Abstract
Oxidative stress has been shown to play a contributory role in the pathogenesis of rheumatoid arthritis (RA). Recent studies have provided evidence for antioxidant properties of spa therapy. The purpose of this study is to investigate whether spa therapy with saline balneotherapy has any influence on the oxidant/antioxidant status in patients with RA and to assess clinical effects of spa therapy. In this investigator-blind randomized controlled trial, we randomly assigned 50 patients in a 1:1 ratio to spa therapy plus standard drug treatment (spa group) or standard drug treatment alone (control group). Spa group followed a 2-week course of spa therapy regimen consisting of a total of 12 balneotherapy sessions in a thermal mineral water pool at 36–37 °C for 20 min every day except Sunday. All clinical and biochemical parameters were assessed at baseline and after spa therapy (2 weeks). The clinical parameters were pain intensity, patient global assessment, physician global assessment, Health Assessment Questionnaire disability index (HAQ-DI), Disease Activity Score for 28-joints based on erythrocyte sedimentation rate (DAS28–4[ESR]). Oxidative status parameters were malondialdehyde (MDA), nonenzymatic superoxide radical scavenger activity (NSSA), antioxidant potential (AOP), and superoxide dismutase (SOD). The NSSA levels were increased significantly in the spa group (p = 0.003) but not in the control group (p = 0.509); and there was a trend in favor of spa therapy for improvements in NSSA levels compared to control (p = 0.091). Significant clinical improvement was found in the spa group compared to the control in terms of patient global assessment (p = 0.011), physician global assessment (p = 0.043), function (HAQ-DI) (p = 0.037), disease activity (DAS28–4[ESR]) (0.044) and swollen joint count (0.009), and a trend toward improvement in pain scores (0.057). Spa therapy with saline balneotherapy exerts antioxidant effect in patients with RA as reflected by the increase in NSSA levels after spa therapy; whether this antioxidant effect contributes to the clinical improvements observed remains to be verified.
Similar content being viewed by others
Abbreviations
- AOP:
-
Antioxidant potential
- CO2 :
-
Carbon dioxide
- CRP:
-
C-reactive protein
- DAS28–4:
-
Disease Activity Score for 28-joints of 4 variables
- DMARD:
-
Disease-modifying antirheumatic drug
- ESR:
-
Erythrocyte sedimentation rate
- H2S:
-
Hydrogen sulfide
- HAQ-DI:
-
Health Assessment Questionnaire Disability Index
- MDA:
-
Malondialdehyde
- NaCl:
-
Sodium chloride
- NBT:
-
Nitroblue tetrazolium
- NSSA:
-
Nonenzymatic superoxide radical scavenger activity
- RA:
-
Rheumatoid arthritis
- RNS:
-
Reactive nitrogen species
- ROS:
-
Reactive oxygen species
- SD:
-
Standard deviation
- SOD:
-
Superoxide dismutase
- TCA:
-
Trichloroacetic acid
- TNF :
-
Tumor necrosis factor
- VAS :
-
Visual analog scale
References
Annegret F, Thomas F (2013) Long-term benefits of radon spa therapy in rheumatic diseases: results of the randomised, multi-Centre IMuRa trial. Rheumatol Int 33:2839–2850
Ardiç F, Ozgen M, Aybek H, et al. (2007) Effects of balneotherapy on serum IL-1, PGE2 and LTB4 levels in fibromyalgia patients. Rheumatol Int 27:441–446
Arnett FC, Edworthy SM, Bloch DA, et al. (1988) The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324
Bazzichi L, Da Valle Y, Rossi A, et al. (2013) A multidisciplinary approach to study the effects of balneotherapy and mud-bath therapy treatments on fibromyalgia. Clin Exp Rheumatol 31:S111–S120
Bender T, Bariska J, Vághy R, et al. (2007) Effect of balneotherapy on the antioxidant system--a controlled pilot study. Arch Med Res 38:86–89
Bender T, Karagülle Z, Bálint GP, Gutenbrunner C, Bálint PV, Sukenik S (2005) Hydrotherapy, balneotherapy, and spa treatment in pain management. Rheumatol Int 25:220–224
