FatiguE in Sjögren’s Syndrome: a randomised controlled trial of cOmbined Non-phArmacological therapeutic strategies (FESSONA)

Abstract

Fatigue is a prevalent and debilitating symptom of Sjögren’s syndrome (SjS), affecting up to 70% of patients, with limited effective therapeutic options available. The FESSONA trial will evaluate the efficacy of combined non-pharmacological strategies, including adapted physical activity (APA), acupuncture (ACU) and transcutaneous vagus nerve stimulation (tVNS), in alleviating fatigue in SjS. This monocentric, randomised controlled trial will compare three intervention arms: APA alone, APA combined with ACU and APA combined with tVNS (with sham ACU and simulated tVNS when relevant). The primary outcome will focus on fatigue reduction, assessed by the difference in FACIT-F score between weeks 0 and 12. Secondary outcomes will include physiological and psychological fatigue-related and disease-specific measurements at both short (weeks 0 and 12) and long terms (weeks 24 and 48). A longitudinal biobank will also be established for further mechanistic studies. The trial aims to enrich clinical practice and global understanding of SjS-associated fatigue to improve its management.Trial registration number: NCT06875102.

DH and MK are joint senior authors.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Chronic fatigue affects two-thirds of the patients with Sjögren’s syndrome (SjS), with deleterious effects on their quality of life and an unmet therapeutic need. Adapted physical activity (APA) is recommended in any situation of unexplained chronic fatigue, but its implementation can be challenging (eg, due to fatigue itself, exercise intolerance, availability), hence potentially limiting its efficiency.

WHAT THIS STUDY ADDS

• The original approach of the FESSONA trial aims at evaluating if combining acupuncture or transcutaneous vagus nerve stimulation with APA can improve its efficiency/tolerance.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Our findings should bring novel insights into the clinical utility of combined non-pharmacological interventions in SjS-related fatigue.

Introduction

Sjögren’s syndrome (SjS) is the second most common connective tissue disease after rheumatoid arthritis, affecting 0.01–0.3% of the adult population worldwide, depending on the studies and criteria used.¹ This systemic autoimmune disease is characterised by diffuse mucosal involvement, generally presenting with dry eye and/or mouth, linked to the infiltration of the corresponding glands by immune cells (notably T and B lymphocytes), as well as by the production of autoantibodies whose main targets are the self-ribonucleoproteins Ro/Sicca Syndrome A (Ro/SSA, which corresponds to two distinct proteins, Ro60/SSA/TROVE2 and Ro52/SSA/TRIM21) and La/Sicca Syndrome B (La/SSB).² The early signs of keratoconjunctivitis (dry eyes) are primarily due to damage to both the corneal and bulbar conjunctival epithelium, often leading to the expansion of bulbar conjunctival vessels and an increase in gland size, as a result of which patients with SjS commonly report symptoms such as burning sensations, redness and sensitivity to light.³ Similarly, xerostomia is marked by dry mouth, poor dental health, cavities, swelling of one or both salivary glands and reduced saliva production, making it difficult to swallow, speak and taste food.⁴ Many previous studies have focused on alleviating the dryness of patients with SjS,^{5 6} while fatigue, one of its most commonly reported systemic symptoms, has not been well understood and treated,⁷ which leaves us a challenge to resolve.

Chronic fatigue is defined as impairing and unexplained fatigue lasting at least 3–6 months,⁸ frequently reducing the patient’s quality of life and forcing them to reduce their professional, leisure, physical and sporting activities. The management of chronic fatigue, as an isolated or associated problem, is always challenging, with adapted physical activity (APA) programmes being the only approach, which has been identified as helpful in clinical trials, but these programmes have limits in terms of access, tolerance and feasibility.⁹ In SjS, chronic fatigue is present in 70% of the cases (thus not limited to the most severe forms of the disease) and is often described as the most disabling symptom by patients.¹⁰ Furthermore, the beneficial effect of immunosuppressants on chronic fatigue is rather inconsistent, with a benefit/risk ratio usually considered unfavourable, mainly due to the increased risk of infection.¹¹ Hence, current guidelines primarily recommend APA for patients with SjS and chronic fatigue, even if the number of published dedicated studies is limited to date, all with a small sample size (n<30 per group) and short-term evaluation (up to 16 weeks maximum).¹¹ Interestingly, other less common non-pharmacological therapeutic modalities, such as acupuncture (ACU) and transcutaneous vagus nerve stimulation (tVNS), have also been evaluated with promising results in addressing fatigue across various chronic conditions, including cancer-related fatigue,¹² fibromyalgia¹³ and inflammatory bowel disease.¹⁴

