The authors have no conflicts of interest to declare.
Fibromyalgia (FM) is a condition of chronic and widespread pain, with several associated symptoms. Previous studies suggested that gluten could influence the severity and frequency of FM symptoms. This work aimed to assess the impact of a gluten-free diet (GFD) in the symptoms and severity of this disease. Fourteen patients with previous FM diagnosis were kept on a gluten-free diet for eight weeks (Phase 1). After that, they were held on the gluten-free diet and received capsules of isolated rice protein (placebo) for seven days, followed by capsules containing 8.4g/day vital gluten for additional seven days (Phase 2). Questionnaires evaluating the number and severity of FM symptoms, the impact of FM on daily routine as well as inflammatory blood markers were assessed in each phase. Results showed that after eight weeks of GFD, we observed a reduction in the impact of FM on daily routine and number of symptoms and sensitive points. However, a seven days challenge with 8.4g of gluten did not worsen these symptoms or the inflammatory markers compared with the placebo challenge. We concluded that the gluten-free diet was associated with the attenuation of main symptoms and improvement of life quality in FM patients. Nonetheless, gluten challenge had no impact on those parameters, suggesting that gluten is not the major dietary component responsible for these improvements. Further studies are needed to elucidate the relationship between gluten intake and fibromyalgia.
Fibromyalgia (FM) is a rheumatological syndrome mainly characterized by chronic diffuse musculoskeletal pain. Its etiology has not yet been well clarified, however, involve a disturbance in the processing of pain. Moreover, these patients often report other symptoms, such as fatigue and cognitive disorders
Some studies pointed to the improvement of FM symptoms after the adoption of a gluten-free diet
It was a single-blind controlled study in which the sample cohort was determined by convenience. The study was approved by the UFMG Research Ethics Committee (COEP), register 1.269.563, and registered in ClinicalTrials.gov (NCT03129906). This study was conducted from September 2015 to October 2016. Women over 18-year-old attending the Mateus Leme Clinical Specialty Center (Minas Gerais, Brazil) with the previous diagnosis of FM, according to American College of Rheumatology of 2010
`The study was divided into two phases: In Phase 1 (8 weeks), we initially enrolled seven women and evaluated the effect of a gluten-free diet on the quality of life and symptoms of FM. At baseline (week 0) and week 8, we evaluated anthropometric measurements, 72h food record, blood samples, and three questionnaires: Fibromyalgia Impact Questionnaire (FIQ), Symptoms Severity scale (SSS), Widespread pain index (WPI), (
In Phase 2 (placebo and gluten challenge), the 7 participants were kept in the gluten-free diet and took 12 placebo capsules daily (containing 6,4g of isolate rice protein in total) for one week. After a three days washout period, they were submitted to the second challenge, taking 12 capsules containing a total of 8.4 g of vital gluten daily for another week. The capsules containing gluten or placebo were encoded and indistinguishable. At the end of each challenge, blood was collected and FIQ, SSS, and WPI questionnaires evaluated (
All questionnaires assessing FM symptoms were applied related to the last seven days from the date of application. Patients received nutritional advice regarding the implementation of a gluten-free diet. The data was collected at the Specialty Center of Mateus Leme (MG/Brazil) and by telephone calls.
The FIQ evaluates the impact of fibromyalgia on the diary routine through the evaluation of 10 different items. The result was given as the average of the ten items
The SSS is used to quantify the severity of the FM symptoms. The final score is obtained by the sum of the severity score of 3 symptoms: 1-fatigue, 2-waking unrefreshed, and 3-cognitive symptoms and the number of FM symptoms present at that moment
The 72h food record was evaluated for three days, on alternate days, and covering one day of the weekend. The volunteers received instructions about how to record daily intake
To evaluate participants' compliance with the gluten-free diet, the weekly Food Frequency Questionnaire (FFQ) was applied by the dietitian.
