From the bench to the bed side by Prof. Karin Schallreuter – Presentation Transcript
1. From the bench to the bedside Treatment of vitiligo with combined climatotherapy at the Dead Sea 10 years experience Karin U Schallreuter Institute for Pigmentary Disorders in Association with Ernst-Moritz-Arndt University Greifswald, Germany Clinical and Experimental Dermatology Centre for Skin Sciences , University of Bradford, Bradford, UK Institute for Pigmentary Disorders University of Bradford, Clinical and Experimental Institute for Pigmentary Greifswald, Germany Dermatology, Bradford, United Kingdom Disorders Greifswald, Germany
2. canities mixed (segmental et vulgaris) inflammatory segmental vulgarisvulgaris universalis segmental vulgaris totalis Koebner poliosis lips lips ears facial hands Vitiligo – clinical pictures
3. Vitiligo is a disease characterised by an acquiredspontaneous loss of the inherited skin colour• 0.5-2% of the world population are affected• no significant gender difference• positive family history in 35-45 %• onset at any time in life (more frequent in puberty, pregnancy, menopause) Institute for Pigmentary Disorders Greifswald, Germany
4. World wide prevalence of vitiligo in population- studies children total population Krueger et al 2009 Institute for Pigmentary Disorders Greifswald, Germany
5. Course of the disease is unpredictable for the affected individual -• mostly progressive ranging from slow to very rapid patchy loss of skin / hair / mucosa colour• seldom spontaneous repigmentation Institute for Pigmentary Disorders Greifswald, Germany
6. The cause of vitiligo is still unknown – Institute for Pigmentary Disorders Greifswald, Germany
7. Genetic predisposition positive family history Institute for Pigmentary Disorders Greifswald, Germany
8. Genes identified in association/susceptibility with vitiligo and oxidative stress CAT vitiligo Casp et al 2003, Kemp et al 2006, Lee et al 2006 COMT vitiligo Tursen et al 2002 Institute for Pigmentary Disorders University of Bradford, Clinical and Experimental Greifswald, Germany Dermatology, Bradford, United Kingdom
9. Autoimmune reactions presence of antibodies presence of T and B lymphocyte reactions Institute for Pigmentary Disorders Greifswald, Germany
10. Genes identified in association/susceptibility with vitiligo and other autoimmune diseases________________________________________ NALP1 vitiligo/ other autoimmune diseases innate immune response ? (Jin et al, 2007) Aire APS / type I (Halonen et al 2004) CTLA-4 Grave’s disease, DM typeI (Ueda et al 2003) AIS1 Hashimoto’s thyroiditis, generalised vitiligo (Blomhoff et al 2005; Alkatheeb et al 2002) LMP/TAP vitiligo (Casp et al 2003)Tyrosinase vitiligo (2011 Spritz group) Institute for Pigmentary Disorders Greifswald, Germany
11. Neural abnormalities dermatomal & Blascko-linear distribution Endocrine abnormalities increased noradrenalin levels increased catecholamine metabolite levels in the periphery (Orrechia et al , Schallreuter et al) Institute for Pigmentary Disorders Greifswald, Germany
12. Epidermal melanocyte detachmenta pathognomonic phenomenon for vitiligo? (Gauthier et al 2003) Institute for Pigmentary Disorders Greifswald, Germany
13. is not specific for vitiligo Institute for Pigmentary Disorders Greifswald, Germany
14. Evidence for impaired redox- balance in vitiligo – Institute for Pigmentary Disorders Greifswald, Germany
15. Generation / accumulation of ROS and freeradicals in the entire epidermis of vitiligo H2O2 – mediated oxidative stress Peroxynitrite – mediated stress Phenol / semiquinone – induced stress Institute for Pigmentary Disorders Greifswald, Germany
