Phytothermotherapy in Osteoarthritis: A Randomized Controlled Clinical Trial

Abstract

Objective:

The aim of this study was to assess the efficacy of adding a cycle of phytothermotherapy (a traditional treatment with fermenting grass used in Trentino-Alto Adige, Italy) to the usual drug treatment, in patients with primary symptomatic osteoarthritis (OA) of the knee, hip, or lumbar spine.

Methods:

In this randomized, single-blind, controlled trial, 218 outpatients were enrolled; 109 patients were treated with a cycle of phytothermotherapy at the thermal resort of Garniga Terme (Trento, Italy) for 10 days; the other 109 patients continued regular outpatient care. Patients were assessed at baseline, after 2 weeks, and after 3 months from the beginning of the study and were evaluated using a visual analogue scale (VAS) for spontaneous pain, a Health Assessment Questionnaire, the Lequesne index for hip and knee osteoarthritis, and the Rolland Morris Questionnaire for lumbar spine OA and symptomatic drug consumption.

Results:

In patients treated with phytothermotherapy, a significant improvement of VAS and a reduction of nonsteroidal anti-inflammatory drug consumption at the end of treatment and 3 months later were observed. In the control group, no significant differences were noted. The analyses performed separately for each subgroup for OA localization showed that the best results were evident in lumbar spine OA. Concerning tolerability, in the group treated with phytothermotherapy 10% of patients presented side-effects due to treatment, but these were of low intensity and did not interrupt the therapy.

Conclusions:

In conclusion, the results show beneficial effects of a cycle of phytothermotherapy in patients with OA of the hip, knee, or lumbar spine. Phytothermotherapy may therefore be a useful aid alongside the usual pharmacologic and physiokinesic therapies, or may be used as a valid alternative for patients who do not tolerate pharmacologic treatments.

Introduction

O steoarthritis (oa) is the most common rheumatic disease in developed countries, and is becoming increasingly widespread due to the rise in the average life expectancy of the population in general.^l Current treatments for OA include nonpharmacologic and pharmacologic modalities.² Pharmacologic therapy has been largely confined to analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), or selective COX-2 inhibitors (COXibs). However, the use of NSAIDs is limited by their negative side-effects on the gastrointestinal tract³ and on cartilage metabolism,⁴ and the use of COXibs is characterized by an increase in cardiovascular side effects.^5,6 Acetaminophen is better tolerated compared to NSAIDs and COXibs, but does not always provide adequate pain relief.^7,8

These reasons often lead patients to seek other complementary or alternative therapies.⁹ In the Alpine area of Italy, there is a long tradition of treating rheumatic diseases using phytothermotherapy (i.e., the “immersion” of the body in fermenting freshly mown grass [“hay baths”]). This treatment is used and studied especially in the area of Monte Bondone, a mountain above Trento (Italy). The traditional treatment usually consists of 10 daily immersions in warm grass (50°C–58°C) of 20 minutes each.¹⁰

The efficacy of phytothermotherapy in rheumatic diseases has been bolstered by ancient tradition. However, despite its long history and popularity, there is a marked lack of clinical validation of its efficacy and tolerability in current literature.

Materials and Methods

Aim and design

The aim of this study was to assess the efficacy of adding a cycle of phytothermotherapy to the usual drug treatment in patients with primary symptomatic OA of the knee, hip, or lumbar spine.

This was a prospective randomized, single-blind controlled trial. The study protocol followed the Principles of the Declaration of Helsinki, and was approved by the Ethics Committee of the Provincial Health Authority of the autonomous Province of Trento (decision number 45/06 of June 29, 2006).

Participants

Two hundred and eighteen (218) outpatients of both sexes (83 males, 135 females), affected by primary symptomatic OA of the lumbar spine (n = 130), knee (n = 44) or hip (n = 44), were included in the study. Patients were recruited by 2 general practitioners from the rural area within 30 km of the spa center of Garniga Terme (Trento, Italy), between June 2007 and March 2008. All patients resided in the area near the thermal center of Garniga Terme and continued to live at home and carry out their daily routines.

