Dr. Ron’s Research Review – April 2, 2014

© 2014

This week’s research review focuses on RA and infections.

Several recent studies show that rheumatoid arthritis may be caused by infections:

Patients with new-onset RA exhibited a high prevalence of periodontal disease. (Scher, Ubeda et al. 2012)

Intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. (Scher, Sczesnak et al. 2013)

Rheumatoid arthritis is caused by a Proteus urinary tract infection. (Ebringer and Rashid 2013)

Wyburn-Mason proposed that naeglerial amoebae causes rheumatoid disease and many human cancers. (Wyburn-Mason 1979)

Antibiotic treatment for rheumatoid arthritis (RA) commenced in the 1930s with the use of sulfasalazine. Later, tetracyclines were successful. In double-blind and randomized studies, levofloxacin and macrolide antibiotics (including clarithromycin and roxithromycin) were also shown to be effective in the treatment of RA. (Ogrendik 2013) (Ogrendik 2009)

Clotrimazole was effective, but associated with significant side effects.(Wojtulewski, Gow et al. 1980)

One study found a high frequency of small intestinal bacterial overgrowth (SIBO) in patients with RA; it was associated with a high disease activity and observed in patients with hypochlorhydria or achlorhydria and in those with normal acid secretion. (Henriksson, Blomquist et al. 1993)

Dr. Ron


Articles

Rheumatoid arthritis is caused by a Proteus urinary tract infection

         (Ebringer and Rashid 2013) Download

Genetic, molecular and biological studies indicate that rheumatoid arthritis (RA), a severe arthritic disorder affecting approximately 1% of the population in developed countries, is caused by an upper urinary tract infection by the microbe, Proteus mirabilis. Elevated levels of specific antibodies against Proteus bacteria have been reported from 16 different countries. The pathogenetic mechanism involves six stages triggered by cross-reactive autoantibodies evoked by Proteus infection. The causative amino acid sequences of Proteus namely, ESRRAL and IRRET, contain arginine doublets which can be acted upon by peptidyl arginine deiminase thereby explaining the early appearance of anti-citrullinated protein antibodies in patients with RA. Consequently, RA patients should be treated early with anti-Proteus antibiotics as well as biological agents to avoid irreversible joint damages.

Small intestinal bacterial overgrowth in patients with rheumatoid arthritis

         (Henriksson, Blomquist et al. 1993) Download

OBJECTIVES: To examine the microflora of the upper small intestine in patients with seropositive rheumatoid arthritis (RA) using a combination of microbial cultivation and tests for microbial metabolic activity. METHODS: Twenty five patients with seropositive RA, 12 achlorhydric control subjects, and 11 control subjects with normal gastric acid secretion were investigated. Disease activity was evaluated in the patients with RA by three different indices. Eight (32%) of the patients with RA had hypochlorhydria or achlorhydria. The acid secretory capacity was determined with pentagastrin stimulation. A modified Crosby capsule was used to obtain biopsy specimens and samples of intestinal fluid from the proximal jejunum; aerobic and anaerobic microbial cultivation of mucosal specimens/intestinal fluid was carried out, and gas production and microflora associated characteristics in jejunal fluid were determined. Additionally, a bile acid deconjugation breath test was performed. RESULTS: Subjects with at least one of the following findings were considered to have bacterial overgrowth: positive bile acid deconjugation test; growth of Enterobacteriaceae; positive gas production; or low tryptic activity. By these criteria half of the patients with RA with hypochlorhydria or achlorhydria and half of the achlorhydric controls had bacterial overgrowth. Thirty five per cent of the patients with RA with normal gastric acid secretion had bacterial overgrowth compared with none of the normal controls. Disease activity indices and rheumatoid factor titres were significantly higher in patients with RA with bacterial overgrowth than in those without. CONCLUSIONS: A high frequency of small intestinal bacterial overgrowth was found in patients with RA; it was associated with a high disease activity and observed in patients with hypochlorhydria or achlorhydria and in those with normal acid secretion.