ACU is an ancestral approach from traditional Chinese medicine, which consists of specific acupoint stimulation and has been applied for a long time in different forms of chronic fatigue, more or less associated with other pathologies (eg, fibromyalgia, cancer).^15–17 The mechanisms behind ACU (which can vary from one acupoint to another) are not completely elucidated. However, it seems to be at least partially mediated by the autonomic nervous system.¹⁸ A recent controlled randomised clinical trial (n=60 per group) by Zhou et al¹⁹ evaluated the effects of ACU (2–3 times per week for 8 weeks) in SjS and did not show any significant benefit on fatigue. However, improving fatigue was not the primary objective of this study, where the acupoints were essentially chosen to improve sicca symptoms.

tVNS is a non-invasive approach whose goal is to specifically stimulate the parasympathetic autonomic nervous system via a transcutaneous route on the surface of the ears (where a branch of the vagus nerve passes). It was initially developed for the treatment of epilepsy and has since been validated in major depressive episodes, sleep disorders and chronic pain.^20–22 A recent SjS randomised controlled study (n=20 per group)²³ showed an improvement in different subjective measures of fatigue at 2 months in the intervention arm compared with the control group.

Thus, FESSONA has been designed as the first randomised controlled clinical trial, evaluating the potential benefits of two non-pharmacological combined therapeutic strategies (APA+tVNS or APA+ACU) compared with APA alone in improving SjS-related chronic fatigue. By evaluating the short-term and long-term impacts of these interventions, this trial seeks to establish evidence-based guidelines for comprehensive fatigue management in SjS.²⁴

Methods and analysis

Study design

FESSONA, with a total of 174 patients (ie, 58 per group) expected to be enrolled, has been designed as a randomised controlled monocentric trial, aiming at comparing the effects of three different programmes on fatigue in SjS: APA alone, APA+ACU or APA+tVNS. Relevant controls will also be included (sham ACU and tVNS simulation (tVNSsim)). Multiple fatigue and SjS-related features will be measured before (V0: at inclusion) and after the intervention (V1: week 12±1 week), with follow-up visits at week 24±1 week (V2) and week 48±1 week (V3), to evaluate the short-term and-long term impact of each programme (figure 1). Tolerance and feasibility will also be evaluated.

• Group 1: APA+sham ACU+ tVNS simulation

• Group 2: APA+ACU+tVNS simulation

• Group 3: APA+sham ACU+tVNS

Figure 1. Trial flow and study design. 1st outcome: the change in fatigue score assessed by Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-F) between weeks 0 and 12. 2nd outcome: FACIT-F score at weeks 24 and 48; root mean square of the successive differences in heart rate; proportion of the 24 APA sessions carried out; ClinESSDAI score (clinical part of the EULAR Sjögren’s Syndrome Disease Activity Index); ESSPRI questionnaire (EULAR Sjögren’s Syndrome Patient-Reported Index); Hospital Anxiety and Depression Scale; Self-measurement questionnaire SF-36; EQ-5D-5L self-measurement questionnaire; Schirmer test; unstimulated salivary flow; VO2max; handgrip test; number of daily steps measured via a connected watch on average over the week, at weeks 0, 12, 24 and 48. ACU/SACU, acupuncture/sham acupuncture; APA, adapted physical activity; n, number; SjS, Sjögren’s syndrome; tVNS/tVNSsim, transcutaneous vagus neurostimulation/transcutaneous vagus neurostimulation simulation; V, visit.

Randomisation and blinding

Participants will be randomly assigned at a 1:1:1 ratio using a computer-generated sequence to avoid selection bias. The sequence will be recorded and can be displayed when necessary. The presence of an APA control group alone will limit confusion bias. Randomisation will be centralised via REDCap software and stratified on the presence or absence of a diagnosis of concomitant fibromyalgia (pathology frequently associated with SjS and known to be responsible for chronic fatigue that is difficult to manage) and the age of the patients (<60 or ≥60 years). Patients will be blinded to treatment for ACU and NSVt using simulated ACU/NSVt devices, with the primary outcome measure being a patient-completed self-report questionnaire. The intention-to-treat analysis was used to avoid attrition bias.

Participants

Patients with SjS will be prescreened in the Internal Medicine and Rheumatology Departments of Saint-Etienne University Hospital.

