Assessing the itching intensity using visual analogue scales in atopic dermatitis patients against the background of a therapy with calcineurin inhibitors

Cover Page


Cite item

Full Text

Abstract

Goal. To assess the effect of topical treatment of atopic dermatitis patients with the 0.1% tacrolimus ointment on the itching intensity and skin expression level of growth factor proteins affecting the intensity of cutaneous innervation. Materials and methods. Fifteen patients suffering from atopic dermatitis underwent treatment with the 0.1% tacrolimus ointment. The SCORAD index was calculated to assess the severity of clinical manifestations. The itching intensity was assessed using a visual analogue scale. The skin expression of nerve growth factors, amphiregulin, semaphorin 3A and PGP9.5 protein (a nerve fiber marker) was assessed by the indirect immunofluorescence method. Results. An increased expression of the nerve growth factor and reduced semaphorin 3A expression levels were noted in the patients’ epidermis; there was an increase in the quantity, mean length and fluorescence intensity of PGP9.5+ nerve fibers. As a result of the treatment, the disease severity and itching intensity were reduced, the nerve growth factor expression level was reduced while semaphorin 3A expression level increased in the epidermis, and the mean length and fluorescence intensity of PGP9.5+ nerve fibers was also reduced. A positive correlation among the itching intensity and nerve growth factor expression level, quantity and mean length of PGP9.5+ nerve fibers in the epidermis was revealed, and negative correlation between the itching intensity and semaphorin 3A expression level in the epidermis was established. Conclusion. Topical treatment with the 0.1% Tacrolimus ointment reduces the itching intensity in atopic dermatitis patients, which is related to the therapy-mediated reduction in the epidermis innervation level, decreased expression of epidermal nerve growth factor and increased semaphorin 3A expression level.

About the authors

V. V. Chikin

State Research Center of Dermatovenereology and Cosmetology, Ministry of Healthcare of the Russian Federation

Author for correspondence.
Email: noemail@neicon.ru
Россия

V. A. Smolyannikova

I. M. Sechenov First Moscow State Medical University

Email: noemail@neicon.ru
Россия

D. V. Proshutinskaya

State Research Center of Dermatovenereology and Cosmetology, Ministry of Healthcare of the Russian Federation

Email: diana.dika@mail.ru
Россия

M. A. Nefedova

State Research Center of Dermatovenereology and Cosmetology, Ministry of Healthcare of the Russian Federation

