Infections (General)

Recent scientific forays into the human microbiome have found a remarkably close association to imbalances in gut microbiota, the lack or overabundance of particular microbes, and rheumatoid arthritis (RA). In the following selection of contemporary research, breaches in the mucosal barrier of the gut (also known as “leaky gut”), as well as slow-infection translocation to joints and soft tissues from other mucosal sites, is described, such as those originating in the mouth, lungs, and genitourinary tract. This has led to strong associations being made by researchers worldwide regarding numerous potential infectious causes for RA, their effects on autoantibody production, and the disease’s progressive course.

A study of pre-operative presence of micro-organisms in affected knee joints of rheumatoid arthritis patients who need total knee arthroplasty. Knee. 2017 Mar;24(2):409-418.

Study authors state that infections in the knee joints of rheumatoid arthritis patients who need joint replacement are a common finding (24.5%). They recommend that intraoperative synovial tissue specimens be collected for microbial culturing and diagnostic testing to prevent post-operative prosthetic replacement infection and to initiate appropriate antimicrobial treatment.

Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp Biol Med (Maywood). 2017 Feb;242(4):355-373. doi: 10.1177/1535370216681549. Epub 2016 Nov 26.

A strong hypothesis, founded in “coherence theory,” a systems biology approach in which seemingly unrelated factors are brought together to form a consistent picture of the etiology of rheumatoid arthritis (RA), is presented.  Research partners in the UK and South Africa make the case for recurring bacterial infection as a major cause of RA. Microbial dormancy, reactivation of these dormant persisters, iron dysregulation, inflammation and blood coagulation (fibrin), are important contributing co-factors. These authors conclude by stating that this theory can be empirically tested, both diagnostically and with successful treatment, using common DMARDs that are known to have antimicrobial effects, including minocycline and doxycycline, anti-inflammatories and chelation. For prognosis assessment and in the treatment of RA, normalizing gut microbiota is also suggested.

An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016 Apr 21;8(1):43. doi: 10.1186/s13073-016-0299-7.

Study authors attempt to define the microbial and metabolite profile of rheumatoid arthritis (RA) from human fecal samples, both to determine the role of gut microbiota imbalances and to identify an RA-associated microbe. Findings suggest a lack of gut microbial diversity with an abundance of certain rare lineage microbes, such as Collinsella, believed to alter gut permeability and increase proinflammatory cytokines (IL-17a), which may influence disease severity. Authors state that their findings suggest a correlation between intestinal microbiota and metabolic signatures that may help to create a predictive profile for RA causation and progression.

Altered composition of gut microbiota in rheumatoid arthritis patients. Nihon Rinsho Meneki Gakkai Kaishi. 2016;39(1):59-63. doi: 10.2177/jsci.39.59.

Mouse and human models have demonstrated a strong association with the development of rheumatoid arthritis (RA) and gut dysbiosis. These Japanese researchers state that it is becoming more evident that gut microbiota is one of the critical environmental factors (in addition to genetics) that influence the development and progression of RA. Authors conclude that a focus on modifying microbial balance and diversity in the guts of RA patients may form the basis for novel therapeutics and preventive strategies.

Molecular Insight into Gut Microbiota and Rheumatoid Arthritis. Int J Mol Sci. 2016 Mar 22;17(3):431. doi: 10.3390/ijms17030431.

Chinese researchers call for better understanding of the complex interplay of gut microbial imbalances (specifically gut, dental, and saliva microbiota), genetic factors, and the development and progression of rheumatoid arthritis (RA). They describe how clinical indices, such as the titers of immunoglobulin, autoantibodies, anticyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF), appear to be relative to such gut imbalances. They also state that while disease-modifying anti-rheumatic drugs (DMARDs) may partially reduce gut dysbiosis, RA patients were also predisposed to symbiotic microbial gut overgrowths of opportunistic bacteria, leading to co-morbidities. As increased understanding is achieved of the human gut microbiome, these authors point to a progressive ability to create novel, individualized, and more effective therapies for RA patients.

Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. Int J Rheum Dis. 2016 Jan;19(1):8-20.

Researchers in India propose a comprehensive whole body mechanistic approach to the pathogenesis of rheumatoid arthritis (RA), which they assert is the result of a combination of host genetics, dietary factors, environmental cues, infections that originate in the lungs, mouth, gut and genitourinary tract, as well as direct microbial DNA evidence for infection translocation to the joints. The authors detail the antimicrobial effects of commonly used disease-modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine and hydroxychloroquinine, as well as tetracycline antibiotics, macrolides, levofloxacin, dapsone, ceftriaxone and metronidazole, acknowledging their antimicrobial, immune-modulatory effects. A prevention and treatment approach is outlined, employing antimicrobials in addition to dietary modifications, probiotics, and DMARDs to modulate RA pathogenesis, along with the acknowledgement that gaps in understanding RA continue to be challenging.

The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015 Aug;21(8):895-905. doi: 10.1038/nm.3914. Epub 2015 Jul 27.

In a controlled study of rheumatoid arthritis (RA) patients, Chinese researchers conducted gene-sequencing studies of fecal, dental, and salivary samples taken from these patients and compared them with control subjects. With these detection methods, they established that there were specific alterations in the gut and oral microbiomes of RA patients, some microbes being over- or under-represented, which in turn affected the transport and metabolism of iron, sulfur, zinc, and arginine. The authors recognize the potential for using microbiome composition for the prognosis and diagnosis of RA.

Germs and joints: the contribution of the human microbiome to rheumatoid arthritis. Nat Med. 2015 Aug;21(8):839-41.

Study revealing the gut and oral microbiome dysbiosis in rheumatoid arthritis (RA) and why this finding provides clues to the variations in disease onset and progression.