The blood was collected after 8h fasting, between 7 to 10 am. We analyzed total IgA (Phadia Uppsala Sweden), IgE for wheat (Beckman Coulter, BreaCa, US), IgA anti-transglutaminase (Orgentec Diagnostika Gmbh, Mainz Germany), the cytokines IL1ß, IL6, IL8 (R&D System, Minneapolis, MN, US) and the cytokines IL1RA, IL4, IL10 (U-Plex Assay - Meso Scale Diagnostics, Rockville, MD, US).Haptoglobin genotyping was done with specific primers designed in exon two and exon 5 of HP1 matching to exons 2 and 7 of HP2 amplified by high Fidelity PCR System. After PCR, the amplicons were run on a 1% agarose gel and read under a UV bulb. The size difference allowed differentiation of the two genotypes (HP1:2.5 KB and HP2:5.3 kb).
Statistical analyses were performed using the software SPSS 19 (SPSS Inc., Chicago, IL, USA). Graphs were plotted at the software GraphPad Prism 5.0. The normal distribution of the data set was evaluated using the Shapiro-Wilk test. Parametric data were analyzed by Student's paired t-test and nonparametric variables by Wilcoxon Mann–Whitney test (2 groups). The Kruskal-Wallis test was used to compare the genotypes of haptoglobin with the changes in cytokines levels, FIQ, and the number of disease symptoms after a gluten-free diet. For those variables that presented p-values lower than 0.20 (FIQ, IL10, and IL8), a regression model was used to investigate a relation with the number of alleles of pre-haptoglobin 2 (HP2).
Twenty-six patients selected from Specialty Center of Mateus Leme (MG/Brazil), met the criteria of ACR, 2010. Of these, six were excluded because they had an autoimmune disease, and one did not answer the questionnaires. None of the volunteers presented positive serology for CD (IgA anti- transglutaminase and total IgA) and wheat allergy (IgE for wheat). Therefore 19 patients were enrolled in the study. Five patients withdrew the study due to: personal reasons (n=3), hypothyroidism diagnosis during phase 1 (n=1), and chronic use of anti-inflammatory agents (n=1). The remaining 14 women that completed the phase 1 period (aged 41-62) presented the following associated disorders: arterial hypertension (n=7), orthopedic problems (n=3), and labyrinthitis (n=2). Some patients were underuse of drugs at the beginning of this study. Most of them were antihypertensive, antidepressants, or hypocholesterolemic agents. All drugs and posology were kept unchanged throughout the experimental period. Analgesics (dipyrone, paracetamol, ibuprofen, tramadol) were used only sporadically during the experimental period. Volunteers were advised to avoid the use of non-steroidal anti-inflammatory drugs throughout the study. None of them were in physiotherapy, and 7 (50%) practiced physical activity: hydrogymnastics 2 to 3 times a week (4 volunteers) or walking 2 to 3 times per week (3 volunteers). We didn't ask about cognitive compartmental therapy. None of them were in use of phytotherapy. The treatment was monitored by telephone and in individual meetings. All patients adhered to the gluten-free diet, according to the analysis of FFQ.