Patient involvement

Patients will be involved in the design and conduct of this research. During the feasibility stage, the priority of the research question, interventions, choice of outcome measures and recruitment methods will be informed and signed in the consent form. Once the trial is terminated and finally published, we will disseminate the main results to trial participants. We will seek patient and public involvement in the development of an appropriate method of dissemination.

Inclusion criteria

• Patients with health insurance rights

• Age>18 years.

• Patient informed and has signed the information form and consent to participate in the study.

• Patient with SjS according to the American College of Rheumatology/European Alliance of Associations for Rheumatology 2016 or the American European Consensus Group 2002 criteria.

• Fatigue present for ≥6 months, with a current Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-F) score<34.

Exclusion criteria

• Pre-existing atrial fibrillation or severe cardiac conduction disorders.

• Recent stroke or myocardial infarction (<6 months).

• Left ventricular ejection fraction<40% or severe heart failure (New York Heart Association functional class III or IV).

• Recurrent episodes of vasovagus syncope or history of vagotomy.

• People with dermatological problems in the area where the stimulation electrodes are to be placed

• Current episode of venous or arterial thrombosis.

• Pregnancy or breastfeeding

• Patient under protective measures (legal protection, curatorship, guardianship)

• Inability or refusal to understand and/or sign informed consent to participate in the study or to perform follow-up examinations required under the study.

Interventions

Adapted physical activity

APA is widely recommended (by extrapolating data on the management of chronic fatigue syndrome as there are few SjS-specific encouraging studies) in all disorders associated with chronic fatigue, including SjS. The chosen APA programme is used routinely in Saint-Etienne University Hospital’s Department of Sports Medicine in fibromyalgia, notably in the context of the FIMOUV study.²⁵

In FESSONA, the APA programme will be implemented in all three groups at a rate of two sessions of 90 min (with 60 min of aerobic exercise and 30 min of resistance exercises per session) per week for 12 consecutive weeks, supervised by a teacher specialised in APA, within the Department of Sports Medicine. Each session will be directly followed by a session of ACU or sham ACU and tVNS or tVNSsim, depending on the group allocation.

Acupuncture

In the study, the experienced acupuncturist will be trained on the sham needles and apply both the sham and real needles throughout the trial with similar techniques. The selected acupoints are Baihui (GV20) with even technique; Zhongwan (CV12), Guanyuan (CV4) and bilateral Zusanli (ST36) with reinforcing technique; bilateral Taichong (LV3) with reducing technique. During the needle manipulations, twirling, lifting and thrusting to elicit Deqi or needle sensation (a composite of unique sensations interpreted as the flow of qi induced by ACU and essential for clinical efficacy)²⁶ will be applied and the needles will be retained for 20 min. Subjects will receive ACU or sham ACU twice weekly during the 12-week intervention. In the control group, the shallow puncture technique was used at Baihui (GV20) point, and blunt needles with adhesive pads were used at other acupoints in the non-acupoint area 2 cm away from the real acupoints, which is a classic control procedure used in ACU studies, making groups as comparable as possible (figure 2). ACU and sham ACU from Hwato ACU needles (40×0.25 mm; Suzhou Medical Appliance Factory, Suzhou, China) will be used by a recognised specialist (XZ) in the field.

Figure 2. Acupuncture and sham acupuncture. CV, conception vessel meridian; GV, governor vessel meridian; LV, liver meridian; ST, stomach meridian.

Transcutaneous vagus nerve stimulation

tVNS stimulates the afferent auricular branch of the vagus nerve, which is located in the cymba conchae.²⁷ To avoid stimulation of fibres to the heart, tVNS is safe to be applied to the left but not the right ear.²⁸ The tVNS device consisted of two titan electrodes mounted on a gel frame and connected to a wired neuro-stimulating device (ECO TENS 2, Schwa Medico, France) (figure 3).

Figure 3. Transcutaneous vagus nerve stimulation (tVNS) and tVNS simulation. The device stimulates the afferent auricular branch of the vagus nerve, which is located in the cymba conchae. tVNS simulation will be applied by placing the electrodes over the centre of the left ear lobe instead of the outer auditory canal as the ear lobe is free of vagus innervation and its stimulation produces no activation in the cortex and brain stem.

Following the suggestions by Dietrich et al²⁹ for optimal stimulation, the tVNS device was programmed to a stimulation intensity of 0.5 mA, delivered with a pulse width of 200–300 μs at 25 Hz. Active and sham stimulation alternated between active stimulation for 30 s and a break of 30 s. Consistent with Kraus et al,³⁰ sham stimulation was applied by placing the electrodes over the centre of the left ear lobe instead of the cymba conchae as the ear lobe is free of vagus innervation, and its stimulation produces no activation in the cortex and brain stem.

