Introduction
Methods
Search strategy and data extraction
Eligibility criteria
Inclusion criteria | Exclusion criteria | |
---|---|---|
Participants | Fibromyalgia patients (FM) or FM and a healthy population | Patients with other diseases, mixed types of patients (i.e., FM patients with other disorders), only a healthy population |
No restrictions on the number of participants and the diagnostic procedures were applied | ||
Biomarkers | Cytokines, neuropeptides and CRP | Other biomarkers |
Interventions | Non-pharmacological interventions were eligible | Mixed or blended non-pharmacological interventions, only pharmacological interventions |
Outcome | At least one biomarker (cytokine or neuropeptide or CRP) outcome | Studies in which biomarkers were used as predictors to identify the participants were excluded |
Study design | RCTs, Non-RCTs | |
Publications | Published in English, French or Spanish and as full-text articles in peer-reviewed scientific journals from January 1990 to March 2015 | Published in other languages and as reviews, case reports or letters |
Assessment of study quality
Results
Characteristics of included studies
Cytokines
Reference | Participants | Study design | Diagnosis of FM | Treatment group | Control group | Study duration | Outcomes | Findings |
---|---|---|---|---|---|---|---|---|
Ardiç et al. (2007) [37] | N = 31 | RCT | ACR 1990 | Balneotherapy | Usual care | N/A | IL-1α, CRP, PGE2, LTB4, RF, ESR | In the balneotherapy group, the levels of serum IL-1α significantly decreased after intervention therapy (p <0.05) |
Mean age: | (n = 12) | (n = 9) | Two time points | |||||
43.5 ± 10.2 years (balneotherapy) | 3 weeks | 3 weeks | (before and at the end of therapy) | |||||
48.8 ± 8.8 years (usual care) | 5 days per week | Healthy | Serum | |||||
43.4 ± 8.2 years (healthy) | 20 minutes each | (n = 10) | ||||||
Gender: | ||||||||
female only | ||||||||
Ortega et al. (2009) [28] | N = 27 | Non-RCT (pilot) | ACR | Patients | Healthy | N/A | IL-1β, IL-2, IFN-γ, TNF-α, IL-8, IL-6, IL-4, | After 4 months of exercise, the levels of circulating serum IL-8 and IFN-γ in FM patients decreased significantly (p <0.001, p <0.05, respectively) |
Age range: | (unspecified year) | (n = 14) | (n = 13) | IL-10, CRP, NA, cortisol | ||||
30–60 years (patients) | Pool-aquatic exercise | 2 time points | ||||||
28–55 years (healthy) | 4 months | (before and two days after finishing the exercise) | ||||||
Gender: | 3 days per week | |||||||
female only | 60 minutes each | serum | ||||||
Wang et al. (2009) [34] | N = 100 | Non-RCT | ACR 1990 | Patients (inpatients) | Healthy | 6 months | IL-8 | At the beginning of the study, the levels of serum IL-8 in FM patients were significantly higher than the healthy control group (p <0.001) |
Mean age: | (n = 20) | (n = 80) | 4 time points | |||||
49.9 ± 6.8 years (patients) | Multidisciplinary therapy | (the beginning of the study, 10 days after | At the end of the study (6 months), the levels of serum IL-8 in FM patients decreased significantly compared to the beginning of the study (p <0.05) with a decline to the normal range | |||||
48.4 ± 11.1 years (healthy) | 3 weeks | treatment, at resignation (21 days), and at 6 | ||||||
Gender: | 5 days per week | months follow up) | ||||||
male 15 %, female 85 % (patients) | 8-hour session each | serum | ||||||
male 45.2 %, female 54.8 % (healthy) | ||||||||
