Summary of Findings
Introduction
Rheumatoid arthritis (RA) is an auto-immune systemic condition characterized mainly by joint inflammation, which causes pain, swelling and stiffness. The inflammatory process leads, in the long term, to irreversible destruction of joints, with consequent disability, incapacity and increased mortality.1 It affects 0.5% to 2% of the world population, representing a significant socio-economic burden.2 The disease is associated with negative consequences in almost all domains of well-being, both physical and emotional, causing high levels of fatigue, sleep disturbances, anxiety and depression.3-6 According to patients, this impact is felt mainly in seven domains: pain, functional disability, fatigue, emotional well-being, sleep, coping and physical well-being. Disease impact is assessed and targeted through treatment, parallel with the biological disease process.5,6
There have been dramatic improvements in the treatment of RA in recent years, not only through new drugs (such as biological drugs) but also new treatment strategies (such as "Treat-to-Target [T2T]" strategy).7-9 Remission of the disease, i.e. complete abrogation of inflammatory activity, has become a viable option for most patients with a recent diagnosis,7,8 which provides an opportunity for them to reduce their suffering, stop joint damage, prevent disability and improve long-term quality of life (QoL).7 This supports the current paradigm of RA treatment, epitomized by the so-called T2T strategy,7-9 which establishes that remission is the core therapeutic target and should be achieved as early and as permanently as possible. Remission is currently defined as the control of three inflammatory indicators (number of painful and swollen joints, and acute phase reactants) and by the Patient Global Assessment (PGA) of disease activity.8-10
Effective control of inflammation through immunosuppressive therapy, which is the pillar of current medical intervention, has a markedly positive impact on patient well-being.8,9,11-14 However, a considerable proportion (14% to 38%) of those who are in biological remission, i.e. without objective signs of relevant inflammation, still report significant levels of disease impact, similar to those with active disease.4,15-18 This so called "near-remission" is at least as frequent as remission and typifies a common failure of the disease process strategy to achieve the ultimate goal of therapeutic intervention: to enable the patient to fully enjoy his/her life.19 These patients will not have their condition improved by additional immunosuppressive therapy, but rather require adjunctive interventions targeting the uncontrolled domains of disease impact. Optimal care of patients with RA therefore requires an integrated approach including both pharmacologic and non-pharmacologic interventions,20 ideally with the help of a multidisciplinary team.19,21,22 Many options are available for this purpose, such as patient counselling, advice and support,20,23-25 occupational therapy,26 cognitive behavioral therapy and other psychological interventions,27 physical interventions (exercise, physical activity, psychotherapy), and others.28
Several systematic reviews have summarized available evidence on the effect of non-pharmacological interventions on patients with RA. However, insufficient evidence, conflicting results and knowledge gaps indicate the need for an umbrella review to better understand and evaluate the effectiveness of available interventions and identify priorities for research.23,24,28 The information on implemented and evaluated interventions, their characteristics, contexts of application, and healthcare professionals responsible for their application lacks systematisation, which hinders the implementation of the interventions in practice. Additionally, most of the reviews were poorly reported, had significant methodological flaws and predated very significant developments in the definition of the disease and in its management.20,29 In fact, the criteria for classifying the disease have changed over time to encompass earlier disease classifications, and modern treatments and strategies have changed the face of RA and patients' needs.30,31 Furthermore, several domains of the impact of the disease elected by patients, such as emotional well-being and physical well-being, have not been addressed.
An umbrella review of the available information, its quality and its limitations is needed by patients, healthcare professionals and researchers in order to improve clinical practice, set priorities for research and foster development in this field. The only umbrella review available had a limited scope (pain, function and patient global assessment) and was published in 2007,28 well before the updated classification criteria for RA31 and the T2T strategy were in place.32
A preliminary search of the JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Database of Systematic Reviews, PROSPERO, PubMed and CINAHL revealed that there was no other umbrella review published or in progress. Therefore, an umbrella review was conducted to uncover the best available evidence, evaluate its quality and provide an up-to-date synthesis to inform healthcare professionals.
Review questions
The review questions are:
i. What is the effectiveness of non-pharmacological and non-surgical interventions on pain, functional disability, fatigue, emotional well-being, sleep, coping and physical well-being in patients with RA?
ii. What is the effectiveness of non-pharmacological and non-surgical interventions for reducing the global impact of disease and QoL of patients with RA?
Inclusion criteria
Participants
This umbrella review included existing systematic reviews involving:
* Patients satisfying current RA criteria.30,31 If at least one of these criteria was fulfilled, the review was included.
* Adult patients aged 18 years or over.
Patients with other concomitant musculoskeletal diseases were excluded.
Interventions
This umbrella review included systematic reviews that evaluated the effectiveness of non-pharmacological and/or non-surgical interventions in adult patients with RA with the aim of reducing its impact, used either as a single intervention or as part of multiple non-pharmacological and/or non-surgical interventions. Non-pharmacological interventions included, but were not limited to, any treatment that is not a registered drug,23 such as physical activity and exercise; hydrotherapy and balneotherapy; occupational therapy; electro-physical modalities such as thermotherapy, electrotherapy, and others; manual therapies such as massage, orthoses, aids, devices and adaptations of the physical environment and others; and psychosocial interventions. Non-surgical interventions were considered to be all interventions not related in any way to surgery. No limitations regarding frequency/intensity/who delivered the intervention were applied. Patients only received pharmacological treatment targeting the control of inflammation, according to international guidelines.32
Comparator
This umbrella review considered systematic reviews that compared the intervention to placebo, usual care or other non-pharmacological and non-surgical interventions.
Outcomes
The primary outcomes were quantitative measures of impact of disease, measured individually, in at least one of the following domains: pain, functional disability, fatigue, emotional well-being, sleep, coping and physical well-being by validated instruments (e.g. Visual Analog Scale [VAS], Health Assessment Questionnaire [HAQ], Functional Assessment of Chronic Illness Therapy [FACIT], Rheumatoid Arthritis Impact of Disease (RAID]).
The secondary outcomes were quantitative measures of global impact of the disease, measured by the Rheumatoid Arthritis Impact of Disease (RAID),5,6 and/or global QoL, measured by validated instruments (e.g. 36-Item Short Form Survey [SF36], EuroQol-5 Dimension [EQ5D]).33
Context
There were no context limitations in this umbrella review.