The inclusion criteria considered patients with knee or hip OA according to the ACR criteria,^11,12 and patients with lumbar spine OA defined at x-ray by disc space narrowing and at least one level of osteophyte or osteosclerosis.¹³ All patients had to be symptomatic (visual analogue scale [VAS] > 30 mm), for at least 3 months prior to inclusion in the study.

The exclusion criteria were as follows: significant severe comorbidity of the heart, lung, liver, cerebrum, or kidney; systemic blood diseases; severe peripheral vascular diseases; acute illness; neoplasm; presence of other rheumatic diseases; asthma or allergies to herbal products; sciatica; documented lumbar disc herniation; pregnancy or nursing; and a body–mass index >30 kg/m². Patients with hip or knee OA with a grade IV (Kellgren/Lawrence)¹⁴ radiological score, and subjects who had had joint lavage, arthroscopy, or treatment with intra-articular corticosteroids or hyaluronic acid during the preceding 3 months were excluded from the study. Furthermore, all patients treated with chondroprotective agents less than 6 months prior to the study or with phytothermotherapy in the year preceding the start of the trial were excluded from the study.

Interventions

After confirming fulfillment of the screening criteria as defined above and obtaining written informed consent, patients were randomized 1:1 and allocated into two groups by using a computer-generated table of random numbers: group I (109 patients) was submitted to phytothermotherapy at the thermal center of Garniga Terme, and group II (109 patients), as control group, continued regular outpatient care (exercises, NSAIDs, and/or acetaminophen). Patients allocated to the control group were offered phytothermotherapy at the end of the study in order to prevent withdrawal from the study and for ethical reasons.

Group I patients were submitted to 10 generalized daily immersions of 20 minutes each in warm (50°C–58°C) hay. The grass used was grown 1200–1500 m above sea level, on Monte Bondone (Trento, Italy) and was taken from locations that had been found in previous trials to be suitable for this use: Malga Campo in the Municipality of Luserna; Avalina in the Municipality of Roncone; and Viote del Monte Bondone in the Municipality of Garniga Terme (Trento, Italy). The grass was cut, gathered, and transported to the spa center of Garniga Terme according to traditional methods, before it dried. At the spa, a 50-cm layer of hay was placed in baths, where fermentation produced heat that reached a temperature of approximately 60°C in the deepest layers after 1–2 days. The patients were immersed in this fermenting hay and covered with a layer 10–20 cm thick. The cycle comprised 10 baths, with a day of rest after the fifth bath.

Patients in both groups were advised that they should continue their established pharmacologic and nonpharmacologic treatments, with the exception of analgesic drugs (500 mg acetaminophen tablets) and NSAIDs (150 mg diclofenac tablets, 20 mg piroxicam tablets, 750 mg naproxen tablets, and 200 mg aceclofenac tablets), which were to be consumed freely and noted daily in a diary. Furthermore, patients were advised not to have corticosteroid or hyaluronic acid infiltrations, arthroscopic surgery, or joint lavage, and they were told not to begin treatment with new chondroprotective agents. Patients were not permitted to have other spa treatments or physical therapy during the follow-up period either.

Assessment

Patients in both groups had three assessments, performed by a physician, kept in blind, who was not employed by the spa center and was autonomous from the general practitioners who recruited the patients initially. To prevent observer bias, the spa center was made responsible for the random group allocation, the patients' appointments with the investigators, and the management of the course of treatments. The first examination occurred at baseline, before the randomization (T₀); the second took place 15 days later, at the end of the phytothermotherapy (T₁); and the last was conducted after 3 months (T₂). At each assessment, the following characteristics were recorded: spontaneous pain on a 0–100-mm VAS, with 0 for the absence of pain; the Lequesne Index for severity of knee and hip OA¹⁵; the Rolland Morris Questionnaire (RMQ)¹⁶ for the lumbar spine OA; and the Health Assessment Questionnaire (HAQ).^17,18

Regarding NSAID and acetaminophen consumption, the number of days per week in which patients consumed the drugs was considered. This information, reported in a daily diary given to each patient, was only evaluated at basal time and after 3 months. For the whole period of the study, patients were advised not to modify their therapeutic program, except for the occurrence of adverse events.