16. In vivo evidence Patients with vitiligoaccumulate millimolarconcentrations of H2O2 in their epidermis(Schallreuter et al. 1999, Schallreuter KU, 2005, Schallreuter et al 2007, 2008) Clinical evidence for high H2O2 levels under Wood’s light Institute for Pigmentary Disorders Greifswald, Germany
17. Generation of epidermal H2O2 in vitiligo Schallreuter et al 2008 Phenols X-ray ortho-, para- UVA/UVB quinones XanthineTNF ?, TGF ß oxidase PDGF, EGFPhenylalanine hydroxylase H2O2 NADPH- oxidase Tyrosine Nitric oxide hydroxylase synthases Photo-oxidation Aromatic steroids Monoamine of pterins (estrogens/progesterons/androgens) oxidase A
18. Bhawan & Bhutani 1983Tobin et al 2000 Vacuoles In situ H2O2 – induced lipid-peroxidation in epidermal keratinocytes and melanocytes in vitiligo Institute for Pigmentary Disorders Greifswald, Germany
19. catalase thioredoxin reductasecontrol vitiligo control vitiligo H2O2 decreases epidermal catalase and thioredoxin reductase protein expression / activities in vitiligo (Schallreuter et al 1987, 1991, 2008) Institute for Pigmentary Disorders Greifswald, Germany
20. H2O2 deactivates epidermal catalase in vitiligo due to 14.0 oxidation of met and trp residues (Schallreuter et al 1991, Gibbons et al 2006) 12.0CATALASE [µg/mg protein] 10.0 8.0 ** 6.0 ** 4.0 2.0 0.0 non-lesional lesional CONTROL VITILIGO Institute for Pigmentary Disorders Greifswald, Germany
21. H2O2 – mediated oxidation in vitiligo affects Cofactor 6BH4 de novo synthesis and recycling in epidermal melanocytes and keratinocytes (oxidation of 6BH4, deactivation of PCD and DHPR) (Schallreuter et al 1994 Science, JID 2001, Rokos et al BBRC 2002, Hasse et al JID 2002 Chavan et al Inher Mol Metabolism 2009) Institute for Pigmentary Disorders Greifswald, Germany
22. H2O2 oxidises 6BH4 and its 7- isomerto 6-biopterin and 7-biopterin The clinical hallmark of vitiligo – Fluorescence under Wood’s light H2O (Schallreuter KU et al, Science, 1994) 1000 6-biopterin Total Biopterin 900 6-Biopterin 7-biopterin BIOPTERIN [pmoles/mg protein] 800 7-Biopterin 700 600 500 400 300 200 100 0 CONTROL VITILIGO non-lesional lesional Biopterin levels in epidermal cell extracts Institute for Pigmentary Disorders Greifswald, Germany
23. H2O2-mediated oxidation in vitiligo affects * POMC-cleavage and derived peptides (Furin, PC1, PC2, ?-MSH, ?-endorphin) (Spencer et al 2007, Spencer et al 2007) * MITF expression (Jeminez-Cervantes et al 2001 ) * TRP1 function (Jimbow et al 2000) Institute for Pigmentary Disorders Greifswald, Germany
24. In situ evidenceforH2O2-mediated control control ?-MSH ?-endorphinoxidationof ?-MSH and?-endorphinin vitiligoSpencer et al 2007 vitiligo vitiligo Institute for Pigmentary Disorders Greifswald, Germany
25. Increased epidermal peroxynitrite (ONOO-)control expression in vitiligo control ns 70 Staining intensity (Arbitrary values)lesional 60 50 40 30 20 10 0 control les non les (n=4) (n=10) (n=10)non lesional Image analysis epidermal N-tyrosine Salem et al 2009, FASEB N-tyrosine = footprint for ONOO-
26. Proof of the concept Reduction of epidermal H2O2 bypseudocatalase PC-KUS yields recovery of many affected signals including catalase……(Hasse et al 2000, Schallreuter et al 2003, 2007,2008, Salem et al 2009) Institute for Pigmentary Disorders Greifswald, Germany
27. Concentration dependent recovery/upregulation ofepidermal catalase expression after H2O2 reduction withPseudocatalase PC-KUS Control Vitiligo Vitiligo +H2O2 -H2O2 Institute for Pigmentary Disorders Greifswald, Germany
2. From the bench to the bedside Reduction of epidermal H2O2 bypseudocatalase PC-KUS yields recovery of skin colour Institute for Pigmentary Disorders Greifswald, Germany
29. Recovery of the skin colour after epidermal H2O2 -reduction Institute for Pigmentary Disorders Greifswald, Germany