Bjersing et al. (2012) [26] | N = 49 | RCT | ACR 1990 | Nordic walking | Active control: Low-intensity walking | 30 weeks | IL-6, IL-8, IGF-1, IGFBP-3, NGF, | There were no significant differences pre- and 15-week post-intervention in the levels of serum IGF-1 and IGFBP-3 between the intervention and active control group |
Mean age: | (n = 26) | (n = 23) | SP, NPY, MMP-3 | |||||
52 years (total) | 15 weeks | 15 weeks | 3 time points: serum IGF-1, IGFBP-3 | The change in serum free IGF-1 correlated positively with an alteration in CSF SP levels (p <0.1), NPY (p = 0.001) and pain threshold (p <0.1) | ||||
Gender: | twice a week | twice a week | (baseline, after 15 weeks of exercise, 30 | |||||
female only | 40–45 minutes each | 40–45 minutes each | weeks of follow up) | |||||
Two time points: CSF IL-6, IL-8, NGF, SP, | ||||||||
NPY, MMP-3 | ||||||||
(baseline and after 15 weeks of exercise) | ||||||||
serum, CSF | ||||||||
Ortega et al. (2012) [29] | N = 18 | Non-RCT | ACR 1990 | Patients | Healthy | N/A | IL-1β, TNF-α, IL-6, IL-10, CRP | After 4 months of exercise, the spontaneous and LPS-induced production of IL-6 in FM patients increased and spontaneous TNF-α decreased compared to their basal state |
Age range: | (n = 9) | (n = 9) | 3 time points | |||||
30–60 years (patients) | Pool-aquatic exercise | (before, midway through: 4 months and | ||||||
28–55 years (healthy) | 8 months | at the end of program: 8 months) | After 8 months of exercise, the production of IL-1β, TNF-α, IL-6 in FM patients decreased compared to their basal state (both spontaneously and in response to LPS activation), with levels similar to (and even lower than in the case of the spontaneous release of TNF-α) those in the healthy control group | |||||
Gender: | twice a week | (samples were collected 2 days after | ||||||
female only | 60 minutes each | finishing the last session of the exercise) | ||||||
serum | ||||||||
After 8 months of exercise, the spontaneous production of IL-10 decreased and the LPS-induced production of IL-10 increased compared to their basal state, with levels higher than those in the healthy control group | ||||||||
Senna et al. (2012) [30] | N = 83 | RCT | ACR 1990 | Dietary weight loss | Usual care | N/A | IL-6, CRP | The levels of serum IL-6 in the intervention group were significantly lower than the usual care group after 6 months of intervention (p <0.05), although there were no significant differences between the two groups at baseline. |
Mean age: | (n = 41) | (n = 42) | two time points | |||||
44.8 ± 13.6 years (intervention) | 6 months | 6 months | (baseline and after 6 months of intervention) | |||||
(BMI 32.3 ± 1.4) | 1200 kcal/day | serum | ||||||
46.3 ± 14.4 years (usual care) | (with 15–20 % of energy intake in the form of protein, 50–55 % in the form of carbo-hydrates, and approximately 30 % in the form of fat divided across three meals) | |||||||
(BMI 32.8 ± 1.4) | ||||||||
Gender: | ||||||||
male 9.8 %, female 90.2 % (intervention) | ||||||||
male 9.5 %, female 90.5 % (usual care) | ||||||||
Bjersing et al. (2013) [27] | N = 48 | RCT | ACR 1990 | Nordic walking | Active control: low-intensity walking | 30 weeks | IGF-1, IGFBP3, NGF, adiponectin, leptin, resistin, NPY | In lean patients, the levels of total serum IGF-1 increased after 15 weeks of exercise (p <0.05). |
Mean age: | (n = 26) | (n = 22) | ||||||
52.0 years (lean group) | (lean 4, overweight 15, obese 7) | (lean 5, overweight 11, obese 6) | 3 time points | The change in the levels of total serum IGF-1 differed significantly between lean and obese patients (p = 0.01). | ||||
