Chronic inflammatory arthritic diseases are multifactorial diseases characterized by auto-antibody production and systemic features. Synovial inflammation induces pannus and joint destruction unless aggressively managed with disease modifying therapies. Inflammatory arthritis can be highly disabling with immense personal, social and economic costs. Healthcare costs alone for rheumatoid arthritis (RA) in Australia were estimated at AUD550 million in 2015.1 Worldwide, the prevalence of RA has been estimated at 0.24% and attributed as being responsible for 4.8 million disability-adjusted life years (95% CI: 3.7 million to 6.1 million) in 2010.2 The reported prevalence estimates of the family of spondyloarthropathies (SpA), including psoriatic arthritis (PsA), ankylosing spondylitis (AS), reactive arthritis (ReA), inflammatory bowel disease (IBD), associated arthritis (also known as enteropathic arthritis [EA]) and undifferentiated SpA, have varied considerably.3 However, recent estimates of disease impact suggest that the burden from SpA is similar to that experienced by those living with RA.4 For inflammatory arthritis, patient reported outcomes (PROs) are viewed as particularly necessary for measuring the impact and burden of disease, as serum measures of systemic inflammation such as C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are affected by population demographic such as age and gender, and can rate poorly on “what matters” to patients.5
While debate continues over the etiology of inflammatory arthritis, there is emerging evidence that microbial dysbiosis at mucosal sites (in combination with environmental triggers) could be involved in the disease in genetically predisposed individuals.6 Key findings supporting this theory include elevated serum-related auto-antibodies being found in early RA without clinically evident synovitis, suggesting that pathology develops outside of the joint.7 The gut has been suggested as a key mucosal site which may trigger auto immune reactions in distant sites, such as the joints, as dysbiotic gut microbiota have been found in individuals with early stage auto-immune inflammatory RA, which can be partly normalized after treatment.7-8 Such is the specificity of the dysbiotic changes that genetic markers of these gut microbes can be used to identify individuals with RA from a control group.9
Microbial dysbiosis has been widely researched in people with RA, but there is growing evidence to link microbial dysbiosis with the whole clinical spectrum of inflammatory arthropathies. Studies are now emerging on the gastrointestinal (GI) microbiota in people with SpA and juvenile idiopathic arthritis (JIA). Evidence exists which supports a closer link between gut microbiota and the pathogenesis of SpA than the link between gut microbiota and the pathogenesis of RA. Subclinical gut inflammation has been estimated to occur in up to 70% of patients with AS and up to 100% of patients with PsA.10-11 This association may have been masked by a lack of reportable bowel symptoms despite the prevalence of colonoscopic changes in patients with PsA and psoriasis.11 Similarly, subclinical evidence of gut inflammation has been found using magnetic resonance enterography (MRE) in a sample population of JIA patients. Whilst the small sample size in this study may have increased the likelihood of type II error, the prevalence of clinically diagnosed IBD is also higher in JIA than in the general population.12-13
Pharmaceutical management using disease modifying anti-rheumatic drugs (DMARDS) remains the mainstay of interventions for inflammatory arthritis, often coupled with non-pharmacologic management strategies. However, adverse drug effects are common and remission is not guaranteed. About 20–40% of patients treated with newer version biological DMARDS – the tumor necrosis factor inhibitors (TNFi) – have failed to achieve a 20% improvement in American College of Rheumatology criteria and even more experienced loss of response over time (secondary failure or acquired therapeutic resistance).14-15 In juvenile arthritis, new pharmaceutical therapy has increased the likelihood of attaining inactive disease in up to 70–90% of children within two years, yet sustaining remission remains problematic for almost 50% of children.16 Consequently, the use of complementary medicines by patients as a means to seek or maintain symptom control remains high and searching for adjuvant interventions to reduce the burden of disease in inflammatory arthritis is common.17 As a review of probiotic interventions for JIA is not currently available, this review aims to generate capacity for clinicians to understand the likelihood of benefits and harms from the application of current probiotic formulations, and be confident in discussing these with families as they transition into adult care.
