中度全身熱療和補充藥物治療類風濕性關節炎的初步研究

Effects of moderate whole-body hyperthermia and complementary medicine in the treatment of rheumatoid arthritis: a preliminary study

Abstract
It is estimated that more than two-thirds of patients with rheumatoid arthritis (RA) use complementary and alternative medicine (CAM). The rationale for the use of some CAM therapies is supported by reasonable evidence. 8 patients with RA were included in the preliminary study. Patients received treatment that included whole-body hyperthermia, ozone major autohemotherapy, intravenous vitamin C and individual nutrition counselling for 4 weeks. The patient’s perceptions of pain, stiffness, and fatigue were measured on a 100-mm visual analogue scale and were considered as primary outcomes. In all patients, a significant improvement was seen at the end of the treatment and post-treatment. Pain and stiffness reduced over 40%, while fatigue nearly 60% for patients with RA. More importantly, the treatment was found to be safe and did not relate with any adverse events. The results of this study are encouraging and may become a platform for future planning of long-term studies with the complementary treatments in combination with existing standard therapies in RA.

Introduction
Rheumatoid arthritis (RA) is a symmetric, inflammatory, peripheral polyarthritis of unknown aetiology, which affects multiple small joints of the hands and feet. The evolution of hyperplastic synovial tissue, leads to deformity through the stretching of tendons and ligaments and destruction of joints through the erosion of cartilage and bone.
It is estimated that 60% to 90% of persons with arthritis, particularly those with rheumatoid arthritis, have used complementary and alternative medicine (CAM) [1]. The rationale for the use of some therapies is supported by a reasonable and fairly consistent body of evidence.

Heat treatment in patients with rheumatic disorders has been used through the ages. Initially,
the application of hyperthermia treatment was mainly empirical. In the last few decades evidence from clinical studies documented its beneficial effects in RA [2,3]. Pain and stiffness decrease, and grip strength and range of motion improve after application of local hyperthermia [4]. Some studies reported beneficial effects of whole-body hyperthermia (WBH) [5,6].In this preliminary study, the effectiveness of whole-body hyperthermia and complementary therapies in the treatment of rheumatoid arthritis was evaluated.

Material and methods

8 patients with RA were included in the study. Patients received treatment for 4 weeks. After oral and written information about the treatment and the possible clinical effects of applied therapies, patients were invited to the study. Informed consent was obtained from all patients. Clinical measurements were performed before the start of the treatment, at the end of the 4-week period of therapy and one month after the end of the treatment series. The patient’s perceptions of pain [7], stiffness [8], and fatigue [9–11] were measured on a 100-mm visual analogue scale and were considered as primary outcomes.

Statistical analysis

The conformity assessment was carried out by the Shapiro-Wilk test. The homogeneity of variance was tested with Bartlett’s test. The significance of differences in mean values (M) in more than two populations for parameters of normal distribution and of homogeneous variances was assessed with analysis of variance (ANOVA). In case of rejection of the null hypothesis of homogeneity of variance, to verify the differences between the mean values in pairs, post-hoc tests were performed (Scheffe test). The level p = 0.05 was assumed as the critical significance level. Data was expressed as M±SD and analysed with the statistical program STATISTICA v.12 (StatSoft, Inc. Tulsa, USA).

