REVIEW ARTICLE | VOLUME 2, ISSUE 1 | OPEN ACCESS DOI: 10.23937/2572-4215.1510007

New Therapeutıc Aproach in Rheumatoıd Arthrıtıs: Ozone

Gulnur Tasci Bozbas* and Omer Faruk Sendur

Department of Physical Medicine and Rehabilitation, Adnan Menderes University Medical Faculty, Aydin, Turkey

*Corresponding author: Gulnur Tasci Bozbas, Physical Medicine and Rehabilitation Department, Adnan Menderes University Medical School, Aydin, Turkey, Tel: 0090-505-8313224.

Published: May 16, 2016

Citation: Bozbas GT, Sendur OF (2016) New Therapeutıc Aproach in Rheumatoıd Arthrıtıs: Ozone. Int J Physiatry 2:007.

Copyright: © 2016 Bozbas GT, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Rheumatoid arthritis is an autoimmune disorder, which leads to progressive articular destruction and disability. There are numerous agents used for treatment of the disease. However, since these agents may not provide remission or lead to serious complications, search for new treatments continues today. Ozone is a complementary therapy applied successfully for long years in treatment of treatment of circulatory disorders, cancer, inflammatory diseases and various metabolic diseases and anti-aging. The effect could be seen in activation of antioxidant defense system, improvement of circulation, oxygen delivery, inhibition of cytokine release in rheumatoid arthritis. But there is need additional studies on the humans of ozone administration.


Rheumatoid arthritis, Ozone, Cytokine, Antioxidant, Oxidative stress

Ozone is a gas, which consists of three oxygen atoms. Medical ozone therapy is a complementary treatment method in which ozone-oxygen mixture (0.05-5% O3; 95-99.95% O2) that obtained from oxygen generatore. Ozone that discovered for the first time in 1840 began to be used for therapeutic purposes since the early 1900s. It was applied successfully for long years in treatment of circulatory disorders, cancer, inflammatory diseases, various metabolic diseases and anti-aging. It has been argued that ozone affects as antimicrobial, antihypoxic, immunomodulatory, and anti-inflammatory agent [1]. The mild oxidative stress is revealed by ozone for its medical effects but no toxicity [2].

Rheumatoid arthritis (RA) is a chronic, inflammatory disease affecting approximately 1% of the population. It primarily affects the small joints in a symmetrical pattern with a potential for progressive joint destruction, and extra-articular and systemic manifestations may also be present. As the disease progresses, there are irreversible joint destruction and damage causing substantial disability. The aim of RA treatment is diminished inflammation and to decreased progression of erosion. Numerous biological and non-biological disease modifiying antirheumatic drugs (DMARDs) was used in the treatment of RA [3]. The therapy of RA remains one of the most actual problems of modern rheumatology, because in a great number of cases the best therapeutic efforts do not give expected results and are often associated with numerous complications and serious side effects [4]. Therefore, search for new treatment continues today. The interest of ozone in treating RA is increasing in recent years and several studies have been made in this issue.

How Do the Effects of Ozone in RA

The effect on cytokines

After administration, ozone is readily dissolves into H2O2 and aldehids such as 4-hydroksi-2E-nonenal (4-HNE) at the plasma and epithelium. H2O2 in plasma generates a 10% differences of gradient between plasma and intracellular area in cells [5]. Mild oxidative stress that caused by increasing of H2O2 in monocytes and lymphocytes activates nuclear factor-erythroid 2-related factor 2 (Nrf2) which an important cytoprotective nuclear transcription factor. Activated Nrf2 suppresses nuclear factor-kB (NF-γB) activation. NF-γB plays an important role in secretion of proinflammatory cytokine such as interleukin(IL)-8 and interferon (IF)-γ and its inhibition suppresses the releasing of these cytokines [2,6]. During each ozone therapy session, this immunmodulation appears of about 4% of the lymphocytes and monocytes present in the blood exposed to ozone ex vivo [7]. The cytokine levels in various autoimmune disease is reduced by ozone administration [3,8-11]. It has been shown that ozone decrease the cytokines such as IL-1 ve tumor necrosis factor (TNF)-α of serum, spleen homogenates and synovial fluid in RA [4,9].

The effect on antioxidants

The polymorphonuclear leukocytes (PMNs) in sinovial fluid is increase in the patients of RA. Reactive oxygen species (ROS) in which revealed in PMNs during phagocytosis disrupts the structure of hyaluronic acid, proteoglycans and collagen [12]. Thus, ROS leads to cartilage damage [2]. The antioxidants such as GSH-peroxidase, SOD and catalase play an important role the reduction of ROS. Several researchers has been suggested that enzymatic and/or nonenzymatic antioxidant systems are impaired in RA, and thus exposed to oxidant stress [13,14]. This patients are more prone to lipid peroxidation because of the reduced antioxidant defense system [15]. As a result of oxidative stress plays an important role in the pathogenesis of RA [12].