Email: noemail@neicon.ru
Россия

References

  1. Metz м., Wahn U., Gieler U. et al. Chronic pruritus associated with dermatologic disease in infancy and childhood: Update from an interdisciplinary group of dermatologists and pediatricians. Pediatr Allergy Immunol 2013: 24: 527-539.
  2. Nedoszytko B., Sokołowska-Wojdyło M., Ruckermann-Dziurdzinska K. et al. Chemokines and cytokines network in the pathogenesis of the inflammatory skin diseases: atopic dermatitis, psoriasis and skin mastocytosis. Postepy Dermatol Alergol 2014; 31 (2): 84-91.
  3. Brandt E.B., Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol 2011; 2 (3): pii: 110.
  4. Rahman S., Collins M., Williams C.M., Ma H.L. The pathology and immunology of atopic dermatitis. Inflamm Allergy Drug Targets 2011; 10 (6): 486-496.
  5. Grewe M., Gyufko K., Schopf E., Krutmann J. Lesional expression of interferon-gamma in atopic eczema. Lancet 1994; 343: 25-26.
  6. Trautmann A., Akdis M., Kleemann D. et al. T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 2000; 106: 25-35.
  7. Breuer K., Werfel T., Kapp A. Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis. Am J Clin Dermatol 2005; 6: 65-77.
  8. El-Batawy M.M., Bosseila M.A., Mashaly H.M., Hafez V.S. Topical calcineurin inhibitors in atopic dermatitis: a systematic review and meta-analysis. J Dermatol Sci 2009; 54: 76-87.
  9. Ashcroft D.M., Dimmock P., Garside R. et al. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomized controlled trials. BMJ 2005; 330 (7490): 516.
  10. Gutfreund K., Bienias W., Szewczyk A., Kaszuba A. Topical calcineurin inhibitors in dermatology. Part I: properties, method and effectiveness of drug use. Postep Derm Allergol 2013; 3: 165-169.
  11. Ho S., Clipstone N., Timmermann L. et al. The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol 1996; 80 (3 Pt 2): S40-45.
  12. Schreiber S.L., Crabtree G.R. The mechanism of action of cyclosporin A and FK506. Immunol Today 1992; 13 (4): 136-142.
  13. Liu J., Farmer J.D. Jr, Lane W.S. et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP506 complexes. Cell 1991; 66: 807-815.
  14. Nghiem P., Pearson G., Langley R.G. Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 2002; 46: 228-241.
  15. Прошутинская Д.В., Бутарева М.М., Иноятова Л.А. Новые возможности терапии атопического дерматита у детей и взрослых. Вестн дерматол венерол 2013; (3): 78-82
  16. Соколовский Е.В., Монахов К.В., Аксенова О.И. Эффективность и переносимость 0,1% мази такролимуса при лечении больных атопическим дерматитом средней тяжести. Влияние препарата на микроциркуляцию в коже. Вестн дерматол венерол 2012; (4): 85-89
  17. Белоусова Т.А., Парамонов А.А., Горячкина М.В. Наружная терапия атопического дерматита: фокус на такролимус. Поликлиника 2014; 4: 98-102
  18. Самцов А.В., Сухарев А.В., Патрушев А.В. Лечение атопического дерматита: преимущества такролимуса перед топическими глюкокортикостероидами. Эффективная фармакотерапия. Дерматовенерология и косметология 2014; 19 (2): 4-10
  19. Кочергин Н.Г. Такролимус в практике врача-дерматолога. Эффективная фармакотерапия. Дерматовенерология и косметология 2013; 25 (2): 30-33
  20. Самцов А.В., Сухарев А.В., Патрушев А.А., Бондарь О.И. клиническая эффективность, безопасность и переносимость 0,1% мази такролимуса при лечении атопического дерматита средней и тяжелой степени тяжести. Вестн дерматол венерол 2012; (2): 71-77
  21. Бакулев А.Л., Кравченя С.С. Эффективность топической терапии такролимусом при атопическом дерматите у взрослых. Вестн дерматол венерол 2012; (5): 106-111
  22. Hanifin J.M., Ling M.R., Langley R. et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol 2001; 44 (1 Suppl): S28-38.
  23. Paller A., Eichenfield L.F., Leung D.Y. et al. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001; 44 (1 Suppl): S47-57.
