Efficacy of therapeutic fasting and plant-based diet in patients with rheumatoid arthritis (NutriFast): study protocol for a randomised controlled clinical trial

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  1. http://orcid.org/0000-0002-0135-9643Anika M Hartmann1,
  2. Melanie Dell'Oro2,
  3. Christian S Kessleri,two,
  4. Dania Schumann1,
  5. Nico Steckhan1,
  6. Michael Jeitler1,2,
  7. January Moritz Fischerone,
  8. Michaela Spoo1,ii,
  9. Martin A Kriegeliii,4,
  10. Jochen K Schneiderv,half-dozen,
  11. Thomas Häuplvii,
  12. Farid I Kandil1,8,
  13. Andreas Michalsen1,ii,
  14. Daniela A Koppold-Liebscher1
  1. one Institute of Social Medicine, Epidemiology and Health Economics, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Federal republic of germany
  2. 2 Department of Internal and Integrative Medicine, Immanuel Infirmary Berlin-Wannsee Branch, Berlin, Germany
  3. 3 Institute for Musculoskeletal Medicine, Department of Translational Rheumatology and Immunology, University of Münster, Münster, Germany
  4. 4 Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
  5. 5 Department of Internal Medicine Two, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg, Federal republic of germany
  6. 6 Grand duchy of luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, Luxembourg
  7. seven Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
  8. 8 Department of Neurology, Campus Benjamin Franklin, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Deutschland
  1. Correspondence to Mrs Anika M Hartmann; anika.hartmann{at}charite.de

Abstruse

Groundwork Previous studies have shown beneficial furnishings of therapeutic fasting and plant-based dietary interventions on affliction activity in patients with rheumatoid arthritis (RA) for a duration of upwards to 1 year. To engagement, the furnishings of such interventions on the gut microbiome and on modern diagnostic markers in patients with RA have not been studied. This trial aims to investigate the clinical effects of therapeutic fasting and a plant-based diet in patients with RA, additionally considering current immunological diagnostic tools and microbiome analyses.

Methods/design This trial is an open-label, unmarried-centre, randomised, controlled, parallel-group clinical trial. Nosotros will randomly assign 84 patients with RA under a stable standard therapy to either (1) therapeutic fasting followed by a plant-based dietary intervention or (2) to a conventional nutritional counselling focusing on an anti-inflammatory dietary pattern according to the recommendations of the Deutsche Gesellschaft für Ernährung (German lodge for nutrition). Master outcome parameter is the group deviation from baseline to 12 weeks on the Wellness Assessment Questionnaire (HAQ). Other secondary outcomes include established clinical criteria for disease activity and treatment response in RA (Disease Activeness Score 28, Simple Disease Action Index, ACR-Response Criteria), changes in self-reported wellness and physical functional power, mood, stress, quality of life, dietary behaviour via three-twenty-four hours food records and a modified Food Frequency Questionnaire, body composition, changes in the gut microbiome, metabolomics and cytometric parameters. Outcomes will be assessed at baseline and twenty-four hour period vii, subsequently vi weeks, 12 weeks and later 6 months.

Ethics and dissemination Upstanding approval to process and analyse data, and to publish the results was obtained through the institutional review board of Charité-Universitätsmedizin Berlin. Results of this trial will be disseminated through peer-reviewed publications and scientific presentations.

  • complementary medicine
  • rheumatology
  • rheumatology
  • nutrition & dietetics

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  • complementary medicine
  • rheumatology
  • rheumatology
  • nutrition & dietetics

Strengths and limitations of this study

  • This is the first arroyo to generate a dietary therapeutic concept for patients with rheumatoid arthritis (RA) involving therapeutic fasting.

  • Fasting has emerged equally an constructive, economic and safe therapeutic intervention for patients with rheumatoid arthritis.

  • This report design tin can contribute to the understanding of pathomechanisms in RA, specially in the context of nutrition and the microbiome, through an extensive biorepository of claret and stool samples and large amounts of information to be collected.

  • A limitation is the open up-label dietary intervention, which may not exclude bias like non-specific treatment effects, confirmation and observer bias.

