Introduction
Spa therapy comprises a broad spectrum of therapeutic modalities, including hydrotherapy, balneotherapy, physiotherapy, mud-pack therapy, and exercise [1, 2]. This therapeutic approach has been successfully used in many European countries, as well as in Japan and Israel, in classical medicine as a cure for various illnesses. Today, it continues to be a popular treatment for many rheumatic diseases (RD) [3] due to their chronic nature, problems related to the use of drugs that often have significant side effects and the occasional lack of valid therapeutic strategies [4–8]. Thousands of years of history and the abundance of spa resorts in many European countries have undoubtedly contributed to the popularity of these therapies. Spa therapy aims to reduce pain, relieve muscle spasms and improve muscle strength and functional mobility [1, 2]. Nevertheless, despite their long history and popularity, spa treatments are still the subject of debate and their role in modern medicine continues to be unclear [9].
The action mechanisms of mud-packs and thermal baths are not fully known, and it is difficult to distinguish the effects of thermal applications from the benefits that could be derived from a stay in a spa environment [1].
In an era of evidence-based medicine, it is necessary to ask what real medical and scientific value these therapies have. The objective of this review is to summarize the currently available information on mechanisms of action and possible effects of spa therapy in RD. We also provide some suggestions for further development in this area.
MEchanical effects
Spa therapy may have beneficial effects on muscle tone, joint mobility and pain intensity. Increased buoyancy and hydrostatic pressure during immersion in thermal mineral water cause many physiological changes. Immersion to the suprasternal notch in spa water (35C) results in a cascade of reactions including increased diuresis, natriuresis and cardiac output [10–12]. The basis of these physiological effects is considered to be hydrostatic pressure, which forces approximately 700 ml from the lower extremities to the central compartment. Distension of volume receptors by this central hypervolemia is regarded as the trigger for the observed physiological effects [10–12]
Thermal effects
The effects of mud-packs and thermal baths are partially related to temperature. Thermal stimuli may influence muscle tone and pain intensity, helping to reduce muscle spasm and to increase the pain threshold in nerve endings. According to the ‘‘gate theory’’, pain relief may be due to the temperature and hydrostatic pressure of water on the skin [13]. Thermal stress provokes a series of neuroendocrine reactions. In particular, the heat stimulates the release of adrenocorticotropic hormone (ACTH), cortisol, prolactin., and growth hormone (GH), although it does not alter the circadian rhythm of these hormones [14]. The effect of thermal stress on the hypothalamus-pituitary-adrenal axis seems to be particularly crucial for the anti-edemigenous and anti-inflammatory actions of corticosteroids, as well as for the frequent alteration of the axis during some rheumatic diseases [15]. The increase in beta-endorphin demonstrated to occur with various spa therapy techniques [16–19] has an analgesic and antispastic effect that is particularly important in patients for whom pain is the prevalent symptom. Interestingly, it has been revealed that the application of mature thermal mud in healthy individuals brings about a rapid increase in plasma beta-endorphin, which returns to pre-treatment levels within the period of so-called thermal reaction [19]. This increase in beta-endorphin is probably the key factor in the mechanism of individual tolerance to thermal mud baths. Recent data have demonstrated the possibility that normal keratinocytes can produce and secrete a precursor proopiomelanocortin (POMC) following various stimuli (e.g. ultraviolet rays, thermal stimuli) which is the common precursor of various endorphins [20]. This finding allows us to formulate the fascinating hypothesis that ultraviolet radiation or thermal stimuli could be used to condition the skin’s production of opioid peptides, thus altering the personal emotional sphere or pain threshold. If we add that ß-endorphin also has immunomodulatory effects [21], the hypothesis of a close correlation between spa therapies and the psychoneuroendocrine system becomes increasingly convincing. Furthermore, hyperthermia plays an important role in immune system function. Hyperthermia also has many effects on granulocytes. Heat increases their mobility, phagocytic and bactericidal properties and enzymatic activity [1]. Furthermore, thermal stimulation increases the extensibility of collagen-rich tissues, such as tendons, fasciae and articular capsules, which may improve the range of motion of joints [1]. The effects described make it possible to break the vicious circle of pain–muscle contraction–altered joint dynamics–pain that characterizes many chronic arthropathies. The reduction in muscle tone and better use of joints represent just two of the most important elements that show the medium- and long-term beneficial effects documented in various clinical studies [22–31].