Treatment protocol
The treatment protocol consisted of: 4 moderate whole-body hyperthermia sessions (once every week), 8 sessions (twice every week) of ozone major autohemotherapy (MAHT) and intravenous vitamin C (IVC), as well as two individual nutrition counselling.
Results
Patient characteristics. A total of 8 patients (6 female, 2 male) with RA were included in the study with mean age of 51 (Table 1). One patient dropped out in the treatment period due to nonmedical reasons and could not be measured for follow-up. Hence, the mean group results of 7 patients are presented in Table 2. Pain and stiffness (p<0.05) as well as fatigue (p<0.001) significantly decreased at the end of the treatment and post-treatment periods.
Discussion
In all patients, a clinically significant improvement was seen at the end of the treatment and post-treatment. Pain and stiffness reduced over 40%, while fatigue nearly 60% for patients with RA (Table 2). The effect of whole-body hyperthermia upon local joint inflammation or disease activity is not clear. The findings of earlier studies were ambiguous [12-18], and many studies have no optimal quality as summarized in the COCHRANE study [2]. It is known that whole-body hyperthermia can enhance immune surveillance, including increased mobility and activity of white blood cells [19,20]. It is hypothesized that increased temperature can modulate the immune response by targeting the intracellular signalling pathways, cytokines, and other mediators of the phases of RA.
Ozone major autohemotherapy was first described in 1954 [21] and since then, after Wolff’s modification [22], it has been carried out worldwide millions of times without side-effects and with therapeutic results [23]. The rationale for the use of ozone is based on its immunosoppressive action if it is used at high concentration (45-65 μg/ml) [24]. Several studies described its anti-inflammatory and analgesic effects [25,26], the functional
recovery of muscle and joint groups [27,28], as well as perfusion improvement of microcirculation [29]. A study by Chang et al. demonstrated that ozone applied externally ameliorated the inflammatory reaction of RA without toxicity or serious side effects [30]. The authors found that the decrease in cytokine synthesis and secretion was due to the pouring of ozone into the inflamed and infiltrated area via oxidation and eliminating the hyperplastic synovial fibroblasts. Our study showed that ozone in the form of MAHT was well-tolerated and contributed to the beneficial outcome of the therapy.
Oxidative stress and severe systemic inflammation have been considered as important pathophysiologic mechanisms involved in the development of RA [31, 32]. Oxidative stress occurs in response to the oxidative damage resulting from imbalance between antioxidant and scavenging ability and the active oxidants produced by a harmful stimulant [32, 33]. Previous reports showed that significantly elevated production of reactive oxygen species (ROS) in the serum of RA patients can be observed comparing with healthy donors [34]. ROS are indirectly involved in joint damage as the secondary messengers in inflammatory and immunological cellular response in RA, which also can degrade directly the joint cartilage, influencing its proteoglycan and inhibiting its synthesis [35, 36].
In this study, the rationale for the use of IVC and diet modification has been based on their anti-inflammatory action. Vitamin C has direct antioxidant capacity and contributes to the protection of cells from the damaging effects of endogenously produced or exogenous reactive oxygen radicals and reactive nitrogen species, e.g. during immune activation. Vitamin C prevents oxidative damage to lipids, proteins, and DNA, which has been implicated as a major contributing factor in the development of chronic diseases such as cardiovascular disease, cancer, and cataract, respectively [37,38]. Evidence further suggests that vitamin C provides indirect antioxidant protection by regenerating other biologically important antioxidants such as glutathione and vitamin E to their active state [39]. The nutritional and physiological aspects of this essential nutrient have been widely reviewed in a large number of comprehensive publications on vitamin C [37,40]. To our knowledge, this is the first study that evaluated the demonstrated that IVC is safe and does not correlate with any adverse events.
Among a number of small clinical trials of dietary manipulation in RA, modest benefit has been noted for high-dose omega-3 fatty acids, fasting, vegetarian diet, and Mediterranean-type diet [41-43]. In a recent study by Tedeschi et al. [44] 24.0% of subjects in a prospective,