Background

Rheumatoid arthritis (RA) is a systemic autoimmune disease, characterised by a destructive inflammation of the joints. With a prevalence of approximately 1% in Europe and the The states RA is the most mutual rheumatic disorder, affecting several 1000000 people worldwide.ane Patients with RA feel painful, swollen joints which tin severely impair physical role and quality of life; untreated information technology may atomic number 82 to irreversible articular deformation and stiffness as well as to increased cardiovascular adventure and mortality.two

So far, disease progression can only be stopped by permanent suppression of the inflammatory response.3 In recent years, therapeutic concepts with non-steroidal anti-inflammatory drugs and conventional disease modifying antirheumatic drugs (DMARDs) accept been extended by targeted antibody therapies that can specifically block various inflammatory pathways (biological DMARDs).4–6 Although being more efficient in comparison to conventional DMARDs, individual treatment responses tin differ widely; every bit a upshot, the optimal drug needs to be identified for each patient individually and has to be monitored for habituation and side furnishings.6 Nutritional medicine (NM) besides equally Complementary and Integrative Medicine (CIM) aslope conventional drug therapy might be a supportive and possibly cost-effective way to relieve RA symptoms, limit adverse effects of conventional drug therapies or even influence the course of the affliction.7 Patients increasingly demand CIM and NM approaches; surveys indicate that up to two-thirds of patients with rheumatological atmospheric condition already use CIM, mainly for pain command.8 ix

A complex coaction of genetic predispositions, lifestyle-related factors and ecology aspects is thought to account for the not however fully understood pathogenesis of RA.x Moreover, interactions with the intestinal microbiota have increasingly been discussed over the final three decades.11–15 A gut microbial imbalance (dysbiosis), characterised by the loss of metabolically and immunologically benign leaner and a concomitant increment in potentially pathogenic microbes (pathobionts), is associated with several chronic inflammatory syndromes.16–22 In the example of RA, a predominance of Prevotella species in the abdominal microbiota has been associated with early-stage patients with RA in previous studies.23–25 Contempo translational publications suggest that such an altered microbiota might exist associated with the germination of RA-specific autoantibodies, that is, anticitrullinated poly peptide antibodies (ACPAs), maybe triggering autoinflammatory illness in predisposed individuals.26–29

Nutrition is a pivotal variable in shaping the gut microbiota composition and function. Information technology influences the complex host-microbiota cross-talk and hence affects host metabolism and the immune system in a multifaceted manner; thus, changes in dietary regimens may have either beneficial or detrimental consequences for the gut microbiota and thus for overall health.11 30 This also applies to caloric restriction or fasting, an chemical element which can be implemented in different types of diets.31 32

In the by few decades, mounting experimental and translational evidence regarding the biological fundamentals of caloric brake and different fasting regimes, such as periodic and intermittent fasting, has evolved. It encompasses a wide spectrum of cellular and molecular mechanisms affecting health and disease processes; fasting non only involves ketogenesis to fuel cellular energy production simply also elicits a coordinated adaptive stress response: signalling pathways are activated, which bolster mitochondrial health, DNA repair and autophagy. Fasting also seems to enhance immune functions by downregulating proinflammatory cytokine expression.33–36 These well-orchestrated processes may hold promising therapeutic options for a variety of fields in medicine, including autoimmune diseases such equally RA.35 37–40

By contrast, robust clinical prove on the therapeutic effects of dietary and fasting interventions in patients wih RA has been sparse; in 2009 a Cochrane review concluded 'uncertain effects' of specific dietary regimens on RA due to a lack of sufficient data.41 Currently, a growing body of literature reports on clinical comeback through plant-based nutrition and fasting in inflammatory arthritis.42–45

In early clinical trials, modified fasting (up to 500 kcal energy intake per solar day) for vii–10 days followed by plant-based diet showed positive effects such every bit decreased morning stiffness, reduced pain and increased function in RA patients for up to 1 year.22 46 For this reason, it is already in regular use by a number of clinical departments in Europe for the integrative treatment of RA.47 Kjeldsen-Kragh et al22 and Sköldstam et al48 49 were able to demonstrate the effectiveness of such an approach in clinical studies, of which occurred two in a randomised setting.46

Data from several clinical trials have already suggested that therapeutic fasting produces anti-inflammatory furnishings.21 22 47 50 Still, in the menses following fasting interventions, inflammation and symptoms frequently reoccur. Previous studies take demonstrated that this process tin can be delayed by the implementation of specific diets or food items.46 51 52 All the same, until now no standardised recommendations for long-term stabilisation of the positive fasting furnishings take been adult.

In what follows, we present the protocol of a randomised, controlled clinical trial comparing an experimental antirheumatic fasting and diet protocol to a conventional guideline-based anti-inflammatory diet.

We hypothesise that the experimental protocol will improve RA symptoms in the mid-term and long term. In an boosted experimental context, we volition investigate changes (1) in metabolism and (2) in the microbiome. Nosotros further hypothesise that the anti-inflammatory effects of fasting and found-based diets are related to changes in the composition of the individual gut microbiota.

