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Introduction: Whole-body cryotherapy (WBC) has shown to be beneficial in the treatment of fibromyalgia (FM). There is cumulative evidence that cytokines play a crucial role in FM. It’s unknown whether clinical effects of WBC can be demonstrated at the molecular level and how long the effects last. Methods: We compared effects of serial WBC (6 sessions (− 130 °C in 6 weeks) in FM patients and healthy controls (HC). Primary outcome was the change in pain level (visual analogue scale 0–100 mm) after 6 sessions. Secondary outcomes were a change in disease activity (revised Fibromyalgia Impact Questionnaire) and pain after 3 sessions and 3 months after discontinued therapy and in cytokine levels (interleukin (IL-)1, IL-6, tumor necrosis factor α (TNF- α) and IL-10). The patients’ opinions on the satisfaction, effectiveness and significance of WBC were evaluated. Results: Twenty-three FM patients and 30 HC were enrolled. WBC resulted in a significant reduction in pain and disease activity after 3 and 6 sessions. No clinical benefit could be measured 3 months after discontinued treatment. Overall, probands were satisfied with WBC and considered WBC to be important and effective. FM patients had significantly different levels of IL-1, IL-6, TNF-α and IL-10 at each reading point compared to HC. Levels of IL-1, IL-6 and IL-10 were significantly altered over time in FM patients. Compared to HC FM patients showed a significantly different response of IL1, − 6 and − 10 to WBC. Conclusion: Serial WBC is a fast acting and effective treatment for FM. Proven effects of WBC may be explained by changes in cytokines. Keywords: Whole-body cryotherapy, Fibromyalgia, Cytokines, Physical therapy, Fibromyalgia impact questionnaire Introduction calculated that even a minimal increase in the Fibro- Fibromyalgia (FM) is a chronic pain syndrome. It is myalgia Impact Questionnaire (FIQ) score increases characterized by widespread pain and somatic symptoms costs in Europe by approximately €865 per year . FM such as fatigue, sleep disorders, cognitive impairment is therefore a problem of high social importance and and depressive disorders . Women around the age of represents a high economic burden . 50 are affected more frequently [2, 3]. The global mean The pathogenesis of FM is elusive. However, several prevalence of FM is 2.7% . Not only can FM lead to a factors seem to be of importance. These include abnor- high level of individual impairment, but it has been mal pain sensitivity and pain inhibition [7, 8], a dis- turbed hypothalamic-pituitary-adrenal axis [9, 10] and * Correspondence: firstname.lastname@example.org cytokine dysregulation . In addition, both genetic Department of Rheumatology, Immunology, Osteology and Physical and environmental factors seem to play a role [7, 8]. Medicine, Justus-Liebig-University Giessen, Campus Kerckhoff, Bad Nauheim, Eventually, there is increasing evidence of neurogen- de- Germany Full list of author information is available at the end of the article rived inflammatory mechanisms . These affect © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Klemm et al. Advances in Rheumatology (2021) 61:3 Page 2 of 9 peripheral tissues as well as the spinal cord and brain Materials and methods and involve a variety of neuropeptides, chemokines, and Participants cytokines. Both the innate and adaptive immune system Patients with FM and HC were treated at Campus Ker- appear to be activated in this process  and could play ckhoff of Justus-Liebig University Gießen, Dept. of an essential role. In neuropathic pain, for example, a bal- Rheumatology, Immunology, Osteology and Physical ance between pro-inflammatory and anti-inflammatory Medicine. Eligible participants had to be between 18 and cytokines is crucial, so that, an imbalance ultimately 80 years old. Only patients with primary FM were eli- leads to pain and impaired pain processing [13, 14]. In- gible and the diagnosis of primary FM had to be con- deed, in neuropathic pain models, pharmacological firmed on the basis of the 2016 revised 2010/11 blocking of the pro-inflammatory cytokines interleukin diagnostic criteria of FM . HC was not allowed to (IL-)1, IL-6 