All adverse events, whether spontaneously reported by the patients or observed by the physician at the spa center, were reported in a diary, noting the severity and the possible correlations with the treatments.

Statistical analysis

Power analysis (α = 0.05; β = 0.80) determined that a sample size of 20 patients in each subgroup was needed to detect a decrease ≥15, with a standard deviation (SD) of 20, in VAS score at week 12 of the study.

Data are expressed as mean and SD, or median and interquartile range. A p < 0.05 is considered significant. The basal conditions of the two groups of patients were compared using the χ2 chi-square test, the t-test, or Mann–Whitney test for independent data. The comparison of variables during the follow-up was performed with repeated-measures analysis of variance or with the Friedman test. The post hoc Dunnett's test or Dunn's test was applied when necessary. All analyses were performed with SAS System v. 9.0 (SAS Institute Inc., Cary, NC) and GraphPad Prism v. 5.

Response to treatment was analyzed for all patients who entered the trial (intent-to-treat analysis); the last observation carried forward approach was used for patients who did not complete the study according to the protocol.

Results

One (1) patient in group I was lost to follow-up after 15 days for personal reasons (Fig. 1). Patients suffered from hip OA (n = 44: 22 in group I, 22 in group II), knee OA (n = 44: 24 in group I and 20 in group II), or lumbar spine OA (n = 130: 63 in group I and 67 in group II).

FIG. 1.

Study flowchart.

The baseline characteristics of the patients enrolled in the study are summarized in Table 1. At baseline there were no statistically significant differences in demographic and clinical variables between the two groups, both in the general analysis and in the stratified analysis for OA localization.

Table 1.

Demographic and Baseline Clinical Characteristics of Study Patients

	Group I (n = 109)	Group II (n = 109)	p-Value
Age (years)	61.64 ± 9.00^a	61.08 ± 10.49	0.67
Gender (female/male)	67/42	68/41	0.89
Disease duration	6.54 ± 6.48	7.11 ± 4.89	0.46
BMI	26.43 ± 3.94	25.88 ± 4.59	0.34
Number of comorbidity	1.72 ± 1.07	1.99 ± 1.12	0.07
Pain (VAS)	53.87 ± 14.76	54.87 ± 18.85	0.66
HAQ	0.53 ± 0.35	0.51 ± 0.38	0.68
NSAIDs weekly consumption (days)	3.28 ± 5.73	1.75 ± 5.79	0.06
Acetaminophen weekly consumption (days)	0.33 ± 2.26	0.96 ± 4.62	0.22

Values are mean (± standard deviation) unless otherwise indicated.

BMI, body–mass index; VAS, visual analogue scale; HAQ, Health Assessment Questionnaire; NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 2 shows that in patients treated with phytothermotherapy, a significant reduction of pain (VAS: p < 0.001) was observed at the end of the treatment and persisted for 3 months (p < 0.001), accompanied by a significant improvement in the HAQ index (p < 0.01) after 15 days. In the control group, the variables remained stable throughout the follow-up period. Statistically significant differences were found between the two groups at 15 days (p < 0.001) and at 3 months (p < 0.001).

Table 2.

Clinical Variables at Entry and During the Follow-Up Period in Each Group

Variable	Group	T₀	T₁	T₂
VAS	I	53.87 ± 14.76^a	41.55 ± 19.58***	30.74 ± 22.29***
	II	54.87 ± 18.85	54.89 ± 22.69°°°	49.22 ± 22.47°°°
HAQ	I	0.53 ± 0.35	0.42 ± 0.29**	0.46 ± 0.44
	II	0.51 ± 0.38	0.56 ± 0.37°°°	0.53 ± 0.48°°°
NSAIDs consumption	I	3.28 ± 5.73	—	0.62 ± 2.18***
	II	1.75 ± 5.79	—	1.57 ± 3. 68°
Acetaminophen consumption	I	0.33 ± 2.26	—	0.1 ± 0.70
	II	0.96 ± 4.62	—	0.21 ± 0.86

Values are mean (±standard deviation) unless otherwise indicated.

p < 0.01; ^*** p < 0.001 each time versus basal time.

p < 0.05; °°°p < 0.001 group I versus group II in each time.