  24. Reitamo S., Rustin M., Harper J. et al. A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients. Br J Dermatol 2008; 159: 942-951.
  25. Boguniewicz M., Fiedler V.C., Raimer S. et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children: pediatric tacrolimus study group. J Allergy Clin Immunol 1998;102: 637-644.
  26. Nakagawa H., Etoh T., Ishibashi Y. et al. Tacrolimus ointment for atopic dermatitis. Lancet. 1994; 344 (8926): 883.
  27. Pereira U., Boulais N., Lebonvallet N. et al. Mechanisms of the sensory effects of tacrolimus on the skin. Br J Dermatol 2010; 163 (1): 70-77.
  28. Stander S., Luger T. Antipruritische Wirkung von Pimecrolimus und Tacrolimus. Hautarzt 2003; 54: 413-417.
  29. Ring J., Alomar A., Bieber T. et al. Guidelines for treatment of atopic eczema (atopic dermatitis). Part I. J Eur Acad Dermatol Venereol 2012; 26: 1045-1060.
  30. Simon D., Vassina E., Yousefi S. et al. Reduced dermal infiltration of cytokine-expressing inflammatory cells in atopic dermatitis after short-term topical tacrolimus treatment. J Allergy Clin Immunol 2004; 114: 887-895.
  31. Reynolds N.J., Al-Daraji W.I. Calcineurin-inhibitors and sirolimus: mechanisms of action and application in dermatology. Clin Exp Dermatol 2002; 27: 555-561.
  32. Caproni M., Torchia D., Antiga E. et al. The comparative effects of tarcolimus and hydrocortisone in adult atopic dermatitis: an immunohistochemical study. Br J Dermatol 2007; 156; 312-319.
  33. Park C.W., Lee B.H., Han H.J. et al. Tacrolimus decreases the expression of eotaxin, CCR3, RAN-TES and interleukin-5 in atopic dermatitis. Br J Dermatol 2005; 152: 1173-1181.
  34. Tominaga M., Tengara S., Kamo A., et al. Psoralen ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis. J Dermatol Sci 2009; 55: 40-46.
  35. Tominaga M., Takamori K. Itch and nerve fibers with special reference to atopic dermatitis: Therapeutic implications. J Dermatol 2014; 41: 205-212.
  36. Tominaga M., Takamori к. An update on peripheral mechanisms and treatments of itch. Biol Pharm Bull 2013; 36 (8): 1241-1247.
  37. Albers K.M., Wright D.E., Davis B.M. Overexpression of nerve growth factor in epidermis of transgenic mice causes hypertrophy of the peripheral nervous system. J Neurosci 1994; 14: 1422-1432.
  38. Crowley C., Spencer S.D., Nishimura M.C. et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 1994; 76: 1001-1011.
  39. Nilsson A., Kanje M. Amphiregulin acts as an autocrine survival factor for adult sensory neurons. Neuroreport 2005; 16: 213-218.
  40. Kim H., Caspar T.W., Shah S.B., Hsieh A.H. Effects of proinflammatory cytokines on axonal outgrowth from adult rat lumbar dorsal root ganglia using a novel three-dimensional culture system. Spine J 2015; 15 (8): 1823-1831.
  41. Matsumura S., Terao M., Murota H., Katayama I. Th2 cytokines enhance TrkA expression, upregulate proliferation, and downregulate differentiation of ke-ratinocytes. J Dermatol Sci 2015; 78 (3): 215-223.
  42. Takahashi H., Tsuji H., Hashimoto Y. et al. Cell proliferation and cytokine induction by TNF-alpha of psoriatic keratinocytes are different from normal keratinocytes in vitro. Indian J Dermatol 2009; 54 (3): 237-239.
  43. Cook P.W., Piepkorn M., Clegg C.H. et al. Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J Clin Invest 1997; 100 (9): 2286-2294.
  44. Cook P.W., Brown J.R., Cornell K.A., Pittelkow M.R. Suprabasal expression of human amphiregulin in the epidermis of transgenic mice induces a severe, early-onset, psoriasis-like skin pathology: expression of amphiregulin in the basal epidermis is also associated with synovitis. Exp Dermatol 2004; 13 (6): 347-356.
  45. Pastore S., Mascia F., Mariani V., Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 2008; 128 (6): 1365-1374.
  46. Berasain C., Avila M.A. Amphiregulin. Semin Cell Dev Biol 2014; 28: 31-41.