Thereby, this trial aims to contribute to an improved understanding of underlying pathophysiological processes and to extend non-pharmacological therapeutic options for patients with RA.

Methods and analysis

Study pattern

In this prospective, open-label, clinical, randomised, controlled trial, we intend to recruit and randomise 84 participants between 18 and 70 years of historic period, diagnosed with RA, into two groups (figure i). This protocol meets the standard recommendations and guidelines for randomised clinical trials.53

Patient and public involvement

Patients are non involved in the design, or conduct, or reporting, or broadcasting plans of our research, but they are a key element in the choice of our outcome measures. Both the primary and several secondary endpoints consist of patient-reported outcomes (PROs). Furthermore, we provide bones educational material to promote long-term wellness literacy (online supplemental file 1) and assess regularly the brunt of the trial interventions on participants. Once the trial has been published, we intend to inform participants of the results through a newsletter suitable for a not-specialist audience.

Supplemental material

Recruitment and randomisation

Participants are recruited using iii sources (figure 2): (1) past direct referral from either physicians at the Immanuel Infirmary Berlin and the Charité-Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology Berlin or (ii) by directly referral from office-based rheumatologists and (3) by non-personal advertising strategies (eg, flyers, social media).

Eligibility criteria are designed to target patients with RA who are sufficiently healthy to participate safely in the interventional fasting trial-arm (table 1). Participants meeting all inclusion and no exclusion criteria are randomly assigned to one of the two treatment artillery, using a one:1 ratio. An independent research team member, outside of the project, has generated the randomisation list using blockrand library (V.ane.four) with a randomised variable block arroyo within the statistical calculating language R (V.iii.5). The computer-generated randomisation allocation sequence has been consecutively numbered, sealed in opaque envelopes and curtained from the written report personnel responsible for conducting the studies. Participants are allocated after written informed consent (online supplemental file 1 and successful screening by the responsible study physician.

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Table 1

Eligibility criteria

Discontinuation and adherence criteria are displayed in table two. Missed consultation appointments can either be made up in the following groups or the omitted topic must be worked on at abode. Food records measure adherence to the prescribed intervention (see outcome parameters).

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Tabular array 2

Discontinuation and adherence criteria

Study settings

This is a single-centre trial: screening visits, blood drove and dietary counselling are conducted at the Charité-Universitätsmedizin Berlin, Section of Internal and Complementary Medicine in Berlin, Germany, located at the Section of Internal and Integrative Medicine, Immanuel Hospital Berlin, Germany.

Interventions

Dietary counselling for both trial arms is carried out in small groups of upwardly to 10 persons within 3 individual and 9 grouping sessions over 3 months (figure 2). The entire intervention takes place in an outpatient setting.

Both groups brainstorm with a 7-day intensive course (corresponds to a fasting calendar week in the intervention group) with daily group coaching sessions of 2 hours each and one individual coaching of 60 min per participant. Afterwards, participants receive one group coaching of i.v hours and 30 min of individual phone coaching in the 2d calendar month and third calendar month of the study. Additionally, a cooking lesson of three hours is hosted in the 2d month. Due to the spread of COVID-nineteen, the written report protocol is beingness inverse to maintain social distancing measures. Face-to-face consultations are carried out online using secured web-based video conferences. The cooking course is replaced by a tasting with max. 5 participants respecting hygiene measures (preparation by a single person wearing gloves, listing of the participants, distance rule, mouth covering in between tasting).

No changes to existing drug therapies are fabricated in the course of the trial, unless undertaken past the treating rheumatologist.

Fasting and plant-based dietary counselling

The experimental intervention group undergoes a seven-day therapeutic fasting regime (two days of low-cal found-based diet, vii days of fasting, 3 days of light plant-based diet), and a following menses of xi weeks with a specific plant-based normocaloric diet.

During the first 2 days of lite plant-based earlier fasting, the subjects are given a depression-calorie (approx. 1200 kcal) nutrition with reduced intake of salt, fatty and poly peptide (online supplemental file 2). During the following fasting period, participants can eat unlimited amounts of water or herbal tea (no black or green tea, no caffeine, no alcohol), 2×150 mL of vegetable juice low in carbohydrate and 250 mL of light vegetable broth with a maximum total daily energy intake of i.255 kJ (300 kcal). Participants are encouraged to beverage at to the lowest degree 2.5 litres of fluid daily (online supplemental file two).