Anthropometric parameters, body weight, body mass index (BMI), and abdominal circumference were unaltered during Phase 1 (
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Weight (kg) | 74.9 (± 15.9) | 74.5 (± 16.1) | 0.404 |
BMI (kg/m2) | 30.6 (± 6.6) | 30.4 (± 6.6) | 0.356 |
AC (cm) | 103.0 (± 12.8) | 102.3 (± 12.2) | 0.117 |
IL1RA (pg/mL) | 1209.4 (703.4 – 5495.6) | 913.4 (476.8 – 4212.6) | 0.096 |
IL1ß (pg/mL) | 5.7 (3.8 – 30.6) | 4.9 (3.7 – 37.4) | 0.127 |
IL6 (pg/mL) | 14.7 (10.7 – 44.6) | 13.0 (10.4 – 48.0) | 0.463 |
IL4 (pg/mL) | 0.1 (0.1 – 0.8) | 0.1 (0.0 – 0.8) | 0.275 |
IL10 (pg/mL) | 130.0 (0.2 – 2.0) | 125.0 (0.7 – 2.3) | 0.703 |
1Values presented as mean (SD) and 2median (min-max). #Paired t-test for anthropometric parameters and Wilcoxon for paired samples for blood cytokines. BMI, Body mass index; AC, Abdominal circumference. n = 14
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kcal/day | 1439.9 (± 468.1) | 1287.6 (± 450.2) | 0.357 |
Protein (%) | 17.7 (± 1.6) | 20.0 (± 4.0) | 0.085 |
Lipids (%) | 27.5 (± 7.2) | 33.6 (± 5.1) | 0.089 |
Carbohydrate (%) | 52.5 (± 9.3) | 46.3 (± 6, 6) | 0.049 |
Fibers (g) | 13.5 (± 4.5) | 8.8 (± 2.9) | 0.012 |
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Score on FIQ1 | 7.2 (± 1.2) | 5.5 (± 2.6) | 0.009 |
Score at sss2 | 9.6 (± 1.7) | 7.0 (± 4.1) | 0.100 |
Number of symptoms | 15.0 (± 3.7) | 10.4 (± 4.7) | 0.000 |
WPI3 | 15.0 (± 3.7) | 10.9 (±4.6) | 0.014 |
Values presented as mean (SD). Test T Paired:1Fibromyalgia impact questionnaire; 2Symptom severity scale; 3Widespread pain index. n = 14
Regarding the questionnaires, we found a significant reduction in FIQ scores, the number of FM symptoms, and the number of painful body points measured by the WPI. Nonetheless, a reduction in the severity of symptoms, assessed by SSS, was not significant (
Next, we investigated if this improvement in the FM symptoms was associated with a reduction of serum inflammatory markers such as the pro-inflammatory cytokines IL1ß, IL1RA, IL6, and IL8, and the anti-inflammatory cytokine IL10 and IL4. No changes were seen in the levels of those cytokines comparing the initial and final of Phase1 (
The patients were genotyped for haptoglobin genes to observe the presence of the HP2 allele, which codifies zonulin (pre-haptoglobin 2) and its possible association with the response to gluten withdrawal. The distribution of the HP allele was: 16.7% of patients have no HP2 allele (HP 1-1), 58.3% have only one allele (HP 2-1), and 25% have two alleles (HP 2-2). The regression model showed an association between the number of HP2 alleles and FIQ (
Seven patients completed the two challenges of phase 2. None of the patients presented worsening of the symptoms with the reintroduction of the gluten compared to the placebo.
When the placebo was compared with the gluten challenge period, we did not find any changes in FM impact on daily routine, symptoms severity, or the number of painful body points as demonstrated by the results of FIQ, SSS, and WPI questionnaires (
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Weight (kg) | 6a8 (± 10.4) | 68.8 (± 10.0) | 0.974 |
BMI3 (Kg/m2) | 28.0 (± 3.2) | 28.0 (± 3.2) | 0.993 |
AC4 (cm) | 97.6 (± 10.3) | 97.5 (±12.5) | 0.940 |
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Score in FIQ5 | 4.8 (± 2.5) | 4.6 (± 3.0) | 0.636 |
Score at SSS6 | 7.0 (± 4.1) | 5.7 (± 4.0) | 0.253 |
Number of symptoms | 10.6 (± 5.5) | 9.4 (± 4.0) | 0.231 |
VVPI 7 | 10.9 (± 4.6) | 11.1 (± 3.9) | 0.726 |
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IL 1 RA(pg/mL) | 1209.4 (703.4 - 5495.6) | 1064.2 (576.1- 3507.0) | 0.219 |
IL1ß (pg/mL) | 5.7 (3.8 - 30.6) | 5.56 (4.0 - 27.0) | 0.688 |
IL6 (pg/mL) | 14.7 (10.7-44.6) | 14.25 (11.0 - 20.2) | 0.813 |
IL4 (pg/mL) | 0.1 (0.1 - 0.8) | 0.3 (0.2 - 0.6) | 0.735 |
IL10 (pg/mL) | 1.3 (0.2 - 2.0) | 1.70 (0.8- 2.0) | 0.823 |
1Values presented as mean (SD) and 2median (min-max). #Paired t-test for anthropometric parameters and questionnaires scores and Wilcoxon for paired samples for blood cytokines. 3Body mass index; 4Abdominal circumference 5Fibromyalgia Impact Questionnaire; 6Symptom Severity Scale; 7Widespread Pain Index. n=7
The main finding of our study was that the adoption of a gluten-free diet improved FM symptoms reduced painful points, and improved the quality of life in 12 of the 14 FM patients. Two patients showed an improvement in almost all evaluated questionnaires except for FIQ score (increased in one patient) and FM symptoms (increased in another participant). Nonetheless, gluten isolate challenge had no impact on those parameters, suggesting that gluten is not the major dietary component responsible for these improvements.
