Crisaborole and Its Potential Role in Treating Atopic Dermatitis: Overview of Early Clinical Studies. Immunotherapy, 8, 853-866.
https://doi.org/10.2217/imt-2016-0023
[61]
Shepherd, M.C., Baillie, G.S., Stirling, D.I. and Houslay, M.D. (2004) Remodelling of the PDE4 cAMP Phosphodiesterase Isoform Profile upon Monocyte-Macrophage Differentiation of Human U937 Cells. British Journal of Pharmacology, 142, 339-351. https://doi.org/10.1038/sj.bjp.0705770
[62]
Schafer, P.H., Parton, A., Gandhi, A.K., et al. (2010) Apremilast, a cAMP Phosphodiesterase-4 Inhibitor, Demonstrates Anti-Inflammatory Activity in Vitro and in a Model of Psoriasis. British Journal of Pharmacology, 159, 842-855.
https://doi.org/10.1111/j.1476-5381.2009.00559.x
[63]
Siebert, S., Tsoukas, A., Robertson, J. and McInnes, I. (2015) Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases. Pharmacological Reviews, 67, 280-309. https://doi.org/10.1124/pr.114.009639
[64]
Hoffmann, M., Kumar, G., Schafer, P., et al. (2011) Disposition, Metabolism and Mass Balance of Apremilast Following Oral Administration. Xenobiotica, 41, 1063-1075. https://doi.org/10.3109/00498254.2011.604745
[65]
Chaplin, S. (2013) Apremilast for the Treatment of Psoriasis and Psoriatic Arthritis. Future Prescriber, 14, 8-9. https://doi.org/10.1002/fps.102
[66]
Crowley, J., Thaci, D., Joly, P., et al. (2017) Long-Term Safety and Tolerability of Apremilast in Patients with Psoriasis: Pooled Safety Analysis for >/=156 Weeks from 2 Phase 3, Randomized, Controlled Trials (ESTEEM 1 and 2). Journal of the American Academy of Dermatology, 77, 310-317.
https://doi.org/10.1016/j.jaad.2017.01.052
[67]
Elyoussfi, S., Thomas, B.J. and Ciurtin, C. (2016) Tailored Treatment Options for Patients with Psoriatic Arthritis and Psoriasis: Review of Established and New Biologic and Small Molecule Therapies. Rheumatology International, 36, 603-612.
https://doi.org/10.1007/s00296-016-3436-0