Review

New evidence on mechanisms of action of spa therapy in rheumatic diseases

Sara Tenti, Antonella Fioravanti*, Giacomo Maria Guidelli, Nicola Antonio Pascarelli, Sara Cheleschi

Rheumatology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Italy

ABSTRACT
Spa represents a treatment widely used in many rheumatic diseases (RD). The mechanisms by which
immersion in mineral or thermal water ameliorates RD are not fully understood. The net benefit is
probably the result of a combination of factors, among which the mechanical, thermal and chemical
effects are most prominent. Buoyancy, immersion, resistance and temperature play important roles.
According to the gate theory, pain relief may be due to the pressure and temperature of the water on skin;
heat may reduce muscle spasm and increase the pain threshold. Mud-bath therapy increases plasma β-
endorphin levels and secretion of corticotrophin, cortisol, growth hormone and prolactin. It has recently
been demonstrated that thermal mud-bath therapy induces a reduction in circulating levels of
prostaglandin E2, leukotriene B4, interleukin-1β and tumour necrosis factor-α, important mediators of
inflammation and pain. Furthermore, balneotherapy has been found to cause an increase in insulin-like
growth factor-1, which stimulates cartilage metabolism, and transforming growth factor-β. Beneficial
anti-inflammatory and anti-degenerative effects of mineral water were confirmed in chondrocytes cultures,
too. Various studies in vitro and in humans have highlighted the positive action of mud-packs and thermal
baths, especially sulphurous ones, on the oxidant/antioxidant system. Overall, thermal stress has an
immunosuppressive effect. Many other non-specific factors may also contribute to the beneficial effects
observed after spa therapy in some RD, including effects on cardiovascular risk factors (e.g. adipokines)
and changes in the environment, pleasant surroundings and the absence of work duties.

Keywords spa therapy, balneotherapy, rheumatic diseases, mechanisms of action

INTRODUCTION Nowadays it represents an useful alternative to the

pharmacological therapy, because of problems related to the
Recent treatment regimens of some chronic rheumatic diseases use of drugs that often have significant side effects and the
(RD) comprise multimodal concepts including pharmacologic, occasional lack of valid therapeutic strategies (Bresalier et al.,
physical/exercise, occupational and psychological therapies to 2005; Kearney et al., 2006; Ofman et al., 2002; Zhang et al.,
support the long-term management of disease. Spa therapy is 2004). The efficacy of spa treatments in RD has been bolstered
widely used for musculoskeletal system disorders, such as low by ancient tradition, but in spite of their long history and
back pain, Fibromyalgia or Osteoarthritis (OA) (Annegret and popularity, only a few randomized, controlled trials (RCTs) on
Thomas, 2013). Thermal therapy is very popular in many the use of these therapies in patients with RD have been
European and Middle Eastern countries, as well as in Japan and conducted and this topic is still the subject of debate and its
Israel. This treatment comprises a broad spectrum of role in modern medicine continues to be unclear (Verhagen et
therapeutic modalities including hydrotherapy, balneotherapy, al., 2007). Existing clinical researches are not sufficiently
physiotherapy, mud-pack therapy and exercise. The terms strong to draw firm conclusions; additional large and well-
hydrotherapy and balneotherapy were accepted for all forms of designed RCTs are needed to confirm preliminary evidences.
treatment with water. Balneotherapy uses natural thermal The aim of spa therapy is to reduce pain, relieve muscle
mineral waters, whose definition is based on the sum of the spasms and improve muscle strength and functional mobility
cations Na, K and Mg and the anions SO4, Cl and HCO3; the (Bender et al., 2005; Sukenik et al., 1999). The action
water is generally used at a temperature of around 34 degrees mechanisms of mud packs and thermal baths are not
Celsius. Mud-pack is defined as a natural product that consists completely known, and it is difficult to distinguish the effects
of a mixture of mineral or mineral-medicine water with organic of thermal applications from the benefits that could be derived
or inorganic material produced from biological and/or from a stay in a spa environment (Sukenik et al., 1999).
geological processes and used as a therapeutic treatment in the Although the results of the existing studies are not strong
form of a mud wrap applied locally or to the whole body enough to draw firm conclusions, it is necessary to ask what
(Bender et al., 2005; Nicholas, 1999; Sukenik et al., 1999). real medical and scientific value these therapies have. The
*
objective of this review is to summarize the currently available
Correspondence: Antonella Fioravanti information on mechanisms of action and possible effects of
E-mail: fioravanti7@virgilio.it spa therapy in RD. We also provide some suggestions for
Received October 23, 2013; Accepted February 18, 2014; Published
February 28, 2014
further development in this area.
doi: http://dx.doi.org/10.5667/tang.2013.0029
© 2014 by Association of Humanitas Medicine Mechanisms of action of spa therapy in RD
This is an open access article under the CC BY-NC license. The mechanisms by which immersion in thermal mineral water
(http://creativecommons.org/licenses/by-nc/3.0/)