Chemical effects
The chemical effects of mud packs and balneotherapy are less precise than the physical effects. In theory, it cannot be excluded that the organic substances or minerals in the water or mud, sometimes present in trace amounts, can be absorbed through the skin and then act at a systemic level. However, experimental evidence available in this field is scarce. Shani et al. [32] documented a significant increase in serum concentrations of bromine, rubidium, calcium and zinc in patients with psoriatic arthritis who bathed in the Dead Sea. Solute penetration is presumably influenced by the length of bathing time, the temperature of the thermal water, its composition, and other factors, some of which may still be unknown. An in vitro study has demonstrated that substances in aqueous mud extracts can permeate through human full-thickness skin in quantities that have definite effects on the spontaneous contractile activity of smooth muscle tissue [33]. Furthermore, it has been reported that the direct application of mud pack has greater clinical outcomes than the use of nylon-covered mud pack in patients with knee osteoarthritis (OA) [34]. This finding implies a contribution of the chemical properties of the dirt to the overall beneficial effects of mud-pack treatment, thus ruling out that the results are linked exclusively to the action of heat.
Immunologic Aspects
Since sulfur spa baths have been successfully used in various skin immuno-mediated afflictions, it has been suggested that absorption through the skin of trace elements present in mineral water and mud packs may affect the immune system [35]. Overall, thermal stress has an immunosuppressive effect. Concerning hyperthermia, a stimulatory effect of the immune response appears to prevail at a moderate increase in local skin temperature, with increases in the proinflammatory cytokines interleukin (IL)-6 [36] and IL-1ß [37], whereas higher temperatures (40–41C) apparently suppress immune functions [38, 39]. A significant reduction in the circulating levels of T lymphocytes have been demonstrated in healthy volunteers treated with hyperthermal baths [1] and in patients with respiratory and cutaneous atopy [40]. Hyperthermia induced T lymphocytopenia and eosinopenia may result from a redistribution of the cells, probably due to the increase in ACTH and cortisol provoked by thermal stress [14]. In vitro studies have demonstrated that sulfurous spa waters have a dose-dependent inhibitory effect on the blast transformation and proliferation of T lymphocytes obtained from peripheral blood in both healthy subjects and subjects affected by chronic inflammatory diseases [40]. On the other hand, immersion in thermal waters at a temperature of 40C reduces the lymphocyte response to phytohaemoagglutinin [41]. Sulfurous spa waters also seem to exert an intense inhibitory action on the production of cytokines, especially IL-2 and interferon-gamma (IFN-c). As Does CD4 mainly produce these cytokines? Lymphocytes, it can be hypothesized that memory T cells are the principal target of sulfur-rich waters. The application of sulfurous streams reduces the capacity of memory T cells to proliferate and produce cytokines, thus resulting in an alteration of the immune response [42]. Hyperthermia-induced modification of the cytokine milieu has been recently confirmed in patients affected by ankylosing spondylitis (AS) [43]. Tarner et al. showed that the serum levels of tumor necrosis factor (TNF)-a, IL-1b, and IL-6, which were measured before, during, and after whole-body hyperthermia, were significantly reduced in patients with AS. In contrast, the changes in healthy subjects were not statistically significant.
Anti-inflammatory and chondroprotective aspects
Recent studies have shown a reduction in the 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 [44, 45] (Table 1). Crenotherapy also affects the synthesis of various cytokines involved in the ongoing chondrolysis and inflammation in RD; in fact, a reduction in the cytokines IL-1ß and TNF-a and the soluble receptors of the latter has been demonstrated following a cycle of mud-bath therapy (temperature [41C) in patients with OA [46–48] (Table 1). Several studies have provided evidence for a significant role of matrix metalloproteinases (MMPs), particularly MMP-3 or stromelysin-1, produced by activated chondrocytes and other cell types in the development of cartilage degradation in joint diseases [49, 50]. A recent study by Bellometti et al. [51] showed that MMP-3 serum levels were significantly reduced by mud-bath therapy in patients with OA. Cycles of mud applications and balneotherapy also bring about an increase in some growth factors, such as insulin-like growth factor 1 (IGF1) [47], which stimulates cartilage anabolism [52]. Furthermore, a significant increase in the circulating levels of transforming growth factor-beta (TGF-ß) has been found in patients with AS after combined spa-exercise therapy (exercise, hyperthermia, and exposure to low doses of radon) [53] (Table 1). TGF-ß is a very potent immunomodulating and anti-inflammatory cytokine which plays a major role in tissue healing, bone remodeling, and fibrosis [54, 55]. Among the various factors responsible for inflammatory and degenerative phenomena in joints in various forms of RD, reactive oxygen species (ROS) and nitric oxide (NO) should be taken into consideration [56, 57]. Sulfurous waters have been demonstrated to have an the antioxidant effect in vitro; in fact, the incubation in sulfurous mineral water significantly reduces the release of ROS and the reactive nitrogen species (RNS) peroxynitrite by polymorphonucleate leukocytes (PMNs) stimulated by N-formyl-methionyl-leucyl-phenylalanine and phorbol-12- myristate-13-acetate [58]. Various studies in humans have highlighted the positive action of mud packs and thermal baths, especially sulfurous ones, on the oxidant/antioxidant system. Grabski et al. [59] reported the reduction in superoxide dismutase (SOD) activity in patients