Outcome measures

Primary outcome

The primary outcome is the change in fatigue score assessed using the FACIT-F questionnaire (ranging from 0 to 52, 0 meaning extreme fatigue and 52 the total absence of fatigue) between V0 (inclusion) and V1 (week 12±1 week).³¹

Secondary outcomes

• FACIT-F score at weeks 24 and 48.

• Heart rate variability illustrated by the measure of root mean square of the successive differences in milliseconds from a nocturnal ECG recording by Holter ECG at weeks 12, 24 and 48.

• Proportion (in %) of the 24 APA sessions carried out (at least 80% of the exercises proposed).

• ClinESSDAI score (clinical part of the EULAR Sjögren’s Syndrome Disease Activity Index) at weeks 12, 24 and 48.

• ESSPRI questionnaire (EULAR Sjögren’s Syndrome Patient-Reported Index) at weeks 12, 24 and 48.

• HADS questionnaire (Hospital Anxiety and Depression Scale) at weeks 12, 24 and 48.

• Self-measurement questionnaire SF-36 (Short Form Health Survey 36) at weeks 12, 24 and 48.

• EQ-5D-5L self-measurement questionnaire at weeks 12, 24 and 48.

• Schirmer test at weeks 12, 24 and 48,

• Unstimulated salivary flow (in mL/min over 5 min) at weeks 12, 24 and 48.

• VO2max (in mL/min/kg; via a cardiopulmonary exercise test) at weeks 12, 24 and 48.

• Handgrip test (in kg; via a grip test on the dominant upper limb) at weeks 12, 24 and 48.

• Number of daily steps measured via a connected watch (Garmin vivofit 4) on average over the week at weeks 12, 24 and 48.

• Blood samples (rheumatoid factors, IgG, IgA and IgM).

Sample size

The primary endpoint is the fatigue score assessed by the FACIT-F questionnaire measured after 12-week interventions. Several works^{32 33} accepted that the minimal clinically important difference for the FACIT-F was at least 3 points. Thus, based on the assumption of a difference of 3 points (with an SD±5) between groups, an alpha risk of 5% (adjusted downwards to be able to combine each treatment group with the APA group alone) and a power of 80%, it is necessary to include 68 subjects per physical training group (calculation made with MedCalc). Considering the possibility of a 5% loss to follow-up, we proposed including 58 subjects in each group or 174 patients.

Data management

Data protection

Following the European Data Protection Regulation, individuals participating in this research will be informed, via the information notice and the consent form, of the following rights:

• The nature and purpose of the data collected as part of the research and the retention period for this data

• The possibility of stopping the study at any time and the retention, by the sponsor, of the information collected (unless otherwise indicated by the person concerned)

• Their rights of access, rectification, opposition, limitation, erasure and portability of data collected as part of the research. These rights may be exercised at any time during the research either by requesting the doctor who is monitoring the individuals in the research (and who will contact the sponsor) or by filing a request with the Data Protection Officer of the sponsor

It was specified in the agreement that the investigator will allow monitoring by the sponsor, possible audits and inspections by ethics committees, institutional review boards and competent authorities by providing direct access to the source documents.

Data collection

Study data will be collected directly in the observation notebooks as and when the study visits occur. The investigator will validate these data and sign the observation notebooks (manually or electronically).

Missing data must be justified (eg, in a protocol violations table). Any correction made in the case report form (CRF) must be traceable (crossed out, dated and initialled by the corrector on a ‘paper’ CRF, via the ‘audit trial’ on an e-CRF).

Data quality control

Quality control will be carried out by the Clinical Research Associate of the Clinical Research Unit for Innovation and Pharmacology of the Saint-Étienne University Hospital. Only part (inclusion/non-inclusion criteria, evaluation criteria, randomisation, severe adverse events, treatment accounting) of the data in the observation notebook (except for the high level) and the presence of all signed consents will be verified.

Archiving of data

Following the decree of 11 August 2008 setting the retention period by the sponsor and the investigator of documents and data relating to biomedical research other than that relating to medicinal products for human use, at the end of the research, all documents (different versions of the protocol, observation notebooks, investigator’s folder, consents, correspondence, etc) appearing on paper will be archived, in each centre and with the sponsor, for at least 15 years. The data on computer media will be kept until the final research report is produced and archived for at least 15 years.

