Results of Combining Phosphorylase Kinase Inhibition with Removal of Precipitating Factors in Large Cohort of Psoriatic Patients: A Proof of Concept Study
Madalene C. Y. Heng, Judith Harker, Ming K. Heng
DOI: 10.4236/jcdsa.2011.13013   PDF    HTML     7,064 Downloads   13,302 Views   Citations


Background: Phosphorylase kinase (PhK) activity is induced by injurious stimuli, which is known to precipitate psoriasis. We had previously reported that elevated PhK activity in psoriatic epidermis correlated with increased psoriatic activity, and that suppression of PhK activity by its inhibitor, curcumin gel, correlated with disease resolution. Objective: We evaluated the efficacy of a strategy of combining PhK inhibition by topical curcumin with elimination of PhK-generating precipitating factors from various injurious stimuli in producing improvement of psoriatic activity, aiming at complete resolution. Patients and Methods: We studied a cohort of 647 consecutive patients with mild to severe psoriasis in a single center. Our therapeutic regimen consisted of curcumin gel, topical steroids, strict avoidance of contact allergens, avoidance of dairy products in lactose-intolerant patients, and treatment of infections to eliminate bacterial superantigens. Results: PASI scores at 0 wk was 24.7 +/– 17.1 (SD), n = 647. PASI scores improved significantly at 4 weeks to 11.5 +/– 8.1 (n = 638; p < 0.0001), at 8 weeks to 4.5 +/– 4.2 (n = 636, p < 0.0001), and at 16 weeks to 0.9 +/– 2.5 (n = 641, p < 0.0001). At 16 weeks, 72.2% of patients were completely clear of psoriatic activity (PASI = 0). Conclusion: Our results indicate that a regimen of PhK inhibition by topical curcumin with elimination of PhK-generating factors is effective in producing significant reduction of psoriatic activity at 16 weeks, with complete clearance of psoriasis in 72.2% of patients.

Share and Cite:

M. Heng, J. Harker and M. Heng, "Results of Combining Phosphorylase Kinase Inhibition with Removal of Precipitating Factors in Large Cohort of Psoriatic Patients: A Proof of Concept Study," Journal of Cosmetics, Dermatological Sciences and Applications, Vol. 1 No. 3, 2011, pp. 79-94. doi: 10.4236/jcdsa.2011.13013.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] E. J. Van Scott and T. M. Ekel, “Kinetics of Hyperplasia in Psoriasis,” Archives of Dermatology, Vol. 88, No. 4, 1963, pp. 373-381.
[2] S. Gelfant, “The Cell Cycle in Psoriasis: A Reappraisal,” British Journal of Dermatology, Vol. 95, No. 6, 1976, pp. 577-579. doi:10.1111/j.1365-2133.1976.tb07028.x
[3] J. G. Krueger, P. Berstresser, J. L. Nicholas and J. J. Voorhees, “Psoriasis,” Journal of the American Academy of Dermatology, Vol. 11, No. 5, 1994, pp. 937-947. doi:10.1016/S0190-9622(84)80018-3
[4] B. S. Baker, A. E. Swain, L. Fry and H. Valdimarsson, “Epidermal T Lymphocytes and HLA-DR Expression in Psoriasis,” British Journal of Dermatology, Vol. 110, No. 5, 1984, pp. 555-564. doi:10.1111/j.1365-2133.1984.tb04678.x
[5] B. S. Baker and L. Fry, “The Immunology of Psoriasis,” British Journal of Dermatology, Vol. 126, No. 1, 1992, pp. 1-9. doi:10.1111/j.1365-2133.1992.tb08394.x
[6] J. Tomfohrde J. A. Silverman A, B. Barnes, M. A. Fernandez-Vina, M. Young, D. Lori, L. Morris, et al., “Gene for Familial Psoriasis Susceptibility Mapped to the Distal end of Human Chromosome 17q,” Science, Vol. 264, No. 5162, 1994, pp. 1141-1145. doi:10.1126/science.8178173
[7] R. P. Nair, T. Henseler, S. Jenisch, P. Stuart, C. K. Bichakjian, W. Lenk, et al., “Evidence for Two Psoriasis Susceptibility Loci (HLA and 17q) and Two Novel Candidate Regions (16q and 20p) by Genome-Wide Scan,” Human Molecular Genetics, Vol. 6, No. 5, 1997, pp. 813-820.