with rheumatoid arthritis (RA) undergoing treatment with sulphuric water. Eckmekcioglu et al. [60] demonstrated that 3 weeks of sulfur baths can reduce the antioxidative defense system (SOD and glutathione (GSH) peroxidase) in the blood of patients with OA. They suggested two possible causes for the decline of these enzyme activities: either as a consequence of reduced oxidative stress during sulfur therapy leading to a lower expression of these enzymes or as an enhanced generation of superoxide radicals were exhausting the superoxide-scavenging enzyme. Bender et al. [61] demonstrated that therapeutic baths in mineral water reduced the activity of catalase, SOD, malondialdehyde (MDA), and GSH peroxidase. Other authors have observed a significant decrease in NO and myeloperoxidase (MPO) and a slight increase in GSH peroxidase in the sera of subjects with OA undergoing cycles of mud applications and balneotherapy [62]. The slight increase in GSH peroxidase does not correlate with the reduction in the other biochemical markers, suggesting that thermal mud possesses different mechanisms of action. In a recent study, we assessed the possible modifications of plasma levels of leptin and adiponectin in patients with OA treated with a cycle of spa therapy [63]. Our data showed a slight but not significant increase in plasma leptin concentrations and a significant decrease in serum adiponectin levels at the end of the mud-bath therapy cycle. These adipocytokines play an important role in the pathophysiology of OA [64, 65]. In particular, there is some evidence that adiponectin in skeletal joints may have proinflammatory effects and may be involved in cartilage degradation [64, 66]. Because of these recent findings, the decrease in adiponectin after spa therapy demonstrated in our study may play a protective role in OA. Experimental studies in animal models of arthritis corroborate the evidence of beneficial effects of mud-bath therapy on inflammatory and degenerative joint diseases. Cozzi et al. [67] have recently demonstrated an antiinflammatory effect of mud-bath applications in Freund’s adjuvant-induced arthritis in rats. Following the application of crenotherapy, a reduction in edema in the rat paws (measured by plethysmometry) was accompanied by a significant decrease in the levels of circulating TNF-a and IL-1b. In 2007, Britschka et al. [68] confirmed the antiinflammatory and chondroprotective effects of the application of mud in Zymosan-induced arthritis in rats, by performing histological analysis on synovial tissues and cartilage is taken from the sacrificed animals on day 21 of treatment. Examination of the synovial membrane in particular revealed reduced hyperplasia of the lining, reduced vascularization and cellular infiltration in the group of rats treated with mud applications, in contrast to the group of rats treated with heated tap water and the untreated (control) group of rats. Concerning cartilage, there was a macroscopically visible reduction in erosive lesions as well as an increase in chondrocyte density and collagen and proteoglycan content only in the mud-treated animals (Figs. 1, 2).
Other aspects
Many other non-specific factors may also contribute to the beneficial effects observed after spa therapy in some RDs, including effects on cardiovascular risk factors. The lipid-normalizing effects of mud applications and balneotherapy, especially with sulfurous waters, have been reported for decades. The results of such research have documented reductions in total cholesterol, triglycerides and non-esterified cholesterol and a significant increase in HDL cholesterol [69, 70]. More recently, attention has focused on plasma homocysteine, a risk factor for coronary heart disease, congestive heart failure, systolic hypertension, atherothrombotic events, complications in diabetes mellitus, cancer and oxidative stress [71–75]. A significant reduction in plasma homocysteine has been demonstrated in OA patients after a cycle of sulfurous thermal baths [76]. Recently Ola´h et al. [77] explored changes in diverse cardiovascular risk factors in a group of patients suffering from degenerative musculoskeletal disorders subjected to a cycle of balneotherapy. The authors showed a statistically significant and lasting (3 months after the sequence of balneotherapy) decrease in serum levels of C-reactive protein (CRP) in patients treated with mineral thermal baths. The reduction in cardiovascular risk factors through the use of mud packs and balneotherapy is especially important considering the clear and much-stressed association between various RDs and atherosclerotic processes [78]. Finally, other elements need to be taken into consideration concerning the mechanisms of action of mud applications and balneotherapy in RD, such as the particular climatic and environmental conditions of spas and the fact that people rest more and are far from daily stress during stays at spa resorts [1, 2].
Unresolved issues concerning the mechanisms of action of spa therapies
Although the data presented are stimulating, it is impossible to ignore the existence of a complex series of problems and uncertainties that prevent spa therapies from gaining the full consensus of the scientific community [9]. One of the critical points is the controversial problem of the absorption of the minerals dissolved in thermal waters, i.e. the demonstration of specific effects other than those linked to the simple action of heat. Unfortunately, few studies have been conducted on this topic, and little is known about the specific facts of various mineral waters. It is still not clear which elements are essential and what the ideal concentration of each component is to attain an optimal response to treatment. It remains to be clarified which mineral waters are most suitable for various diseases and whether the different parts exert specific actions. Such evidence would lead to a specialization of spa resorts, which could finally target their therapies more accurately and rationally.