The high doses of 4-HNE which another product resulting from the metabolism of ozone is toxic to the organism. For this reason, it is rapidly metabolised by the detoxification, dilution and excretion [16]. At submicromolar or picomolar levels, 4-HNE can act as a signaling molecule, able to activate the synthesis of g-glutamate cysteine ligase, g-glutamyl transferase, g-glutamyl transpeptidase, heat shock proteins-70 (HSP-70), heme-oxygenas-1 (HO-1), and antioxidant enzymes such as superoxide dismutase (SOD), GSH-peroxidase, catalase, and glucose-6-phosphate dehydrogenase [17]. Another way to increase antioxidants after the ozone administration is through the Nrf2. Nrf2 is usually present within the cytosol as a complex with Keap-1 protein. Due to the mild oxidative stress by produced ozone, Nrf2 is released from this complex and is transported into nucleus. The transported Nrf2 forms a new complex with Maf protein, and induces the transcription of various antioxidant and phase II detoxification enzymes [2]. This step inhibits chronic inflammation in disorders such as RA, in pathogenesis of which oxidative stress plays a role [18].

Taking into account that medical ozone is a bioregulator which protects against damage by chronic oxidative stress through an oxidative pre/postconditioning mechanism [9]. The increasing of antioxidants inhibits chronic inflammation in disorders such as RA, in which oxidative stress plays a role in pathogenesis [18]. It has been shown that SOD which a potent antioxidant reduced nitrotyrosine formation and joint inflammation in RA [19]. Several experimental studies have demonstrated that controlled ozone administration could bring about a state of ozone oxidative preconditioning or adaptation to oxidative stress, preventing the damage caused by ROS [20-22]. The antioxidant capacity of plasma should not exceed more than 25% to avoid toxic effects [2].

The Effect on Clinical and Histopathological Findings

Vaillant et al. has been shown that arthritis index was decreased in the RA group of treated with 20 μg/ml ozone compared with the non-treating RA group. In this study, ozone has been applied 3 times/ week for a total 10 times and clinical effect was observed after 4 times [9]. Chen et al. has been detected to improvement in arthritis with 40 μg/ml ozone [4]. Ozone improves not only clinical findings but also histopathological findings in RA. It has been shown that the proliferation of angioblast and new capillaries in synovial membran in RA recovered with ozone administration [9]. In addition, 5% ozone aplication for RA sinovial fibroblast cell culture have resulted in decrease an inflammation [8].

IL-17 activates nuclear factor-kappaB ligand (RANKL) which leading to NF-γB activation and thus helps to differantiation of osteoclasts in RA. Osteoclasts also play a major role to the development of erosion in RA [23]. Nrf2 which increasing with ozone administration can prevent erosions in RA by supressing NF- γB activity. In addition, osone can be benefical in the prevention of RA dependent systemic osteoporosis [2,24].

The studies on ozone treatment of RA is very limited and we need additional studies on the humans of ozone administration.

Therapeutic Dose in Rheumatoid Arthritis

The response of organism to ozone is dose-dependent. In order to acquire a stimulating and suppressing effect, the chosen dose varies according to the oxidative load and antioxidant capacity of tissue to be applied. The “therapeutic window” for O3 was stated as 10-80 μg/ml [2]. In applications with doses under the necessary dose, a response cannot be obtained and in unnecessarily high doses, since the antioxidant capacity is exceeded, carbohydrates, enzymes, DNA, and RNA might be affected by the reactions. An ozone concentration below 10 μg/ml is in most cases totally quenched by the hydrosoluble antioxidants and therefore no biological effects can be elicited [17]. Chen et al. were determined that exacerbation of arthritis was found to emerge with 50 μg/ml dose of O3 in treatment of RA, and the most effective dose was reported to be 40 μg/ml [4]. In other study, after intraarticular osone administration with a dose of 20 μg/ml, improvement in arthritis index was detected [9]. Ozone is administrated via major autohemotherapy, intrarectal and intraarticular in RA [4,9].

There is neither damage to erythrocytes nor to other cells: hemolysis is negligible (from 0.4 up to 1.2%), there is no leakage of K+ and methemoglobin remains normal [25]. As well as no toxic effects have been observed [4,9,19-21,26].

In conclusion; ozone is an effective and reliable complementary therapy that can used in treatment of RA. But it is quite assertive to say that the use of ozone alone cures the RA. Nevertheless it can reduce to need for DMARD's or accelerate to occurence of remission. Ozone should be applied as support of medical treatment, as soon as diagnosis of RA.


  1. Bocci VA (2006) Scientific and medical aspects of ozone therapy. State of the art. Arch Med Res 37: 425-435.

  2. Sagai M, Bocci V (2011) Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress? Med Gas Res 1: 29.

  3. Firestein GS (2005) Etiology and pathogenesis of rheumatoid arthritis. In: Ruddy S, Harris ED, Sledge CB, Kelley WN, Kelley's Textbook of Rheumatology. (7th edn), W.B. Saunders, Philadelphia, PA, 996-1042.