30. Recovery of the skin colour after epidermal H2O2 -reduction Schallreuter et al 2008 Institute for Pigmentary Disorders Greifswald, Germany
31. Recovery of the skin colour after epidermal H2O2 –reduction (segmental vitiligo) Schallreuter et al 2008 Institute for Pigmentary Disorders Greifswald, Germany
32. Vitiligo of the lipsand earsbefore and aftertreatment mitPC-KUS Institute for Pigmentary Disorders Greifswald, Germany
33. Repigmentation of vitiligo is independent of skin colour -face/neck – trunk – extremities -hands/feet Schallreuter et al 2008 Institute for Pigmentary Disorders Greifswald, Germany
34. Duration of the diseasehas no influence on repigmentation ! -face /neck / -abdomen / back -extremities -hands / feet Schallreuter et al 2008 Institute for Pigmentary Disorders Greifswald, Germany
35. Why Dead Sea Treatment? Institute for Pigmentary Disorders Greifswald, Germany
36. Early references in Bible – Ezekiel 47:9: […] And it shall be that every livingthing that moves […] will live. There will be a very great multitude of fish […] forthey will be healed, and everything will live…Chemical composition of the Dead Sea – High concentration of salt (?350g/litre) and minerals, metals ? weak pseudocatalase effect due to solubletransition metal ions (Schallreuter et al 2002)Filtered sunlight – Deepest point on earth ? haze ? shorter erythematic UVBradiation is filtered (Kudish et al 2003) Institute for Pigmentary Disorders Greifswald, Germany
37. Dead SeaLocationDead Sea is 400 m belowSea LevelDepth 400 mSalt concentration 28-36%TemperatureinApril/May/June 24-40degrees Celsius Institute for Pigmentary Disorders Greifswald, Germany
38. Solar Wavelengths UVB- narrow-band (311- 315 nm) UVC UVB UVA2 UVA1 Visible IR100 280 315 340 400 780 5000 nm Formation of Erythema Institute for Pigmentary Disorders Greifswald, Germany
39. No evidence for increased incidence of solar induced skin cancer(Calanchini-Postizzi & Frenk 1989, Schallreuter et al 2002) Institute for Pigmentary Disorders Greifswald, Germany
40. In vivo evidence for pseudocatalase activity of the Dead Sea water(Schallreuter et al 2002) Institute for Pigmentary Disorders Greifswald, Germany
41. Concentrations of Transition Metals in Dead Sea Water Total salt content: 346 g/l (34.6 %) Transition Concentration Concentration metal (ppm) (10-6 M)Manganese Mn2+ 7140 13.0 Iron Fe2+ 1398 2.5 Copper Cu2+ 582 0.9 Institute for Pigmentary Disorders Greifswald, Germany
42. Treatment ProtocolTwice daily 15mins bath in the Dead Sea, followed by application of PC-KUS and 15mins sun exposure on each body site (Schallreuter et al, 2002) Institute for Pigmentary Disorders Greifswald, Germany
43. The clinic and solariumat the Dead Sea in Jordan Institute for Pigmentary Disorders Greifswald, Germany
44. A novel medical concept… 21 days of combined climatotherapy with pseudocatalase PC-KUS SolariumThe open Sea Indoor pool(Schallreuter et al, 2002, 2011) Institute for Pigmentary Pool with sun roof Disorders Germany Greifswald,
45. Treatment in a group under the Sun Roof… Institute for Pigmentary Disorders Greifswald, Germany
46. Dead Sea Jordan?Significant faster initiation of re-pigmentation comparedto PC-KUS monotherapy? This effect lasts for 3 months after returning home (Schallreuter et al, 2002) Institute for Pigmentary Disorders Greifswald, Germany
47. Beginning of repigmentation at the Dead SeaAt day 0 15 16 19 Institute for Pigmentary Disorders Greifswald, Germany
48. Clinical picture before and after treatment with combined climatotherapy and PC-KUSDay 0 at the Dead Sea 3 months follow up Institute for Pigmentary Disorders Greifswald, Germany
49. Clinical picture before and after treatment with combined climatotherapy and PC- KUSDay 0 at the Dead Sea 3 months follow up Institute for Pigmentary Disorders Greifswald, Germany
50. Repigmentation of hands Day 0 after combined climatotherapy at the Dead Seaafter 3 months Institute for Pigmentary Disorders Greifswald, Germany
51. Facial vitiligo (under Wood’s light) before and aftercombined climatotherapy with PC-KUS and Dead Sea Day 0 After 3 months Institute for Pigmentary Disorders Greifswald, Germany
52. Facial vitiligo (under Wood’s light) before and after 21 days withcombined climatotherapy with PC-KUS and Dead SeaDay 0Day 20 Clinical picture at day 20 Institute for Pigmentary Disorders Greifswald, Germany
53. What are the effects on well-being? Institute for Pigmentary Disorders Greifswald, Germany
54. „Staring Eyes“ by Angelika Peruth Taken from the book„Damned White Spots – A collection of words and images by patients with vitiligo“ KU Schallreuter (Ed.), Bradford 1999 Institute for Pigmentary Disorders Greifswald, Germany
55. The Dead Sea study Article available for free on-line at Acta Dermato-Venereologica www.medicaljournals.se/acta Institute for Pigmentary Disorders Greifswald, Germany
56. Dermatology Life Quality Index (DLQI)Dead Sea 2007 n=71 *** n=36 *** *** Institute for Pigmentary Disorders Greifswald, Germany
57. Does the improvement last over time? Institute for Pigmentary Disorders Greifswald, Germany
58. Dermatology Life Quality Index (DLQI) Dead Sea 2007 and 2008 Institute for Pigmentary Disorders Greifswald, Germany
59. Significant improvement of the quality of life after combined climatotherapy at the Dead Sea in patients with vitiligoDLQI [n] Treatment modality Country Authors2.5 71 Dead Sea 2007 worldwide (Krüger et al 2009) end4.59 34 Dead Sea 2007 worldwide (Krüger et al 2009) F/U4.95 119 Vitiligo Belgium (Ongenae et al. 2005)7.0 71 Dead Sea 2007/ worldwide (Krüger et al 2009) beginning9.4 9 Vitiligo after 1 year NB-UVB / Germany (Hartmann et al. 2005) calcipotriol treatment13 9 Vitiligo before treatment Germany (Hartmann et al. 2005) Institute for Pigmentary Disorders Greifswald, Germany
60. Decrease of beta-endorphin levels in saliva(pg/ml) at the Dead Sea in patients and controls n.s. * * n.s. Day1 n.s. n.s. Day10 Day20 Significance by paired t-test Institute for Pigmentary Disorders Greifswald, Germany
61. Combined Balneotherapy at the Dead Sea improvessignificantly quality of life of patients with vitiligo….. Institute for Pigmentary Disorders Greifswald, Germany
62. Life at theDead Sea Treatment and Fun Institute for Pigmentary Disorders Greifswald, Germany
63. Patients numbers Israel 1999 52 Israel 2000 86Jordan 2009 21Jordan 2002 120Jordan 2003 78Jordan 2003 38 (Pilot study November)Jordan 2004 108Jordan 2005 69Jordan 2006 69Jordan 2007 79Jordan 2008 105Jordan 2009 94Jordan 2010 67Jordan 2011 90 Totals 1076 patients Institute for Pigmentary Disorders Greifswald, Germany
64. Conclusions1. Treatment with pseudocatalase PC-KUS at the Dead Sea (combined climatotherapy) initiates significantly faster repigmentation in patients with vitiligo.2. The new skin colour is stable when the patients continues home treatment with pseudocatalase PC-KUS.3. Therapy in the group at the Dead Sea improves significantly Quality of Life in these patients.This is a long-lasting result. Institute for Pigmentary Disorders Greifswald, Germany
65. AcknowledgementsThis research was kindly supported by the German Vitiligo Association (Deutscher Vitiligo Verein) and by private donations. For more information http://www vitiligo.eu.com Email:vitiligo@biotechnikum.de The author has no conflict of interest. Institute for Pigmentary Disorders Greifswald, Germany