Supplemental material

In the effect that a participant regularly takes medication for other diseases, his/her medication may accept to be adjusted during the fasting days. Fasting is known to lower blood pressure, affect electrolyte balance and claret carbohydrate levels. Information technology may also prolong bleeding time and trigger migraine attacks.54–56 For this reason, diuretic, antihypertensive and antidiabetic drugs as well every bit coumarins are adjusted past the responsible study physician (online supplemental file 3).

Supplemental material

Fasting is followed by 3 days of light found-based nutrition with successive reintroduction of institute-based solid food. Subsequently, a specific plant-based normocaloric diet is to be resumed. The latter is enriched with kitchen herbs and kitchen spices known for their anti-inflammatory potential. The recommended nutrition is also high in prebiotics and integrates the concept of time restricted eating (TRE), with 16 hours of fasting overnight for at least six days per week.

Standard dietary counselling

The control group receives a wholefood nutrition considered to be fundamentally health-promoting according to the electric current recommendations of the Deutsche Gesellschaft für Ernährung (DGE, German society for nutrition; online supplemental file four).57

Supplemental textile

The omega-6-fatty acrid arachidonic acid (AA), which is particularly found in animate being derived poly peptide, has been suggested to play a role in RA as it leads to the formation of inflammation-promoting messenger substances. Therefore, a reduction of the former is thought to have an anti-inflammatory effect.58 59 Thus the focus of the control intervention is a lower intake of this substance, pregnant a maximum of 2 portions per week of foods such pork lard, liver, and egg yolk. If consumption of dairy products cannot be avoided, low-fat dairy products should exist preferred. Loftier amounts of salt, carbohydrate and booze should be avoided (online supplemental file iv).

The three main omega-3 fat acids alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been described to have anti-inflammatory effects.60 61

An enzymatic desaturation step of variable efficiency (1%–five%), is required to convert dietary ALA to EPA and DHA.62 Acting as competitive inhibitors for AA, the intake of these long-concatenation omega-3 fatty acids in therapeutic doses of three g/solar day inhibits the product of proinflammatory eicosanoids.

ALA is mainly found in oilseeds such as canola, flaxseed, soybean, chia besides as walnut. DHA and EPA are found in fish like mackerel, salmon and herring. In accord with the current recommendation of the DGE, an optimal ratio of 1:five omega-three to omega-half-dozen FA is considered. The recommended daily dose of 250 mg EPA and DHA tin can be met with two servings per calendar week of the above fish species; that of ALA using twenty chiliad of walnuts, 10 g of linseed or 15 mL of either rapeseed or linseed oil per day.

An adequate supply of antioxidants, vitamins, minerals and secondary constitute compounds can exist achieved with five portions of fruit and vegetables daily.

Agin events

In that location are no major risks expected for participants in this trial. Fasting without underlying weather condition is considered safe and at that place are no reports of major risks whatsoever.63 Small-scale adverse effects of fasting therapy are described every bit initial headaches (java withdrawal, etc), mild circulatory reactions, feelings of hunger and increased sensitivity to cold. These side effects are known, occur by and large during the first 3 days of fasting and are cocky-limiting.63 64

Occurring adverse events are recorded at each clinical visit using open questions. Agin events are also documented at whatsoever time between visits whenever a participant communicates such an effect to report personnel. Serious adverse events are announced to the written report coordinator and the principal investigator inside 24 hours of their written report.

Outcome parameters

The primary endpoint is the group difference of the Health Assessment Questionnaire (HAQ) after 12 weeks compared with baseline. Target parameters are surveyed at baseline, on day 7, after 6 and 12 weeks and on follow-up later 6 months (table three).

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Table three

SPIRIT flow diagram of the NutriFast trial

Boosted secondary outcomes are standard RA assessment tools (Disease Action Score 28, DAS28; ACR-Response-Criteria; Uncomplicated Illness Activity Alphabetize) and questionnaires for functional ability (Funktionsfragebogen Hannover), mood (Profile of Mood States), stress (Cohen's Perceived Stress Calibration-10), quality of life (WHO-v) and subjective strength of the principal complaint on the Visual Counterpart Scale. Both groups go along a pain diary likewise recording pain medication intake. Occupational stress, domestic stress, interpersonal conflicts, digestion, menstruation, adherence on diet and boggling events are documented by means of a diary containing verbal numerical rating scale scores.