(BMI 18.5 to 24.9, n = 9) | 15 weeks | 15 weeks | (baseline, after 15 weeks of exercise, 30 | |||||
53.0 years (overweight group) | twice a week | twice a week | weeks of follow up) | |||||
(BMI 25 to 29.9, n = 26) | 40–45 minutes each | 40–45 minutes each | serum, CSF | |||||
51.0 years (obese group) | ||||||||
(BMI ≥30, n = 13) | ||||||||
Gender: | ||||||||
female only | ||||||||
Bote et al. (2014) [35] | N = 20 | Non-RCT | ACR 1990 | Patients | Inactive patients | N/A | IL-8, NA, neutrophils’ function | After 4 months of exercise, there were no significant changes between exercised and non-exercised FM patients in the concentration of serum IL-8 |
Mean age: | (n = 10) | (n = 10) | 3 time points | |||||
53 ± 2 years (patients) | Pool-aquatic exercise | (before, midway through: 4 months and | After 8 months of exercise, the concentration of serum IL-8 in exercised FM patients decreased significantly compared to the control group (p <0.05). | |||||
50 ± 4 years (inactive patients) | 8 months | at the end of program: 8 months) | ||||||
Gender; | twice a week | (samples were collected 2 days after | ||||||
female only (patients) | 60 minutes each | finishing the last session of the exercise) | ||||||
not described (inactive patients) | serum, plasma | |||||||
Menzies et al. (2014) [31] | N = 64 | RCT | ACR 1990 | Guided imagery | Usual care | N/A | IFN-γ, TNF-α, IL-1β, IL-2, GM-CSF, | There were no statistically significant differences between the intervention and control groups in the levels of pro- and anti-inflammatory cytokines at baseline, 6 weeks or 10 weeks |
Mean age: | (n = 30) | (n = 34) | IL-12, IL-17, IL-8, MCP-1, MIP-1β, IL-6, | |||||
44.5 ± 13.1 years (guided imagery) | 10 weeks | 10 weeks | IL-7, IL-4, IL-5, IL-10, IL-13, G-CSF, CRP | |||||
49.1 ± 12.4 years (usual care) | Use CD tracks at least once a daily | 3 time points | There was a notable trend in the increase of plasma IL-7 in the intervention group, whereas the control group means remained relatively constant across the study interval | |||||
Gender: | For the first 6 weeks, listen to the three | (baseline, week 6, week10) | ||||||
female only | CD tracks (each one CD in two weeks). | plasma | ||||||
For the last 4 weeks, listen to the tracks in any order |
Neuropeptides
Reference | Participants | Study design | Diagnosis of FM | Treatment group | Control group | Study duration | Outcomes | Findings |
---|---|---|---|---|---|---|---|---|
Bojner-Horwitz et al. (2003) [36] | N = 36 | RCT | ACR 1990 | Dance/movement | Waiting control | 14 months | PRL, NPY, DHEA-S, cortisol | The levels of serum PRL in both groups increased across the study interval, with the largest increase in the intervention group |
Mean age: | (n = 20) | (n = 16) | 4 time points (at baseline, and at months 4, 6, and 14 of the study) | |||||
57 ± 7.2 years (total) | 6 months | 6 months | There were no significant differences between baseline and 14 months in the levels of serum PRL between the two groups | |||||
Gender: | once a week | |||||||
female only | 1 h each | serum, saliva | The levels of serum NPY in both groups increased from baseline to month 4, decreased from months 4 − 6, and increased from months 6 − 14 | |||||
There were no significant differences in the levels of serum NPY between the two groups across the study interval | ||||||||
Lund et al. (2006) [32] | N = 19 | RCT | ACR 1990 | Massage | Guided relaxation | 10 weeks | CRF-LI | In the massage group, the concentrations of urinary CRF-LI decreased after 6 weeks of massage treatment (p = 0.01) and 1 month after completion of treatments (p <0.5) |