Data publication

The data will be the property of the sponsor. Their access and use will be under the responsibility of the principal investigator. MK will be responsible for the publication. The Saint-Étienne University Hospital will be cited as the sponsor of the study (see details on the University Hospital website: http://www.chu-st-etienne.fr/Recherche/Pro/Publication.asp).

Statistical analysis

Analysis of the outcomes

The evolution between 0 and 12 weeks of the FACIT-F score (ranging from 0 to 52) will be compared between each intervention group via a Student’s t-test after verification of the normal nature of the distribution of this variable in these populations (by a Shapiro-Wilk test). In case of non-normal distribution, a rank test will be used instead. Since the secondary endpoints are also quantitative, they will be analysed similarly to the primary endpoint.

Degree of statistical significance

The results will be considered significant at the 2.5% threshold as the study design includes three treatment arms to take into account the multiplicity of statistical tests and, therefore, independently compare the two intervention groups (APA+ACU and APA+tVNS) to the comparator group (APA alone).

Managing changes to the initial strategy analysis plan

The statistical analysis plan will be written blind to the data. If changes need to be made to the methods described in this protocol’s ‘statistical analysis’ paragraph, they will be validated by the reference statistician. Any deviations will be described and justified in the final report.

Which data to be included in the analysis

The analysis will be performed on an intention-to-treat basis. A sensitivity analysis on the primary endpoint will be performed per protocol. Patients not performing 50% of the exercises will be excluded from the per-protocol statistical analysis.

Discussion

The FESSONA trial is a significant effort to address the challenge of fatigue in SjS, an often underappreciated yet profoundly impactful symptom, via a novel combination of promising non-pharmacological approaches.

Previous studies, such as those evaluating APA in fibromyalgia³⁴ and ACU in cancer-related fatigue,³⁵ have demonstrated substantial benefits, but only a few studies have specifically targeted SjS-related fatigue. The FESSONA trial builds on this foundation by employing a rigorous randomised controlled design, focusing on fatigue reduction as the primary outcome. This aligns with earlier findings that neuromodulatory therapies, such as tVNS, can modulate autonomic balance, improve fatigue³⁶ and reduce inflammation, probably due to activating the anti-inflammatory cholinergic pathway.³⁷

Compared with other studies, such as trials evaluating biologics (eg, rituximab) for fatigue reduction in autoimmune diseases,³⁸ the FESSONA trial uniquely emphasises non-pharmacological strategies. These approaches are especially valuable given pharmacological interventions’ potential side effects and limited efficacy in managing SjS-related fatigue. Moreover, including subjective measurements, such as the FACIT-F score, and objective physiological markers enhances the robustness of the trial’s outcomes.

However, this study is not without limitations. The monocentric design may limit generalisability, and adherence to APA may vary among participants, potentially generating bias. Furthermore, the subjective nature of fatigue assessment poses an inherent weakness despite efforts to standardise evaluations.³⁹

The results of the FESSONA trial have the potential to inform clinical guidelines and provide a framework for integrating combined non-pharmacological interventions into the standard of care for SjS. By comparing three distinct intervention arms, this study may provide novel insights into the field and practical solutions for improving the patient’s quality of life, paving the way for more personalised approaches to managing SjS-related fatigue. The trial’s findings may also be a reference for designing future studies on non-pharmacological interventions for autoimmune diseases.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).

Ethics approval

This study involves human participants. The protocol follows ethical principles established by the 18th World Medical Assembly (Helsinki 1964) and was approved on 7 January 2025 by the Comité de Protection des Personnes Ile de France V under the reference 2024-A02116-41. Participants gave informed consent to participate in the study before taking part.

Footnote

XZ and JC contributed equally.

Contributors All authors were involved in the study design and manuscript preparation. XZ designed and implemented the acupuncture section and, along with JC, contributed to drafting the manuscript. MK acted as the coordinating investigator, with support from co-investigator DH; both provided critical revisions and approved the final version of the manuscript. MK is the guarantor.

Funding XZ’s work was supported by the National Natural Science Foundation of China (grant no. 82374285) and the National Administration of Traditional Chinese Medicine Overseas Training Program for Talents in Traditional Chinese Medicine—China Scholarship Council (grant no. 202305350013). JC’s work was supported by the 'Xinglin Scholar' Discipline Talent Scientific Research Enhancement Program—Hospital Special Project of Chengdu University of Traditional Chinese Medicine (grant no. XJ2023000701). The funding bodies had no role in the study's design, collection, analysis and interpretation of data or manuscript writing.

Competing interests None declared.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

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