For safety monitoring, body weight and composition, food intake and vital signs are surveyed at regular intervals also equally urinalysis and a clinical standard laboratory, including blood count, liver and kidney values, vitamin B12, erythrocyte sedimentation rate and CrP (Biospecimen and data collection). ACPA and rheumatoid factor (IgM) are nerveless at baseline to complete the rheumatological assessment.

Cytometric parameters indicating changes in cell activation are determined to analyse the immunological effects of the intervention: detailed changes in subpopulations of immunological importance for inflammation (eg, monocytes) are quantified past transcriptome analysis of allowed cells (microarray /RNAseq). A preliminary study by the same research group identified inflammatory profiles of individual foods as well as molecular markers of disease activeness in RA, whose diagnostic value has been tested and interpreted under the influence of fasting.65 In this trial, these markers are being clinically evaluated.

Moreover, polar metabolic plasma metabolites are of interest and are analysed using a GC/MS metabolomics platform. Stool samples are nerveless in a subgroup of participants for 16s-18s rRNA sequencing.

Private dietary habits are surveyed in week −i, 4 and 9. Each measurement consists of a weighed three-day food record (two weekdays and one weekend twenty-four hours) where all consumed nutrient and drinks are recorded by the participants themselves. Verbal time, mood and location during nutrient intake are too to be recorded.

All surveys and endpoints shall exist collected and assessed by trained and experienced staff. Participants are informed about any aberrant findings and referred to their full general practitioner for farther treatment equally soon as such findings may occur.

Biospecimen and data collection

Clinical data

Clinical visits are carried out past study personnel at the Establish of Social Medicine, Epidemiology and Health Economics, Charité-Universitätsmedizin Berlin, Germany. Study participants are called in with an empty stomach between 8:00 am and 2:00 pm.

Diet and lifestyle cess

Standardised electronic questionnaires (LimeSurvey 5.3) are used to assess baseline data and deviations over the study period. Questionnaires are sent out online via email and completed on the day of the respective visit (table 3).

Adherence

Daily group consultations with a nutritionist back up adherence to the initial fasting week. The study team examines iii-day food records in week −ane, 4 and 9 as well every bit disseminates electronic questionnaires at the time of report visits to appraise applicability (tabular array 2). Food records are analysed for nutrient content using NutriGuide software. This software'southward database is based on the High german Federal Nutrient Code (BLS) of the German Federal Institute for the Protection of Consumer Wellness and Veterinarian Medicine (BGVV) and provides comprehensive information about the limerick/ingredients of more than 15 000 foods. Participants are farther asked to provide information on their lifestyle factors (including physical activity, nicotine, alcohol and illicit drug consumption) and consummate a modified Food Frequency Questionnaire (FFQ) which queries the consumption frequency of sure spices and herbs at all three food recording points. The FFQ has been generated for the purpose of this trial on the footing of the clinically used FFQ of our department for integrative medicine. Its focus lies on nutrition, fasting and chronobiology.

Anthropometric measurements and body composition

Weight and height are determined at baseline, six weeks and 12 weeks with regularly calibrated personal scales (seca, model 920). Trunk composition is assessed using a bioelectrical impedance analyser (Data Input, Nutriguard Chiliad/S, model BIA-2000S) and the corresponding software by the aforementioned supplier (Data Input, NutriPlus 6.0) at each clinical evaluation.

Claret samples

Claret samples are taken at each clinical visit (baseline, 7 days, vi weeks, 12 weeks). These are either transported straight to the study laboratory or centrifuged and frozen. Serum and EDTA samples are centrifuged at 2800 rpm for 10 min to obtain serum and plasma, aliquoted (minimum 200 µL per aliquot) and and so stored at −80°C for subsequent analysis. Samples from this report are only used for the ongoing procedure. Should further research with biological samples obtained exist planned in the futurity, renewed informed consent volition exist sought.

Metabolomics

Claret samples are collected as dried blood spots and metabolites volition be extracted using an established protocol66 earlier assessment via GC/MS. The raw GC/MS data will be analysed using the MetaboliteDetector software (http://metabolitedetector.tu-bs.de) to excerpt pure mass spectra and semi-quantitative values for all detected compounds in a non-targeted approach.67 If possible, the software will perform an identification of compounds present in a reference library. Finally, statistical analyses of the results volition yield metabolites significantly affected by our treatments.