  4. Chen H, Yu B, Lu C, Lin Q (2013) The effect of intra-articular injection of different concentrations of ozone on the level of TNF-a, TNF-R1, and TNF-R2 in rats with rheumatoid arthritis. Rheumatol Int 33: 1223-1227.

  5. Bocci V, Aldinucci C (2005) The use of hydrogen peroxide as a medical drug. Riv Ital Ossigeno-Ozonoter 4: 30-39.

  6. Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, et al. (2014) Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications World J Orthop 5: 516-536.

  7. Bocci V, Borrelli E, Valacchi G, Luzzi E (1999) Quasi-total-body exposure to an oxygen-ozone mixture in a sauna cabin. Eur J Appl Physiol Occup Physiol 80: 549-554.

  8. Chang J, Lu HS, Chang YF, Wang D (2005) Ameliorative effect of ozone on cytokine production in mice injected with human rheumatoid arthritis synovial fibroblast cells. Rheumatol Int 26: 142-151.

  9. Vaillant JD, Fraga A, Díaz MT, Mallok A, Viebahn-Hänsler R, et al. (2013) Ozone oxidative postconditioning ameliorates joint damage and decreases proinflammatory cytokine levels and oxidative stress in PG/PS-induced arthritis in rats. Eur J Pharmacol 15: 318-324.

  10. Cho HY, Morgan DL, Bauer AK, Kleeberger SR (2007) Signal transduction pathways of tumor necrosis factor--mediated lung injury induced by ozone in mice. Am J Respir Crit Care Med 175: 829-839.

  11. Fakhrzadeh L, Laskin JD, Laskin DL (2004) Ozone-induced production of nitric oxide and TNF-alpha and tissue injury are dependent on NF-kappaB p50. Am J Physiol Lung Cell Mol Physiol 287: L279-285.

  12. Hitchon CA, El-Gabalawy HS (2004) Oxidation in rheumatoid arthritis. Arthritis Res Ther 6: 265-278.

  13. Karatas F, Ozates I, Canatan H, Halifeoglu I, Karatepe M, et al. (2003) Antioxidant status & lipid peroxidation in patients with rheumatoid arthritis. Indian J Med Res 118: 178-181.

  14. 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.

  15. Gambhir JK, Lali P, Jain AK (1997) Correlation between blood antioxidant levels and lipid peroxidation in rheumatoid arthritis. Clin Biochem 30: 351-355.

  16. Bocci VA, Zanardi I, Travagli V (2011) Ozone acting on human blood yields a hormetic dose-response relationship. J Transl Med 9: 66.

  17. Bocci V, Zanardi I, Travagli V (2011) Ozone: a new therapeutic agent in vascular diseases. Am J Cardiovasc Drugs 11: 73-82.

  18. Nabil Mawsouf M, Maha El-Sawalhi M, Martínez-Sánchez G, Hebatalla Darwish A, Amira Shaheen A (2011) Effect of ozone therapy on redox status in experimentally induced arthritis. Revista Española de Ozonoterapia 1: 32-43.

  19. Salvemini D, Mazzon E, Dugo L, Serraino I, De Sarro A, et al. (2001) Amelioration of joint disease in a rat model of collagen-induced arthritis by M40403, a superoxide dismutase mimetic. Arthritis Rheum 44: 2909-2921.

  20. Ajamieh HH, Menéndez S, Martínez-Sánchez G, Candelario-Jalil E, Re L, et al. (2004) Effects of ozone oxidative preconditioning on nitric oxide generation and cellularredox balance in a rat model of hepatic ischaemia-reperfusion. Liver Int 24: 55-62.

  21. Borrego A, Zamora ZB, González R, Romay C, Menéndez S, et al. (2004) Protection by ozone preconditioning is mediated by the antioxidant system in cisplatin-induced nephrotoxicity in rats. Mediators Inflamm 13: 13-19.

  22. Calunga JL, Zamora ZB, Borrego A, Río Sd, Barber E, et al. (2005) Ozone therapy on rats submitted to subtotal nephrectomy: role of antioxidant system. Mediators Inflamm 31: 221-227.

  23. Baum R, Gravallese EM (2014) Impact of inflammation on the osteoblast in rheumatic diseases. Curr Osteoporos Rep 12: 9-16.

  24. Bozbas GT, Kilimci FS, Yilmaz M, Gurer G, Demirci B The Effect of Ozone on Bone Strenght in Animal Model of Rheumatoid Arthritis. Turk J Osteoporos.

  25. Travagli V, Zanardi I, Silvietti A, Bocci V (2007) A physicochemical investigation on the effects of ozone on blood. Int J Biol Macromol 41: 504-511.

  26. Erken HA, Genc O, Erken G, Ayada C, Gundogdu G, et al. (2015) Ozone partially prevents diabetic neuropathy in rats. Exp Clin Endocrinol Diabetes 123: 101-105.