[8] A. Karason, J. E. Gudjonsson, R. Upmanyu, A. A. Antonsdottir, V. B. Hauksson, E. H. Runasdottir, et al., “A Susceptibility Gene for Psoriatic Arthritis Maps to Chromosome 16q: Evidence for Imprinting,” The American Journal of Human Genetics, Vol. 72, No. 1, 2003, pp. 125-131. doi:10.1086/345646
[9] International Psoriasis Genetics Consortium, “The International Psoriasis Genetics Study: Assessing Linkage to 14 Candidate Susceptibility Loci in a Cohort of 742 Affected Sib Pairs,” The American Journal of Human Genetics, Vol. 73, No. 2, 2003, pp. 430-437. doi:10.1086/377159
[10] R. C. Trembath, R. L. Clough, J. L. Rosbotham, A. B. Jones, R. D. Camp, A. Frodsham, et al., “Identification of a Major Susceptibility Locus on Chromosome 6p and Evidence for Further Disease Loci Revealed by a Two Stage Genome-Wide Search in Psoriasis,” Human Molecular Genetics, Vol. 6, No. 5, 1997, pp. 813-820. doi:10.1093/hmg/6.5.813
[11] R. P. Nair, K. C. Duffin, C. Helms, J. Ding, P. E. Stuart, D. Golgar, et al., “Genome-Wide Scan Reveals Association of Psoriasis with IL-23 and NF-KappaB Pathways,” Nature Genetics, Vol. 41, No. 2, 2009, pp.199-204. doi:10.1038/ng.311
[12] M. C. Heng, S. G. Kloss and D. G. Chase, “Erythroderma Associated with Mixed Lymphocyte-Endothelial Cell Interaction and Staphylococcus aureus Infection,” British Journal of Dermatology, Vol. 115, No. 6, 1986, pp. 693-705. doi:10.1111/j.1365-2133.1986.tb06650.x
[13] B. J. Nikoloff, M. S. Mitra, J. Green, Y. Shimizu, C. Thompson and L. A. Turka, “Activated Keratinocytes Present Bacterial-Derived Superantigens to T Lymphocytes: Relevance to Psoriasis,” Journal of Dermatological Science, Vol. 6, No. 2, 1993, pp. 127-133. doi:10.1016/0923-1811(93)90002-7
[14] H. Sigmundsdottir, B. Sigurgeirsson, M. Troye-Blomberg, M. F. Good, H. Valdemarsson and I. Jonsdottir, “Circulating T Lymphocytes of Patients with Active Psoriasis Respond to Streptococcal M Peptides Sharing Sequences with Human Epidermal Keratins,” Scandinavian Journal of Immunology, Vol. 45, No. 6, 1997, pp. 688-697. doi:10.1046/j.1365-3083.1997.d01-438.x
[15] J. E. Gudjonsson, A. M. Thorainsson, B. Sigurgeirsson, K. G. Kristinsson and H. Valdimarsson, “Streptococcal Throat Infections and Exacerbation of Chronic Plaque Psoriasis: A Prospective Study,” British Journal of Dermatology, Vol. 149, No. 3, 2004, pp. 530-534. doi:10.1046/j.1365-2133.2003.05552.x
[16] D. D. Balci, N. Duran, B. Ozer, R. Gunesacar, Y. Onlen and J. Z. Yennin, “High Prevalence of Staphylococcus aureus Cultivation and Superantigen Production in Patients with Psoriasis,” European Journal of Dermatology, Vol. 19, No. 3, 2009, pp. 238-242.
[17] M. C. Heng, S. G. Kloss, C. S. Kuehn and D. G. Chase, “The Sequence of Events in Psoriatic Plaque Formation after Tape-Stripping,” British Journal of Dermatology, Vol. 112, No. , 1985, pp. 517-532.