Types of studies
This umbrella review considered quantitative systematic reviews with or without meta-analysis, comprehensive systematic or mixed methods (only quantitative elements) reviews.
Additionally, systematic reviews needed to meet the following criteria:
* A clear, articulated and comprehensive search strategy using multiple databases.
* Critical appraisal and assessment of risk of bias.
In case of doubt, due to unclear inclusion criteria, authors were contacted for clarification before exclusion. General literature reviews, primary research and qualitative reviews were also excluded.
Systematic reviews published and unpublished in English, French, Spanish and Portuguese, from 2010 to the present, were considered for inclusion. The criteria for classifying the disease were changed in 2010 to include patients in earlier stages of the disease, and the impact of disease has changed dramatically in recent years due to more effective drug treatment.20,31
Methods
The review was conducted according to the Joanna Briggs Institute methodology for umbrella reviews,34 following a previously published protocol35 and prepared using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.36
Search strategy
The search strategy aimed to find both published and unpublished systematic reviews. A three-step search strategy was performed.
An initial search limited to PubMed and CINAHL has been undertaken to identify articles on this topic, followed by analysis of the text words contained in the titles or/and abstracts, and of the index terms used to describe these articles. This informed the development of a search strategy including identified keywords and index terms, which were tailored for each information source. A second search using all identified keywords and index terms was undertaken across all included databases, after appropriate adaptation to each information source. Finally, the reference lists of all studies selected for critical appraisal were searched for additional studies.
Information sources
The following electronic databases/sources were broadly searched for published systematic reviews: CINAHL Plus with Full Text, PubMed, Cochrane Database of Systematic Reviews, Scopus, Embase, PsycINFO, PEDro, Epistemonikos, JBI Database of Systematic Reviews and Implementation Reports, the PROSPERO register, Campbell Collaboration Library of Systematic Reviews.
The search for unpublished studies and gray literature included: RCAAP - Repositorio Cientifico de Acesso Aberto de Portugal; OpenGrey - System for Information on Grey Literature in Europe.
The final search strategy is included in Appendix I.
Study selection
Following the search, all identified citations were uploaded into EndNote VX7 (Clarivate Analytics, PA, USA) and duplicates removed. Titles and abstracts were screened by two independent reviewers (ES and AM) to assess eligibility according to the inclusion criteria for the review. The full articles were retrieved for all studies that, clearly or probably, met these inclusion criteria and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; Joanna Briggs Institute, Adelaide, Australia). Based on full texts, two reviewers (ES and AM) independently examined whether the studies conform to the inclusion criteria. Any disagreements that arise between the reviewers were resolved through discussion, or with a third reviewer (CD).
Full-text studies that did not meet the inclusion criteria were excluded, and reasons for exclusion were provided in Appendix II.
The results of the search were reported in full in the final report and presented in a flow diagram.36
Assessment of methodological quality
Reviews selected for retrieval were assessed by two independent reviewers (ES and AM) for methodological validity prior to inclusion in this review, using a standardized critical appraisal instrument (JBI Critical Appraisal Checklist for Systematic reviews and Research Syntheses). Authors of reviews were contacted to request missing or additional data for clarification, where required. Any disagreements between the reviewers were resolved through discussion, or with a third reviewer (CD). The results of critical appraisal were reported in a narrative form. The quality of each eligible review was based on the following cut-offs: 0-3 was considered a very low-quality score; 4-6 was considered a low-quality score; 7-9 was considered a moderate-quality score; and 10-11 was considered a high-quality score. A minimum score of 4 was pre-established as a criterion for inclusion in this umbrella review.
Data extraction
Data were extracted from the selected reports by two independent reviewers (ES and AM) using the standardized JBI data extraction tool in JBI SUMARI.37 The following information was extracted from each included review: i) type of review; ii) countries where the primary studies were conducted; iii) databases; iv) search timeframes; v) number of studies included in the review; vi) participants (number, age, comorbidities); vii) type(s) of intervention(s) (including duration and frequency); viii) outcomes of significance (types and characteristics); ix) outcome measures; x) inclusion/exclusion criteria; xi) methods of analysis; xii) heterogeneity; xiii) effect size and confidence intervals.
Any disagreements between the reviewers were resolved through discussion or with a third reviewer (CD). Authors of papers were contacted to request missing or additional data, when needed.
Data synthesis
The studies were analyzed in separate categories based on the domain of outcome measure. Findings were tabulated and subjected to a narrative synthesis to address the review objective and specific questions. The overall effect sizes and a clear description of the non-pharmacological intervention(s) were presented for interpretation of consistency. The previous referred tables included a high level of detail for each systematic review, such as the number of studies, total number of participants and its specificities, assessment tool, heterogeneity and complete information about the non-pharmacological intervention(s). The overlap of original research studies included in systematic reviews was rigorously checked to avoid double counting. Where possible, the review's findings were considered based on its quality, as assessed by critical appraisal, to explore the consequences of synthesizing reviews of differing quality. The results of the umbrella review were provided in an "Evidence Summary" table that includes the intervention, the included systematic review(s) and a simple visual indicator of the effectiveness of the intervention using the three colors of the traffic light: a beneficial or effective intervention (green), no effect or difference compared to a control treatment (orange) and a detrimental intervention or one that is less effective than a control treatment (red).34
An overall assessment of the quality of the evidence for each comparison using The Grading of Recommendations, Assessment, Development and Evaluation (GRADE)38 approach for grading the certainty of evidence and the creation of a Summary of Findings (SoF) was performed using GRADEPro GDT software. A four-point rating scale was used to rate the quality of the evidence: high, moderate, low and very low. The quality of evidence was classified according to the following criteria: risk of bias, inconsistency, imprecision, indirectness and publication bias. A narrative SoF form was preferred due to the differences in metrics used by the included systematic reviews (standard mean difference [SMD], weighted mean difference [WMD], Hedges' g effect size [g], narrative synthesis) which did not allow the calculation of a pooled effect size. The significant heterogeneity between the reviews in terms of characteristics of interventions, settings of conducted studies, differences in time points of the outcome measurements also contributed to this decision.