Benedetti S, Canino C, Tonti G, et al. (2010) Biomarkers of oxidation, inflammation and cartilage degradation in osteoarthritis patients undergoing sulfur-based spa therapies. Clin Biochem 43:973–978
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Stat Methodol 57:289–300
Bjelakovic G, Nikolova D, Gluud LL et al (2012) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases Cochrane Database Syst Rev CD007176
Bjelakovic G, Nikolova D, Gluud C (2014) Antioxidant supplements and mortality. Curr Opin Clin Nutr Metab Care 17:40–44
Boros M, Kemény Á, Sebők B, et al. (2013) Sulphurous medicinal waters increase somatostatin release: it is a possible mechanism of anti-inflammatory effect of balneotherapy in psoriasis. Eur J Integr Med 5:109–118
Braga PC, Ceci C, Marabini L, Nappi G (2013) The antioxidant activity of sulphurous thermal water protects against oxidative DNA damage: a comet assay investigation. Drug Res (Stuttg) 63:198–202
Braga PC, Dal Sasso M, Culici M, et al. (2012) Free radical-scavenging activity of sulfurous water investigated by electron paramagnetic resonance (EPR) spectroscopy. Exp Lung Res 38:67–74
Bruce B, Fries JF (2005) The Health Assessment Questionnaire (HAQ). Clin Exp Rheumatol 23:S14–S18
Burguera EF, Vela-Anero A, Magalhães J, Meijide-Faílde R, Blanco FJ (2014) Effect of hydrogen sulfide sources on inflammation and catabolic markers on interleukin 1β-stimulated human articular chondrocytes. Osteoarthr Cartil 22:1026–1035
Caporali R, Bellometti S, Rossi S, et al. (2010) Safety of mud-bath applications in moderately active rheumatoid arthritis. J Musculoskelet Pain 18:81–87
Carter HH, Spence AL, Pugh CJ, et al. (2014) Cardiovascular responses to water immersion in humans: impact on cerebral perfusion. Am J Phys Regul Integr Comp Phys 306:R636–R640
Cimen MY, Cimen OB, Kaçmaz M, et al. (2000) Oxidant/antioxidant status of the erythrocytes from patients with rheumatoid arthritis. Clin Rheumatol 19:275–277
Codish S, Abu-Shakra M, Flusser D, et al. (2005) Mud compress therapy for the hands of patients with rheumatoid arthritis. Rheumatol Int 25:49–54
Dahle LK, Hill EG, Holman RT (1962) The thiobarbituric acid reaction and the autoxidations of polyunsaturated fatty acid methyl esters. Arch Biochem Biophys 98:253–261
De Bandt M, Grossin M, Driss F, et al. (2002) Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum 46:522–532
Dogliotti G, Galliera E, Iorio E (2011) Effect of immersion in CO2-enriched water on free radical release and total antioxidant status in peripheral arterial occlusive disease. Int Angiol 30:12–17
Dönmez A, Tütüncü ZN, Öztürk K, et al. (2000) Evaluation of the effects of H2S-and CO2-water baths on peripheral circulation disorders. Phys Med Rehab Kuror 10:58–59
Durak I, Canbolat O, Kaçmaz M, et al. (1998) Antioxidant interferences in superoxide dismutase activity methods using superoxide radical as substrate. Clin Chem Lab Med 36:407–408
Durak I, Bingöl NK, Avci A, et al. (2000) Acute effects of smoking of cigarettes with different tar content on plasma oxidant/antioxidant status. Inhal Toxicol 12:641–647
Ekmekcioglu C, Strauss-Blasche G, Holzer F, Marktl W (2002) Effect of sulfur baths on antioxidative defense systems, peroxide concentrations and lipid levels in patients with degenerative osteoarthritis. Forsch Komplementarmed Klass Naturheilkd 9:216–220
Elkayam O, Wigler I, Tishler M, et al. (1991) Effect of spa therapy in Tiberias on patients with rheumatoid arthritis and osteoarthritis. J Rheumatol 18:1799–1803
Falkenbach A, Kovacs J, Franke A, Jörgens K, Ammer K (2005) Radon therapy for the treatment of rheumatic diseases--review and meta-analysis of controlled clinical trials. Rheumatol Int 25:205–210
Fioravanti A, Cantarini L, Guidelli GM, Galeazzi M (2011a) Mechanisms of action of spa therapies in rheumatic diseases: what scientific evidence is there? Rheumatol Int 31:1–8
Fioravanti A, Cantarini L, Bacarelli MR, et al. (2011b) Effects of spa therapy on serum leptin and adiponectin levels in patients with knee osteoarthritis. Rheumatol Int 31:879–882