[18] N. Hatta N, M. Takata, S. Kawara, T. Hirone and K. Takehara, “Tape-Stripping Induces Marked Epidermal Proliferation and Altered TGF-Alpha Expression in Non-lesional Psoriatic Skin,” Journal of Dermatological Science, Vol. 14, No. 2, pp. 154-161.
[19] M. C. Heng, S. G. Allen, G. Haberfelde and M. K. Song, “Electron Microscopic and Immunocytochemical Study of the Sequence of Events in Psoriatic Plaque Formation after Tape-Stripping,” British Journal of Dermatology, Vol. 125, No. 6, 1991, pp. 517-532. doi:10.1111/j.1365-2133.1991.tb14792.x
[20] E. Ferezli, L Jenbazian, N. Rubeiz, A. G. Kibbi, S. Zaynoun and A. M. Abdeinoor, “Streptococcus sp. and Staphylococcus aureus Isolates from Patients with Psoriasis Possess Genes that Code for Toxins (Superantigens): Clinical and Therapeutic Implications,” Immunopharmacology and Immunotoxicology, Vol. 30, No. 2, 2008, pp. 195-205. doi:10.1080/08923970801946808
[21] M. R. Kell, E. G. Kavanaugh, A. Goebel, C. C. Soberg and J. A. Lederer, “Injury Primes the Immune System for an Enhanced and Lethal T Cell Response against Bacterial Superantigen,” Shock, Vol. 12, No. 2, 1999, pp. 139-144.
[22] S. Sriskandan, L. Faulkner and P. Hopkins, “Streptococcus Pyogenes: Insight into the Function of the Streptococcal Superantigens,” The International Journal of Biochemistry & Cell Biology, Vol. 39, No. 1, 2007, pp. 12-19. doi:10.1016/j.biocel.2006.08.009
[23] T. Proft and J. D. Fraser, “Streptococcal Superantigens,” Chemical Immunology and Allergy, Vol. 93, 2007, pp. 1-23. doi:10.1159/000100851
[24] C. Bueno, G. Criado, J. K. McCormick and J. Madrenas, “T Cell Signaling Induced by Bacterial Superantigens,” Chemical Immunology and Allergy, Vol. 93, 2007, pp. 161-180. doi:10.1159/000100894
[25] J. E. Alouf and H. Muller-Alouf, “Staphylococcal and Streptococcal Superantigens: Molecular, Biological and Clinical Aspects,” International Journal of Medical Microbiology, Vol. 292, No. 7-8, 2003, pp. 429-440. doi:10.1078/1438-4221-00232
[26] F. W. Leung, M. C. Heng, S. Allen, K. Seno, J. W. Leung and M. K. Heng, “Involvement of Luminal Bacteria, Heat Shock Protein 60, Macrophages and γδ T Cells in Dextran Sulfate Sodium-Induced Colitis in Rats,” Digestive Diseases and Sciences, Vol. 45, No. 7, 2000, pp 1472-1479. doi:10.1023/A:1005545128954
[27] C. J. Yuan, C. Y. Huang and D. J. Graves, “PhK: A Metal Ion-Dependent Dual Specificity Kinase,” The Journal of Biological Chemistry, Vol. 268, No. 24, 1993, pp. 17683-17686.
[28] D. Graves, C. Bartleson, A. Biorn and Pete M, “Substrate and Inhibitor Recognition of Protein Kinases: What Is Known about the Catalytic Subunit of Phosphorylase Kinase?” Pharmacology & Therapeutics, Vol. 82, No. 2-3, 1999, pp. 43-155.