  47. Yamane S., Ishida S., Hanamoto Y. et al. Proin-flammatory role of amphiregulin, an epidermal growth factor family member whose expression is augmented in rheumatoid arthritis patients. J Inflamm (Lond) 2008; 5: 5.
  48. Dontchev V.D., Letourneau P.C. Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. J Neurosci 2002; 22 (15): 6659-6669.
  49. Tominaga M., Kamo A., Tengara S. et al. In vitro model for penetration of sensory nereve fibres on a Matrigel basement membrane: implications for possible application to intractable pruritus. Br J Dermatol 2009; 161 (5): 1028-1037.
  50. Taneda K., Tominaga M., Negi O. et al. Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch. Br J Dermatol 2011; 165 (2): 277-284.
  51. Fujisawa H. Discovery of semaphoring receptors, neutropilin and plexin, and their functions in neural development. J Neurobiol 2004; 59: 24-33.
  52. Sakai T., Takahashi D., Nikaido K. et al. Costimulation with interleukin-4 and tumor necrosis factor-a increases epidermal innervation accompanied by suppression of semaphorin 3A. J Dermatol Sci 2014; 76 (1): 69-71.
  53. Katunina O.R., Chikin V.V., Znamenskaya L.F., Inoyatova L.A. Role of neuromediators in the development of skin irritation in patients with atopic dermatitis. Vestnik Dermatologii i Venerologii 2013; (5): 91-101. [катунина О.Р., Чикин В.В., Знаменская Л.Ф., Иноятова Л.А. Роль нейромедиаторов в развитии воспаления в коже больных атопическим дерматитом. Вестник дерматологии и венерологии 2013; (5): 91-101.]
  54. Jackson P., Thomson V.M., Thompson R.J. A comparison of the evolutionary distribution of the two neuroendocrine markers, neurone-specific enolase and protein gene product 9.5. J Neurochem 1985; 45: 185-190.
  55. Day I.N., Thompson R.J. Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel cytoplasmic marker for neurones and neuroendocrine cells. FEBS Lett 1987; 210: 157-160.
  56. Wilkinson K.D., Lee K.M., Deshpande S. et al. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 1989; 246: 670-673.
  57. Day I.N. Enolases and PGP9.5 as tissue-specific markers. Biochem Soc Trans 1992; 20: 637-642.
  58. Day I.N., Thompson R.J. UCHL1 (PGP 9.5): neuronal biomarker and ubiquitin system protein. Prog Neurobiol 2010; 90: 327-362.
  59. Wilson P.O., Barber P.C., Hamid Q.A. et al. The immunolocalization of protein gene product 9.5 using rabbit polyclonal and mouse monoclonal antibodies. Br J Exp Pathol 1988; 69 (1): 91-104.
  60. Wilson J.R., Conwit R.A., Eidelman B.H. et al. Sensorimotor neuropathy resembling CIDP in patients receiving FK506. Muscle Nerve 1994; 17: 528-532.
  61. Bronster D.J. Yonover P., Stein J. et al. Demyelinating sensorimotor polyneuropathy after administration of FK506. Transplantation 1995; 59: 1066-1088.
  62. Echaniz-Laguna A., Battaglia F. Ellero B. et al. Chronic ionflammatory demyelinating polyradiculoneuropathy in patients with liver transplantation. Muscle Nerve 2004; 30: 501-504.
  63. Hontanilla B., Auba C., Arcocha J., Gorria O. Nerve regeneration through nerve autografts and cold preserved allografts using tacrolimus (FK506) in a facial paralysis model: A topographical and neurophysiological study in monkeys. Neurosurgery 2006; 58: 768-779.
  64. Lee M., Doolabh B., Mackinnon S.E., Jost S. FK 506 promotes functional recovery in crushed rat sciatic nerve. Muscle Nerve 2000;23:633-640.
  65. Rustemeyer J., Krajacic A., Dicke U. Histomor-phological and functional impacts of postoperative motor training in rats after allograft sciatic nerve transplantation under low-dose FK 506. Muscle Nerve 2009; 39: 480-488.
  66. Jifeng H., Dezhong L., Qiongjiao Y. et al. Evaluation of PRGD/FK506/NGF conduits for peripheral nerve regeneration in rats. Neurol India 2010; 58: 384-391.