T_0, basal time; T_1, after 2 weeks; T_2, after 3 months; VAS, visual analogue scale; HAQ, Health Assessment Questionnaire; NSAIDs, nonsteroidal anti-inflammatory drugs.

Concerning drug consumption, a significant decrease (p < 0.001) was noted in NSAID use in group I, and a significant difference between the two groups (p < 0.05). The acetaminophen consumption showed slight but not significant reduction in both groups at the end of the follow-up period without significant differences between groups.

Table 3 shows the median values of the considered variables stratified for OA localization during the follow-up period.

Table 3.

Clinical Variables During the Follow-Up Period in Each Group

OA localization	Variable	Group	T₀	T₁	T₂
	VAS	I (n = 22)	67 (57–68)	53 (32–59)**	47 (20–55)**
		II (n = 22)	57 (43–71)	61 (52–86)°	59 (40–65)°
	HAQ	I	0.5 (0.25–0.75)	0.25 (0.25–0.75)*	0.5 (0.38–1)
		II	0.63 (0.25–0.85)	0.63 (0.38–0.88)°°°	0.5 (0.25–0.88)
	Lequesne	I	8 (7–12)	7 (6–11)	6 (3–11)*
Hip OA		II	9 (8–9.75)	10 (7–11)°°°	10 (6.25–10)°°°
	VAS	I (n = 24)	52.5 (46.5–62.5)	42.5 (30.25–51.75) *	27.5 (0.25–34)***
		II (n = 20)	51.5 (36.5–67.25)	50 (22.5–75.25)	49 (31–62)°°
	HAQ	I	0.5 (0.27–0.63)	0.38 (0.16–0.5)	0.25 (0.13–0.75)
		II	0.5 (0.22–0.63)	0.5 (0.3–0.75)	0.48 (0.25–0.72)°°°
	Lequesne	I	9 (7.25–11.5)	7 (6–8.75)**	5.5 (3–10)**
Knee OA		II	9 (7.25–12.25)	9.5 (6.25–10)°°°	8 (6–12)°°°
	VAS	I (n = 63)	52 (45–63)	41 (27–51)***	30 (10–47)***
		II (n = 67)	58 (45–66)	62 (38–69)°°°	53 (35–64)°°°
	HAQ	I	0.5 (0.25–0.75)	0.375 (0.25–0.625)	0.345 (0.125–0.5)**
		II	0.375 (0.25–0.625)	0.45 (0.25–0.75)	0.345 (0–0.845)
	RMQ	I	11 (9–13)	7 (6–10)***	6 (3–8)***
Lumbar spine OA		II	10 (9–12)	11 (8–12)°°°	10 (7–12)°°°

Data are expressed as interquartile range.

OA, osteoarthritis; T_0, basal time; T_1, after 2 weeks; T_2, after 3 months; VAS, visual analogue scale; HAQ, Health Assessment Questionnaire; RMQ, Rolland Morris Questionnaire.

p < 0.05; ^** p < 0.01; ^*** p < 0.001 each time versus basal time.

p < 0.05; °°p < 0.01; °°°p < 0.001 group I versus group II in each time.

For all the OA localizations in group I, significant decreases were observed in the VAS scale, which persisted until the 3-month checkup. The control group did not show statistically significant differences from baseline to follow-up. Comparisons between the two groups showed statistically significant differences in the VAS scale in all the follow-up assessments and in all OA localizations, except at 15 days for knee OA.

In patients affected by hip OA, the HAQ score was significantly lower in group I at 15 days (p < 0.05). Regarding the Lequesne index, a significant difference (p < 0.05) was observed in group I at the 3-month evaluation. There were no statistically significant differences between baseline and the other assessments for either of these variables in the control group.