[29] M. C. Heng, M. K. Song and M. K. Heng, “Elevated Phosphorylase Kinase Activity in Psoriatic Epidermis: Correlation with Phosphorylation and Psoriatic Activity,” British Journal of Dermatology, Vol. 130, No. 3, 1994, pp. 298-306. doi:10.1111/j.1365-2133.1994.tb02924.x
[30] M. C. Heng, M. K. Song, J. Harker and M. K. Heng, “Drug Induced Suppression of Phosphorylase Kinase Activity Correlates with Resolution of Psoriasis as Assessed by Clinical, Histological and Immunohistochemical Parameters,” British Journal of Dermatology, Vol. 143, No. 5, 2000, pp. 937-949. doi:10.1046/j.1365-2133.2000.03767.x
[31] S. Reddy and B. B Aggarwal, “Curcumin Is a Non-competitive and Selective Inhibitor of PhK,” FEBS Letters, Vol. 341, No. 1, 1994, pp. 19-22. doi:10.1016/0014-5793(94)80232-7
[32] P. Scheunch, B. Thoma, U. Ucer and K. Pfizenmaier, “Immunoregulatory Activity of Recombinant Human Tumor Necrosis Factor (TNF)-Alpha: Induction of TNF Receptors on Human T Cells and TNF-Alpha-Mediated Enhancement of T Cell Responses,” The Journal of Immunology, Vol. 138, No. 6, 1987, pp. 1786-1790.
[33] S. Singh and B. B. Aggarwal, “Activation of Transcription Factor NF-Kappa B is Suppressed by Curcumin (Diferuloylmethane),” The Journal of Biological Chemistry, Vol. 270, No. 42, 1995, pp. 24995-25000. doi:10.1074/jbc.270.42.24995
[34] S. Aggarwal, H. Ichikawa, Y. Takada, S. K. Sandur, S. Shishodia and B. B. Aggarwal, “Curcumin (Diferuloylmethane) Downregulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of IkappaBalpha Kinase and Akt Activation,” Molecular Pharmacology, Vol. 69, No. 1, 2006, pp. 195-206.
[35] S. Tournier, F. P. Gerbaud, W. B. Anderson, S. M. Lohmann, D. Evain-Brion and F. Raynaud, “Post-Translational Abnormality of the Type II Cyclic AMP-Dependent Protein Kinase in Psoriasis: Modulation by Retinoic Acid,” Journal of Cellular Biochemistry, Vol. 57, No. 4, 1995, pp. 647-654. doi:10.1002/jcb.240570409
[36] S. Tournier, F. Raynaud, P. Gerbaud, S. M. Lohmann, W. B. Anderson and D. Evain-Bion, “Retinoylation of the Type II Cyclic AMP-Binding Cyclic AMP-Dependent Protein Kinase is Increased in Psoriatic Human Fibroblasts,” Journal of Cellular Physiology, Vol. 167, No. 2, 1996, pp. 196-203.
[37] Y. S. Cho-Chung and T. Clair, “The Regulatory Subunit of cAMP-Dependent Protein Kinase as a Target for Chemotherapy of Cancer and Other Cellular Dysfunctional-Related Diseases,” Pharmacology & Therapeutics, Vol. 60, No. 2, 1993, pp. 265-288. doi:10.1016/0163-7258(93)90010-B
[38] G. Sozzi, I. Bongarzone, M. Miozzo, M. G. Borrello, M. G. Blutti, S. Pilotti, et al., “A t(10:17) Translocation Creates the RET/PTC2 Chimeric Transforming Sequence in Papillary Thyroid Carcinoma,” Genes, Chromosomes and Cancer, Vol. 9, No. 4, 1994, pp. 244-250. doi:10.1002/gcc.2870090404
[39] U. Francke, B. T. Darras, N. F. Zander and M. W. Kilimann, “Assignment of Human Genes for Phosphorylase Kinase Subunits Alpha (PHKA) to Xq12-q13 and Beta (PHKB) to 16q12-q13,” The American Journal of Human Genetics, Vol. 45, No. 2, 1989, pp. 276-282.
[40] R. J. North and E. A. Havell, “Glucocorticoid-Mediated Inhibition of Endotoxin-Induced Intratumor Tumour Necrosis Factor Production and Tumour Hemorrhagic Necrosis and Regression,” The Journal of Experimental Medicine, Vol. 170, No. 3, 1989, pp. 703-710.
[41] M. Tsujimoto and H. Adachi, “Effects of Steroid Hormones on the Cytotoxic Activity of Tumor Necrosis Factor,” The Journal of Biochemistry, Vol. 103, No. 3, 1988, pp. 395-405.