longitudinal RA registry reported that foods affect their RA symptoms, and 24.3% avoid foods due to worsening of their RA. Among a list of 20 specific foods, blueberries and spinach were most often noted to improve RA, while soda with sugar and desserts were most commonly reported to worsen RA. Past work has shown that greater consumption of sugar-sweetened beverages is associated with increased risk for developing RA [45].
In this study, a certified nutritionist provided face-to-face counselling that was individually tailored to each patient. Each counselling session lasted 30 to 60 minutes, during which nutritionists educated and strongly recommended patients to follow an anti-inflammatory diet. The Western-type diet, which is high in red meat, high-fat dairy products, refined grains, and simple carbohydrates, has been associated with higher levels of CRP and IL-6 [46]. On the other hand, the anti-inflammatory Mediterranean diet, which is high in whole grains, fish, fruit and green vegetables, and associated with moderate alcohol and olive oil intake and low intake of red meat and butter has been associated with lower levels of inflammation [47–51]. Diets high in fruit and vegetable intake have been associated with lower levels of CRP [52–54]. Specific nutrients such as (n-3) fatty acids [55–56], fiber [57–58], moderate alcohol intake [59-60], vitamin C [61-62], β-carotene [63-64], and magnesium [65-66] have also consistently been shown to be associated with lower levels of inflammation. In our study, we observed that individual counselling can greatly affect engagement and compliance to the prescribed diet. Post-treatment all patients reported that they follow the dietary guidelines.
In conclusion, WBH and complementary therapies were safe and well-tolerated when given up to 4 weeks. Although our present data are limited in terms of small sample size and lack of control group they are encouraging and may become a platform for future planning of long-term studies with the complementary treatments in combination with existing standard therapies in RA. The multifaceted approach presented in this research consisted of immunomodulating heat therapy in the form of WBH, immunosuppressive and regenerative therapy in the form of MAHT and anti-inflammatory IVC and nutritional counselling. While we cannot draw strong conclusions based on this study, the suggested multimodal approach may be beneficial in the management of refractory RA.

Tables

Table 1

Gender 2 males, 6 females
Age 51 yrs. [SD=11.21; range=33-63]
Disease duration 8.2 yrs. [SD=6.36; range=1-17]

Table 2

Before treatment End of treatment Post-treatment
Pain 44 (4) 24 (5)* 25 (5)*
Stiffness 38 (6) 21 (3)* 23 (4)*
Fatigue 41 (7) 17 (3)** 18 (4)**

VAS, 0–100 mm; mean (SD), *p<0.05; ** p<0.01 vs. before treatment

References

 

 

  1. Rao, Jaya K., et al. Use of complementary therapies for arthritis among patients of rheumatologists. Annals of internal medicine 1999: 409-416.
  2. Robinson VA, Brosseau L, Casimiro L, Judd MG, Shea BJ, Tugwell P, Wells

Thermotherapy

for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: D002826.DOI:10.1002/14651858.CD002826.

  1. French SD, Cameron M, Walker BF, Reggars JW, Esterman AJ. Superfical heat or cold for low

back pain. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004750. DOI: 10.1002/14651858.CD004750.pub2.

  1. Oosterveld FGJ, Rasker JJ. Treating Arthritis With Locally Applied Heat or Cold. Semin Arthritis Rheum 1994;24:82-90.
  2. Sukenik S, Abu-Shakra M, Flusser D. Balneotherapy in autoimmune disease. Isr J Med Sci 1997;33:258-61.
  3. Verhagen AP, Bierma-Zeinstra SMA, Cardoso JR, de Bie RA, Boers M, de Vet

 

Balneotherapy for rheumatoid arthritis Cochrane Database of Systematic Reviews 2004 Issue 1. Art. No:CD000518.DOI:10.1002/14651858.CD000518.