Results
Review selection
The literature search identified a total of 1140 records, of which 1084 records were from bibliometric databases and 56 from gray literature. After removing duplicates (n = 367), titles and abstracts of 773 records were screened independently by two reviewers and 681 were excluded as they were irrelevant to the umbrella review. Full-text reviews assessing the eligibility of the remaining 92 records were conducted by two reviews independently, and 84 failed to meet at least one of the four eligibility criteria (participants, interventions, outcomes and study design). See Appendix II for reasons for their exclusion. The interrater agreement was strong39 (kappa statistic [k] = 0.851; 95% CI = 0.631-1.0; p < 0.005) and consensus could always be achieved without intervention of the third reviewer. Only one contact to the authors of a review was undertaken to request missing or additional data for clarification.40 Finally, the remaining eight records were critically appraised by two reviews independently and included in this umbrella review. See Figure 1 for the process described above.36
Methodological quality
The critical appraisal results for each of the eight systematic reviews are summarized in Table 1.
There was agreement among the reviewers to include all studies appraised. Based on the JBI critical appraisal checklist for systematic reviews and research syntheses,47 five of the eight systematic reviews selected for inclusion were deemed of high quality23,27,41-43 and three were of moderate quality.44-46 The minimum number of criteria met was nine and the maximum was 11 out of 11. Criteria 1 through 5 and criteria 11, relating to the review question, search strategy and critical appraisal, were met by all included systematic reviews. Only one systematic review46 had critical appraisal of studies and extraction performed by one reviewer (criteria 6 and 7). Finally, four systematic reviews assessed the likelihood of publication bias (criteria 9).23,27,42,46 No reviews were excluded on the basis of methodological quality criteria.
In terms of risk of bias assessment, the inter-rater agreement between the two reviewers was strong39 (k = 0.88; 95% CI = 0.651-1.0; p < 0.005). No intervention by a third reviewer was needed.
Characteristics of included studies
The eight systematic reviews included a total of 103 randomized controlled trials (RCTs) and nine observational studies, but only 91 RCTs were considered to be relevant to this review as 12 RCTs (11.7%) were duplicated in the systematic reviews. Specific information and characteristics from these systematic reviews were extracted and are summarized in a table (Appendix III).
The number of participants involved was 6740 but one review27 did not report the number of participants and their characteristics. The mean age ranged from 18 to 80 years and two studies did not report the mean age.27,41 Four systematic reviews reported on the gender of the participants from included studies42,43,45,46 and the majority were female, ranging from 46.7% to 100%. Regarding the classification of the disease (RA criteria), all included systematic reviews used the 1987 ACR (American College of Rheumatology) criteria30 and four of them used the ARA (American Rheumatism Association) criteria,48 two used the Steinbrocker criteria49 and one used the 2010 ACR/EULAR (European League Against Rheumatism)31 criteria.
The included studies were from a diversity of countries, namely, Australia, Austria, Bosnia, Canada, Denmark, Finland, France, Germany, Israel, The Netherlands, Sweden, Turkey, United Kingdom and United States of America. Three systematic reviews did not provide information about the countries where the included studies were conducted.23,41,44 The reviews were published between 2010 and 2015. The majority of the individual RCTs included in the systematic reviews (n = 91) were conducted in or after 2000 (n = 49; 53.8%), 34 RCTs were conducted between 1990 and 2000, and only eight RCTs (8.8%) were dated 1990 or earlier. With observational studies, six were conducted in or after 2000 (66.7%), two in 1999 (22.2%) and only one in or before 1990 (11.1%).
All included systematic reviews performed meta-analysis and calculated heterogeneity in addition to a narrative synthesis, with the exception of one.45
Intervention characteristics
Type
Four systematic reviews examined the effects of multicomponent or single exercise/physical activity interventions23,41,42,46 compared with no exercise, usual care, non-aerobic exercises, range of motion exercises or education. With these interventions, four trials included multi-component exercises involving resistance, strengthening, aerobic exercises and flexibility. The remaining trials (n = 31) examined the effects of single modalities of exercise.
Two systematic reviews examined the effects of hydrotherapy/balneotherapy interventions43,45 compared with usual care, home exercises, land-based exercises, relaxation and other types of baths or mudpacks. The interventions included were based on aquatic exercises in six of the included trials and different types of baths in nine trials.
The other two systematic reviews evaluated the effects of psychosocial interventions in 51 trials,23,27 which included expressive writing, cognitive skills training, cognitive behavioral therapy, mindfulness, lifestyle management, education, energy conservation, self-management, group education and counseling, relaxation, contracting/goal setting, coping, guided imagery, self-instruction and others, compared to education or usual care.
The remaining systematic review44 only evaluated the effects of custom orthoses for the foot and ankle compared to no orthoses or placebo orthoses in 17 trials.
All these interventions were performed by different healthcare professionals, namely, medical doctors, nurses, physical therapists, psychologists, occupational therapists, counselors, dieticians, clinical psychologists and other professionals, namely, yoga teachers, PhD students and laypersons (information stated only in two systematic reviews).23,27
Although most of the settings were not stated, it was reported that the interventions were supervised by health professionals. Some interventions were undertaken in temperate pools, fitness centers and homes.
Frequency/duration/intensity
All of the included systematic reviews reported on the frequency of interventions with a range of one to five sessions per week,23,27,41-43,45,46 with the exception of one review.44
The total duration ranged from 10 minutes to 4.5 hours per session. One systematic review reported a treatment duration of two to four weeks.43
The intensity of the interventions (exercise/physical activity) can be measured by "how hard the heart is working". This was only reported in two systematic reviews41,42 and ranged from 30-100% or 50-90%. Some studies, as examined in two systematic reviews,23,45 reported a moderate intensity; however these definitions were presented without further clarification. Usually, low-intensity exercises raise the heart rate to 40-50% of an individual's maximum heart rate (MHR). Moderate-intensity exercises increase the heart rate to 50-70% of the MHR, while vigorous-intensity exercises elevate the heart rate to above 70% of the MHR. The remaining systematic reviews did not include any information about this phenomenon.27,43,44,46
Review findings
Effects on impact of disease per domain
Pain
Pain was measured using the Visual Analog Scale for Pain (VAS Pain), the Numerical Rating Scale (NRS), the McGill Pain Questionnaire, the Impact Measurement Scales Health Status Questionnaire (AIMS2), the Impact of Rheumatic Diseases on General Health and Lifestyle (IRGL), the Pain Disability Index, the Bodily Pain subscale of the SF-36, and the Manchester Foot Pain Disability Questionnaire.