Fioravanti A, Lamboglia A, Pascarelli NA, et al. (2013) Thermal water of Vetriolo, Trentino, inhibits the negative effect of interleukin-1B; on nitric oxide production and apoptosis in human osteoarthritic chondrocyte. J Biol Regul Homeost Agents 27:891–902
Fioravanti A, Giannitti C, Cheleschi S, et al. (2015b) Circulating levels of adiponectin, resistin, and visfatin after mud-bath therapy in patients with bilateral knee osteoarthritis. Int J Biometeorol 59:1691–1700
Fioravanti A, Adamczyk P, Pascarelli NA, et al. (2015a) Clinical and biochemical effects of a 3-week program of diet combined with spa therapy in obese and diabetic patients: a pilot open study. Int J Biometeorol 59:783–789
Forestier R, André-Vert J, Guillez P, et al. (2009) Non-drug treatment (excluding surgery) in rheumatoid arthritis: clinical practice guidelines. Joint Bone Spine 76:691–698
Fortunati NA, Fioravanti A, Seri G, et al. (2016) May spa therapy be a valid opportunity to treat hand osteoarthritis? A review of clinical trials and mechanisms of action. Int J Biometeorol 60:1–8
Franke A, Reiner L, Pratzel HG, et al. (2000) Long-term efficacy of radon spa therapy in rheumatoid arthritis—a randomized, sham-controlled study and follow-up. Rheumatology (Oxford) 39:894–902
Franke A, Reiner L, Resch KL (2007) Long-term benefit of radon spa therapy in the rehabilitation of rheumatoid arthritis: a randomised, double-blinded trial. Rheumatol Int 27:703–713
Grabski M, Wozakowska-Kapłon B, Kedziora J (2004) Hydrogen sulfide water balneum effect on erythrocyte superoxide dismutase activity in patients with rheumatoid arthritis—in vitro study. Przegl Lek 61:1405–1409
Gutenbrunner C, Bender T, Cantista P, Karagülle Z (2010) A proposal for a worldwide definition of health resort medicine, balneology, medical hydrology and climatology. Int J Biometeorol 54:495–507
Hall J, Skevington SM, Maddison PJ, Chapman K (1996) A randomized and controlled trial of hydrotherapy in rheumatoid arthritis. Arthritis Care Res 9:206–215
Hirao M, Yamasaki N, Oze H, et al. (2012) Serum level of oxidative stress marker is dramatically low in patients with rheumatoid arthritis treated with tocilizumab. Rheumatol Int 32:4041–4045
Hitchon CA, El-Gabalawy HS (2004) Oxidation in rheumatoid arthritis. Arthritis Res Ther 6:265–278
Jokić A, Sremcević N, Karagülle Z, et al. (2010) Oxidative stress, hemoglobin content, superoxide dismutase and catalase activity influenced by sulphur baths and mud packs in patients with osteoarthritis. Vojnosanit Pregl 67:573–578
Kageyama Y, Takahashi M, Nagafusa T, et al. (2008) Etanercept reduces the oxidative stress marker levels in patients with rheumatoid arthritis. Rheumatol Int 28:245–251
Karagülle M, Karagülle MZ (2015) Effectiveness of balneotherapy and spa therapy for the treatment of chronic low back pain: a review on latest evidence. Clin Rheumatol 34:207–214
Karagülle M, Kardeş S, Dişçi R, Gürdal H, Karagülle MZ (2016) Spa therapy for elderly: a retrospective study of 239 older patients with osteoarthritis. Int J Biometeorol. doi:10.1007/s00484-016-1138-7
Karagulle MZ, Tutuncu ZN, Aslan O, et al. (1996) Effects of thermal sulphur bath cure on adjuvant arthritic rats. Phys Med Rehab Kuror 6:53–57
Karagülle MZ, Karagülle M (2004) Balneotherapy and spa therapy of rheumatic diseases in Turkey: a systematic review. Forsch Komplementarmed Klass Naturheilkd 11:33–41
Karagülle O, Candir F, Kalinin J, Gehrke A, Karagülle MZ, Gutenbrunner C (2004) Akutwirkungen kalter CO2- Teilbäder auf Mikrozirkulation und Schmerzempfindlichkeit. Phys Med Rehab Kuror 14:13–17
Katz U, Shoenfeld Y, Zakin V, et al. (2012) Scientific evidence of the therapeutic effects of dead sea treatments: a systematic review. Semin Arthritis Rheum 42:186–200
Kim LB, Zhilyakov IV (2008) Content of fibronectin and glycosaminoglycans in blood serum of rats with SiO2-induced inflammation after radon-containing water bath. Bull Exp Biol Med 146:717–718