Probiotics have been defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host”.18 (p.507) Probiotics are one of several potential “therapies” that are being investigated in terms of their positive benefits for the GI system. The GI system is home to most human microbiota which have significant benefits for their human hosts, including contributing to an effective immune system that can tolerate safe commensal bacteria whilst ensuring a rapid inflammatory response to pathogenic organisms.19-20 A bourgeoning literature base has investigated the effects of probiotics on the GI system, theorizing that they address “dysbiosis” or imbalance in the gut microbiome, and can down regulate the pro-inflammatory cytokine cycle implicated in triggering auto immune diseases, such as inflammatory arthritis.21-26
Despite a lack of rigorous trials, probiotics are booming business. The global probiotics market totaled USD34 billion in 2015 and is set to grow to USD50 billion by 2020.27 Whilst levels of probiotic supplementation in rheumatology populations are unknown, research has provided evidence that up to a third of the community does use probiotics with little concern about side effects and without informing health professionals of their use.28-29 Further, a sizable proportion of people with inflammatory arthritis are believed to use complementary and alternative medicines.30
However, potential adverse health effects from probiotic use, such as systemic infection, deleterious metabolic activities, immune dysregulation and gene transfer, have been identified.31 A recent systematic review revealed that the most common adverse effects were noted in immune-compromised patients and included sepsis, fungemia and GI ischemia.32 Furthermore, the associated dangers should not be underestimated, as demonstrated in a study where a multispecies probiotic was used enterally for individuals with acute pancreatitis.33 Mortality in the group that received the probiotics was 16%, significantly above that of the placebo group at 6%.33 Therefore, rheumatologists, general practitioners and pharmacists should be well informed and capable of discussing the evidence-based risk benefit ratio of probiotics with their patients, based on evidence for safety and benefit.34
The clinical benefits of probiotics on the microbiome have been most extensively studied in IBD. A systematic review and meta-analysis in IBD have demonstrated that probiotics can induce remission and help prevent a relapse.24 Furthermore, in animal studies, probiotics have been found to be capable of down regulating the pro-inflammatory cytokine cycle.35 The interest in harnessing probiotics proven anti-inflammatory responses for managing inflammatory arthritis is growing, with the emerging evidence highly relevant to researchers, clinicians, industry and patients. A rigorous identification, appraisal and synthesis of the current evidence is urgently needed to inform practice and enable reliable, accurate information for health consumers.
A preliminary search of the Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports, PubMed, CINAHL and PROSPERO was conducted to identify systematic reviews related to this topic. Two recent systematic reviews, which included six and nine studies, respectively, explored the benefits of probiotics for a single inflammatory classification, RA, and only in adults.36-37 The outcomes of studies were divided across a range of outcome markers including patient outcomes, clinician reported outcomes and surrogate clinical blood serum inflammatory markers. The restriction of studies to randomized controlled trials (RCTs) resulted in a limited number of included studies, which prevented subgroup analysis of the different preparations and compositions of probiotics. However, positive outcomes are more often reported for studies utilizing a mixture of probiotics, such as a mixture containing Bifidobacterium genera and Lactobacillus casei species, and for those using a synbiotic preparation. Growing evidence now supports the capacity of probiotics to enhance the immunological response at the GI interfaces through a range of methods, including promoting inhibition of inflammatory cytokines and promoting anti-inflammatory cytokine pathways, and not simply by affecting digestion through enzymatic action or competitive exclusion of pathogens.38-40 Therefore, keeping abreast of the rapidly growing literature in this field until the clinical effects are better clarified is important.