Seven systematic reviews23,27,42-46 involving 86 relevant trials evaluated the effectiveness of non-pharmacological and non-surgical interventions on pain. Two systematic reviews showed small positive effects (effect size is < 0.40) of multicomponent or single exercise/physical activity interventions42,46 (n = 545) and one did not perform meta-analysis either because it was not possible and/or because there were no statistically significant differences between the trial arms.23 Two systematic reviews showed insufficient effects/power (no statistically significant differences or the inability to provide an overall effect size) of hydrotherapy/balneotherapy interventions43,45 against usual care, exercise, mudpacks or relaxation therapy. One systematic review showed small positive effects of psychosocial interventions27 (n = 1316) and one did not perform meta-analysis for the reasons mentioned previously.23 The remaining systematic review44 (n = 340) showed moderate positive effects (effect size is > 0.40 and < 0.80) of custom orthoses.
With overall effect, multicomponent or single exercise/physical activity interventions, psychosocial interventions and custom orthoses appeared to be the most effective in alleviating pain.
Functional disability
Functional disability was measured using the Health Assessment Questionnaire (HAQ), the Foot Function Index (FFI), the IRGL and the AIMS2.
Six systematic reviews23,27,42,44-46 involving 82 relevant trials evaluated the effectiveness of non-pharmacological and non-surgical interventions on functional disability. Two of these systematic reviews showed small positive effects of multicomponent or single exercise/physical activity interventions (n = 1384).42,46 Two systematic reviews did not perform meta-analysis and for this reason showed insufficient effects/power of hydrotherapy/balneotherapy interventions43,45 or multicomponent or single exercise/physical activity and psychosocial interventions.23 One systematic review (n = 1180) showed small positive effects of psychosocial interventions27 and finally one systematic review44 (n = 220) showed small positive effects of custom orthoses.
With overall effect, multicomponent or single exercise/physical activity interventions, psychosocial interventions and custom orthoses appeared to be the most effective in improving functional disability.
Fatigue
Fatigue was measured using the Multidimensional Assessment of Fatigue (MAF), the Visual Analog Fatigue Scale (VAFS), the Functional Assessment of Chronic Illness Therapy (FACIT), the Checklist Individual Strength (CIS), the Profile of Mood States (POMS), the Short Form 36 Vitality subscale and the perception of change in fatigue from baseline using a four-point Likert scale.
Only two systematic reviews evaluated the effect of non-pharmacological and non-surgical interventions on fatigue.23,41 These two reviews (n = 628) showed small positive effects of multicomponent or single exercise/physical activity interventions but one41 demonstrated that the benefits of these effects were more frequent in the short term (defined as < 12 weeks; n = 257). Only one systematic review (n = 1556) reported on psychosocial interventions23 also showing small positive effects.
With overall effect, multicomponent or single exercise/physical activity interventions and psychosocial interventions appeared to be the most effective in improving fatigue.
Emotional well-being, sleep, coping or physical well-being
None of the included systematic reviews reported on emotional well-being, sleep, coping or physical well-being as an outcome measure.
The summary of the disease domains or global dimension of the impact of disease as assessed by the included systematic reviews are presented in Table 2.
Effects on global impact of disease and quality of life
The global impact of disease and QoL were measured using the 36-Item Short Form Survey (SF-36), the EuroQol-5 Dimension (EQ-5D), the Nottingham Health Profile (NHP), the Rheumatoid Arthritis Quality of Life (RAQol) questionnaire, the Arthritis Impact Measurement Scales (AIMS) health status questionnaire and the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR).
Only two systematic reviews evaluated the effectiveness of non-pharmacological and non-surgical interventions on the global impact of disease.45,46 Of these, one systematic review45 did not perform meta-analysis and showed insufficient effects/power (hydrotherapy/balneotherapy interventions). The other systematic review46 (n = 586) showed small positive effects of multicomponent or single exercise/physical activity interventions on QoL.
With overall effect, only multicomponent or single exercise/physical activity interventions appeared to be effective in reducing the global impact of disease.
The interventions assessed by the included systematic reviews and the summary of evidence are presented in Table 3 and 4, respectively.
Discussion
With the introduction of biological drugs, the management of RA has recently incorporated a more targeted and aggressive pharmacological approach.32 However, not all patients achieve full inflammatory remission, and a significant proportion of those who do describe continued impact of the disease in different health domains. Both these groups of patients require adjunctive non-pharmacological interventions targeting the uncontrolled domains of disease impact.19,20 This umbrella review provides important knowledge in this field because it appraises and brings together the available evidence on the effectiveness of non-pharmacological and non-surgical interventions on RA (both globally and by domain). This review summarized evidence from eight systematic reviews and included four major groups of interventions: multicomponent or single exercise/physical activity interventions (n = 4 reviews), hydrotherapy/balneotherapy interventions (n = 2 reviews), psychosocial interventions (n = 2 reviews), and custom orthoses (n = 1 review). Overall, the results showed that non-pharmacological and non-surgical interventions were effective in reducing the impact of RA in some health domains.
Type of interventions and effects on impact of disease per domain
Multicomponent or single exercise/physical activity interventions can be recommended for people with RA to reduce pain, functional disability and fatigue. Psychosocial interventions were also suggested as being beneficial for reducing pain, functional disability and fatigue, and custom orthoses for reducing pain and functional disability.
Other types of interventions were not sufficiently examined and their effectiveness is not yet established, namely, hydrotherapy/balneotherapy interventions due to its overall non-significant effect in most of the studies, which generally had significant limitations and were of low quality.
None of the included systematic reviews reported on emotional well-being, sleep, coping or physical well-being as outcome measures.
These findings support current recommendations stressing the benefits of exercise and physical activity for RA.50 However, health professionals do not often recommend exercise to patients and even when they do, the acceptance and adherence rates are not of expected levels.42,51 Also, psychosocial interventions are widely recommended for patients with RA23,27,52,53 due to the benefits highlighted in this review. On the other hand, adherence and acceptance rates of exercise and physical activity can also be improved through the use of psychosocial interventions, suggesting that their combined use can provide better overall outcomes.23
With custom orthoses, several reviews previously showed its benefits for reducing pain and its potential to reduce functional disability,44,54,55 which also corroborates our results.