Regarding knee OA, in patients treated with phytothermotherapy a significant reduction (p < 0.01) was observed in the Lequesne index between baseline and all the other follow-up assessments. The HAQ index did not show significant changes during the study. There were no statistically significant differences in the control group between baseline and the other assessments for both variables.

In group I patients with lumbar spine OA, the RMQ decreased significantly (p < 0.001) after treatment and remained stable during the rest of the follow-up period, whereas in group II there was not a significant modification of the RMQ score in any of the follow-up assessments. Concerning the HAQ, the median values changed significantly in group I at 3 months (p < 0.01), whereas they remained unvaried in the control group.

Concerning tolerability, in the group treated with phytothermotherapy 10% of patients presented side-effects due to treatment, but these were of low intensity and did not interrupt treatment. In particular, these patients presented with asthenia, cutaneous reactions, postbath tachycardia, and inflammation of the knee. In the control group, 6% of patients presented mainly with gastrointestinal side-effects.

Discussion

A randomized, single-blind, controlled clinical trial was performed in patients with OA of the hip, knee, or lumbar spine, using a phytothermotherapeutic treatment with fermenting grass. The study was performed to assess the efficacy of this treatment at both 2 weeks (the end of the phytobalneotherapy) and 3 months later. The results show the beneficial carryover symptomatic effects of a cycle of phytothermotherapy in patients with OA. The persistent symptomatic effects of phytothermotherapy in OA demonstrated in this study are in line with those of other trials of spa therapy for various rheumatic diseases performed previously^{13,19

–24} and with the previous contribution on phytothermotherapy in patients affected by fibromyalgia.²⁵ Nguyen et al.¹³ reported that spa therapy of 3 weeks' duration had a carryover of beneficial symptomatic effects (6 months) in patients with lumbar spine, knee, and hip OA. Guillemin et al.¹⁹ concluded that the addition of spa therapy for patients with low-back pain had a positive short-term and a moderate long-term (9 months) effectiveness on chronic low-back pain. Van Tubergen et al.²⁰ reported that in patients with ankylosing spondylitis, a 3-week course of combined spa and exercise therapy, in addition to drug treatment, provided beneficial effects for at least 40 weeks. In a previous study,²⁵ the current authors investigated the effects of phytothermotherapy in patients affected by fibromyalgia, demonstrating pain relief and significant improvement of the fibromyalgia-related symptoms and quality of life during follow-up (12 and 24 weeks).

However, it is important to emphasize that a randomized trial on the effects of phytothermotherapy in OA has never been performed previously.

In this study, the differences in clinical variables between groups was explained by an improvement in the group treated with phytothermotherapy, while no significant changes, or worsening, was observed in the group treated with conventional therapies alone. The significant reduction in NSAID consumption induced by the phytothermotherapy is particularly important, considering the toxicity of these drugs,^3

–6 especially for the elderly, and their cost, given that their use is often coupled with gastroprotective therapies. The analysis performed separately for each subgroup for OA localization showed that the best results were evident in the lumbar spine OA, with a significant improvement (p < 0.001) in VAS and RMQ scores at the end of the therapy and after 3 months. Similar results have been reported by other authors,^13,26 who evaluated the efficacy of other thermal therapies (balneotherapy, mudpack therapy) in various OA localizations.

The mechanisms of action of phytothermotherapy are not known, although it is recognized that its effects are, in part, related to temperature. Hot stimuli may influence muscle tone and pain intensity, helping to reduce muscle spasm and increase the pain threshold in the nerve endings. Furthermore, thermal stress brings about a significant increase in the serum levels of pituitary hormones and opioid peptides such as endorphins and encephalin.²⁷ This effect leads to an intense and progressive improvement of muscular and articular pain. An increase in blood levels of heat shock protein 70 (Hsp70) has been demonstrated in patients with OA during phytobalneotherapy.²⁸ In cell cultures of chondrocytes and in models of arthritis, Hsp70 has been shown to provide protection from cellular injuries and apoptosis.²⁹

Other effects of phytothermotherapy may be due to the active ingredients contained in the fermenting grasses, which are rich in aromatic species that, aided by vasodilatation, are able to enter the organism in the form of essential oils, terpenes, and other aromatic substances.³⁰

Other specific factors may also contribute to the clinical improvement observed after phytothermotherapy, including the change in environment, pleasant scenery/surroundings, and the absence of work duties.³¹ In an attempt to eliminate these factors from our study, however, all patients resided in areas surrounding the spa and continued their work activities without modifying their lifestyles.