Urine and stool samples

Midstream urine samples are nerveless at each clinical visit (baseline, seven days, 6 weeks, 12 weeks) and analysed immediately using semiquantitative urine dipsticks. Stool samples are nerveless in a subgroup of participants (north=20) to the indicated timepoints (table 3). Longitudinal changes in the limerick of the abdominal microbiome will be assessed using 16S rDNA gene-based next-generation sequencing on the Illumina MiSeq platform. The V4 region of 16S rDNA will be amplified by PCR, normalised, pooled and sequenced with the Illumina MiSeq 2×250 bp paired end as described.68 69 Assay of the 16S sequencing results will be performed as described.70

Statistical analysis

Sample size and power calculation

Based on the estimated yearly turnover of the associated hospitals and clinics in Berlin, 84 patients were enclosed in this airplane pilot report. Nether the standard assumptions of a significance level of blastoff=0.05, a beta=0.twenty (corresponding to a power of 80 %) and a repeated analysis of variance design with a hypothesis only for the interaction term, a nonsphericity correction of epsilon=ane, an assumed correlation amongst repeated measures of 0.5, and a driblet-out rate of 10%, the number is sufficient to find all effects with effect sizes of f=0.20 (d=0.40) or higher, and thus all medium and big furnishings. The number is thus apt to decide whether the effect is larger or smaller than the disquisitional effect size of d=0.5, indicating whether the treatment effect is to be termed clinically important.

Blinding

This is an open-label randomised controlled trial. Complete blinding of both the participants and the nutrionist to the treatments in this study is non possible due to obvious differences between the intervention arms.

Data direction

Each participant receives his/her private study ID (pseudonym) when enrolling in the written report. In order to guarantee the confidentiality of participant's personal data this pseudonym is used for all information documentation. Initially, data are collected in source documents and transferred to analogue example written report forms. Data sheets relating the participant's study ID to the person's contact details are stored in a locked chiffonier in a locked office to which but members of the research team accept access. Later, data are digitised and stored in a key database at Charité-Universitätsmedizin Berlin, Germany. Accuracy of the data entry is to be improved by double-checking the entries for expected scope and correct format. Participant files and other source data (including copies of protocols, questionnaires, original reports of test results, informed consent records and other documents concerning the conduct of the report) will be kept for at least 10 years subsequently completion of the study. Any modifications to the current study protocol will be communicated to the institutional review board, all study participants and the study investigator.

Information monitoring

Given the minimal risks of the dietary interventions, this trial is monitored on a regular ground by the protocol team, without the use of a formal information monitoring committee.

The master investigator, in close cooperation with the report coordinator and protocol team, may take the decision to discontinue the report. Such decision may exist based either on agin or serious adverse events attributed to the written report intervention or for the reasons mentioned in the section 'Exclusion criteria' or considering not enough participants could be recruited. Further details about its operating procedures can be obtained by contacting the corresponding author via email. The protocol team and the principal investigators meet every 3–6 months to monitor, review and talk over the written report progress and trial related issues.

There is no endpoint cess committee and no study steering committee. In that location are no stakeholder and public involvement groups involved.

Data analysis

The primary endpoint is the grouping deviation in the HAQ after 12 weeks. Baseline variables with prognostic and demographic relevance, as well as the totality of the target criteria, are described appropriately and compared by Student's t-test. Statistical variables included are, in addition to absolute and relative frequency, the number of valid values, the formation of the SD, minimum, maximum, median and mean value (depending on the numerical calibration used). For the protocol adding of a primary endpoint, a repeated variance analysis is performed.

Based on prior publications, no detrimental effects of the study intervention are expected that would consequence in a premature termination of the study.63 64 Hence, we do non plan an interim analysis. For an intention to treat analysis, nosotros intend to supervene upon missing values by multiple imputation using the amelia Ii package.71

Due to the consultation methods initiated to meet the restrictions associated with COVID-19, we introduced the additional covariate of 'rate of visits/consultations done only virtually' (ie, online video conferences or telephone calls). These additional tests volition be done every bit a sensitivity analysis, and are therefore separate from the assay of the primary upshot.

Follow-upward and evaluation of data

In society to investigate the feasibility and the long-term effects of a dietary alter after the study, we conduct a follow-up of all participants who accept completed the study afterwards half-dozen months. Electronic questionnaires are used to collect follow-upwardly outcomes including HAQ, wellness questionnaires and questionnaires on function and nutrition/lifestyle (tabular array iii).

Ethics and dissemination

The trial, including participant data and informed consent, has been approved past the institutional review lath of Charité-Universitätsmedizin Berlin and is conducted in accordance with the Declaration of Helsinki in its currently valid version, the guidelines of the International Conference on Harmonisation of Good Clinical Practise and the applicative German laws. An amendment for adaptations to our trial due to the COVID-19 pandemic was approved by the same ethics commission. Written informed consent is obtained from all participants preceding study entry by the responsible report doctor (online supplemental file 1). We just ask for consent to employ data and samples for the research bailiwick described in this protocol, and do not intend to use participant data or biological samples in further hereafter studies.