Kloesch B, Liszt M, Krehan D, et al. (2012) High concentrations of hydrogen sulphide elevate the expression of a series of pro-inflammatory genes in fibroblast-like synoviocytes derived from rheumatoid and osteoarthritis patients. Immunol Lett 141:197–203
Kocabas H, Kocabas V, Buyukbas S, et al. (2010) Relationship of cellular oxidant and antioxidant status with disease activity in patients with rheumatoid arthritis. Turk J Rheumatol 25:141–147
Lange U, Müller-Ladner U, Schmidt KL (2006) Balneotherapy in rheumatic diseases—an overview of novel and known aspects. Rheumatol Int 26:497–499
Leibetseder V, Strauss-Blasche G, Holzer F, et al. (2004) Improving homocysteine levels through balneotherapy: effects of sulphur baths. Clin Chim Acta 343:105–111
Leicht CA, Kouda K, Umemoto Y, et al. (2015) Hot water immersion induces an acute cytokine response in cervical spinal cord injury. Eur J Appl Physiol 115:2243–2252
Liang J, Kang D, Wang Y, et al. (2015) Carbonate ion-enriched hot spring water promotes skin wound healing in nude rats. PLoS One 10(2):e0117106
Loos W, Griebenow S, Winkler R, Porta S (2006) Single cure treatments influence the pro/antioxidative balance. Phys Med Rehab Kuror 16:326–329
Lowry CA, Lightman SL, Nutt DJ (2009) That warm fuzzy feeling: brain serotonergic neurons and the regulation of emotion. J Psychopharmacol 23:392–400
Marković M, Majkić-Singh N, Ignjatović S (2009) Beneficial effects of cellular stress response in traditional spa treatment of rheumatoid arthritis. Clin Lab 55:235–241
Martins DF, Brito RN, Stramosk J, et al. (2015) Peripheral neurobiologic mechanisms of antiallodynic effect of warm water immersion therapy on persistent inflammatory pain. J Neurosci Res 93:157–166
McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219
Mourad E, Harzy T (2012) Sulphur thermal water improves blood lipids but not total anti-oxidant capacity in knee osteoarthritis patients. Shiraz E-Med J 13:54–58
Nugraha B, Neues-Lahusen M, Candir F, Gutenbrunner C (2011) Effect of a series of H2S mineral water bathing on pain in patients with fibromyalgia syndrome—a pilot study. Phys Med Rehab Kuror 21:284–289
O’Hare JP, Heywood A, Dodds P, et al. (1984) Water immersion in rheumatoid arthritis. Br J Rheumatol 23:117–118
O'Hare JP, Heywood A, Summerhayes C, et al. (1985) Observations on the effect of immersion in bath spa water. Br Med J (Clin Res Ed) 291:1747–1751
Oláh M, Koncz A, Fehér J, et al. (2010) The effect of balneotherapy on C-reactive protein, serum cholesterol, triglyceride, total antioxidant status and HSP-60 levels. Int J Biometeorol 54:249–254
Oláh M, Koncz Á, Fehér J, et al. (2011) The effect of balneotherapy on antioxidant, inflammatory, and metabolic indices in patients with cardiovascular risk factors (hypertension and obesity)—a randomised, controlled, follow-up study. Contemp Clin Trials 32:793–801
Ozkan Y, Yardým-Akaydýn S, Sepici A, et al. (2007) Oxidative status in rheumatoid arthritis. Clin Rheumatol 26:64–68
Oztürk HS, Cimen MY, Cimen OB, et al. (1999) Oxidant/antioxidant status of plasma samples from patients with rheumatoid arthritis. Rheumatol Int 19:35–37
Pagourelias ED, Zorou PG, Tsaligopoulos M, et al. (2011) Carbon dioxide balneotherapy and cardiovascular disease. Int J Biometeorol 55:657–663
Pendergast DR, Lundgren CE (2009) The underwater environment: cardiopulmonary, thermal, and energetic demands. J Appl Physiol 106:276–283
Prevoo ML, van't Hof MA, Kuper HH, et al. (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–48
Proceedings of the International Conference; International Congress on Spa Therapy with Saline Waters in Health Resorts (2010) ÖZPMR, Österr Z Phys Med Rehabil 20:51–63
Reginster JY, Badurski J, Bellamy N, et al. (2013) Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis 72:179–186
Santos I, Cantista P, Vasconcelos C (2015) Balneotherapy in rheumatoid arthritis—a systematic review. Int J Biometeorol. doi:10.1007/s00484-015-1108-5