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 Spa therapy and rheumatic diseases

alleviates suffering in RD are not fully understood. The net of collagen-rich tissues, such as tendons, fasciae and articular
benefit is probably the result of a combination of factors, capsules, which may improve the range of motion of joints
among which the mechanical, thermal and chemical effects are (Sukenik et al., 1999).
most prominent (Sukenik et al., 1999). The effects described make it possible to break the vicious
A distinction can be made between the non-specific circle of pain-muscle contraction-altered joint dynamics-pain
(hydrotherapeutic in a broad sense) mechanisms common to that characterizes many chronic arthropathies. The reduction of
simple baths in hot tap water, and specific (hydromineral and muscle tone and better use of joints represent just two of the
crenotherapeutic) mechanisms, which depend on the chemical most important elements that show the medium and long-term
and physical properties of the water used. While the former are beneficial effects documented in various clinical studies
well known, the latter are difficult to identify and assess (Cantarini et al., 2007; Elkayam et al., 2000; Fioravanti et al.,
(Sukenik et al., 1999). 2007; Fioravanti et al., 2010; Forestier et al., 2009; Guillemin
et al., 1994; Harzy et al., 2009; Nguyen et al., 1997; van
Mechanical, thermal and chemical effects Tubergen et al., 2001).
Spa therapy may have beneficial effects on muscle tone, joint The chemical effects of mud-packs and thermal therapy are
mobility, and pain intensity. less clear than the physical effects. In theory, it cannot be
Increased buoyancy and hydrostatic pressure during excluded that the organic substances or minerals of water or
immersion in thermal mineral water cause many physiologic mud, sometimes present in traces, can be absorbed through the
changes. Immersion to the suprasternal notch in mineral water skin and then act at a systemic level. However, experimental
(35°C) results in a cascade of reactions including increased evidence available in this field is scarce. Shani et al. (1985)
diuresis, natriuresis, and cardiac output (Epstein, 1992; O’Hare documented a significant increase in serum concentrations of
et al., 1985; Weston et al., 1987). The basis of these bromine, rubidium, calcium and zinc in patients with psoriatic
physiological effects is considered to be the hydrostatic arthritis who bathed in the Dead Sea. The penetration of the
pressure, which forces approximately 700 ml from the lower solutes is presumably influenced by the length of bathing time,
extremities to the central compartment. Distension of the the temperature of the thermal water, its composition and other
volume receptors by this central hypervolemia is regarded as factors, some of which may still be unknown. Furthermore, it
the trigger for the observed physiological effects (Epstein, 1992; has been reported that the direct application of mud-pack has
O’Hare et al., 1985; Weston et al., 1987). greater clinical effects than the application of nylon covered
The effects of thermal baths are partially related to mud pack in patients with knee OA (Odabasi et al., 2008).
temperature. Hot stimuli may influence muscle tone and pain
intensity, helping to reduce muscle spasm and to increase the Immunologic aspects
pain threshold in nerve endings. According to the “gate theory”, Since sulphur baths have been successfully used in various skin
pain relief may be due to the temperature and hydrostatic immunomediated afflictions, it has been suggested that
pressure of water on the skin (Melzack and Wall, 1965). absorption through the skin of trace elements present in mineral
Thermal stress provokes a series of neuroendocrine water and mud packs may affect the immune system (Sukenik
reactions. In particular, the heat stimulates the release of et al., 1997).
adrenocorticotropic hormone (ACTH), cortisol, prolactin and Overall, thermal stress has an immunosuppressive effect.