Collectively, these findings suggest that the probiotic approaches that have been proven to be successful in IBD could be more widely used in rheumatology practice for a wider range of conditions; however, the previous systematic reviews are not well placed to provide an evidence base for this change in clinical practice. This review aims to fill the gap by assessing the delivery of probiotic/synbiotic preparations using the newly elucidated mechanisms of probiotic action on the auto immune system, as previous studies used probiotic species selected for enzymatic action or based purely on their commensal nature. This review will consider a wider spectrum of disease states by including the rheumatological SpA that sit in the middle of the autoimmune spectrum, including enteropathic arthritis, and IBD-related arthralgia which affects both bowel and joints, to clarify which rheumatological conditions are most appropriate for considering probiotic use. This review aims to include studies with individuals earlier in their disease journey with a working diagnosis of inflammatory arthritis when interventions may be more effective at changing the course of the disease as opposed to only providing symptomatic relief.41 As significant time lags often exist between the onset of symptoms and diagnosis, individuals may be at a more advanced disease stage by the time they meet more stringent classification criteria and can be accepted into clinical trials. Whilst some classification criteria have shifted to capture earlier disease states, this issue remains in many probiotic intervention studies, where the participants have an established disease, i.e. disease duration of more than three years.42-49 Therefore, the previous systematic reviews may not accurately reflect the true treatment effect size of probiotics for all individuals with inflammatory arthritis by having trial populations of individuals with longstanding disease. Whilst some classification criteria have shifted to capture earlier disease states, they are also known to limit external validity and this is particularly problematic in the heterogeneous and overlapping conditions seen in rheumatology practice.41,42,50,51 There is also suggestion that a wider age range of patients with auto-immune arthritis may benefit from probiotics, as relative instability of the microbial community has been demonstrated in younger children, suggesting more opportunity for an early age intervention that promotes a healthy microbial endotype.52-53
In summary, this systematic review aims to contribute to the growing literature on the potential effectiveness and safety of probiotics as a sole or adjuvant therapeutic intervention for individuals with inflammatory arthritic disease by including a wider range of inflammatory arthritides. This will allow for the heterogeneous overlapping nature of inflammatory disease and will enable individuals with earlier disease states to be included in order to provide clearer guidance to the range of patients seen by clinicians in daily practice by increasing the transferability of findings. Furthermore, this review will be undertaken in a manner that is meaningful for clinical practice by focusing data analysis on the strain and composition of probiotics that have been used within a wider variety of quantitative study designs.
Many potential probiotic bacterial species have been described, with potentially unique anti-inflammatory and immune modulating properties.54 This review aims to match emerging science on strain specific benefits to the specific formulations in each study along with applying strict definitions of probiotics, and undertaking greater consideration of important factors such as concentration, inclusion of prebiotics and encapsulation methods. Finally, it must be recognized that to direct clinical intervention and patient counselling regarding the use of probiotics, more information on risks and harms is required. Therefore, this review will include the adverse effects of probiotics as a primary outcome.
This review will consider studies that include individuals (adult or child) of any gender living with diagnosed RA, adult spondyloarthritis (of any form) or JIA (of any form). Individuals with early, established or severe forms may be included.
Study participants should have been diagnosed for a minimum of three months. Diagnosis is being used rather than clinical classification as whilst this may lower specificity it increases external validity and matches clinical practice in early rheumatology intervention.41
This review will include studies that evaluate probiotics administered to the GI system (either orally or via enteral feed) and which utilize any concentration of probiotics, measured in colony forming units (CFU). Studies that utilize probiotics as a sole therapy or an adjuvant therapeutic intervention, in combination with standard pharmacotherapy, will be considered. Probiotic formulations may employ any strain, species or combination of species and may include probiotics administered with prebiotics (selectively fermented foods capable of supporting the activity of specific gut microbiota) thereby termed a synbiotic. Studies will be included that use products that do not require refrigeration, i.e. freeze dried products or naturally shelf stable spore-forming bacteria, as whilst the spores are dormant, there is evidence to suggest that these spores can germinate within the GI system and may exhibit benefits.55
This review will exclude studies that utilize formulations that supply probiotics within functional foods or supply probiotics through fecal matter transplants (FMT), as they include many microbial species in unknown and unstandardized quantities.18
Studies that compare probiotics to inactive control, alternative probiotic formulations or standard care alone will be considered.
This review will consider studies that include any outcomes specified in the core set of appropriate measures by the international consortium known as OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials).56
Outcomes will include: single measure patient reported outcomes, for example, Patient Global Assessment (PtGA); composite measures of patient reported outcomes, for example, the short Health Assessment Questionnaire (HAQ) which is based on three patient centered dimensions (pain, PtGA and disability); and composite indices that include outcomes from patient, provider and a laboratory based score of inflammatory markers, for example, the Clinical Disease Activity Index comprising the PtGA, Provider Global Assessment and a tender/swollen joint score.
Composite indices that include surrogate lab markers for inflammation are currently included as a core part of all major guidelines and are accepted quality indicators for effective management. However, it is recognized that they may be affected by the weighting of specific elements and this will be considered in the results analysis by looking at the individual elements of the composite indices separately (where possible).
Safety and patient reported adverse effects will also be considered including mild adverse events related to tolerability of the intervention, such as gastrointestinal upset or flatulence, and serious adverse events, such as sepsis, interaction with concurrent standard care/medication or mortality.