Sarban S, Kocyigit A, Yazar M, Isikan UE (2005) Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis. Clin Biochem 38:981–986
Sato M, Kanikowska D, Iwase S, et al. (2009) Effects of immersion in water containing high concentrations of CO2 (CO2-water) at thermoneutral on thermoregulation and heart rate variability in humans. Int J Biometeorol 53:25–30
Seven A, Güzel S, Aslan M, Hamuryudan V (2008) Lipid, protein, DNA oxidation and antioxidant status in rheumatoid arthritis. Clin Biochem 41:538–543
Shehata M, Schwarzmeier JD, Hilgarth M, et al. (2006) Effect of combined spa-exercise therapy on circulating TGF-beta1 levels in patients with ankylosing spondylitis. Wien Klin Wochenschr 118:266–272
Steiner FJ, Valkenburg HA, van de Stadt RJ, et al. (1979) Balneology treatment of patients with rheumatoid arthritis. Ned Tijdschr Geneeskd 123:661–664
Staalesen Strumse YA, Nordvag BY, Stanghelle JK, et al. (2009) The efficacy of rehabilitation for patients with rheumatoid arthritis: comparison between a 4-week rehabilitation programme in a warm and cold climate. Scand J Rheumatol 38:28–37
Stamp LK, Khalilova I, Tarr JM, et al. (2012) Myeloperoxidase and oxidative stress in rheumatoid arthritis. Rheumatology (Oxford) 51:1796–1803
Sukenik S, Buskila D, Neumann L, et al. (1990a) Sulphur bath and mud pack treatment for rheumatoid arthritis at the Dead Sea area. Ann Rheum Dis 49:99–102
Sukenik S, Neumann L, Buskila D, et al. (1990b) Dead Sea bath salts for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 8:353–357
Sukenik S, Neumann L, Flusser D, et al. (1995) Balneotherapy for rheumatoid arthritis at the Dead Sea. Isr J Med Sci 31:210–214
Sukenik S, Flusser D, Abu-Shakra M (1999) The role of spa therapy in various rheumatic diseases. Rheum Dis Clin N Am 25:883–897
Tarner IH, Müller-Ladner U, Uhlemann C, Lange U (2009) The effect of mild whole-body hyperthermia on systemic levels of TNF-alpha, IL-1beta, and IL-6 in patients with ankylosing spondylitis. Clin Rheumatol 28:397–402
Tenti S, Cheleschi S, Galeazzi M, Fioravanti A (2015) Spa therapy: can be a valid option for treating knee osteoarthritis? Int J Biometeorol 59:1133–1143
van Tubergen A, Landewé R, van der Heijde D, et al. (2001) Combined spa-exercise therapy is effective in patients with ankylosing spondylitis: a randomized controlled trial. Arthritis Rheum 45:430–438
Vareka I, Stejskal D, Varekova R, et al. (2009) Changes in clusterin serum concentration levels in oncologic patients during the course of spa therapy—a pilot study. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 153:117–120
Verhagen AP, Bierma-Zeinstra SM, Boers M et al (2015) Balneotherapy (or spa therapy) for rheumatoid arthritis. Cochrane Database Syst Rev CD000518
Wruck CJ, Fragoulis A, Gurzynski A, et al. (2011) Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 70:844–850
Yamamoto N, Hashimoto M (2007a) Immersion in CO2-rich water containing NaCl diminishes blood pressure fluctuation in anesthetized rats. Int J Biometeorol 52:109–116
Yamamoto N, Hashimoto M (2007b) Spinal cord transection inhibits HR reduction in anesthetized rats immersed in an artificial CO2-hot spring bath. Int J Biometeorol 51:201–208
Yurtkuran M, Yurtkuran MA, Dilek K, et al. (1999) A randomized, controlled study of balneotherapy in patients with rheumatoid arthritis. Phys Med Rehab Kuror 9:92–96
Zwerina J, Tzima S, Hayer S, et al. (2005) Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption. FASEB J 19:2011–2013
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
None.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Karagülle, M., Kardeş, S., Karagülle, O. et al. Effect of spa therapy with saline balneotherapy on oxidant/antioxidant status in patients with rheumatoid arthritis: a single-blind randomized controlled trial. Int J Biometeorol 61, 169–180 (2017). https://doi.org/10.1007/s00484-016-1201-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00484-016-1201-4