growth hormone (GH), although it does not alter the circadian With regard to hyperthermia a stimulatory effect of the immune
rhythm of these hormones (Kuczera and Kokot, 1996). response appear to prevail at a moderate increase of local skin
The effect of thermal stress on the hypothalamus-pituitary- temperature, with increase of pro-inflammatory cytokines
adrenal axis seems to be particularly important for the interleukin (IL)-6 (Sobieska et al., 1993) and IL-1β (Olszewski
antiedemigenous and anti-inflammatory actions of et al., 1989), whereas higher temperatures (40 - 41°C)
corticosteroids, as well as for the frequent alteration of the axis apparently suppress immune functions (Lange et al., 2006;
during some RD (Gur et al., 2004). The increase in beta- Schmidt and Simon, 2001).
endorphin demonstrated to occur with various spa therapy A significant reduction in circulating levels of T-
techniques has an analgesic and anti-spastic effect that is lymphocytes has been demonstrated in healthy volunteers
particularly important in patients for whom pain is the treated with hyperthermal baths (Sukenik et al., 1999) and in
prevalent symptom (Cozzi et al., 1995; Kubota et al., 1992). patients with respiratory and cutaneous atopy (Valitutti et al.,
Recent data have demonstrated the possibility that normal 1990). Hyperthermia-induced T-lymphocytopenia and eosino
keratinocytes can produce and secrete a precursor pro- penia may be due to a redistribution of the cells, probably due
opiomelanocortin (POMC) following various stimuli (e.g. to the increase of ACTH and cortisol provoked by thermal
ultraviolet rays, thermal stimuli) which is the common stress (Kuczera and Kokot, 1996).
precursor of various endorphins (Ghersetich et al., 2000). This In vitro studies have demonstrated that sulphurous waters
finding allows us to formulate the fascinating hypothesis that have a dose-dependent inhibitory effect on the blast
ultraviolet radiation or thermal stimuli could be used to transformation and proliferation of T lymphocytes obtained
condition the skin’s production of opioid peptides, thus altering from peripheral blood in both healthy subjects and subjects
the personal emotional sphere or pain threshold. If we add that affected by chronic inflammatory diseases (Valitutti et al.,
ß-endorphin also has immunomodulatory effects, the 1990). On the other hand, immersion in thermal waters at a
hypothesis of a close correlation between spa therapy and the temperature of 40°C reduces the lymphocyte response to
psychoneuroendocrine system becomes increasingly phytohaemoagglutinin (Smith et al., 1978). Sulphurous waters
convincing (Berczi et al., 1996). also seem to exert a potent inhibitory action on the production
Furthermore, hyperthermia plays an important role on of cytokines, especially IL-2 and interferon gamma (IFN-γ). As
immune system function (see below). these cytokines are mainly produced by CD4+ lymphocytes, it
Hyperthermia also has many effects on granulocytes. Heat can be hypothesized that memory T cells are the principal
increases their mobility, phagocytic and bactericidal properties target of sulphur-rich waters. The application of sulphurous
and enzymatic activity (Sukenik et al., 1999). waters reduces the capacity of memory T cells to proliferate
Furthermore, thermal stimulation increases the extensibility and produce cytokines, thus resulting in an alteration of

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 Spa therapy and rheumatic diseases

immune response (Ghersetic and Lotti, 1996). The

hyperthermia-induced alterations of the cytokine milieu has
been recently confirmed in patients affected by ankylosing
spondylitis (AS) (Tarner et al., 2009). Tarner et al. (2009)
showed that the serum levels of tumor necrosis factor (TNF)-α,
IL-1β and IL-6 which were measured before, during and after
whole-body hyperthermia, were significantly reduced in
patients with AS whereas the changes in healthy subjects did
not reach statistical significance.