and tumor necrosis factor α (TNF-α) has have a medical history. In the case of women, a commit- been found to prevent or reverse allodynia and hyper- ment not to become pregnant during the trial was ob- algesia . tained. We excluded patients with secondary FM, Whole-body cryotherapy (WBC) exposes patients to participants with a disease for which WBC is contraindi- extremely cold dry air in an environmentally controlled cated, e.g. unstable coronary disease, heart attack in the chamber or cabin for a short period of time (usually be- last 6 months, active vasculitis or acute infection, partici- tween 1 and 5 min). The exposure to cold air induces pants with a body weight over 120 kg or intolerance to vasoconstriction  and stimulation of dermal thermo- cold. All patients with FM had to be in stable pharmaco- receptors, which leads to slower nerve conduction  logical and non-pharmacological treatment 4 weeks prior ultimately resulting in an analgesic effect. So far, it has to the start of the study. During the entire study period been used as a recovery technique after physical exercise of 3 months no change in pharmacological treatment or  and has been successfully tested in inflammatory non-pharmacological treatment (such as mind-body- diseases such as rheumatoid arthritis [19, 20] and anky- therapy or meditative movement) was allowed. In losing spondylitis [19, 21]. In addition to its symptomatic addition, no physical therapy such as massages or multi- and immediate effects, WBC has been shown to affect component therapy was allowed during the entire dur- the immune system. In healthy controls WBC leads to ation of the study. an increase in white blood cell count, especially lympho- cytes and monocytes. It also affects the overall oxidative Study procedures and antioxidative status, which indicates an increased In this controlled prospective study, all participants re- immune capacity . Furthermore, WBC has an influ- ceived WBC treatment (6 sessions at − 130° for 3 weeks ence on cytokine levels: it has been shown to increase with 2 sessions/week). Outcomes were measured after 3 IL-6 and IL-10 levels and to decrease IL-1 α levels in and 6 sessions and 3 months after discontinued therapy healthy individuals . In a pilot study, a significant im- (follow-up). provement in IL-1 and TNF-α levels could be observed WBC treatment was delivered using a cryosauna ‚ in patients with inflammatory rheumatic diseases . SPACE CABIN’ (~ 230 V, 50 Hz, serial number: 1050, At the other end of the thermotherapy spectrum, it has year of manufacture: 2013) from Cryomed s.r.o., Slowa- been shown that hyperthermia also alters cytokine levels kia. The therapy was delivered to participants in swim- . Nowadays, physical therapy has been shown to suit/underwear and warm socks. Fingers were placed change molecular parameters, which explains its pro- under the armpits during the treatment to avoid frost- found and beneficial effects in rheumatic diseases . damages. Temperatures between − 110 to − 170 °C can Recently WBC has shown effects in the treatment of be applied. In this study, a fixed temperature of − 130 °C FM: it reduces pain [26, 27], fatigue  and improves was selected. The first session was set at 90 s., the sec- health-reported quality of life [26–28]. Positive effects of ond at 120 s and from the third session onwards a time serial WBC (10 sessions in 8 days) are still remarkable 1 of 180 s (3 min) was set. month after discontinued treatment . An effect on disease activity measured by the revised Fibromyalgia Impact Questionnaire (FIQR) has not yet been reported. Assessments and outcomes We conducted a controlled, prospective trial to inves- Primary outcome was a change in pain intensity mea- tigate WBC’s effects on pain and disease activity and sured by a visual analogue scale (VAS) from baseline possible changes in molecular parameters (cytokine after 6 WBC sessions in patients with FM. The measure- levels of IL-1, − 6, − 10 and TNF-α) in FM and healthy ment of pain intensity with a 10 cm VAS, visually repre- controls (HC). To evaluate the long-term effects, we also senting the amplitude of pain (0 (best) to 100 (worst) examined relevant parameters 3 months after WBC