Mean age: | (n = 10) | (n = 9) | 3 time points (prior to treatment, after 6-week treatment and 1 month after completed treatment) urine | |||||
50.7 ± 9.7 years (total) | 6 weeks | 6 weeks | ||||||
Gender: | twice weekly | twice weekly | ||||||
f+emale only | 30 minutes each (feet and legs 18 minutes, hands and arm 8 minutes, face 4 minutes) | 30 minutes each | ||||||
Bjersing et al. (2012) [26] | N = 49 | RCT | ACR 1990 | Nordic walking | Active control: low-intensity walking | 30 weeks | SP, NPY, | The change in the levels of serum IGF-1 correlated positively with alterations in CSF SP (p <0.1), NPY (p <0.01) and pain threshold (p <0.1) |
Mean age: | (N = 26) | (n = 23) | IL-6, IL-8, IGF-1, IGFBP3, NGF, MMP-3 | |||||
52 years (total) | 15 weeks | 15 weeks | 3 time points | |||||
Gender: | twice a week | twice a week | (baseline, after 15 weeks of exercise, 30 weeks of follow up) | |||||
female only | 40–45 minutes each | 40–45 minutes each | ||||||
serum, CSF | ||||||||
Bazzichi et al. (2013) [33] | N = 41 | RCT | ACR 1990 | Balneotherapy | Active control: mud-bath therapy | 12 weeks | BDNF, oxytocin, | The concentrations of serum BDNF significantly decreased in both balneo-therapy and mud-bath therapy after 12 weeks (p < 0.05, p < 0.01, respectively), while there was no significant change in the levels of oxytocin. |
Mean age: | (n = 20) | (n = 21) | SERT binding parameters, ATP | |||||
54.0 ± 7.2 years (balneotherapy) | 2 weeks | 2 weeks | 3 time points | |||||
52.8 ± 10.2 years (mud-bath therapy) | 6 days a week | 6 days a week | (at baseline, after 2 weeks and after 12 weeks) | |||||
Gender: | 20 minutes each | 20 minutes each (mud pack 10 minutes and immersion in thermal water 10 minutes) | ||||||
19/1 female/male (balneotherapy) | plasma, serum, salivary adiponectin, leptin, resistin, NPY, IGF-1, IGFBP3, NGF | |||||||
20/1 female/male (mud-bath therapy) | ||||||||
Bjersing et al. (2013) [27] | N = 48 | RCT | ACR 1990 | Nordic walking | Active control: low-intensity walking | 30 weeks | The levels of serum resistin increased in the group as a whole after 30 weeks (p <0.05) which correlated with decreased fatigue | |
Mean age: | (n = 26) | (n = 22) | ||||||
52.0 years (lean group) | (lean 4, overweight 15, obese 7) | (lean 5, overweight 11, obese 6) | 3 time points | The levels of serum NPY increased in the group as a whole after 30 weeks (p <0.05). This increase was only significant in obese patients (p <0.05) | ||||
(BMI 18.5 to 24.9, n = 9) | 15 weeks | 15 weeks | (baseline, after 15 weeks of exercise, 30 weeks of follow up) serum, CSF | |||||
53.0 years (overweight group) | twice a week | twice a week | ||||||
(BMI 25 to 29.9, n = 26) | 40–45 minutes each | 40–45 minutes each | ||||||
51.0 years (obese group) | ||||||||
(BMI ≥30, n = 13) | ||||||||
Gender: | ||||||||
female only |
CRP
Reference | Participants | Study design | Diagnosis of FM | Treatment group | Control group | Study duration | Outcomes | Findings |
---|---|---|---|---|---|---|---|---|
Ardiç et al. (2007) [37] | N = 31 | RCT | ACR 1990 | Balneotherapy | Usual care | N/A | CRP, IL-1α, PGE2, LTB4, RF, ESR | No declaration of the changes to serum CRP levels between pre- and post-intervention |
Mean age: | (n = 12) | (n = 9) | 2 time points | |||||
43.5 ± 10.2 years (balneotherapy) | 3 weeks | 3 weeks | (before and at the end of therapy) | |||||