Another aspect that often contributes to amplifying the effect of phytothermotherapy is its frequent association with physiokinesitherapy. Such treatments were excluded from the protocol of this study.

Finally, the tolerability of phytothermotherapy seemed to be good, with slight and transitory side-effects seen also in patients who presented pathologies associated with OA.

Some aspects of this study are criticizable and could constitute a potential bias. In particular, the impossibility of a double-blind study design using fermenting grass makes it extremely hard to differentiate between the effects of the thermal therapy and the placebo effects linked to the patient's own expectations. Further studies are obviously warranted; for example, the comparison between two active groups, using thermal therapies for one and fermenting grass for the other, versus a control group (no treatment), could help better clarify the real efficacy of the fermenting grass.

Another negative aspect of this trial is the lack of quality-of-life indexes as outcome measurements for efficacy.

Conclusions

In conclusion, these results, albeit with the abovementioned limitations, show the beneficial symptomatic effects of a cycle of phytothermotherapy in a group of patients with OA of the hip, knee, or lumbar spine. Phytothermotherapy may therefore be a useful aid alongside the usual pharmacologic and physiokinesic therapies, and it may represent an alternative treatment in patients with OA with a high risk of drug-related side-effects. Further studies on a larger number of patients are needed to provide more precise therapeutic guidelines on the modalities of use of such therapies.

Footnotes

Disclosure Statement

No competing financial interests exist.

References

Peat

, McCarney

, Croft

. Knee pain and osteoarthritis in older adults: Review of community burden and current use of primary health care. Ann Rheum Dis, 2001; 60:91–97.

Jordan

, Arden

, Doherty

et al.

EULAR recommendations 2003: An evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT)

Ann Rheum Dis, 2003; 62:1145–1155.

Ofman

, Maclean

, Straus

et al. A meta-analysis of severe upper gastrointestinal complications of nonsteroidal anti-inflammatory drugs. J Rheumatol, 2002; 29:804–812.

Huskisson

, Berry

, Gishen

et al. Effects of anti-inflammatory drugs on the progression of osteoarthritis of the knee: LINK Study Group. Longitudinal investigation of nonsteroidal anti-inflammatory drugs in knee osteoarthritis. J Rheumatol, 1995; 22:1941–1946.

Bresalier

, Sandler

, Quan

et al. Trial investigations: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. NEJM, 2005; 352:1092–1102.

Kearney

, Baigent

, Godwin

et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ, 2006; 332:1302–1308.

Zhang

, Jones

, Doherty

. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis, 2004; 63:901–907.

Pincus

, Wang

, Chung

et al. Patient preference in a crossover clinical trial of patients with osteoarthritis of the knee or hip: Face validity of self-report questionnaire ratings. J Rheumatol , 2005; 32:533–539.

Zochling

, March

, Lapsley

et al. Use of complementary medicines for osteoarthritis: A prospective study. Ann Rheum Dis, 2004; 63:549–554.

10.

Miori

, Contu

, Marzano

et al.

Critical evaluation of phytothermotherapy (“hay baths”) in degenerative arthropathies [in Italian]

Clin Ter, 1994; 144:31–42.

11.

Altman

, Asch

, Bloch

et al. Development of criteria for the classification and reporting of osteoarthritis: Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum, 1986; 29:1039–1049.

12.

Altman

, Alarçon

, Appelrouth

et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum, 1991; 34:505–514.

13.

Nguyen

, Revel

, Dougados

. Prolonged effects of 3 week therapy in a spa resort on lumbar spine, knee and hip osteoarthritis: Follow-up after 6 months. A randomized controlled trial. Br J Rheumatol, 1997; 36:77–81.