mm) experienced by the subject  is well-established treatment. for FM . The minimum clinically important Klemm et al. Advances in Rheumatology (2021) 61:3 Page 3 of 9 difference (MCID) for pain intensity measured with VAS Statistical analysis has been reported to be 2.1 points (respectively 21 mm) Summary statistics (mean, standard deviation, frequen- . cies, and percentages) were used to describe the sample. The secondary outcome was a change in the baseline Differences between groups were tested with t-tests as- pain level (VAS) after 3 sessions of WBC and 3 months suming unequal variances. Differences to baseline were of discontinued therapy in patients with FM. In addition, tested with t-tests for paired values. All p-values are dis- the disease activity measured by the FIQR was assessed played unadjusted. The global hypothesis was tested by after 6 sessions of WBC and after 3 months of discontin- analysis of variance (ANOVA) and p-values less than ued therapy. The FIQR  evaluates 21 items in the 3 0.05 were considered statistically significant. In paired areas of function (n = 9), overall impact (n = 2), and comparisons the p-values are displayed without adjust- symptoms (n = 10) of FM. Each item can be rated from ment, but after Bonferroni-Holm adjustment for multi- 0 (best) to 10 (worst). The domain scores are then di- plicity,they are shown statistically significant. The vided individually and added in a final step creating a analyses were performed with R Version 3.6.1. total FIQR score from 0 (best) to 100 (worst). The re- sults of the total FIQR can be adequately compared with Results the results of older papers reported using the original From July 2014 to July 2015 we screened 89 patients (32 FIQR . Thus, although no MCID for the FIQR has HC and 57 patients with the diagnosis of FM). Of these, been reported, the MCID of a 14% change appears im- 57 participants (26 FM patients, 31 HC) met the inclu- portant for the FIQR . sion criteria and were enrolled (Fig. 1). The main reason The study used ELISA to detect changes in cytokine for the exclusion was that FM was in the background of levels (IL-1, IL-6, IL-10 and TNF-α) in FM patients and an inflammatory rheumatic disease and was therefore HC after 3 and 6 WBC sessions and after 3 months of not diagnosed as “primary FM” (Fig. 1). The mean age of discontinued therapy. To reduce artificially altered cyto- the participants was 46±9.8 years, 66% were female. kine levels, blood samples were immediately cooled and In FM patients the mean duration of the disease was taken to the laboratory. For each sample taken, a time of 13.9±8 years (n=23; disease duration: min. 1 year; max. less than 30 min from collection to centrifugation was 35 years). Three FM patients (nausea 1x, unspecific recorded. Serum was centrifuged at 3500 rpm at 15 °C maculae 1x, private reasons 1x) and one HC (1x acute for 10 min and plasma was centrifuged at 2850 rpm at urinary infection) dropped out during treatment. A stat- 4 °C for 15 min. The samples were stored at − 80 °C until istical analysis was therefore carried out with 23 FM pa- further use. Cytokine levels (IL-10, IL-6, TNF-α and IL- tients and 30 controls (Fig. 1). 1β/IL-1F2) were measured in sera using Quantikine® ELISAs (R&D Systems) according to the manufacturer’s Primary outcome instructions. Optical readings were taken with the SUN- The mean (±SD) pain levels measured by VAS in FM RISE (TECAN) system at 450 nm. So far it could be de- patients changed from 5.91±2.3 mm (confidence interval termined that FM patients apparently have different (CI) 4.9 to 6.92) at baseline to 3.43±2.8 mm (CI 2.2 to 4, levels of cytokines compared to HC. However, there are 7) after 6 WBC sessions (p< 0.0001). The MCID for pain neither established ranges of cytokines for FM patients levels of at least 2.1 was achieved. nor a solid correlation between specific concentrations and disease activity . After 6 WBC sessions, the subjective satisfaction, effi- Secondary outcomes cacy and significance of WBC were assessed. The mean (±SD) pain levels measured by VAS in FM patients changed from 5.91±2.3 mm (CI 4.9 to 6.92) at baseline to 4±2.7 mm (CI 2.8 to 5,2) after 3 WBC ses- Sample size sions (p=0.0016). The