48.8 ± 8.8 years (usual care) | 5 days per week | Healthy | serum | |||||
43.4 ± 8.2 years (healthy) | 20 minutes each | (n = 10) | ||||||
Gender: | ||||||||
female only | ||||||||
Ortega et al. (2009) [28] | N = 27 | Non-RCT (pilot) | ACR | Patients | Healthy | N/A | CRP, IL-1β, IL-2, IFN-γ, TNF-α, IL-8, | The concentrations of serum CRP in FM patients were significantly higher than in the healthy control group between pre- and post-exercise (p <0.05) |
Age range: | (unspecified year) | (n = 14) | (n = 13) | IL-6, IL-4, IL-10, NA, cortisol | ||||
30–60 years (patients) | Pool-aquatic exercise | 2 time points | After 4 months of exercise, the level of serum CRP in FM patients decreased compared to the baseline level (p <0.05) | |||||
28–55 years (healthy) | 4 months | (before and 2 days after finishing the exercise) | ||||||
Gender: | 3 days per week | |||||||
female only | 60 minutes each | serum | ||||||
Ortega et al. (2012) [29] | N = 18 | Non-RCT | ACR 1990 | Patients | Healthy | N/A | CRP, IL-1β, TNF-α, IL-6, IL-10 | The concentrations of serum CRP in FM patients were significantly higher than in the healthy control group across the study interval (p <0.01) |
Age range: | (n = 9) | (n = 9) | 3 time points | |||||
30–60 years (patients) | Pool-aquatic exercise | (before, midway through: 4 months and at the end of program: 8 months) | After 8 months of exercise, the level of serum CRP in FM patients decreased compared to the baseline level (p <0.05) | |||||
28–55 years (healthy) | 8 months | |||||||
Gender: | twice a week | (samples were collected 2 days after finishing the last session of the exercise) serum | ||||||
female only | 60 minutes each | |||||||
Senna et al. (2012) [30] | N = 83 | RCT | ACR 1990 | Dietary weight loss | Usual care | N/A | CRP, IL-6 | The levels of serum CRP in the intervention group were significantly lower than the usual care group after 6 months of intervention (p <0.01), although there were no significant differences between the two groups at baseline |
Mean age: | (N = 41) | (n = 42) | 2 time points | |||||
44.8 ± 13.6 years (intervention) | 6 months | 6 months | (baseline and after 6 months of intervention) | |||||
(BMI 32.3 ± 1.4) | 1200 kcal/day | serum | ||||||
46.3 ± 14.4 years (usual care) | (with 15–20 % of energy intake in the form of protein, 50–55 % in the form of carbo-hydrates, and approximately 30 % in the form of fat divided in three meals) | |||||||
(BMI 32.8 ± 1.4) | ||||||||
Gender: | ||||||||
male 9.8 %, female 90.2 % (intervention) male 9.5 %, female 90.5 % (usual care) | ||||||||
Menzies et al. (2014) [31] | N = 64 | RCT | ACR 1990 | Guided imagery | Usual care | N/A | CRP, IFN-γ, TNF-α, IL-1β, IL-2, GM- | There were no statistically significant differences between the intervention and control groups in the levels of plasma CRP at baseline, 6 weeks or 10 weeks |
Mean age: | (n = 30) | (n = 34) | CSF, IL-12, IL-17, IL-8, MCP-1, MIP-1β, | |||||
44.5 ± 13.1 years (guided imagery) | 10 weeks | 10 weeks | IL-6, IL-7, IL-4, IL-5, IL-10, IL-13, G-CSF | The levels of plasma CRP for all of the participants were elevated but demonstrated little variation from baseline to 6 weeks or to 10 weeks (4.27, 4.57, 4.55 mg/L, respectively) | ||||
49.1 ± 12.4 years (Usual care) | use CD tracks at least once a day | 3 time points | ||||||
Gender: | For the first 6 weeks, listen to the three | (baseline, week 6, week 10) plasma | ||||||
female only | CD tracks (each one CD in 2 weeks). | |||||||
For the last 4 weeks, listen to the tracks in any order |