  1. Melzack R, Katz J (1994) Pain measurement in persons in pain. In: Wall PD, Melzack R (eds) Textbook of pain. 3rd edn. Churchill Livingstone, Edinburgh, pp 337–351
  2. Oosterhof J (1992) The reliability  of Visual Analogue  Scale  measurements for stiffness in patients with rheumatoid arthritis. NPI, Amersfoort
  3. Riemsma RP, Rasker JJ, Taal E, Griep EN, Wouters JMGW, Wiegman O (1998) Fatigue in rheumatoid arthritis: the role of self-efficacy and problematic social   Br  J  Rheumatol 37:1042–1046
  4. van Tubergen A, Coenen J, Landewe R, Spoorenberg A, Chorus A, Boonen A, van der Linden S, van der Heijde D (2002) Assessment of fatigue in patients with ankylosing spondylitis: a psychometric analysis. Arthritis Rheum 47(1):8–16 Feb
  5. Jones SD, Koh WH, Steiner A, Garrett SL, Calin A (1996) Fatigue in ankylosing spondylitis: its prevalence and relationship to disease activity, sleep, and other factors. J Rheumatol 23:487–490
  6. Licht S (1982) Physical therapy in In: Lehman JF (ed) Therapeutic heat and cold. 3rd edn. Williams & Wilkins, Baltimore, pp 263–269
  7. Kirk JA, Kersley GD (1968) Heat and cold in the physical treatment of rheumatoid arthritis of the knee. Ann Phys Med 9:270–274
  8. Mainardi CL, Walter JM, Spiegel PK, Goldkamp OG, Harris ED (1979) Rheumatoid arthritis: failure of daily heat therapy to affect its progression. Arch Phys Med Rehabil 60:390–393
  9. Schmidt KL, Mäurer R, Rusch D (1980) Zum Verhalten der Hauttemperatur über entzündeten Kniegelenken unter täglicher Z Phys Med 9:58–59
  10. Zivkovic M, Cvetkovic S, Jovic D (1986) Effects of thermotherapy on acute phase reactants in rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum 29:57 (suppl)
  11. Schmidt KL, Ott VR, Rocher G, Schaller H (1979) Heat, cold and inflammation (a review). Z Rheumatol 38:391–404
  12. Oosterveld FGJ, Rasker JJ (1994) Treating arthritis with locally applied heat or cold. Semin Arthritis Rheum 24:82–90
  13. Nahas GG, Tannieres ML, Lennon JF. Direct measurement of leukocyte motility: effects of pH and temperature. Proc Soc Exp Biol Med. 1971; 138: 350±52.
  14. Moore TC, Nur K, Storm FK. Localized deep hyperthermia increases the traffic of lymphocytes through peripheral lymph nodes of sheep in J Surg Oncol 1987;

35:75±81.

 

  1. Wehrli F, Steinbart H. Erfahrungen mit der hamatogen oxidation therapie (hot) Ars 1954;10:44–51.
  2. Wolff HH. Die Behandlung peripherer Durchblutungsstorungen mit Ozon. Erfahr Hk. 1971;23:181–184.
  3. Bocci, V. (2013). Oxygen-ozone therapy: a critical evaluation. Springer Science & Business
  4. Plopper CG, Duan X, Buckpitt AR, Pinkerton KE. Dose-dependent tolerance to ozone. IV. Site-specific elevation in antioxidant enzymes in the lungs of rats exposed for  90 days  or  20 months. Toxicol Appl Pharmacol 1994;127(1):124-31.
  5. Christian DL, Chen LL, Scannell CH, Ferrando RE, Welch BS, Balmes Ozone-induced inflammation is attenuated with multiday exposure. Am J Respir Crit Care Med 1998;158:532–

537

  1. Clavo B, Perez JL, Lopez L, Suarez G, Lloret M, Rodriguez V, et Effect of ozone therapy on muscle oxygenation. J Altern Complement Med 2003;9:251–6
  2. Sroczyński J, Antoszewski Z, Rudzki H, Matyszczyk B, Kuźniewicz Various parameters of lipid metabolism after intra-arterial injections of ozone in patients with ischemia of the lower extremities and diabetes mellitus. Pol Tyg Lek1990; 45(47-48):953-5.
  3. Rovira G, Ralindo La ozonoterapia en el tratamiento de las ulceras cronicas de las extremidades inferiors. Angiologia 1991;2:47-50
  4. Peralta C, Leon OS, Xaus C, Prats N, Jalil EC, Planell ES, et Protective effect of ozone treatment on the injury associated with hepatic ischemia-reperfusion: antioxidant-  prooxidant