Most of the included systematic reviews stated an average exercise frequency of one to five sessions per week, with a duration of 10 minutes to 4.5 hours per session and an intensity of 30-100%. However, the optimal parameters and components of these interventions have not yet been established,23 but these findings provide an important practice guide which can be replicated and adjusted to the individual patient's condition, abilities and preferences.50 Furthermore, no evidence on the superiority of intervention delivery or setting over other were found. The delivery modes varied considerably and were described as "land-based", water-based", "supervised and individualized" and most of them were not even reported.
Type of interventions and effects on global impact of disease and quality of life
Multicomponent or single exercise/physical activity interventions are the only interventions that can be recommended for people with RA to reduce the global impact of disease and QoL. This may be due to the fact that few studies reported measures of global impact of disease and/ or QoL. Although there were many studies that evaluated QoL in patients with RA in general in relation to efficacy/intervention studies, we found that more specific endpoints were most frequently used (e.g. pain, fatigue).
Strengths and limitations
The strengths of this umbrella review included the comprehensiveness of the search strategy, the strict inclusion criteria that allowed the selection of quality systematic reviews conveying a large number and variety of RCTs and patients. We used a rigorous process of data extraction and synthesis leading to the development of well supported recommendations. We were able to identify important knowledge gaps that warranted investigation, with emphasis on domains of impact that had not been (sufficiently) addressed by research.
A limitation of this umbrella review was the lack of patient characterization in the included systematic reviews, namely, the definition/criteria used for RA diagnosis and other demographic information such as age and gender. In some cases, the interventions and their characteristics were also poorly described, namely, the intensity of exercise interventions (reported only in two systematic reviews). This has limited the recommendations for each of the interventions. A consistent characterization of patients and interventions would be required to allow for systematic examination of the effects.
Although we were able to summarize the evidence on four of the eight domains (pain, functional disability, fatigue and global impact of disease), this only represents 50% of the domains. The four unaddressed domains (physical and emotional well-being, sleep and coping) are interrelated with and influence the four domains. This limits the ability to "fully" address these four domains (pain, functional disability, fatigue and global impact of disease), since we were unable to account for the interrelationships between domains.
Another limitation was the heterogeneity of the proposed interventions, including different types of exercise, whether they were performed single or multicomponent, different psychosocial interventions, and different hydrotherapy/balneotherapy protocols. Faced with these constraints, we had to adopt the comparisons provided by the systematic reviews (grouped interventions). Furthermore, there was not enough evidence from which we could draw conclusions regarding the effectiveness of several types of interventions and the comparison between them.
Conclusion
To the best of our knowledge, this is the first umbrella review examining the effects of non-pharmacological and non-surgical interventions on the impact of RA, with individual analysis by impact domain and globally. Our results suggest that multicomponent or single exercises/physical activity interventions, psychosocial interventions and custom orthoses are the only interventions with demonstrated efficacy in reducing the impact of RA. This effectiveness is mainly perceived by patients as reduction in pain, functional disability, fatigue and the global impact of disease. These interventions are performed up to five times per week for 10 minutes to 4.5 hours per exercise session, at a moderate to high intensity, and according to the patient's preferences. Other interventions such as hydrotherapy/balneotherapy interventions fail to demonstrate effectiveness.
Recommendations for practice
Multi-component or single exercises/physical activity interventions involving resistance, strengthening and aerobic exercises, and flexibility are an effective strategy to reduce pain, functional disability, fatigue and global impact of disease in people with RA (GRADE B: JBI Grades of Recommendation).47 Psychosocial interventions involving cognitive skills training, cognitive behavioral therapy, mindfulness, lifestyle management, education, self-management, contracting/goal setting, coping, guided imagery, self-instruction, among others, are an effective strategy to reduce pain, functional disability and fatigue in people with RA (GRADE B: JBI Grades of Recommendation).47 Custom orthoses for the foot and ankle are an effective strategy to reduce pain and functional disability in people with RA (GRADE B: JBI Grades of Recommendation).47
Recommendations for research
Future evidence should be generated and synthesized in the areas identified as a knowledge gap, namely, interventions targeting emotional well-being, sleep, coping or physical well-being. Furthermore, systematic reviews should clearly adopt a RA diagnosis definition/criteria and identify the specifics of their target population. Information about the characteristics of the intervention (such as frequency, intensity, duration and type) should always be provided to allow for more specific recommendations on different types of exercises. The effectiveness of several types of interventions (such as hydrotherapy/balneotherapy interventions) is not yet established and warrant research in order to allow more specific recommendations.
Acknowledgments
The authors would like to acknowledge the support provided by Health Sciences Research Unit: Nursing (UICISA: E), hosted by the Nursing School of Coimbra (ESEnfC).
This review will contribute towards a PhD in Nursing Sciences for ES.
Appendix I: Search strategies
CINAHL Plus with Full Text: searched on 30th July, 2018
PubMed: searched on 30th July, 2018
Cochrane Database of Systematic Reviews: searched on 31th July, 2018
Scopus: searched on 30th July, 2018
Embase: searched on 31th July, 2018
PsycINFO: searched on 2nd September, 2018
PEDro: searched on 30th July, 2018
Epistemonikos: searched on 30th July, 2018
JBI Database of Systematic Reviews and Implementation Reports: searched on 30th July, 2018
The PROSPERO register: searched on 30th July, 2018
Campbell Collaboration Library of Systematic Reviews: searched on 30th July, 2018
RCAAP - Repositorio Cientifico de Acesso Aberto de Portugal: searched on 30th July, 2018
OpenGrey - System for Information on Grey Literature in Europe: searched on 30th July, 2018
Appendix II: List of excluded studies after full-text eligibility assessment
Akyuz G, Kenis-Coskun O. The Efficacy of Tai Chi and Yoga in Rheumatoid Arthritis and Spondyloarthropathies: A narrative biomedical review. Rheumatology International. 2018;38(3):321-30.
Reason for exclusion: Ineligible participants.
Alkabeya HA, Adams J, Hughes A-M. Factors associated with hand functional disability in patients with rheumatoid arthritis: a systematic review. 2017.
Reason for exclusion: Ineligible study type.
Balsamo S, Diniz LR, dos Santos-Neto LL, da Mota LM. Exercise and fatigue in rheumatoid arthritis. Isr Med Assoc J. 2014;16(1):57-60.