MCID for pain levels of at least We calculated that a sample size of 18 will have 89,2% 2.1 was not achieved. power to detect a difference in pain (VAS 0–10 cm) in 3 months after the last WBC session, the pain levels means of 1,6, assuming a standard deviation of differ- measured by VAS were 71.7±1,89 mm (CI 6.3 to 8), ris- ences of 2, using a paired t-test with a 5% two-sided sig- ing to values above the baseline (p=0.0037) (Supple- nificance level. Assuming a dropout rate of 20% we ment-Table 1). aimed to recruit 20 patients. The considered difference Disease activity assessed by FIQ decreased significantly in means and standard deviation are conservative esti- from a mean (±SD) FIQ 60.7±18.4 at the start of the mates based on previous studies evaluation the reduc- study to mean FIQ 48.5±23 after WBC treatment (p= tion of pain (VAS) while treating FM by WBC. 0.0006). Three months after discontinued treatment the Calculations were performed in nQuery 8. mean FIQ returned to baseline level of 64.1±15.4 (p= Klemm et al. Advances in Rheumatology (2021) 61:3 Page 4 of 9 Fig. 1 Trial enrollment and follow-up 0.2142) (Fig. 2 and Supplement-Table 1). The MCID of 6 sessions compared to baseline. 3 months after the last 14% for a change in FIQ was missed (here 12.2%). treatment IL-6 was also significantly improved. In con- IL-1 levels in FM patients decreased significantly after trast to healthy controls, FM patients showed signifi- 3 WBC sessions and after 6 WBC sessions and remained cantly decreased IL-6 levels at each reading point significantly lower compared to baseline 3 months after compared to baseline (cf. Figure 3 and Supplement- discontinued WBC treatment. Interestingly, 3 months Table 3). after the last WBC, IL-1 levels in both groups had de- TNF-α levels were not significantly decreased by creased compared to baseline, although healthy controls WBC, neither in FM patients nor in healthy controls (cf. showed no significant change during treatment. In com- Figure 3 and Supplement-Table 4). parison FM patients showed significantly higher IL-1 Levels of IL-10 in FM patients were significantly influ- levels after 3 sessions and 3 months after the last WBC enced after 3 WBC applications and 3 months after dis- session than healthy controls at the start of treatment continued treatment. Compared to healthy controls, FM (see Fig. 3 and Supplemental Table 2). patients showed significantly higher IL-10 levels at base- IL-6 levels were decreased by WBC in both groups. line, after 6 WBC sessions and 3 months after the last While IL-6 levels in healthy individuals returned to base- WBC application (cf- Fig. 3 and Supplement-Table 5). line after 3 months without WBC, FM patients still Taken together, in an analysis of mixed effects, the showed decreased levels. In FM patients, IL-6 levels were concentrations of IL-1, IL-6 and IL-10 as well as pain significantly reduced by WBC after 3 sessions and after (VAS) and disease activity (FIQ) were significantly Klemm et al. Advances in Rheumatology (2021) 61:3 Page 5 of 9 Fig. 2 Course of VAS (a) and FIQ (b) altered over time by WBC treatment. FM patients had Subjective satisfaction, efficacy and significance of WBC significantly different levels of IL-1, IL-6, TNF-α and IL- After completing WBC treatment, patients were asked 10 at each reading point compared to healthy controls. to report on their subjective satisfaction with WBC Most interestingly, FM patients showed a significantly treatment and on the subjective effectivness and signifi- different response to WBC compared to healthy controls cance of WBC treatment. Most patients were highly sat- in terms of changes in IL1, − 6 and − 10 to WBC over isfied with WBC and perceived WBC as an effective and time (cf. Table 1). highly important treatment option (cf. Figure 4). Fig. 3 Course of IL-1 (a), IL-6 (b), TNF-α (c) and IL-10 (d) Klemm et al. Advances in Rheumatology (2021) 61:3 Page 6 of 9 Table 1 Mixed effects analysis of group effects (Fibromyalgia vs. and IL-10 were significantly altered over time in FM pa- Healthy Control) and time effects (Baseline, 3 Applications, 6 tients. In comparison to healthy controls, FM patients Applications, 3 Months) as well as