Periodontal disease and subgingival microbiota as contributors for rheumatoid arthritis pathogenesis: modifiable risk factors? Curr Opin Rheumatol. 2014 Jul;26(4):424-9.

New York University researchers describe the role of periodontal disease (including the alterations in oral microbiota of smokers) in rheumatoid arthritis (RA) and the intense focus of research due to pathogenic commonalities shared by these two disease processes since the early 1900s. Recent studies have further strengthened this association, including findings such as circulating antibodies against periodontopathic bacteria and the associated inflammatory response that is common to both gum disease and RA.

Arthritis susceptibility and the gut microbiome. FEBS Lett. 2014 Nov 17;588(22):4244-9. doi: 10.1016/j.febslet.2014.05.034. Epub 2014 May 27.

There is a growing realization that intestinal bacteria may place a significant role in the adaptive immune response in a complex interplay of genetic and environmental factors. Study authors discuss how genomic sequencing can help to demystify leaky gut syndromes that lead to autoimmune diseases like rheumatoid arthritis (RA) and reveal how gut microbiota influence host immune function and homeostasis. By identifying gut microbial imbalances, the authors speculate how these imbalances can be rectified by profiling genetic markers in at-risk individuals and then using various means to modify gut microbial composition.

Oral status in patients with early rheumatoid arthritis: a prospective, case-control study. Rheumatology (Oxford). 2014 Mar;53(3):526-31.

German dental researchers find a strong association between early rheumatoid arthritis (RA) patients and periodontal disease, resulting in an increased loss of periodontal attachment and alveolar bone structure.

RBF Commentary: Periodontal infections have long been suspected as being a causative agent in RA pathogenesis. For more information on this infectious correlation, please refer to related research here.

Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol. 2014 Jan;26(1):101-7.

A review of emerging novel data implicating mucosal tissue sites, such as in the lung, gut and gingiva – tissues that are continuously assaulted with high bacterial antigen loads due to host-environment interfacing. Authors state that the presence of such bacteria, present in mucosal surfaces, is known to be sufficient to alter local and systemic host immune responses to elicit joint inflammation. Authors conclude that if the mucosal barriers of these sites are proved to represent initial sites of infection that lead to the autoimmune process, this may lead to the identification of helpful biomarkers and therapeutic strategies in both those with RA and at-risk individuals.

Bugs & us: the role of the gut in autoimmunity. Indian J Med Res. 2013 Nov;138(5):732-43.

Researchers have demonstrated in the murine model of transgenic mice with collagen-induced arthritis that susceptibilities to autoimmune arthritis are associated with imbalanced gut microbiota, underscoring the impact of microbes in the gut and the role they play on the pathogenesis of rheumatoid arthritis (RA). The authors assert that modulation of commensal bacteria in the gut and probiotics may be an effective focus for RA therapy.

Polish researchers describe the hypothetical role of bacteria in rheumatoid arthritis and suggest molecular mimicry between bacterial and human antigens as one of possible mechanisms of RA development.

Antibodies against cyclic citrullinated peptides in infectious diseases–a systematic review. Clin Rheumatol. 2010 Dec;29(12):1345-51.

In an systematic review of 25 studies published in MEDLINE (1966-2010) pertaining to the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies, a diagnostic and prognostic marker for rheumatoid arthritis (RA) and specific co-existent infections, study authors found a significant correlation. Anti-CCP antibodies were found in various frequencies, reaching 37% in tuberculosis. Review authors discuss the need for more studies to aid in accurate diagnostics to distinguish between infectious processes that can present with joint symptoms and RA. Reviewers also raise the question of the degree of accuracy of the anti-CCP test in populations where the risk of infections is high.

RBF Commentary: Notable that infections known to elicit anti-CCP responses, such as Porphyromonas gingivalis and Proteus mirabilis, were absent from this review.

[The role of superantigens in infectious diseases]. Rev Med Chil. 1998 Jul;126(7):846-54.

Superantigens, foreign proteins (exogenous antigens, mainly bacterial toxins) that generate a disproportionate and non-specific host immune response by binding to large numbers of T-lymphocytes, are described in this Spanish study as being involved in diseases such as rheumatoid arthritis, Streptococcus pyogenes, and others.

Is Rheumatoid Arthritis Caused by an Infection? Lancet, 1995; May 27, 345, 1319-1320.

No free access abstract available, but the study may be purchased from The Lancet or accessed with a subscription to the journal.

Rheumatoid arthritis: how well do the theories fit the evidence? Clin Exp Immunol. 1993 Apr; 92(1): 1–6.

British researchers review circumstantial evidence for the etiopathogenesis of rheumatoid arthritis (RA) and remark on, “… the striking parallels between slow bacterial infections and RA, in terms of immunogenetics, pathology, IgG glycosylation abnormalities and autoimmune manifestations.”

Do infectious agents cause rheumatoid arthritis? Clin Orthop Relat Res. 1991 Apr;(265):36-41.

Researchers at the Arthritis and Rheumatism Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, in Bethesda, MD, state that an increasing body of data is emerging to implicate bacteria or their products in rheumatoid arthritis (RA). To exemplify this, Lyme disease is described as mimicking RA, as well as other infections being conclusively linked to many forms of inflammatory reactive arthropies, and RA-like disease has been induced animal models using bacterial cell-wall fragments, such as streptococcus and other bacterial peptidoglycans that are measurable in host responses to bacterial proteins, including rheumatoid factors. The authors state, “These data not only support the hypothesis that bacteria may play an important role in RA but also indicate that current concepts of infection and autoimmune disease are broadening and overlapping.”



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