Reason for exclusion: Ineligible participants.
Bearne LM, Byrne AM, Segrave H, White CM. Multidisciplinary team care for people with rheumatoid arthritis: a systematic review and meta-analysis. Rheumatol Int. 2016;36(3):311-24.
Reason for exclusion: Ineligible intervention.
Bergstra SA, Murgia A, Te Velde AF, Caljouw SR. A systematic review into the effectiveness of hand exercise therapy in the treatment of rheumatoid arthritis. Clin Rheumatol. 2014;33(11):1539-48.
Reason for exclusion: Ineligible participants.
Brosseau L, Welch V, Wells GA, de Bie R, Gam A, Harman K, et al. Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2005(4).
Reason for exclusion: Ineligible publication date.
Brosseau L, Yonge KA, Welch V, Marchand S, Judd M, Wells GA, et al. Transcutaneous electrical nerve stimulation (TENS) for the treatment of rheumatoid arthritis in the hand. Cochrane Database of Systematic Reviews. 2003(2).
Reason for exclusion: Ineligible publication date.
Bryer C, Srikesavan C, Williamson E. Effects of web-based interventions on physical function and activity, pain and quality of life in patients with rheumatoid arthritis: A systematic review. Rheumatology (Oxford). 2017;56:ii204.
Reason for exclusion: Ineligible study type.
Camacho-Bautista K, Orjuela-Rodriguez A, Vargas-Pinilla O. Intervencion fisioterapeutica en el manejo de pacientes con artritis reumatoide: una revision sistematica. Fisioterapia. 2017;39(4):174-80.
Reason for exclusion: Ineligible participants.
Carandang K, Pyatak E. A systematic review of the educational approach of occupational therapy for rheumatoid arthritis. Arthritis and Rheumatology. 2014;66:S1014-S5.
Reason for exclusion: Ineligible study type.
Carandang K, Pyatak EA, Vigen CL. Systematic Review of Educational Interventions for Rheumatoid Arthritis. Am J Occup Ther. 2016;70(6):7006290020p1-p12.
Reason for exclusion: Ineligible study type.
Casimiro L, Barnsley L, Brosseau L, Milne S, Welch V, Tugwell P, et al. Acupuncture and electroacupuncture for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2005(4).
Reason for exclusion: Ineligible publication date.
Casimiro L, Brosseau L, Welch V, Milne S, Judd M, Wells GA, et al. Therapeutic ultrasound for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2002(3).
Reason for exclusion: Ineligible publication date.
Chen J, Chen T, Xu J. Efficacy of probiotics on rheumatoid arthritis (RA): a systematic review and meta-analysis. PROSPERO. 2017.
Reason for exclusion: Ineligible study type.
Chou P-C, Chu H-Y. Clinical Efficacy of Acupuncture on Rheumatoid Arthritis and Associated Mechanisms: A Systemic Review. Evidence-Based Complementary and Alternative Medicine. 2018;2018:21.
Reason for exclusion: Ineligible participants.
Conceicao CS, Gomes Neto M, Mendes SM, Sa KN, Baptista AF. Systematic review and meta-analysis of effects of foot orthoses on pain and disability in rheumatoid arthritis patients. Disabil Rehabil. 2015;37(14):1209-13.
Reason for exclusion: Ineligible participants.
Cramp F, Berry J, Gardiner M, Smith F, Stephens D. Health behaviour change interventions for the promotion of physical activity in rheumatoid arthritis: a systematic review. Musculoskeletal Care. 2013;11(4):238-47.
Reason for exclusion: Ineligible participants.
DiRenzo D, Crespo-Bosque M, Bingham C, Gould N, Finan P, Nanavati J. Systematic review: mindfulness-based interventions for rheumatoid arthritis (protocol). PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Efthimiou P, Kukar M. Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities. Rheumatol Int. 2010;30(5):571-86.
Reason for exclusion: Ineligible intervention.
Egan M, Brosseau L, Farmer M, Ouimet MA, Rees S, Tugwell P, et al. Splints and Orthosis for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2001(4).
Reason for exclusion: Ineligible publication date.
Ekelman BA, Hooker L, Davis A, Klan J, Newburn D, Detwiler K, et al. Occupational therapy interventions for adults with rheumatoid arthritis: an appraisal of the evidence. Occup Ther Health Care. 2014;28(4):347-61.
Reason for exclusion: Ineligible study type.
Ernst E, Posadzki P. Complementary and alternative medicine for rheumatoid arthritis and osteoarthritis: an overview of systematic reviews. Curr Pain Headache Rep. 2011;15(6):431-7.
Reason for exclusion: Ineligible participants.
Giacobbi PR, Jr., Stabler ME, Stewart J, Jaeschke AM, Siebert JL, Kelley GA. Guided Imagery for Arthritis and Other Rheumatic Diseases: A Systematic Review of Randomized Controlled Trials. Pain Manag Nurs. 2015;16(5):792-803.
Reason for exclusion: Ineligible participants.
Gijon-Nogueron G, Ramos-Petersen L, Ortega-Avila AB, Morales-Asencio JM, Garcia-Mayor S. Effectiveness of foot orthoses in patients with rheumatoid arthritis related to disability and pain: a systematic review and meta-analysis. Qual Life Res. 2018.
Reason for exclusion: Ineligible participants.
Guillot X, Tordi N, Mourot L, Demougeot C, Dugue B, Prati C, et al. Cryotherapy in inflammatory rheumatic diseases: a systematic review. Expert Rev Clin Immunol. 2014;10(2):281-94.
Reason for exclusion: Ineligible participants.
Hammond A, Jones V, Prior Y. The effects of compression gloves on hand symptoms and hand function in rheumatoid arthritis and hand osteoarthritis: a systematic review. Clin Rehabil. 2016;30(3):213-24.
Reason for exclusion: Ineligible participants.
Hammond A, Prior Y. The effectiveness of home hand exercise programmes in rheumatoid arthritis: a systematic review. Br Med Bull. 2016;119(1):49-62.
Reason for exclusion: Ineligible participants.
Han A, Judd M, Welch V, Wu T, Tugwell P, Wells GA. Tai chi for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2004(3).
Reason for exclusion: Ineligible publication date.