Results will be presented at national and international conferences, published in peer-reviewed journals and disseminated to rheumatologists and medical laymen. Nosotros volition follow the official eligibility guidelines for authorship in all publications and do not intend to use professional person writers.

Discussion

To the authors' cognition, this is the get-go approach to generate a dietary therapeutic concept for patients with RA involving therapeutic fasting. The study aims to provide boosted bear witness on promising existing laboratory research and clinical data on this dietary arroyo in patients with RA.

Previous nutritional recommendations, such equally a gluten-gratis or Mediterranean nutrition, have remained rather experimental therapeutic approaches due to insufficient data regarding their mechanisms and clinical effectiveness.72–74 Likewise, a recently published Swedish trial of an anti-inflammatory, primarily pesco-vegetarian, nutrition in rheumatoid arthritis has shown potential efficacy but lacked significant clinical relevance regarding the called endpoint (DAS28-ESR).75 In this written report, we aim to fill the the cognition and quality gap on both preclinical and clinical sides of fasting and a plant-based diet in RA.

A meta-assay by Genel et al76 suggests health benefits of a depression-inflammatory diet for adults with arthritis (calorie-reduced regimens or fasting excluded). Nevertheless, the quality of existing clinical trials is questionable—what is missing are professionally led nutritional interventions and a combined evaluation of laboratory and PROs. This structural aspect is reflected in the selection of certified nutritionists in this study design, together with the wide-ranging chosen endpoints. In addition, recent epidemiological studies on hazard for RA under Mediterranean nutrition appear controversial and call for a specification into seropositive and seronegative RA,77 78 which will be implemented in the statistical analysis of the results of this study.

As far equally mechanisms of activity are concerned, caloric restrictions harbour potential immunological consequences for patients with RA. As Häupl et al65 take recently suggested, at that place is an enhanced turnover of monocytes with accelerated monocytopoiesis to be seen in RA; the prematurely released monocytes from the bone marrow migrate into, then inflamed, joints.79 Fasting in plough reduces the number and action of circulating inflammatory monocytes in good for you humans and mice, without compromising the acute inflammatory response to infectious agents.80 The influence of fasting on the specific activity of monocytes in humans with RA shall now be the subject of this written report.

Moreover, the written report group of Hashemite kingdom of jordan et al80 revealed that metabolic activity and factor expression patterns predicting improvement of chronic inflammatory and autoimmune disorders, such as RA and multiple sclerosis, are modifiable by fasting in mice. Using GC/MS metabolomics, this written report shall point out the metabolic consequences of fasting in human being subjects with RA as an example of chronic inflammatory weather.

Growing evidence endorses the influence of diet on the imbalanced immune system in RA, which is also characterised past an increased number of proinflammatory T-helper cells 17 (Th17) and hence by a decreased Th1/Th17 ratio compared with salubrious subjects.81 Protective regulatory T-cells (Treg) on the other mitt tend to malfunction.81 A contempo study showed that 28-day high-fibre supplementation induces an uplift in circulating Treg, favourable Th1/Th17 ratios and improvement in symptoms in RA patients.82 Interestingly, a ketogenic nutrition induces like effects: not merely does it result in alteration of the human and murine gut microbiota, merely also reduces the levels of intestinal Th17 cells after human microbiome transplantations into germ-gratis mice.83 This translational study suggests that Th17 cell-promoting bifidobacteria may be suppressed not just past a ketogenic diet, but likewise fasting. Prevotella copri, implicated in the pathogenesis of RA, was likewise shown to induce Th17 cells in an arthritis model and might therefore be suppressed during fasting and ketosis.23 Every bit ketone bodies directly inhibit bacterial growth,83 other taxa may be affected every bit well. According to Ang et al, these should include Lactobacillus species that were sensitive non merely to a ketogenic diet, but also to ketone ester supplementation in mice. Some Lactobacillus species have been linked to translocation to internal organs in lupus-decumbent models; a mechanism which may be as well involved in the pathogenesis of RA that is characterised by a dysfunctional gut barrier.84 85 Lactobacillus also grows out in collagen-induced arthritis that is alleviated by another dietary intervention with resistant starch.86 One tin can thus speculate that these potentially disease-promoting taxa may be repressed in their niche within the gastrointestinal tract by the fasting protocol applied to patients with RA in this study. Similarly, the gut bulwark dysfunction may improve by this intervention, being comparable to a loftier-fibre nutrition that was shown to ameliorate this aspect by increasing the mucus layer in the alimentary canal and preventing from gut commensals to translocate to secondary lymphoid organs.84 87