Anti-inflammatory and chondroprotective aspects

Recent studies have shown a reduction of circulating levels of
Prostaglandin E2 (PGE2) and Leukotriene B4 (LTB4),
important mediators of inflammation and pain, in patients
suffering from OA or fibromyalgia who undergo mud-packs or
balneotherapy (Ardiç et al., 2007; Bellometti and Galzigna,
1998) (Table 1).
Crenotherapy also affects the synthesis of various cytokines Fig. 1. Serum Leptin and Andiponectin levels in 30 knee OA patients
involved in the ongoing chondrolysis and inflammation in RD; treated with spa therapy, evaluate at baseline (T0) and after 2 weeks
in fact a reduction in the cytokines IL-1β and TNF-α and the (T1) through ELISA assay (from Fioravanti et al., 2011). *p < 0.05 vs
Basal time
soluble receptors of the latter has been demonstrated following
a cycle of mud-baths therapy (temperature > 41C°) in patients myristate-13-acetate (Braga et al., 2008). Various studies in
with OA (Bellometti et al., 1997; Bellometti et al., 2002; humans have highlighted the positive action of mud-packs and
Cecchettin et al., 1995) (Table 1). thermal baths, especially sulphurous ones, on the
Several studies have provided evidence for a significant oxidant/antioxidant system. Grabski et al. (2004) reported the
role of matrix metalloproteinases (MMPs), particularly MMP-3 reduction of superoxide dismutase (SOD) activity in patients
or stromelysin-1, produced by activated chondrocytes and other with rheumatoid arthritis undergoing treatment with sulphuric
cell types in the development of cartilage degradation in joint water. Eckmekcioglu et al. (2002) demonstrated that 3 weeks of
diseases (Lohmander et al., 1993). A recent study of Bellometti sulphur baths can reduce the antioxidative defence system
et al. shown that MMP-3 serum levels were significantly (SOD and glutathione (GSH) peroxidase) in the blood of
reduced by mud-bath therapy in patient with OA (Bellometti et patients with OA. They discussed that the decline of these
al., 2005). enzyme- activities may be caused by two reasons: either as
Cycles of mud applications and balneotherapy also bring consequence of reduced oxidative stress during sulphur therapy
about an increase in some growth factors, such as Insulin-like leading to a lower expression of these enzymes or as an
Growth Factor 1 (IGF1) (Bellometti et al., 1997), which enhanced generation of superoxide radicals exhausting the
stimulates cartilage anabolism (Trippel, 1995). Furthermore, a superoxide scavenging enzyme.
significant increase in circulating levels of Transforming Bender et al. demonstrated that therapeutic baths in mineral
Growth Factor-beta (TGF-β) has been found in patients with water reduced the activity of catalase, SOD, malondialdehyde
AS after a combined spa-exercise therapy (exercise, and GSH peroxidise (Bender et al., 2007). Other authors have
hyperthermia and exposure to low doses of radon) (Shehata et observed a significant decrease in NO and myeloperoxidase
al., 2006) (Table 1). TGF-β is a very potent immunomodulating and a slight increase in GSH peroxidase in the sera of subjects
and anti-inflammatory cytokine which plays a major role in with OA undergoing cycles of mud applications and
tissue healing, bone remodelling and fibrosis (Shehata et al., balneotherapy (Bellometti et al., 2000).
2006). In a recent study we assessed the possible modifications of
Among the various factors responsible for inflammatory plasma levels of leptin and adiponectin in patients with OA
and degenerative phenomena in joint during different RD, treated with a cycle of mud-bath therapy (Fioravanti et al,
reactive oxygen species (ROS) and nitric oxide (NO) should be 2011). Our data showed at the end of the therapy, a slight but
taken into consideration (Farrell et al., 1992). not significant increase of plasma leptin concentrations and a
Sulphurous waters have been demonstrated to have an significant decrease in serum adiponectin levels (Fig. 1). These
antioxidant effect in vitro; in fact the incubation in sulphurous adipocytokines play an important role in the pathophysiology
mineral water significantly reduces the release of ROS and the of OA (Lago et al., 2008). In particular, there is some evidence
reactive nitrogen species (RNS) peroxynitrite by that adiponectin in skeletal joints may have proinflammatory
polymorphonucleate leukocytes (PMNs) stimulated with N- effects and may be involved in cartilage degradation (Gomez et
formyl-methionyl-leucyl-phenylalanine and phorbol-12- al., 2009). In view of these recent findings, the decrease of
Table 1. Effect of thermal mineral baths on various mediators or factor of inflammation, immune response, and chondrolysis
1 Reduction of circulating levels of PGE2 and LTB4 (Lago et al., 2008; Lange et al., 2006)
Reduction of TNF-α, IL-6, IL-1β circulating levels (Kuczera et al., 1996; Leibetseder et al., 2004; Lohmander et al., 1993; Melzack et
2
al., 1965)
3 Increase of circulating levels of IGF1 (Odabasi et al., 2008)
4 Increase in circulating levels of TGF-β (exercise, hyperthermia and exposure to low doses of radon) (Ofman et al., 2002)
Reduction of the release of ROS and the RNS by PMNs stimulated with N-formyl-methionyl-leucyl-phenylalanine and phorbol-12-
5
myristate-13-acetate (Oláh et al., 2010)
6 Decrease in NO circulating levels (Shani et al., 1985)
PGE2 = prostaglandin E2; LTB4 = leukotriene B4; TNF-α = tumor necrosis factor-α; IL-6 = interleukin 6; IL-1β = interleukin-1β; IGF1 = Insulin-like
Growth Factor 1; TGF-ß = Transforming Growth Factor-beta; ROS = reactive oxygen species; RNS= reactive nitrogen species; PMNs = polymorpho-
nucleate leukocytes; NO = nitric oxide.