[42] M. C. Heng, M. Khoo, A. Cooperman and S. Fallon-Friedlander, “Hemorrhagic Cellulitis: A Syndrome Associated with Tumour Necrosis Factor-α,” British Journal of Dermatology, Vol. 130, No. 1, 1994, pp. 65-74. doi:10.1111/j.1365-2133.1994.tb06885.x
[43] I. Neri, F. Bardazzi, S. Marzaduri and A. Patrizi, “Perianal Streptococcal Dermatitis in Adults,” British Journal of Dermatology, Vol. 135, No. 5, 1996, pp. 796-798. doi:10.1111/j.1365-2133.1996.tb03894.x
[44] M. Ledoux, V. Chazerain, P. Saiag and E. Mahe, “Streptococcal Perianal Dermatitis and Guttate Psoriasis,” Annales de Dermatologie et de Venereologie, Vol. 136, No. 1, 2009, pp. 37-41. doi:10.1016/j.annder.2008.06.013
[45] E. Mallon, M. Bunce, H. Savoie, A. Rowe, R. Newson, F. Gotch, et al., “HLA-C and Guttate Psoriasis,” British Journal of Dermatology, Vol. 143, No. 6, 2000, pp. 1177-1182. doi:10.1046/j.1365-2133.2000.03885.x
[46] L. Malbris, K. Wolk, F. Sanchez and M. Stahle, “HLA-Cw*0602 Associates with a Twofold Higher Prevalence of Positive Streptococcal Throat Swab at the Onset of Psoriasis: A Case Control Study,” BMC Dermatology, Vol. 29, No. 9, 2009, p. 5. doi:10.1186/1471-5945-9-5
[47] D. Y. Leung, J. B. Travers, R. Giorno, D. A. Norris, R. Skinner, J. Aelion, et al., “Evidence for a Streptococcal Superantigen-Driven Process in Acute Guttate Psoriasis,” The Journal of Clinical Investigation, Vol. 96, No. 5, 1995, pp. 2106-2112.
[48] V. N. Saxena and J. Dogra, “Long-Term Use of Penicillin for the Treatment of Chronic Plaque Psoriasis,” European Journal of Dermatology, Vol. 15, No. 5, 2005, pp. 359-362.
[49] V. N. Saxena and J. Dogra, “Long-Term Oral Azithromycin in Chronic Plaque Psoriasis: A Controlled Trial,” European Journal of Dermatology, Vol. 20, No. 3, 2010, pp. 329-333.
[50] R. G. El-Rachkidy, J. M. Hales, P. P. Freestone, H. S. Young, C. E. Griffiths and R. D. Camp, “Increased Blood Levels of IgG Reactive with Secreted Streptococcus Pyogenes Proteins in Chronic Plaque Psoriasis,” Journal of Investigative Dermatology, Vol. 127, No. 6, 2007, pp. 1337-1342. doi:10.1038/sj.jid.5700744
[51] H. Valdimarsson, H. Sigmundsdottir and I. Jonsdottir, “Is Psoriasis induced by Streptococcal Super Antigens and Maintained by M-Protein Specific T Cells That Cross-React with Keratin?” Clinical & Experimental Immunology, Vol. 107, Supplement 1, 1997, pp. 21-24.
[52] U. Islander, A. Andersson, E. Lindberg, I. Adlerberth, A. E. Wold and A. Rudin, “Superantigenic Staphylococcus aureus Stimulate Production of Interleukin-17 from Memory but Not Na?ve T Cells,” Infection and Immunity, Vol. 78, No. 1, 2010, pp. 381-386. doi:10.1128/IAI.00724-09
[53] G. Fedele, M. Nasso, F. Spensieri, R. Palazzo, L. Frasca, M. Watanabe, et al., “Lipopolysaccharides from Bordetella pertussis and Bordetella parapertussis Differently Modulate Human Dendritic Cell Functions Resulting in Divergent Prevalence of Th17-Polarized Responses,” The Journal of Immunology, Vol. 181, No. 1, 2008, pp. 208-216.
[54] S. Iwamoto, S. Iwai, K. Tsujiyama, C. Kurahashi, K. Takeshita, M. Naoe, et al., “TNF-Alpha Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses,” The Journal of Immunology, Vol. 179, No. 3, 2007, pp. 1449-1457.