balance. Free Radic Res 1999; 31:191–6

  1. Chang, D.S., Lu, HS., Chang, YF. et al. Rheumatol Int (2005) 26: 142.
  2. Meng J, Yu P, Jiang H, Yuan T, Liu N, Tong J, Chen H, Bao N and Zhao Molecular hydrogen decelerates rheumatoid arthritis progression through inhibition of oxidative stress. Am J Transl Res 2016; 8: 4472-4477.
  3. Matyska-Piekarska E, Luszczewski A, Lacki J and Wawer I. The role of oxidative stress in the etiopathogenesis of rheumatoid arthritis]. Postepy Hig Med Dosw (Online) 2006; 60: 617-
  4. Filippin LI, Vercelino R, Marroni NP and Xavier RM. Redox signalling and the inflammatory response in rheumatoid Clin Exp Immunol 2008; 152: 415-422.

 

  1. Mateen S, Moin S, Khan AQ, Zafar A and Fatima N. Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS One 2016; 11:
  2. Mirshafiey A and Mohsenzadegan M. The role of reactive oxygen species in immunopathogenesis of rheumatoid Iran J Allergy Asthma Immunol 2008; 7: 195- 202.
  3. Hadjigogos K. The role of free radicals in the pathogenesis of rheumatoid arthritis. Panminerva

Med 2003; 45: 7-13.

  1. Dietary Reference Intakes for vitamin C, vitamin E, selenium, and A report of

the Panel on Antioxidants and Related compounds, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes; Food and Nutrition Board, Institute of Medicine. Washington, National Academy Press, 2000, chapter 5: Vitamin C, pp 95–185.

  1. Carr AC, Frei B: Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999; 69: 1086–1107.
  2. Ames BN, Shigenaga MK, Hagen TM: Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 1993; 90: 7915–7922.
  3. Jacob RA: The integrated antioxidant system. Nutr Res 1995; 15: 755–766.
  4. Panush RS, Carter RL, Katz P, Kowsari B, Longley S, Finnie Diet therapy for rheumatoid arthritis. Arthritis and Rheumatism 1983;26:462-71.
  5. Kremer JM, Lawrence DA, Petrillo GF, et Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal anti-inflammatory drugs. Clinical and immune correlates. Arthritis and Rheumatism 1995;38:1107-14.
  6. Tedeschi SK, Costenbader KH. Is there a role for diet in the therapy of rheumatoid arthritis? Current Rheumatology Reports 2016;18:23.
  7. Tedeschi, K., Frits, M., Cui, J., Zhang, Z. Z., Mahmoud, T., Iannaccone, C., Lin, T.-C., Yoshida, K., Weinblatt, M. E., Shadick, N. A. and Solomon, D. H. (2017), Diet and Rheumatoid Arthritis Symptoms: Survey Results From a Rheumatoid Arthritis Registry. Arthritis Care &  Research. Accepted Author Manuscript. doi:10.1002/acr.23225
  8. Hu Y, Costenbader KH, Gao X, et al. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. The American Journal of Clinical Nutrition 2014;100:959-67.
  9. Esmaillzadeh A, Kimiagar M, Mehrabi Y, Azadbakht L, Hu FB, Willett Dietary patterns

and markers of systemic inflammation among Iranian women. J Nutr. 2007;137:992–8

 