  67. Gold B.G. FK506 and the role of immunophilins in nerve regeneration. Mol Neurobiol 1997; 15 (3): 285-306.
  68. Kano Y., Hiragami F., Kawamura K. et al. Immunosupressant FK506 induces sustained activation of MAP kinase and promotes neurite outgrowth in PC12 mutant cells incapable of differentiating. Cell Struct Funct 2002; 27 (5): 393-398.
  69. Tanaka K., Fujita N., Higashi Y., Ogawa N. Neuroprotective and antioxidant properties of FKBP-binding immunophilin ligands are independent of the FKBP12 pathway in human cells. Neurosci Lett 2002; 330: 147-150.
  70. Price R.D., Yamaji T., Matsuoka N. FK506 potentiates NGF-induced neurite outgrowth via the Ras/ Raf/MAP kinase pathway. Br J Pharmacol 2003; 140: 825-829.
  71. Klettner A., Baumgrass R., Zhang Y. et al. The neuroprotective actions of FK506 binding protein ligands: neuronal survival is triggered by de novo RNA synthesis, but is independent of inhibition of JNK and calcineurin. Brain Res Mol Brain Res 2001; 97 (1): 21-31.
  72. Lyons W.E., George E.B., Dawson T.M. et al. Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. Proc Natl Acad Sci USA 1994; 91: 3191-3195.
  73. Chen G., Zhang Z., Wang S., Lv D. Combined treatment with FK506 and nerve growth factor for spinal cord injury in rats. 2013; 6: 868-872.
  74. Bullock E.D., Johnson E.M. Jr. Nerve growth factor induces the expression of certain cytokine genes and bcl-2 in mast cells. Potential role in survival promotion. J Biol Chem 1996; 271 (44): 27500-27508.
  75. Kawamoto K., Aoki J., Tanaka A. et al. Nerve growth factor activates mast cells through the collaborative interaction with lysophosphatidylserine expressed on the membrane surface of activated platelets. J Immunol 2002; 168 (12): 6412-6419.
  76. Thorpe L.W., Perez-Polo J.R. The influence of nerve growth factor on the in vitro proliferative response of rat spleen lymphocytes. J Neurosci Res 1987; 18 (1): 134-139.
  77. Otten U., Ehrhard P., Peck R. Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci USA 1989; 86 (24): 10059-10063.
  78. Yamaguchi J., Nakamura F., Aihara M. et al. Semaphorin3A alleviates skin lesions and scratching behavior in NC/Nga mice, an atopic dermatitis model. J Invest Dermatol 2008; 128: 2842-2849.
  79. Negi O., Tominaga M., Tengara S. et al. Topically applied semaphorin 3A ointment inhibits scratching behavior and improves skin inflammation in NC/Nga mice with atopic dermatitis. J Dermatol Sci 2012; 66 (1): 37-43.
  80. Liu Y., Fallon L., Lashuel H.A. et al. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 2002; 111 (2): 209-218.
  81. Hershko A., Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67: 425-479.
  82. Wilkinson K.D. Roles of ubiquitinylation in proteolysis and cellular regulation. Ann Rev Nutr 1995; 15: 161-189.
  83. Kabuta T., Mitsui T., Takahashi M. et al. Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation independently of its hydrolase activity. J Biol Chem 2013; 288. 18: 1475-1478.
  84. Proctor C.J., Tangeman P.J., Ardley H.C. Modelling the role of UCH-L1 on protein aggregation in age-related neurodegeneration. PLoS ONE 2010; 5 (10): e13175.
  85. Setsuie R., Wada K. The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem Int 2007; 51 (2-4), 105-111.
  86. Lombardino A.J., Li X.-C., Hertel M., Nottebohm F. Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels. Proc Natl Acad Sci USA 2005; 102 (22): 8036-8041.
  87. Jara J.H., Frank D.D., Ozdinler P.H. Could dysregulation of UPS be a common underlying mechanism for cancer and neurodegeneration? Lessons from UCHL1. 2013; 67 (1): 45-53.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2016 Chikin V.V., Smolyannikova V.A., Proshutinskaya D.V., Nefedova M.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 60448 от 30.12.2014.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies