1. Effects of Spa therapy on anti- oxidative status, inflammation, immune system Prof. Dr. M. Zeki Karagülle Symposium on Research in Spa Medicine Aix-les-Bains - November 17th 2006

2. Department of Medical Ecology & Hydroclimatology Istanbul Medical Faculty, Istanbul University Exceptional surroundingsxceptional surroundings Bourget lake Famous residents amous residents Practical informationractical information Microclimate Ports

4. Spa therapy and Balneotherapy Do they have biologic effects on Immune system and Inflammation and Oxidation ? Which mechanisms and mediators are involved?

5. Terminology Spa therapy ; a complex intervention at a spa resort, (balneotherapy + others) Balneotherapy ; Mineral/thermal water therapy (Bathing + Drinking + Inhalation)

6. Inflammation the first response of the immune system to infection or irritation characterised by the following quintet: redness (rubor), heat (calor), swelling (tumor), pain (dolor) dysfunction of the organs involved (functio laesa) The first four characteristics have been known since ancient times and are attributed to Celsus; functio laesa was added to the definition of inflammation by Rudolf Virchow in 1858.

7. Immune System A scanning electron microscope (SEM) image of a T-lymphocyte (right), a platelet (center), and a red blood cell (left). Image: The National Cancer Institute at Frederick

8. Chrousos G. N Engl J Med 1995;332:1351-1363 Inflammation

9. Choy E and Panayi G. N Engl J Med 2001;344:907-916 Cytokine Signaling Pathways Involved in Inflammatory Arthritis

10. Chrousos G. N Engl J Med 1995;332:1351-1363 Cytokines and Other Mediators of Inflammation That Influence the Hypothalamic-Pituitary- Adrenal Axis

13. Spa- and Balneotherapy Studies on Anti-oxidative status Anti-oxidant status in patients with Rheumatoid Arthritis after Spa Therapy M KARAGÜLLE, MZ KARAGÜLLE, O KARAGÜLLE, A AVCI, İ DURAK 35th Congress of ISMH, June 6-10, 2006, Istanbul The Effect of Balneotherapy on Oxidant-Antioxidant Systems in Primary Osteoarthritis HN AKSOY, N ERDOĞAN, Ö AKSOY, GÖ ERATA, AH KAYAR, MZ KARAGÜLLE 35th Congress of ISMH, June 6-10, 2006, Istanbul

14. Malondialdehyde (MDA) nmol/mL After 2-week spa therapy; increased in SPA group, decreased in control group No statistically significant change intergroup (p=0.5) and between group (p=0.2) comparisons

15. Nonenzymatic Superoxide Radical Scavenger Activity (NSSA) U/mL After 2-week spa therapy; increased in both groups Statisticaly significant increase in SPA group (p<0,05)

16. Antioxidant Defense Potential (AOP) U/mL After 2-week spa therapy; increased in both groups İn spa group agreater extend but, not statistically significant

17. Discussions Increased levels of MDA (although not statistically significant) suggests that; Per-oxidation reactions are accelerated during or after spa therapy spa therapy may cause an extra oxidative stress

18. Discussions Increased levels of NSSA (statistically significant) and AOP suggests that; antioxidant potential and activity are improved

19. Decrease in MDA levels in patients with high MDA levels Increase in MDA levels in patients with low MDA levels Increase in TAA levels in male patients Decrease in TAA levels in females (menopause-estrogens deficiency?) The Effect of Balneotherapy on Oxidant-Antioxidant Systems in Primary Osteoarthritis HN AKSOY, N ERDOĞAN, Ö AKSOY, GÖ ERATA, AH KAYAR, MZ KARAGÜLLE 35th Congress of ISMH, June 6-10, 2006, Istanbul

20. Spa therapy decreases oxidant stress ?! Decrease in oxidant stress is more prominent Increase of antioxidant defence is less manifest The Effect of Balneotherapy on Oxidant-Antioxidant Systems in Primary Osteoarthritis HN AKSOY, N ERDOĞAN, Ö AKSOY, GÖ ERATA, AH KAYAR, MZ KARAGÜLLE 35th Congress of ISMH, June 6-10, 2006, Istanbul

21. Free radicals and thermal water-controlled pilot study T BENDER,G NAGY,J BARISKA,R VÁGHY,R GOMEZ,I KOVÁCS 4.Turkish-Hungarian Balneological Meeting, 25-26 January, Izmir, 2006 Patients: Spondylosis lumbalis N:30(10 in each group) They got no NSAID and steroids, no other disease Duration of the bath 30 minutes, at 34°C Blood samples were taken before the first bath, after the first bath and at end of 10 baths

22. Free radicals and thermal water-controlled pilot study T BENDER,G NAGY,J BARISKA,R VÁGHY,R GOMEZ,I KOVÁCS 4.Turkish-Hungarian Balneological Meeting, 25-26 January, Izmir, 2006 There is difference between tap water and mineral water therapy concerning the effects on the free radicals The changes during tap water therapy may be due to the thermal effect

23. Effect of sulfur baths on antioxidative defense systems, peroxide concentrations and lipid levels in patients with degenerative osteoarthritis. Forsch Komplementarmed Klass Naturheilkd. 2002 Aug;9(4):216-20. Ekmekcioglu C, Strauss-Blasche G, Holzer F, Marktl W. Effect of 3-week spa therapy, two groups of patients with and without sulfur baths Sulfur bath therapy could cause a reduction in oxidative stress, alterations of SOD activities

24. [Effect of sulfur administration on lipid levels, antioxidant status and peroxide concentration in health resort patients] [Article in German] Forsch Komplementarmed Klass Naturheilkd. 2000 Apr;7(2):75-8. Scheidleder B, Holzer F, Marktl W. Effect of a 3-week spa therapy, two groups of patients with and without drinking sulphurous In both groups similar alterations of the activities of antioxidative enzymes as well as peroxide concentrations could be detected.

25. Spa- and Balneotherapy Studies on Inflammation, Immune System Physiological effects studies in healthy subjects In-vitro studies in cell cultures Experimental (animal) models of arthritis studies Therapeutic affects studies in patients groups; ie in patients with rheumatic or dermatological diseases

26. Experimental (animal) models of arthritis studies

27. The decrease in paw volume in adjuvant injected paws at the end of the experiment was the greatest in the sulfur group followed by tap water group. There was not any significant difference between the two experiment and the control groups.

28. The chronic arthritis which developed in the non-injected left hind paws reached maximum severity on the 9th day after CFA injection in tap water and control groups and not before the 19th day in the sulfur group. Later on, edema in the sulfur group decreased statistically more rapidly (p <0.001) compared to the other two groups.

29. Mud-bath applications reduced inflammation at day 20, at the end of the treatment, the paw volume was significantly reduced in comparison to the controls (p<0.01) Indomethacin therapy caused a more rapid reduction of paw volume, significant both at day 15 and at day 20 (p<0.05)

31. Studies in patient groups Rheumatic diseases –Osteoarthritis –Ankylosing Spondylitis –Fibromyalgia Dermatological diseasesDermatological diseases –Psoriasis –Atopic dermatitis

32. Is immune system influenced in OA patients by balneotherapy ?

33. Is immune system influenced in OA by spa therapy (mud pack + balneotherapy) ?

34. Is immune system influenced in healthy subjects by spa therapy (mud pack + balneotherapy) ?

35. Why does a 3-week spa therapy, in addition to drug treatment and weekly group physical therapy alone, provide beneficial effects that may last for at least 40 weeks, in patients with AS?

36. Answer can be found

38. Why spa therapy in addition to medical therapy has both short- and long-term beneficial effects in female patients with Fibromyalgia ?

39. Answer may be found

41. Conclusions The results of the published clinical, experimental, in-vitro and in-vivo studies suggests that; Spa therapy and balneotherapy provide Anti-inflammatory Immunosuppressive Immunomodulatory Anti-oxidative effects

42. Cytokines influenced by spa-and balneotherapy TNF-α IL-1α IL-1β IL-6 IFN-γ IL-2 IL-4 EGF TGF- β1

43. Prostaglandines influenced by spa- and balneotherapy PGE 2 Leukotriene; LTB 4 PGF 2 α

44. Matrix Metalloproteinases influenced by spa-and balneotherapy MMP-1 MMP-2 MMP-3 MMP-8 MMP-9

45. Cell Populations influenced by balneotherapy Langerhans cells T- and B-cells CD4+, CD4- cells CD8+, CD8- cells

46. Others CRP Haptoglobuline Substance P

47. Conclusions There is high level (1A and 1B) clinical evidence that spa therapy and balneotherapy are effective interventions in the management of rheumatoid arthritis, osteoarthritis, fibromyalgia and ankylosing spondylitis, The mechanisms involved in this efficacy are probably via cytokines and other inflammatory mediators The anti-oxidative mechanisms may be also involved !

48. Perspectives The favorable effects of spa and balneotherapy on the cytokines and other mediators of inflammation may create an interesting future for these interventions in the anti-cytokine / ‘‘biologic’’ therapy era.

49. Perspectives The favorable effects of spa and balneotherapy on oxidative stress and anti-oxidative status suggest that they may have an important role to play in the rheumatic diseases, as they lower the oxidative stress and the resultant inflammatory damage.

50. Conclusions These effects of balneo- and spa therapy seems to differ among different patient groups, but may be also different among spa resorts, thermal/mineral waters used and type of spa treatments provided

51. Questions to be answered What are the values of different mineral waters and the specific chemical constituents of mineral waters in observed effects of balneotherapy on inflammatory and oxidative processes?

52. Questions to be answered Do exercise, massage and other therapeutic modalities administered during spa therapy course besides balneotherapy, contribute to the overall favorable effects of spa therapy on inflammation and immune processes?

53. Questions to be answered If yes, to what extend? And then, how many spa treatments and/or what treatments when combined with balneotherapy constitute the optimal effect ?

54. Spa therapy and Balneotherapy Do they have biologic effects on Immune system and Inflammation and Oxidation ? Answer seems to be yes; Which mechanisms and mediators are involved? It is not completely understood yet

55. in search of reaching a comprehensive understanding of the ways and mechanisms how the biomarkers, cytokines, hormones and other mediators of inflammation and immune system and oxidative stress and anti-oxidation status are involved, and the roles they play in the effectiveness of spa and balneotherapy

58. Merci de votre attention