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Fig. 2. Micrographs of cultured OA chondrocytes labeled with iNOS antibody. (A) DW-DMEM, controls; (B) Incubation with IL-1β (5 ng/ml); (C)
25% or 50% VW-DMEM; (D) 25% or 50% VW-DMEM with IL-1β; (E) 100% VW-DMEM; (F) 100% VW-DMEM with IL-1β. The cells show a
different immunolabelling pattern (arrows). Bar: 5 μm (from Fioravanti et al., 2013).

adiponectin after spa therapy demonstrated in our study may IL-1β. They analyzed the effects of different concentrations of
play a protective role in OA. a fast (NaHS) or a slow (GYY4137) release H2S donor on
Partial contradictory data were observed in a recent pilot three key aspects of the inflammatory process in OA. The
study conducted by Shimodozono et al. (2012). Authors Authors demonstrated a significant reduction of NO and
reported a significant increase of serum levels of leptin in 7 inducible Nitric Oxide Synthase (iNOS) gene expression, PGE-
healthy men after a single 10 min warm-water bath (WWB) at 2, and ROS levels induced by IL-1β in culture medium, after
41°C with tap water or WWB with inorganic salts and carbon incubation with H2S donors.
dioxide (ISCO2), and remained significantly higher than those A recent study by Fioravanti et al. (Fioravanti et al., 2013)
at baseline even 30 min after WWB with tap water; serum showed similar results in human OA chondrocytes cultivated
levels of adiponectin showed a slight, but not significant, with mineral Vetriolo’s thermal water (VW) in the presence or
increase immediately and 30 min after a single WWB under in the absence of IL-1β. OA chondrocytes were cultivated in
both conditions. These differences might be due to the Deionized Water (DW) (DW-DMEM, controls), or in one of
difference in subjects (relatively healthy, young, lean and male three different VW-DMEM media, in which DW had been
in this last study) and in modalities of bathing (duration of totally (100%) or in part (50% or 25%) substituted with VW.
thermal stimulation and the substances used in the mineral The results showed that VW alone at 25% or 50%
water). concentration did not affect the viability of cultured OA
Experimental studies in animal models of arthritis chondrocytes, and determined a significant survival recovery
corroborate the evidence of beneficial effects of mud-bath rate in cultures stimulated with IL-1β. On the contrary, the VW
therapy on inflammatory and degenerative joint diseases. Cozzi alone at 100% of concentration reduced, in a significant (p <
et al. (Cozzi et al., 2004) have recently demonstrated an anti- 0.05) manner, the cells viability. NO levels were low both in
inflammatory effect of mud–bath applications in Freund’s DW-DMEM cultures and in those reconstituted with 25% or 50%
adjuvant-induced arthritis in rats. In 2007 Britschka et al. (2007) of VW, and were significantly (p < 0.05) increased in cultures
confirmed the anti-inflammatory and chondroprotective effects with 100% of VW. VW at 25% or 50% concentration
of the application of mud in Zymosan-induced arthritis in rats, significantly (p < 0.001) reduced the NO production induced by
by performing histological analysis on synovial tissues and IL-1β. The data of the NO levels were confirmed by the
cartilage taken from the sacrificed animals on day 21 of immunocytochemistry assay for iNOS (Fig. 2). Furthermore,
treatment. the Authors confirmed the pro-apoptotic effect of IL-1β and
The possible chondroprotective role of mineral water or demonstrated a protective effect of VW at 25% or 50%
mineral components was confirmed by some pilot in vitro concentration. These findings were confirmed by transmission
studies in chondrocyte cultures. Burguera et al. (Burguera et al., electron microscope (TEM) assessment (Fig. 3).
2012), in 2012 studied the possible activity of hydrogen
sulphide (H2S) as an anti-inflammatory and anti-oxidant agent Other aspects
in human osteoarthritic articular chondrocytes stimulated with Many other non-specific factors may also contribute to the