Hernandez-Hernandez MV, Diaz-Gonzalez F. Role of physical activity in the management and assessment of rheumatoid arthritis patients. Reumatologia Clinica. 2017;13(4):214-20.
Reason for exclusion: Ineligible study type.
Hurkmans E, van der Giesen FJ, Vliet Vlieland TPM, Schoones J, Van den Ende E. Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2009(4).
Reason for exclusion: Ineligible publication date.
Hurkmans EJ, Jones A, Li LC, Vliet Vlieland TP. Quality appraisal of clinical practice guidelines on the use of physiotherapy in rheumatoid arthritis: a systematic review. Rheumatology (Oxford). 2011;50(10):1879-88.
Reason for exclusion: Ineligible study type.
Hurkmans EJ, Van Der Giesen FJ, Vlieland TPMV, Schoones JW, Van Den Ende CHM. Home-based exercise therapy in patients with rheumatoid arthritis: A systematic review. Arthritis and Rheumatism. 2010;62:2283.
Reason for exclusion: Ineligible study type.
Jones GT, Paudyal P, MacPherson H, Sim J, Doherty M, Ernst E, et al. The effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatoid arthritis. Rheumatology (Oxford). 2012;51:131-2.
Reason for exclusion: Ineligible study type.
Kelley GA, Kelley KS, Callahan LF. Aerobic Exercise and Fatigue in Rheumatoid Arthritis Participants: A Meta-Analysis Using the Minimal Important Difference Approach. Arthritis Care Res (Hoboken). 2018.
Reason for exclusion: Ineligible participants.
Kelley GA, Kelley KS, Hootman JM. Effects of exercise on depression in adults with arthritis: a systematic review with meta-analysis of randomized controlled trials. Arthritis Res Ther. 2015;17:21.
Reason for exclusion: Ineligible participants.
Kelley GA, Kelley KS, Hootman JM, Jones DL. Effects of community-deliverable exercise on pain and physical function in adults with arthritis and other rheumatic diseases: a meta-analysis. Arthritis Care Res (Hoboken). 2011;63(1):79-93.
Reason for exclusion: Ineligible participants.
Langdon K, Phie J, Thapa C, Biros E, Nagaraja H, Loukas A. Helminth-based therapies for rheumatoid arthritis: a systematic review and meta-analysis of the CIA animal model literature. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Larkin L, Gallagher S, Cramp F, Brand C, Fraser A, Kennedy N. Behaviour change interventions to promote physical activity in rheumatoid arthritis: a systematic review. Rheumatol Int. 2015;35(10):1631-40.
Reason for exclusion: Ineligible outcomes.
Larmer PJ, Bell J, O'Brien D, Dangen J, Kersten P. Hydrotherapy outcome measures for people with arthritis: A systematic review. New Zealand Journal of Physiotherapy. 2014;42(2):54-67.
Reason for exclusion: Ineligible participants.
Lee JA, Son MJ, Choi J, Jun JH, Kim JI, Lee MS. Bee venom acupuncture for rheumatoid arthritis: A systematic review of randomised clinical trials. BMJ Open. 2014;4(11).
Reason for exclusion: Ineligible participants.
Li J YJ, Wu S, Wang M-R, Zhu J-M. Effects of acupuncture on rheumatoid arthritis: a systematic review and meta-analysis African Journal of Traditional, Complementary, and Alternative Medicines 2016.
Reason for exclusion: Ineligible outcomes.
Lourenzi FM, Jones A, Pereira DF, dos Santos JHCA, Furtado RNV, Natour J. Effectiveness of an overall progressive resistance strength program for improving the functional capacity of patients with rheumatoid arthritis: A randomized controlled trial. Clinical Rehabilitation. 2017;31(11):1482-91.
Reason for exclusion: Ineligible study type.
Martinez-Calderon J Pt M, Meeus M Pt P, Struyf F Pt P, Luque-Suarez A Pt P. The role of self-efficacy in pain intensity, function, psychological factors, health behaviors, and quality of life in people with rheumatoid arthritis: A systematic review. Rheumatol Int. 2018:1-17.
Reason for exclusion: Ineligible participants.
McKenna S, Comber L, A. D, Kennedy N, Fraser A. The effectiveness of exercise on sleep in people who have rheumatoid arthritis: a systematic review and meta-analysis. PROSPERO. 2015.
Reason for exclusion: Ineligible study type.
McKenna S, Comber L, Donnelly A, Kennedy N, Fraser A, Herring M. The effects of exercise on depression and anxiety in people who have rheumatoid arthritis: a systematic review and meta-analysis. PROSPERO. 2016.
Reason for exclusion: Ineligible study type.
Melainie C, Joel JG, Sigrun C. Herbal therapy for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2011(2):CD002948.
Reason for exclusion: Ineligible intervention.
Mildner AR, Machado RS, Sbruzzi G. The use of hand splints on functionality in patients with rheumatoid arthritis: systematic review. PROSPERO. 2017.
Reason for exclusion: Ineligible study type.
Nagel MA, Guendling PW. Effects of exercise therapy on patients with rheumatoid arthritis-A systematic review. European Journal of Integrative Medicine. 2010;2(4):238-9.
Reason for exclusion: Ineligible study type.
Nasir, S. H., Troynikov, O., & Massy-Westropp, N. (2014). Therapy gloves for patients with rheumatoid arthritis: a review. Ther Adv Musculoskelet Dis, 6(6), 226-237. doi: 10.1177/1759720x14557474
Reason for exclusion: Ineligible participants.
Oishi A, Prior M, Worley A. The use of foot orthoses in the management of the rheumatoid arthritis patient. Internet Journal of Allied Health Sciences & Practice. 2011;9(2):11p-p.
Reason for exclusion: Ineligible participants.
Park Y, Chang M. Effects of rehabilitation for pain relief in patients with rheumatoid arthritis: a systematic review. J Phys Ther Sci. 2016;28(1):304-8.
Reason for exclusion: Ineligible participants.
Pelland L, Brosseau L, Casimiro L, Welch V, Tugwell P, Wells GA. Electrical stimulation for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2002(2).
Reason for exclusion: Ineligible study type.
Peres D, Sagawa Y, Dugue B, Domenech SC, Tordi N, Prati C. The practice of physical activity and cryotherapy in rheumatoid arthritis: systematic review. Eur J Phys Rehabil Med. 2017;53(5):775-87.