interaction. A significant showed a significantly different response in IL1, − 6 and interaction effect indicates differences in value development/ − 10 levels to WBC. performance over time depending on the cohort Three previous studies have already tested the effect of Group Effect Time Effect Interaction WBC on FM, but with different settings. Bettoni et al. IL1 p < 0.0001 p < 0.0001 p < 0.0001 treated recruited patients with mandatory aerobic exer- IL6 p = 0.0005 p = 0.0009 p = 0.0053 cise (cycloergometer or treadmill) for 30 min immedi- ately after WBC treatment . Because aerobic exercise IL10 p = 0.0008 p = 0.0032 p < 0.0001 is effective in the treatment of FM  and physical ac- TNF-alpha p = 0.0096 p = 0.8783 p = 0.1271 tivity could have influenced WBC treatment by vasodila- VAS – p < 0.0001 – tation as opposed to WBC-induced vasoconstriction, the FIQ – p < 0.0001 – distinct role of WBC in the effects observed in this study was limited. Therefore, we tested without background Discussion physical therapy throughout the study and had patients This trial, which examined the clinical and molecular ef- in stable treatment before and during the trial. In the fects of WBC in FM patients and HC, showed that serial study of Rivera et al. the cross-over design did not work WBC (6 sessions) resulted in a significant and clinically because of too short wash-out periods: patients treated important pain reduction in FM patients. Secondary out- with WBC did not initially return to baseline with regard comes showed that disease activity is significantly re- to VAS and FIQ, so that only results of the first se- duced by WBC and that the effects on pain are quence could be reported . Vitenet et al. only treated significantly manifested after only 3 WBC sessions. The 11 FM patients with WBC to investigate changes in the subjects were satisfied with WBC and considered WBC Medical Outcome Study Short Form-36 and, which is to be important and effective. FM patients had signifi- why the study is limited due to sample size . So far, cantly different levels of IL-1, IL-6, TNF-α and IL-10 at only Rivera et al. investigated effects of WBC on FIQ each reading point compared to HC. Levels of IL-1, IL-6  and only Vitenet et al. included a follow-up showing Fig. 4 Patient’s report on satisfaction, efficacy, and significance of WBC treatment Klemm et al. Advances in Rheumatology (2021) 61:3 Page 7 of 9 effects of WBC 1 month after discontinued treatment patients . So far, not all FM patients have been found . The clinically beneficial effects of WBC in this to have elevated TNF-α [11, 44], but the use of TNF in- study appear to be consistent with previous studies. hibitors has been shown to be less effective in secondary This study is limited by the absence of an FM control FM . IL-6 can be associated with hyperalgesia, de- group, that would not receive WBC. As previous studies pression stress, fatigue and sympathetic nervous system already tested such settings and thus demonstrated the activation. Several studies have therefore measured IL-6 proposed clinical benefits of WBC, we focused on a levels in FM – with varying results. Overall, a meta- slightly different aspect in this study and investigated analysis by Üceyler et al. favoured the detection of ele- molecular effects of WBC in addition to the clinical ef- vated plasma levels of IL-6 in FM . Interleukin-10 fects. Thus, we first had to confirm the clinical effects of (IL-10) inherits many anti-inflammatory properties. The WBC in order to test the molecular effects in compari- expression of substance P is regulated by IL-10 in a way son to a healthy control group in a second step. that the pain threshold is increased. Furthermore, IL-10 In our study the acceptance of WBC was high, as most decreases the production of IL-1, IL-6 and TNF-α.In patients reported to be highly satisfied with WBC while addition, WBC has proven to have an influence on cyto- perceiving WBC as an effective and highly important kines in healthy controls . treatment option. Therefore, WBC seems to be an effect- While previous studies hypothesized the cause of ive tool to improve disease activity. Interestingly, a reduc- WBC effects in FM [26–28], we found that WBC