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Fig. 3. TEM micrographs of human OA chondrocytes: (A) DW-DMEM, controls: the cell shows a good state of health. (B) Incubation with IL-1β (5
ng/ml): Vacuolization (V) of the cytoplasm and reduction in quality of Golgi bodies, rough endoplasmic reticulum (RER) and mitochondria (M). (C)
25% or 50% VW-DMEM: not particular morphological alterations. (D) 100% VW-DMEM: Altered status of chromatin and of cytoplasm structure.
Normal plasma membrane and nucleus (N). (E) 25% or 50% VW-DMEM with IL-1β: The cell partially restores its morphology. Euchromatic nucleus
(N), restored organization of cytoplasm [vacuoles (V) very reduced, abundant rough endoplasmic reticulum (RER), well shaped mitochondria (M)].
Plasma membrane with cytoplasmic processes. (F) 100% VW-DMEM with IL-1β: Vacuoles (V), reduction of cytoplasmic organelles, and nucleus
(N). Bar = 1 μm (from Fioravanti et al., 2013).

beneficial effects observed after spa therapy in some RD, therapeutic option in hypertension and obesity and that it
including effects on cardiovascular risk factors. improved some metabolic and inflammatory markers, such as
The lipid normalizing effects of balneotherapy, especially hs-CRP on haemoglobin A1C levels.
with sulphurous waters, have been reported for decades. The The reduction of cardiovascular risk factors through mud-
results of such research have documented reductions in total packs and spa therapy is especially important considering the
cholesterol, triglycerides and nonesterified cholesterol and a clear and much-stressed association between various RD and
significant increase in HDL- cholesterol (Strauss-Blasche et al., atherosclerotic processes (Turesson et al., 2008).
2003). Finally, other elements need to be taken into consideration
More recently, attention has focused on plasma concerning the mechanisms of action of mud applications and
homocysteine, a risk factor for coronary heart disease, spa therapy in RD, such as the particular climatic and
congestive heart failure, systolic hypertension, environmental conditions of spas. One of the most important
artherothrombotic events, complications in diabetes mellitus, aspect of spa therapy is the psychologic effect of removal from
cancer and oxidative stress (Agullo-Ortuno et al., 2002; the stress of home and work. Those receiving spa therapy
Bostom and Selhub, 1999; Sun et al., 2002; Vasan et al., 2003). experienced not only reduced pain and improved function but
A significant reduction in plasma homocysteine has been also experienced greater physical and mental quality of life and
demonstrated in OA patients after a cycle of sulphurous thermal less anxiety and depression (Bender et al., 2005; Sukenik et al.,
baths (Leibetseder et al., 2004). 1999).
Recently Oláh et al. (Oláh et al., 2010) explored changes in
several cardiovascular risk factors in a group of patients
suffering from degenerative musculoskeletal disorders CONCLUSIONS
subjected to a cycle of balneotherapy. For the first one, the
Authors showed a statistically significant and lasting (3 months In this review we highlighted the effects of spa therapy and
after the cycle of balneotherapy) decrease in serum levels of mud applications on various mediators or factors of
high- sensitivity C-reactive protein (hs-CRP) in patients treated inflammation, immune response and chondrolysis. Although
with mineral thermal baths. the data presented are stimulating, it is impossible to ignore the
Always Oláh et al. (Oláh et al., 2011) in a consecutive existence of a complex series of problems and uncertainties that
study explored the changes of antioxidant, inflammatory and prevent spa therapies from gaining the full consensus of the
metabolic parameters in obese and hypertension people after scientific community (Verhagen et al., 2007). One of the
balneotherapy. This study showed that balneotherapy is a safe critical points is the controversial problem of the absorption of

