Rheumatoid Arthritis Abstracts 4

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Antimycoplasma Approach to the Mechanism and the Control of Rheumatoid Disease
            (Brown et al., 1982) Download
An infectious etiology of rheumatoid arthritis has been suspected for many years; however, there is little agreement as to the involved microorganisms. It is generally believed by many investigators that the initiating agent is probably a viral-like agent or mycoplasma. The parasitic nature of some mycoplasmas makes them logical suspects to cause a systemic chronic disease and yet remain undetected. While there is an accumulation of evidence to indicate mycoplasma involvement in the disease process, the failure to isolate a common microbial agent appears to be the greatest deterrent to establishing an antecedent.

An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis.
            (Chen et al., 2016) Download
BACKGROUND:  The adaptive immune response in rheumatoid arthritis (RA) is influenced by an interaction between host genetics and environment, particularly the host microbiome. Association of the gut microbiota with various diseases has been reported, though the specific components of the microbiota that affect the host response leading to disease remain unknown. However, there is limited information on the role of gut microbiota in RA. In this study we aimed to define a microbial and metabolite profile that could predict disease status. In addition, we aimed to generate a humanized model of arthritis to confirm the RA-associated microbe. METHODS:  To identify an RA biomarker profile, the 16S ribosomal DNA of fecal samples from RA patients, first-degree relatives (to rule out environment/background as confounding factors), and random healthy non-RA controls were sequenced. Analysis of metabolites and their association with specific taxa was performed to investigate a potential mechanistic link. The role of an RA-associated microbe was confirmed using a human epithelial cell line and a humanized mouse model of arthritis. RESULTS:  Patients with RA exhibited decreased gut microbial diversity compared with controls, which correlated with disease duration and autoantibody levels. A taxon-level analysis suggested an expansion of rare taxa, Actinobacteria, with a decrease in abundant taxa in patients with RA compared with controls. Prediction models based on the random forests algorithm suggested that three genera, Collinsella, Eggerthella, and Faecalibacterium, segregated with RA. The abundance of Collinsella correlated strongly with high levels of alpha-aminoadipic acid and asparagine as well as production of the proinflammatory cytokine IL-17A. A role for Collinsella in altering gut permeability and disease severity was confirmed in experimental arthritis. CONCLUSIONS:  These observations suggest dysbiosis in RA patients resulting from the abundance of certain rare bacterial lineages. A correlation between the intestinal microbiota and metabolic signatures could determine a predictive profile for disease causation and progression.

The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases.
            (Ciccia et al., 2016) Download
Dysregulation of the intestinal epithelial barrier in genetically susceptible individuals may lead to both intestinal and extraintestinal autoimmune disorders. There is emerging literature on the role of microbiota changes in the pathogenesis of systemic rheumatic diseases such as rheumatoid arthritis, spondyloarthropathies, and connective tissue diseases. Although the role of the gastrointestinal tract in the pathogenesis of spondyloartropathies is well defined and many studies underline the importance of gastrointestinal inflammation in modulating local and systemic inflammation, the data are inconclusive regarding the effect of dysbiosis on rheumatoid arthritis and connective tissue diseases. This review aims to summarize current data on the role of the gastrointestinal involvement and intestinal microbiota in the pathogenesis of systemic rheumatic disease.

Letter: Another look at Mycoplasma.
            (Clark and Brown, 1976) Download
The recent article by the mycoplasmatologists and rheumatologists Cole, Taylor, and Ward (ARTHRITIS RHEUM 18:435-441, 1975) could be misleading to less experienced investigators. In ruling out likely etiologic strains, the authors apparently did not evaluate the three more prevalent human strains of mycoplasma antigens-M salivarium, M orale. and Ureoplasma (T mycoplasma) - in their search for humoral and cell-bound mycoplasma antibodies in RA. Since our first report in 1964 on the incidence of mycoplasma C F antibodies in arthritis patients ( l ) , we have followed mycoplasma an- tibody levels in several thousand patients and still find M salivarium and M orale (pharyngis) to be the more prevalent antibody strains. The highest incidence (60-80%) of humoral mycoplasma antibodies has been found in female patients attending pulmonary, OB- GYN, or VD clinics.