treat- tion of pain and disease activity was reported after only 3 ment significantly altered not only disease activity but sessions with a prolonged effect with increasing serial ap- also levels of IL-1, IL-6 and IL-10 over time. FM patients plications. Since patients with FM are partially impaired in had significantly different levels of IL-1, IL-6, TNF-α their ability to work  and a minimal increase in the and IL-10 at each reading point compared to healthy FIQ score increased costs by approximately €865 per year controls. These differences in cytokines we found correl- , cost-effective WBC can be of great benefit in the treat- ate well with a study by Ernberg et al. comparing circu- ment of acute exacerbations of FM in an individual, but it lating cytokines between FM and healthy controls with can also be important in a social perspective. the mentioned findings of Üceyler et al.  and Lub- Until now, it was not known how long the beneficial kowska et al. . Ernberg et al. investigated the effect effects of WBC on FM would last after treatment. Rivera of 15 weeks of progressive resistance exercise or relax- et al. had problems with their cross-over design as the ation therapy on cytokine levels in FM patients and HC washout period of 1 week for the first WBC group without significant alterations in cytokines and clinical proved to be too short, confirming an effect of WBC for outcomes in FM patients . In accordance with our at least 1 week. Vitenet et al. showed that effects of serial findings, Ernberg et al. found that FM patients had sig- WBC (10 sessions over 8 days) lasted for over 1 month nificantly different levels of cytokines compared to HC, after the last treatment . Our study shows that 3 which play a substantial role in inflammation but also months after stopping treatment, effects of WBC on pain modulation . As IL-1, IL-6 and IL-10 play an pain and disease activity were no longer reduced. Hence, essential role in pain, the observed changes could clearly serial WBC (between 6 and 10 sessions in up to 3 weeks) explain the observed efficacy of WBC. had effects for more than 1 month after termination of WBC treatment, which then decreased over time and Conclusion were not effective after 3 months. WBC is effective in FM and reduces the burden of disease. Overall, WBC seems to be a clinically valid, good and The effects of serial WBC are strongest during application fast-acting treatment for FMS. and are diminished 3 months after WBC treatment. More- In the pathogenesis of FM-related hyperalgesia, central over, the significant long-term alteration of IL-1, IL-6 and pain amplification, known as central sensitization, plays IL-10 by WBC could explain these beneficial effects. a major role [8, 38–40]. Additionally, an imbalance of pro- and anti-inflammatory cytokines plays a role in pain induction and maintenance and is known to be altered Supplementary Information in FM [11, 35]. Prostaglandin synthesis is increased by The online version contains supplementary material available at https://doi. IL-1 alone or in combination with TNF-α. It regulates org/10.1186/s42358-020-00159-z. substance P gene expression, thereby lowering the pain threshold in peripheral nerves . In addition, the Additional file 1. injected IL-1 causes fever, headache, myalgia and arth- ralgia  – symptoms that FM patients regularly ex- perience. In this context, IL-1RA (IL-1 receptor Acknowledgements antagonists) have been found to be higher in FM We thank all participants. Klemm et al. Advances in Rheumatology (2021) 61:3 Page 8 of 9 Consent to participate 11. Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia Study details and protocol were verbally explained to all participants and and cytokines. Immunol Lett. 2014;161:200–3. https://doi.org/10.1016/j.imlet. written information sheets were delivered. Written informed consent was 2014.01.009. obtained from each participant. 12. Littlejohn G, Guymer E. Neurogenic inflammation in fibromyalgia. Semin Immunopathol. 2018;40:291–300. 13. Ahrens C, Schiltenwolf M, Wang H. Cytokines in psychoneuroendocrine Consent to publication immunological context of nonspecific musculoskeletal pain. 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