Several studies have evaluated the impact of a gluten-free diet on the nutritional and metabolic status
The exclusion of gluten-containing foods modified the dietary pattern, reducing the intake of fibers and carbohydrates, as demonstrated by the 72h food record. The reduction of bread and pasta and several recipes containing wheat flour could lead to a decrease in carbohydrates and fiber intake. These data agree with other studies showing that gluten-free products are commonly made up of low- grained starch and flours
Previous experimental studies
Experimental studies also described a pro-inflammatory effect of the gluten or its components
The regression model suggested that the presence of the HP2 allele is associated with a better response to the gluten withdrawal. Haptoglobin encodes for two alleles, of which HP2 carries a duplication of the 3rd and 4th exons
Our results suggested an improvement of several indicators of the severity of FM with the adoption of a gluten-free diet. However, the one-week challenge with 8.4g of vital gluten had no impact on the analyzed parameters in the patients that completed Phase 2. The amount of gluten used in the challenge phase was chosen based on the average gluten intake data in Western countries
Other studies in the literature suggest improvement of FM symptoms after a gluten-free diet mostly in patients with duodenal lymphocytosis
Our results make clear the importance of the gluten challenge to corroborate with the possible improvement of the symptoms of FM with such diets. Without the challenge phase, there could be a misguided conclusion that the gluten exemption would have been the cause of the improvement seen in the first phase of the study.
The factors responsible for the improvement of the gluten-free diet requires further investigation. It may be the consequence of more frequent and closer interaction between health professionals and patients since the study does not present a placebo group maintained without a gluten-free diet. Many symptoms are unspecific or subjective, and so frequent contacts with the professionals involved in the research may have contributed to the improvement of the symptoms. Besides, the expectation of improvement with dietary modification may have contributed to the feeling of improvement
The improvement of the symptoms with the gluten-free diet could also be due to the exclusion of other components such as fermentable oligo, di, monosaccharides, and polyols (FODMAPs), short- chain carbohydrates, present in the wheat and other foods
It can also be assumed that the amount of gluten administered in the challenge is small to trigger the symptoms of FM. The choice of the amount of gluten used in the challenge (about 8.4g/day vital gluten) was calculated from the average gluten intake in the population of Western countries
Among the limitations of the current study is the lack of a control group, the absence of specific markers for the transgression of the diet, and the small sample size. More studies are needed in double-blind design controlled with larger sample size.
The gluten-free diet was associated with the attenuation of main symptoms and improvement of quality of live in this group of FM patients evaluated. Nonetheless, gluten challenge had no impact on those parameters, suggesting that gluten is not the major dietary component responsible for these improvements.
We would like to thank Mateus Leme City Hall for all the support for providing access to the patient's cohort. We thank Professor Dr. Alessio Fasano, from Mucosal Immunology and Biology Research Center (Massachusetts General Hospital, Harvard Medical School) for the HP genotyping, analyzes of serum cytokines, and final revision of the paper.