 

Increased incidence and impact of upper and lower gastrointestinal events in patients with rheumatoid arthritis in Olmsted County, Minnesota: a longitudinal population-based study.
            (Myasoedova et al., 2012) Download
OBJECTIVE:  To assess the incidence and mortality impact of upper and lower gastrointestinal (GI) events in rheumatoid arthritis (RA) compared to non-RA subjects. METHODS:  We identified incident upper and lower GI events and estimated their incidence rates using person-year methods in a population-based incident RA cohort of residents of Olmsted County, Minnesota, USA (1987 American College of Rheumatology criteria first fulfilled between January 1, 1980, and January 1, 2008) and non-RA subjects from the same population. RESULTS:  The study included 813 patients with RA and 813 non-RA subjects (mean followup 10.3 and 10.8 yrs, respectively); 68% women; mean age 55.9 yrs in both cohorts. The rate of upper GI events/100 person-years was 2.9 in RA versus 1.7 in the non-RA cohort (rate ratio 1.7, 95% CI 1.4, 2.2); for lower GI events, the rates were 2.1 in RA versus 1.4 in the non-RA cohort (rate ratio 1.5, 95% CI 1.1, 1.9). The incidence of upper GI bleed, perforation, ulcer, obstruction, and any upper GI event in RA declined over calendar time; the incidence of lower GI events remained unchanged. Exposure to glucocorticoids, prior upper GI disease, abdominal surgery, and smoking were associated with lower GI events in RA. Both upper and lower GI events were associated with increased mortality risk in RA. CONCLUSION:  There is increased risk of serious upper and lower GI events in RA compared to non-RA subjects, and increased GI-related mortality in RA. Prominent declines in incidence of upper, but not lower GI events in RA highlight the need for studies investigating lower GI disease in patients with RA.

Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis.
            (Sandhya et al., 2016) Download
The human body is an environmental niche which is home to diverse co-habiting microbes collectively referred as the human microbiome. Recent years have seen the in-depth characterization of the human microbiome and associations with diseases. Linking of the composition or number of the human microbiota with diseases and traits date back to the original work of Elie Metchnikoff. Recent advances in genomic technologies have opened up finer details and dynamics of this new science with higher precision. Microbe-rheumatoid arthritis connection, largely related to the gut and oral microbiomes, has showed up as a result - apart from several other earlier, well-studied candidate autoimmune diseases. Although evidence favouring roles of specific microbial species, including Porphyromonas, Prevotella and Leptotricha, has become clearer, mechanistic insights still continue to be enigmatic. Manipulating the microbes by traditional dietary modifications, probiotics, and antibiotics and by currently employed disease-modifying agents seems to modulate the disease process and its progression. In the present review, we appraise the existing information as well as the gaps in knowledge in this challenging field. We also discuss the future directions for potential clinical applications, including prevention and management of rheumatoid arthritis using microbial modifications.

Inflammatory Diseases and Copper: The Metabolic and Therapeutic Roles of Copper and Other Essential Metalloelements in Humans
            (Sorenson, 1982) Download
In 1928, it was discovered that copper was essential for normal human metabolism. A decade later, in 1938, it was observed that patients with rheumatoid arthritis exhibited a higher than normal serum copper concentration that returned to normal with remission of this disease. Thirteen years later, it was found that copper complexes were effective in treating arthritic diseases.

Arthritis susceptibility and the gut microbiome.
            (Taneja, 2014) Download
Rheumatoid arthritis (RA) is an autoimmune disease with unknown etiology though both genetic and environmental factors have been suggested to be involved in its pathogenesis. While infections and other environmental factors (e.g. smoking) have been studied extensively and show some association, a direct link between all the factors has been difficult to prove. With the recent advances in technology, it has become possible to sequence the commensals that are residing in our gut. The gut microbiome may provide the missing link to this puzzle and help solve the mystery of many leaky gut syndromes. The gut commensals are involved in maintaining host immune homeostasis and function suggesting that they might be critical in altering the immune system, which leads to autoimmune diseases like RA. Mouse models support the role of the gut microbiota in predisposition to RA. If that is true, the power of gut-derived commensal can be harnessed to our benefit by generating a biomarker profile along with genetic factors to define individuals at risk and by altering the gut microbial composition using various means.


 

Drugs or disease: evaluating salivary function in RA patients.
            (Torres et al., 2016) Download
Oral complications of RA may include temporomandibular joint disorders, mucosa alterations and symptoms of dry mouth. The aim of this study was to evaluate the salivary gland function of subjects with rheumatoid arthritis (RA) comparing it to healthy controls. Subjects with other systemic conditions known to affect salivary functions were excluded. A questionnaire was applied for the evaluation of xerostomia. Resting and chewing-stimulated salivary flow rates (SFR) were obtained under standard conditions. There were 145 subjects included of the study (104 RA and 38 controls). About 66.7% of the RA subjects and 2.4% in control group presented xerostomia. The median resting SFR were 0.24 ml/min for RA subjects and 0.40 mL/min for controls (p = 0.04). The median stimulated SFR were 1.31 mL/min for RA subjects and 1.52 ml/min for controls (p = 0.33). No significant differences were found between resting and stimulated SFR of RA subjects not using xerogenic medications and controls. There was significantly higher number of subjects presenting hyposalivation in the RA group than among controls, even when subjects using xerogenic medications were eliminated from the analysis. In conclusion, hyposalivation and xerostomia were more frequent among RA subjects not using xerogenic medication than among controls, although there were no significant differences in the median SFR between groups.