Types of studies
The review will consider both experimental and epidemiological study designs including randomized controlled trials (RCTs), non-RCTs, quasi-experimental studies, prospective and retrospective cohort studies, case-control studies and analytical cross sectional studies for inclusion. The review will also consider descriptive epidemiological study designs including case series, individual case reports and descriptive cross sectional studies for inclusion.
The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe articles. A second search using all identified keywords and index terms will then be undertaken across all included databases (see below for list of databases and Appendix I for an example search strategy). Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Given that recent research has demonstrated no bias when non- English language restrictions are applied in systematic reviews and considering resources available for this work, only studies published in English will be considered for inclusion in this review.57 Studies published from 2000 onwards will be considered for inclusion in this review as consistent international definitions for probiotics were defined in 2000.18
The databases to be searched will include: PubMed, CINAHL, Embase and Scopus.
The trial registers to be searched will include: Cochrane Central Register of Controlled Trials (CENTRAL), World Health Organization Clinical Trials Portal (ICTRP), United States National Library of Medicine, ClinicalTrials.gov and Australian New Zealand Clinical Trials Register (ANZCTR).
The search for unpublished studies will include: ProQuest Dissertations and Theses (PQDT), HSRProj (Health Services Research Projects in Progress), MedNar, Trove, Bielefeld Academic Search Engine (BASE) and Primary Healthcare Research and Innovation (PHCRIS).
Assessment of methodological quality
Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute.58 Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Given the limited quantity of expected literature in this field, studies will not be excluded on the results of critical appraisal, however study quality will be considered when analyzing and interpreting results.59
Quantitative data will be extracted from papers included in the review using the standardized JBI data extraction tool which includes information that could impact upon the generalisability of the results (e.g. the study settings).58 The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Pilot data extraction will be checked by a second reviewer; however, full data extraction will be conducted by a single reviewer due to resource constraints. The authors of included studies will be contacted if necessary to request any relevant data that may not be available in the published articles.
Quantitative data will, where possible, be pooled in statistical meta-analysis. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and results explored using subgroup analyses where possible. For example, subgroup analysis may be undertaken on data from studies that reach/exceed the gold standard CFU for the probiotic formulation compared to those that do not. Where possible, subgroup analysis based on data for specific strains and combinations of probiotics will be employed, as this has been proven useful to indicate risks of bacterial translocation and adverse effects.33 Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.
This work is being undertaken as part of the Master of Clinical Science for JL.
Appendix I: Proposed PubMed search strategy
(Arthritis[mh] OR Arthritis[tw] OR JIA[tw] OR Enthesitis[tw] OR Polyarthritis[tw] OR Rheumatoid[tw] OR Psoriatic[tw] OR Rheumatoid Arthritis[mh] OR Rheumatoid arthritis[tw] OR Rheumatic disease[tw] OR Rheumatism[tw] OR Spondyloarthritis[mh] OR Spondyloarthropathies[mh] OR Enteropathic arthritis [tw] OR Arthralgia[tw] OR Spondyloarthr*[tw] OR Ankylosing Spondylitis[mh] OR Ankylosing Spondylitis[tw]) AND (Probiotics[mh] OR Probiotic*[tw] OR Synbiotics[mh] OR Synbiotic*[tw] OR Microbiota[mh:noexp] OR Microbiota[tw] OR Gastrointestinal microbiome[mh] OR Gastrointestinal microbiome[tw] OR Microbiome[tw] OR Gut microbiome[tw] OR Dysbiosis[mh] OR Dysbiosis[tw] OR Gut Flora[tw] OR Gut microflora[tw] OR Gastrointestinal flora[tw] OR Gastrointestinal microflora[tw] OR Lactobacillus[mh] OR Lactobacill*[tw] OR Bifidobacterium[mh] OR Bifidobacter*[tw] OR Saccharomyces[mh] OR Saccharomyces[tw] OR Escherichia[mh] OR Escherichia[tw] OR Bacillus[tw] OR Bacillus[mh] OR Dietary supplement[mh] OR Dietary supplement*[tw] OR Food supplement*[tw] OR Diet therap*[tw] OR Nutrition therapy[mh] OR Nutrition therap*[tw] OR Nutritional therap* OR Nutraceutical*[tw] OR Nutriceutical*[tw] OR Neutraceutical*[tw])
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