Efficacy of roxithromycin in adult patients with rheumatoid arthritis who had not received disease-modifying antirheumatic drugs: a 3-month, randomized, double-blind, placebo-controlled trial

         (Ogrendik 2009) Download

BACKGROUND: It has been reported that antibodies to oral anaerobic bacteria are elevated in the serum and synovial fluids of patients with rheumatoid arthritis. Macrolide antibiotics are active against oral anaerobic bacteria. OBJECTIVE: The aim of this work was to evaluate the clinical efficacy of roxithromycin in patients with early seropositive rheumatoid arthritis. METHODS: This was a double-blind trial. We enrolled adult patients with early rheumatoid arthritis who had not previously received disease-modifying antirheumatic drugs and randomized them to receive either once-daily oral roxithromycin 300 mg or once-daily oral placebo for 3 months. The primary efficacy variable was the percentage of patients who had a 20% improvement according to the American College of Rheumatology (ACR) criteria (an ACR 20 response) at 3 months. Secondary outcome measures were 50% improvement and 70% improvement according to ACR criteria (an ACR 50 response and an ACR 70 response, respectively). The 28-joint disease activity score (DAS28) was also calculated. Clinical remission was defined as DAS28 score <2.6, and a low level of disease activity was defined as DAS28 score <3.2 but > or =2.6. Adverse event data (eg, example, type, severity, time of occurrence, time to resolution) were obtained from physical examinations and patient self-reporting. RESULTS: The roxithromycin group had 16 patients (mean [SD] age, 45 [4] years; 11 women, 5 men; all white). The placebo group had 15 patients (mean [SD] age, 42 [5] years; 10 women, 5 men; all white). A significantly greater percentage of patients treated with 300 mg of roxithromycin experienced an ACR 20 re- sponse at 3 months, compared with those who received placebo (75% [n = 12] vs 20% [n = 3]; P = 0.002). Greater percentages of patients treated with 300 mg of roxithromycin also achieved ACR 50 responses (56% [n = 9] vs 7% [n = 1]; P = 0.003) and ACR 70 responses (44% [n = 7] vs 0%; P = 0.004) compared with patients who received placebo. At month 3, DAS28 response rates were significantly greater with once-daily roxithromycin 300 mg than with once-daily placebo (P < 0.001). Adverse events were reported for 11 patients (69%) in the roxithromycin group and 7 patients (47%) in the placebo group. The most common adverse events (>5%) were nausea, abdominal pain, headache, and dry mouth. There were no dose-limiting toxic effects. One participant in the roxithromycin group withdrew from the study because of severe emesis; two withdrew from the placebo group because of lack of efficacy. CONCLUSIONS: In these adult patients with rheumatoid arthritis, 3-month treatment with roxithromycin significantly improved the signs and symptoms of rheumatoid arthritis and was generally well tolerated. Future studies should investigate the relationship between disease activity and serum or joint antibodies to anaerobic bacteria.

Antibiotics for the treatment of rheumatoid arthritis

         (Ogrendik 2013) Download

Antibiotic treatment for rheumatoid arthritis (RA) commenced in the 1930s with the use of sulfasalazine. Later, tetracyclines were successfully used for the treatment of RA. In double-blind and randomized studies, levofloxacin and macrolide antibiotics (including clarithromycin and roxithromycin) were also shown to be effective in the treatment of RA. There have been several reports in the literature indicating that periodontal pathogens are a possible cause of RA. Oral bacteria are one possible cause of RA. In this review, we aimed to investigate the effects of different antibiotics in RA treatment.

Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis

(Scher, Sczesnak et al. 2013) Download

Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA. DOI: http://dx.doi.org/10.7554/eLife.01202.001.

Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis

         (Scher, Ubeda et al. 2012) Download

OBJECTIVE: To profile the abundance and diversity of subgingival oral microbiota in patients with never-treated, new-onset rheumatoid arthritis (RA). METHODS: Periodontal disease (PD) status, clinical activity, and sociodemographic factors were determined in patients with new-onset RA, patients with chronic RA, and healthy subjects. Multiplexed-454 pyrosequencing was used to compare the composition of subgingival microbiota and establish correlations between the presence/abundance of bacteria and disease phenotypes. Anti-Porphyromonas gingivalis antibody testing was performed to assess prior exposure to the bacterial pathogen P gingivalis. RESULTS: The more advanced forms of periodontitis were already present at disease onset in patients with new-onset RA. The subgingival microbiota observed in patients with new-onset RA was distinct from that found in healthy controls. In most cases, however, these microbial differences could be attributed to the severity of PD and were not inherent to RA. The presence and abundance of P gingivalis were also directly associated with the severity of PD and were not unique to RA. The presence of P gingivalis was not correlated with anti-citrullinated protein antibody (ACPA) titers. Overall exposure to P gingivalis was similar between patients with new-onset RA and controls, observed in 78% of patients and 83% of controls. The presence and abundance of Anaeroglobus geminatus correlated with the presence of ACPAs/rheumatoid factor. Prevotella and Leptotrichia species were the only characteristic taxa observed in patients with new-onset RA irrespective of PD status. CONCLUSION: Patients with new-onset RA exhibited a high prevalence of PD at disease onset, despite their young age and paucity of smoking history. The subgingival microbiota profile in patients with new-onset RA was similar to that in patients with chronic RA and healthy subjects whose PD was of comparable severity. Although colonization with P gingivalis correlated with the severity of PD, overall exposure to P gingivalis was similar among the groups. The role of A geminatus and Prevotella/Leptotrichia species in this process merits further study.

Clotrimazole in rheumatoid arthritis

         (Wojtulewski, Gow et al. 1980) Download

Forty-seven patients with active rheumatoid arthritis took part in an 8-week controlled study in which clotrimazole was compared with a standard nonsteroidal anti-inflammatory agent, ketoprofen. Although clotrimazole was shown to be effective in the treatment of the disease and superior to ketoprofen in certain measurements, if was also responsible for a high incidence of adverse effects. Improvement with clotrimazole took place more slowly but was more sustained than with ketoprofen. A significant rise in plasma cortisol and a fall in white cell count was observed in the clotrimazole treated patients.

The naeglerial causation of rheumatoid disease and many human cancers. A new concept in medicine

         (Wyburn-Mason 1979) Download

Man and terrestrial animals live in an environment containing free-living amoebae on the surface soil, in pools, fresh water lakes, rivers and streams. They form cysts, which float in the air and which are continually inhaled and found in the nasopharynx and their trophozoites are present in human and animal faeces. Amoebae of the genus, Naegleria, have been demonstrate; in all human tissues, both healthy and in larger numbers in those taken from cases of rheumatoid disease, in all human cancers and in the unaffected tissues of cancer patients. They can be killed in vitro by a series of different anti-amoebic substances and treatment of active cases of rheumatoid disease by any of these, either causes cessation of disease activity or a temporary exaggeration of symptoms followed by their lessening or disappearance (Herxheimer reaction), indicating the presence of an amoeba in the affected tissues as the causative organism of the inflammation in this disease in subjects genetically sensitive to the organism. Every internal organ may be involved in the inflammatory response in cases of rheumatoid disease and this also ceases with the above treatments. Many of these internal lesions are premalignant, so that infection with the organism either in sensitive subjects or with pathogenic species, appears to be the primary cause of cancer in many cases. The presence in the body of Naegleria represents the source of the constant antigenic stimulation thought to be responsible both for rheumatoid disease and for the development of lymphomata and myelomatosis.

References

Ebringer, A. and T. Rashid (2013). "Rheumatoid arthritis is caused by a Proteus urinary tract infection." APMIS. [PMID: 23992372]

Scher, J. U., A. Sczesnak, et al. (2013). "Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis." Elife 2: e01202. [PMID: 24192039]

Scher, J. U., C. Ubeda, et al. (2012). "Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis." Arthritis Rheum 64(10): 3083-94. [PMID: 22576262]

Wyburn-Mason, R. (1979). "The naeglerial causation of rheumatoid disease and many human cancers. A new concept in medicine." Med Hypotheses 5(11): 1237-49. [PMID: 537542]