14.

Kellgren

, Lawrence

. Radiological assessment of osteoarthritis. Ann Rheum Dis, 1957; 16:494–502.

15.

Lequesne

, Mery

, Samson

, Gerard

. Indexes of severity for osteoarthritis of the hip and knee: Validation-value in comparison with other assessment tests. Scand J Rheumatol, 1987; 65:85–89.

16.

Roland

, Morris

. A study of the natural history of back pain: Part I. Development of a reliable and sensitive measure of disability in low-back pain. Spine, 1983; 8:141–144.

17.

Fries

, Spitz

, Kraines

, Holman

. Measurement of patients' outcome in arthritis. Arthritis Rheum, 1980; 23:137–145.

18.

Ranza

, Marchesoni

, Calori

et al. The Italian version of the functional disability index of the Health Assessment Questionnaire: A reliable instrument for multicenter studies on rheumatoid arthritis. Clin Exp Rheumatol, 1993; 11:123–128.

19.

Guillemin

, Constant

, Collin

, Boulange

. Short and long-term effect of spa therapy in chronic low back pain. Br J Rheumatol, 1994; 33:148–151.

20.

van Tubergen

, Landewé

, van der Heijde

et al. Combined spa-exercise therapy is effective in patients with ankylosing spondylitis: A randomized controlled trial. Arthritis Rheum, 2001; 45:430–438.

21.

Bálint

, Buchanan

, Adám

et al. The effect of the thermal mineral water of Nagybaracska on patients with knee joint osteoarthritis: A double blind study. Clin Rheumatol, 2007; 26:890–894.

22.

Cantarini

, Leo

, Giannitti

et al. Therapeutic effect of spa therapy and short wave therapy in knee osteoarthritis: A randomized, single blind, controlled trial. Rheumatol Int, 2007; 27:523–529.

23.

Evcik

, Kavancu

, Yeter

, Ygit

. The efficacy of balneotherapy and mud-pack therapy in patients with knee osteoarthritis. Joint Bone Spine, 2007; 74:60–65.

24.

Harzy

, Ghani

, Akasbi

et al. Short- and long-term therapeutic effects of thermal mineral waters in knee osteoarthritis: A systematic review of randomized controlled trials. Clin Rheumatol, 2009; 28:501–507.

25.

Fioravanti

, Bellisai

, Capitani

et al. Phytothermotherapy: A possible complementary therapy for fibromyalgia patients. Clin Exp Rheumatol, 2009; 27:S29–S32.

26.

Fioravanti

, Valenti

, Altobelli

et al. Clinical efficacy and cost-effectiveness of spa therapy in osteoarthritis: The results of the “Naiade” Italian Project. Panminerva Med, 2003; 45:211–217.

27.

Cozzi

, Lazzarin

, Todesco

, Cima

. Hypothalamic-pituitary-adrenal axis dysregulation in healthy subjects undergoing mud-bath applications. Arthritis Rheum, 1995; 38:724–726.

28.

Verzelloni

, Russo

, Agostini

et al. Serum heat shock proteins in knee joint osteoarthritis patients treated with grass thermal therapy. Pharmacol Online, 2006; 3:839–844.

29.

Grossin

, Cournil-Henrionnet

, Pinzano

et al. Gene transfer with HSP 70 in rat chondrocytes confers cytoprotection in vitro and during experimental osteoarthritis. FASEB J, 2006; 20:65–75.

30.

Defrancesco

, Nicolini

, Chemini

, Girardi

. Simulator for chemical and physical study in the phyto-bathing-therapy. Bender

, Pratzel

. Health Resort Medicine in 2nd Millennium: 34th World Congress of the I.S.M.H. Budapest, Héviz, Hungary, Berlin: Verlag, 2002; 391–400.

31.

Sukenik

, Flusser

, Abu-Shakra

. The role of spa therapy in various rheumatic diseases. Rheum Dis Clin North Am, 1999; 25:883–897.