Reason for exclusion: Ineligible participants.
Prothero, L., Barley, E., Galloway, J., Georgopoulou, S., & Sturt, J. (2018). The evidence base for psychological interventions for rheumatoid arthritis: A systematic review of reviews. Int J Nurs Stud, 82, 20-29. doi: 10.1016/j.ijnurstu.2018.03.008
Reason for exclusion: Ineligible participants.
Ramsey L, Winder RJ, McVeigh JG. The effectiveness of working wrist splints in adults with rheumatoid arthritis: a mixed methods systematic review. J Rehabil Med. 2014;46(6):481-92.
Reason for exclusion: Ineligible participants.
Ranzani R, Souza D, Oliveira L. Mindfulness for rheumatoid arthritis patients. Systematic review of the literature. PROSPERO. 2017.
Reason for exclusion: Ineligible study type.
Rueda-Vergara R, Sanchez-Perez E. Efectividad de la terapia laser de baja intensidad en pacientes con artritis reumatoide: una revision sistematica de ensayos clinicos. Fisioterapia. 2016;38(3):152-8.
Reason for exclusion: Ineligible participants.
Santos I, Cantista P, Vasconcelos C. Balneotherapy in rheumatoid arthritis-a systematic review. Int J Biometeorol. 2016;60(8):1287-301.
Reason for exclusion: Ineligible participants.
Salmon VE, Hewlett S, Walsh NE, Kirwan JR, Cramp F. Physical activity interventions for fatigue in rheumatoid arthritis: a systematic review. Physical Therapy Reviews. 2017;22(1/2):12-22.
Reason for exclusion: Ineligible study type.
Scarvell J, Elkins MR. Aerobic exercise is beneficial for people with rheumatoid arthritis. Br J Sports Med. 2011;45(12):1008-9.
Reason for exclusion: Ineligible study type.
Seca S, Miranda D, Cardoso D, Greten H, Cabrita A, Rodrigues MA. The effectiveness of acupuncture on pain, physical function and health-related quality of life in patients with rheumatoid arthritis: a systematic review protocol. JBI Database System Rev Implement Rep. 2016;14(5):18-26.
Reason for exclusion: Ineligible study type.
Siegel P, Tencza M, Apodaca B, Poole JL. Effectiveness of Occupational Therapy Interventions for Adults With Rheumatoid Arthritis: A Systematic Review. Am J Occup Ther. 2017;71(1):7101180050p1-p11.
Reason for exclusion: Ineligible participants.
Silva KN, Mizusaki Imoto A, Almeida GJ, Atallah AN, Peccin MS, Fernandes Moca Trevisani V. Balance training (proprioceptive training) for patients with rheumatoid arthritis. Cochrane Database Syst Rev. 2010(5):Cd007648.
Reason for exclusion: Ineligible outcomes.
Sjoquist ES, Almqvist L, Asenlof P, Lampa J, Opava CH. Physical-activity coaching and health status in rheumatoid arthritis: A person-oriented approach. Disability and Rehabilitation: An International, Multidisciplinary Journal. 2010;32(10):816-25.
Reason for exclusion: Ineligible study type.
Srikesavan C, Bryer C, Ali U, Williamson E. Web-based rehabilitation interventions for people with rheumatoid arthritis: A systematic review. J Telemed Telecare. 2018:1357633x18768400.
Reason for exclusion: Ineligible participants.
Steultjens E, Dekker JJ, Bouter LM, Schaardenburg DD, Kuyk M, Van den Ende E. Occupational therapy for rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2004(1).
Reason for exclusion: Ineligible publication date.
Tenten-Diepenmaat M, Dekker J, Vliet Vlieland TPM, Roorda LD, van der Leeden M. A systematic review on the comparative effectiveness of foot orthoses in patients with rheumatoid arthritis. PROSPERO. 2017.
Reason for exclusion: Ineligible study type.
Tenten-Diepenmaat M, Dekker J, Vliet Vlieland TPM, Roorda LD, van der Leeden M. The effectiveness of therapeutic footwear in patients with rheumatoid arthritis: a systematic review and meta-analysis. PROSPERO. 2016.
Reason for exclusion: Ineligible study type.
Tenten-Diepenmaat M, van der Leeden M, Vliet Vlieland TPM, Roorda LD, Dekker J. The effectiveness of therapeutic shoes in patients with rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology International. 2018;38(5):749-62.
Reason for exclusion: Ineligible participants.
Tuntland H, Kjeken I, Nordheim LV, Falzon L, Jamtvedt G, Hagen KB. Assistive technology for rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2009(4).
Reason for exclusion: Ineligible publication date.
Verhoeven F, Tordi N, Prati C, Demougeot C, Mougin F, Wendling D. Physical activity and rheumatoid arthritis, a systematic review. Annals of the Rheumatic Diseases. 2015;74:416.
Reason for exclusion: Ineligible study type.
Welch V, Brosseau L, Casimiro L, Judd M, Shea B, Tugwell P, et al. Thermotherapy for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2002(2).
Reason for exclusion: Ineligible publication date.
Yang K, Zeng L, Yu G. Effectiveness of coenzyme Q10 supplementation for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of curcumin and turmeric extract for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of probiotic for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of probiotic supplementation for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of quercetin for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of sesamin supplementation for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of vitamin D for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of vitamin E for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Yang K, Zeng L, Yu G. Effectiveness of vitamin K for rheumatoid arthritis patients. PROSPERO. 2018.
Reason for exclusion: Ineligible study type.
Zhao X, Gao J, Li Y, Yu J, Lyu J, Xiang Y, et al. Efficacy of Chinese herbal fumigation for rheumatoid arthritis (RA): a systematic review. PROSPERO. 2016.
Reason for exclusion: Ineligible study type.
Zhou B, Li G, Zhang Y, Zhao Z. Effects of nursing interventions on depression of patients with rheumatoid arthritis: A meta-analysis of randomized controlled trials. Archives of Psychiatric Nursing. 2016;30(6):717-21.
Reason for exclusion: Ineligible participants.
Zwolinska J, Gasior M, Sniezek E, Kwolek A. The use of magnetic fields in treatment of patients with rheumatoid arthritis. Review of the literature. Reumatologia. 2016;54(4):201-6.
Reason for exclusion: Ineligible study type.
Appendix III: Characteristics of included reviews
References