[55] S. Siegemund, N. Schutze, M. A. Freudenberg, M. B. Lutz, R. K. Staubinger and G. Alber, “Production of IL-12, IL-23 and IL-27p28 by Bone Marrow-Derived Conventional Dendritic Cells Rather than Macrophages after LPA/TLR4-Dependent Induction by Salmonella Enteritidis,” Immunobiology, Vol. 212, No. 9-10, 2007, pp. 739-750. doi:10.1016/j.imbio.2007.09.004
[56] C. Abraham and J. Cho, “Interleukin-23/Th17 Pathways and Inflammatory Bowel Disease,” Inflammatory Bowel Diseases, Vol. 15, No. 7, 2009, pp. 1090-1100. doi:10.1002/ibd.20894
[57] C. O. Elson, Y. Cong, C. T. Weaver, T. R. Schoeb, T. K. McClanahan, R. B. Fick, et al., “Monoclonal Anti-inter- leukin 23 Reverses Active Colitis in a T Cell-Mediated Model in Mice,” Gastroenterology, Vol. 132, No. 7, 2007, pp. 2359-2370. doi:10.1053/j.gastro.2007.03.104
[58] Z. Liu, J. Jiu, S. Liu, X. Fa, F. Li and Y. Du, “Blockage of Tumor Necrosis Factor Prevents Intestinal Mucosal Inflammation through down-Regulation of Interleukin-23 Secretion,” Journal of Autoimmunity, Vol. 29, No. 2-3, 2007, pp. 187-194. doi:10.1016/j.jaut.2007.07.004
[59] A. Di Cesare, P. Mi-Meglio and F. O. Nestle, “The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis,” Journal of Investigative Dermatology, Vol. 129, No. 6, 2009, pp. 1339-1350. doi:10.1038/jid.2009.59
[60] C. Ortega, S. Fernandez-A, J. M. Carrillo, P. Romero, I. J. Molina, J. C. Moreno, et al., “IL-17 Producing CD8+ T Lymphocytes from Psoriatic Skin Plaques Are Cytotoxic Effector Cells That Secrete Th17-Related Cytokines,” Journal of Leukocyte Biology, Vol. 86, No. 2, 2009, pp. 435-443. doi:10.1189/JLB.0109046
[61] J. H. Saurat, G. Stingl, L. Dubertret, K. Papp, R. G. Langley, J. P. Ortonne, et al., “Efficacy and Safety Results from the Randomized Controlled Comparative Study of Adalimumab vs Methotrexate vs Placebo in Patients with Psoriasis (CHAMPION),” British Journal of Dermatology, Vol. 158, No. 3, 2008, pp. 556-566.
[62] W. Sterry, J. P. Ortonne, B. Kirkham, O. Brocq, D. Robertson, R. D. Pedersen, et al., “Comparison of Two Etanercept Regimens for Treatment of Psoriatic Arthritis: PRESTA Randomized Double Blind Multicenter Trial,” British Medical Journal, Vol. 340, 2010, p. c147. doi:10.1136/bmj.c147
[63] S. N. Al-Surwaidan and S. R. Feldman, “Clearance is Not a Realistic Expectation of Psoriasis Treatment,” Journal of the American Academy of Dermatology, Vol. 42, No. 5, 2000, pp. 796-802. doi:10.1067/mjd.2000.103983
[64] F. C. Victor, A. B. Gottlieb and A. Menter, “Changing Paradigms in Dermatology: Tumor Necrosis Factor Alpha (TNF-Alpha) Blockade in Psoriasis and Psoriatic Arthritis,” Clinics in Dermatology, Vol. 21, No. 5, 2003, pp. 392-397. doi:10.1016/j.clindermatol.2003.08.015
[65] D. Tsurula, “NF-KappaB Links Keratinocytes and Lymphocytes in the Pathogenesis of Psoriasis,” Recent Patents on Inflammation & Allergy drug Discovery, Vol. 3, No. 1, 2009, pp. 40-48. doi:10.2174/187221309787158399

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.