Bated from fasting, a plant-based diet as well seems to event in a significant shift in the microbiota in some studies.88 89 Notwithstanding, a contempo review of Trefflich et alxc could not identify a consequent association between a vegan or vegetarian diet and a specific microbiota composition compared with omnivores. Somewhen, the interplay of diet, microbiota and host physiology may be unique and person-specific, eliciting private responses to dietary inputs.91 Therefore, future microbiome study designs should consider private microbiome stability and evaluate such information rather on the basis of longitudinal intraindividual basis than on interindividual comparing.92 Nosotros will adopt this approach in the evaluation and estimation of gut microbiota composition over the individual course of the study intervention.

Given the epidemiological and preclinical data on the one hand and the lack of consistent clinical data on the other, this trial has the potential to generate substantial information on the mechansims equally well as on the efficacy of fasting and diet. It aims to target key problems on diet and microbiota research and its translation into clinical RA contexts.

A major strength of the study design is the comprehensive corporeality of information to be collected likewise as a sizeable biorepository of claret and stool samples to exist generated. Laboratory tests on inflammation and metabolic processes may contribute to further illuminate the mechanism of fasting in RA. Blood-based biomarkers will enable us to place subgroups of RA patients that benefit to varying extents from our dietary intervention. The longitudinal drove of samples for microbiome analysis will provide further valuable information on the relationship between the microbiota and inflammatory action in RA patients. Linkage to extensive clinical, dietary and lifestyle information volition us provide further information to perform secondary epidemiological analyses to generate new hypotheses for testing in hereafter studies.

Some other strength is the abstention of functioning bias. We designed the trial in such a way that both intervention arms receive the same amount of coaching and medical visits, so that no systematic distortion of the written report results should occur from this.

In addition, the experimental intervention presented, with the support of nutritional experts, is realistically feasible. The short coaching intervals in the offset week of intervention also as the outpatient report pattern is more than likely to be accepted and put into practice by patients than regular dietary consultations that have to be planned in the long term. It is price-constructive and— in view of the recent enquiry on the positive effects of institute-based foods42 93 94 or the adverse effects of fauna products95—has an overall health benefit about likely without serious side furnishings, if communicated by a professional person nutritionist.

Nonetheless, there are some limitations to our study pattern. First, the intervention of a plant-based diet itself includes a reduced intake in AA every bit the recommendations of the command interventions do. The latter, similar to other studied dietary forms, has indicated trends toward clinical improvement of RA in other clinical trials, although without reaching statistical significance.52 75 A establish-based nutrition though represents not only a reduced, but near negligible consumption of AA. Notwithstanding, this attribute might influence our resulting outcomes. Second, our dietary intervention is not blinded. The written report, therefore, may be prone to bias like non-specific treatment effects, confirmation and observer bias. This is a full general problem amid studies aiming to investigate comprehensive dietary interventions and must be taken into account when interpreting results. From past studies in our facility, it is known that many patients apply for studies with a clear preference for 1 specific intervention. This expectation alone tin lead to a change in behaviour and tin can bias the result. Currently, we wait people to favour the fasting-intervention. Patients who are assigned to the control grouping may non want to participate all together, thus distorting the drop-out rate.96 On the other paw, rater and field of study-expectation bias can increment placebo response and affect report consequence.97 We try to evaluate the degree of this effect by assessing both the rater'south and the participant'due south expectation for both intervention arms earlier randomisation.

In summary, fasting and a subsequent specific diet may accept the potential to provide a safe and cost-effective complementary treatment selection for RA. A better understanding of the underlying mechanisms could as well exist applicative to other rheumatic diseases. We hope this report will assistance bridge the gap betwixt promising preclinical information and the lack of clinical data.

Trial status

The NutriFast trial is active with patient recruitment. Recruitment started May 2022 and will be approximately finished in the first quarter of 2021.

Ideals statements

Acknowledgments

Nosotros thank Miriam Rösner and Nadine Sylvester, who contributed to the translation of the report design into a practical protocol. Thanks to Wolfgang Keicher, AHG Ayurveda Handels GmbH, Hamburg and Seyfrieds Naturwaren, Osnabrück for the sponsoring of Pippali (Piper longum).

We acknowledge back up from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité – Universitätsmedizin Berlin.

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