  1. Dalziel K, Segal L, de Lorgeril M. A mediterranean diet is cost-effective in patients with previous myocardial infarction. J Nutr. 2006;136:1879–85.
  2. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process  in  healthy  adults:  The ATTICA Study. J Am Coll Cardiol. 2004;44:152–8.
  3. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, D’Armiento M, D’Andrea F, Giugliano D. Effect of a Mediterranean-style diet on  endothelial  dysfunction and markers of vascular inflammation in the metabolic syndrome:  a  randomized    JAMA. 2004;292:1440–6.
  4. Estruch R, Martinez-Gonzalez MA, Corella D, Salas-Salvado J, Ruiz-Gutierrez V, Covas MI, Fiol M, Gomez-Gracia E, Lopez-Sabater MC, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145:1–11.
  5. Serrano-Martinez M, Palacios M, Martinez-Losa E, Lezaun R, Maravi C, Prado M, Martinez JA, Martinez-Gonzalez MA. A Mediterranean dietary style influences TNF-alpha and VCAM- 1 coronary blood levels in unstable angina patients. Eur J Nutr. 2005;44:348–54.
  6. Gao X, Bermudez OI, Tucker KL. Plasma C-reactive protein and homocysteine concentrations are related to frequent fruit and vegetable intake in Hispanic and non- Hispanic white elders. J Nutr. 2004;134:913–8.
  7. Watzl B, Kulling SE, Moseneder J, Barth SW, Bub A. A 4-wk intervention with high intake of carotenoid-rich vegetables and fruit reduces plasma C-reactive protein in healthy, nonsmoking men. Am J Clin Nutr. 2005;82:1052–8.
  8. Esmaillzadeh A, Kimiagar M, Mehrabi Y, Azadbakht L, Hu FB, Willett WC. Fruit and vegetable intakes, C-reactive protein, and the metabolic syndrome. Am J Clin Nutr. 2006;84:1489–97.
  9. Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, Martin A, Andres- Lacueva C, Senin U, et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab. 2006;91:439–46.
  10. Lopez-Garcia E, Schulze MB, Manson JE, Meigs JB, Albert CM, Rifai N, Willett WC, Hu Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr. 2004;134:1806–11.
  11. Bo S, Durazzo M, Guidi S, Carello M, Sacerdote C, Silli B, Rosato R, Cassader M, Gentile L, et al. Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort. Am J Clin Nutr. 2006;84:1062–9.

 

  1. King DE, Egan BM, Geesey ME. Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol. 2003;92:1335–9. Erratum in: Am J Cardiol 2004;93:812.
  2. Avellone G, Di Garbo V, Campisi D, De Simone R, Raneli G, Scaglione R, Licata Effects of moderate Sicilian red wine consumption  on  inflammatory  biomarkers  of  atherosclerosis. Eur J Clin Nutr. 2006;60:41–7.
  3. Sierksma A, van der Gaag MS, Kluft C, Hendriks HFJ. Moderate alcohol consumption reduces plasma C-reactive protein and fibrinogen levels; a randomized, diet-controlled intervention study. Eur J Clin Nutr. 2002;56:1130–6.
  4. van Herpen-Broekmans WM, Klopping-Ketelaars IA, Bots ML, Kluft C, Princen H, Hendriks HF, Tijburg LB, van Poppel G, Kardinaal AF. Serum carotenoids and vitamins in relation to markers of endothelial function and inflammation. Eur J Epidemiol. 2004;19:915–21.
  5. Chien CT, Chang WT, Chen HW, Wang TD, Liou SY, Chen TJ, Chang YL, Lee YT, Hsu Ascorbate supplement reduces oxidative stress in dyslipidemic patients undergoing apheresis. Arterioscler Thromb Vasc Biol. 2004;24:1111–7.
  6. Gunter MJ, Stolzenberg-Solomon R, Cross AJ, Leitzmann MF, Weinstein S, Wood RJ, Virtamo J, Taylor PR, Albanes D, et al. A prospective study of serum C-reactive protein and colorectal cancer risk in men. Cancer Res. 2006;66:2483–7.
  7. Erlinger TP, Guallar E, Miller ER III, Stolzenberg-Solomon R, Appel LJ. Relationship between systemic markers of inflammation and serum beta-carotene levels. Arch Intern Med. 2001;161:1903–8.
  8. King DE, Mainous AG III, Geesey ME, Woolson RF. Dietary magnesium and C-reactive protein levels. J Am Coll Nutr. 2005;24:166–71.

Song Y, Li TY, van Dam RM, Manson JE, Hu FB. Magnesium intake and plasma concentrations of markers of systemic  inflammation  and  endothelial  dysfunction  in women. Am J Clin Nutr. 2007;85:1068–74.

發佈留言