Possible role of Mycoplasma fermentans in pathogenesis of rheumatoid arthritis.
            (Williams et al., 1970) Download
Mycoplasma fermentans membranes inhibited leucocyte migration in twenty- nine (67%) out of forty-three patients with rheumatoid arthritis. No inhibition was observed with leucocytes from osteoarthritic patients or healthy controls. M. fermentans is often present in affected joints in rheumatoid arthritis, and it is postulated that the chronic course of the inflammatory process is due to a hypersensitivity response to the organism. Immunoglobulin present in the surrounding fluid is bound firmly to the mycoplasma membrane and could be the stimulus for production of rheumatoid factors. If rheumatoid arthritis is due to an infectious process new chemotherapeutic approaches should be possible.

Molecular Insight into Gut Microbiota and Rheumatoid Arthritis.
            (Wu et al., 2016) Download
Rheumatoid arthritis (RA) is a systemic, inflammatory, and autoimmune disorder. Gut microbiota play an important role in the etiology of RA. With the considerable progress made in next-generation sequencing techniques, the identified gut microbiota difference between RA patients and healthy individuals provides an updated overview of the association between gut microbiota and RA. We reviewed the reported correlation and underlying molecular mechanisms among gut microbiota, the immune system, and RA. It has become known that gut microbiota contribute to the pathogenesis of RA via multiple molecular mechanisms. The progressive understanding of the dynamic interaction between gut microbiota and their host will help in establishing a highly individualized management for each RA patient, and achieve a better efficacy in clinical practice, or even discovering new drugs for RA.

The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment.
            (Zhang et al., 2015) Download
We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.

 


References

Brown, T., et al. (1982), ‘Antimycoplasma Approach to the Mechanism and the Control of Rheumatoid Disease’, in Sorenson, John R. J. (ed.), Inflammatory Diseases and Copper (Totowa, NJ: Humana Press), 391-407.
Chen, J, et al. (2016), ‘An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis.’, Genome Med, 8 (1), 43. PubMed: 27102666
Ciccia, F, et al. (2016), ‘The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases.’, Best Pract Res Clin Rheumatol, 30 (5), 889-900. PubMed: 27964794
Clark, HW and TM Brown (1976), ‘Letter: Another look at Mycoplasma.’, Arthritis Rheum, 19 (3), 649-50. PubMed: 938597
Myasoedova, E, et al. (2012), ‘Increased incidence and impact of upper and lower gastrointestinal events in patients with rheumatoid arthritis in Olmsted County, Minnesota: a longitudinal population-based study.’, J Rheumatol, 39 (7), 1355-62. PubMed: 22467929
Sandhya, P, et al. (2016), ‘Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis.’, Int J Rheum Dis, 19 (1), 8-20. PubMed: 26385261
Sorenson, J (1982), Inflammatory Diseases and Copper: The Metabolic and Therapeutic Roles of Copper and Other Essential Metalloelements in Humans, ed. Sorenson, J, (Experimental Biology and Medicine, 2; Springer Science & Business Media).
Taneja, V (2014), ‘Arthritis susceptibility and the gut microbiome.’, FEBS Lett, 588 (22), 4244-49. PubMed: 24873878
Torres, SR, et al. (2016), ‘Drugs or disease: evaluating salivary function in RA patients.’, Braz Oral Res, 30 (1), e106. PubMed: 27737360
Williams, MH, J Brostoff, and IM Roitt (1970), ‘Possible role of Mycoplasma fermentans in pathogenesis of rheumatoid arthritis.’, Lancet, 2 (7667), 277-80. PubMed: 4194360
Wu, X, et al. (2016), ‘Molecular Insight into Gut Microbiota and Rheumatoid Arthritis.’, Int J Mol Sci, 17 (3), 431. PubMed: 27011180
Zhang, X, et al. (2015), ‘The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment.’, Nat Med, 21 (8), 895-905. PubMed: 26214836