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 Spa therapy and rheumatic diseases

the minerals dissolved in thermal waters, e.g. the demonstration glutathione peroxidase serum levels in arthritic patients. Int J
of specific effects other than those linked to the simple action Clin Pharmacol Res. 2000;20:69-80.
of heat. Unfortunately few studies have been conducted on this
topic and little is known about the specific effects of various Bellometti S, Galzigna L, Richelmi P, Gregotti C, Bertè F. Both
mineral waters. It is still not clear which elements are essential serum receptors of tumor necrosis factor are influenced by mud
and what is the ideal concentration of each element in order to pack treatment in osteoarthrotic patients. Int J Tissue React.
attain an optimal response to treatment. It remains to be 2002;24:57-64.
clarified which mineral waters are most suitable for various
diseases and whether the different components exert specific Bellometti S, Richelmi P, Tassoni T, Bertè F. Production of
actions. Such evidence would lead to a specialization of spa matrix metalloproteinases and their inhibitors in osteoarthritic
resorts, which could finally target their therapies more patients undergoing mud bath therapy. Int J Clin Pharmcol Res.
accurately and rationally. 2005;25:77-94.
Furthermore, the results reported only refer to short term
modifications of various mediators of inflammation, immune Bender T, Karagülle Z, Bàlint GP, Gutenbrunner C, Bálint PV,
response and chondrolysis, lasting until the end of the cycle, Sukenik S. Hydrotherapy, balneotherapy, and spa treatment in
and little is known of the possible long term effects. This is a pain management. Rheumatol Int. 2005;25:220-224.
key element in seeking to explain the persistence of the
symptomatic benefit induced by such therapies in some RD, as Bender T, Bariska J, Vàghy R, Gomez R, Imre Kovács. Effect
shown in long term controlled clinical trials (Cantarini et al., of balneotherapy on the antioxidant System – a controlled pilot
2007; Elkayam et al., 2000; Fioravanti et al., 2007; Fioravanti study. Arch Med Res. 2007;38:86-89.
et al., 2010; Forestier et al., 2009; Guillemin et al., 1994; Harzy
et al., 2009; Nguyen et al., 1997; van Tubergen et al., 2001). Berczi I, Chalmers IM, Nagy E, Warrington RJ. The immune
In conclusion, existing researches are stimulating, but are effects of neuropeptides. Baillieres Clin Rheumatol.
not sufficiently strong to draw firm conclusions. More studies 1996;10:227-257.
are needed to help draw firm conclusions regarding the
mechanisms of actions of spa therapy in various RD. Bostom AG, Selhub J. Homocysteine and arteriosclerosis:
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Braga PC, Sambataro G, Dal Sasso M, Culici M, Alfieri M,
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funding sources or study sponsors. human neutrophil bursts: chemiluminescence evaluation.
Respiration. 2008;75:193-201.

CONFLICT OF INTEREST Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B,
Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam
The authors have no conflicting or competing financial MA, Baronet JA; Adenomatous Polyp Prevention on Vioxx
interests. (APPROVe) Trial Investigators. Trial investigations:
cardiovascular events associated with rofecoxib in a colorectal
adenoma chemoprevention trial. N Engl J Med.
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