Taha Rashid

Rheumatoid arthritis is an autoimmune disease triggered by Proteus urinary tract infection

Rheumatoid arthritis (RA) is a chronic and disabling polyarthritic disease, which affects mainly women in middle and old age. Extensive evidence based on the results of various microbial, immunological and molecular studies from different parts of the world, shows that a strong link exists between Proteus mirabilis microbes and RA. We propose that sub-clinical Proteus urinary tract infections are the main triggering factors and that the presence of molecular mimicry and cross-reactivity between these bacteria and RA-targeted tissue antigens assists in the perpetuation of the disease process through production of cytopathic auto-antibodies. Patients with RA especially during the early stages of the disease could benefit from Proteus anti-bacterial measures involving the use of antibiotics, vegetarian diets and high intake of water and fruit juices such as cranberry juice in addition to the currently employed treatments.

Rheumatoid arthritis: proposal for the use of anti-microbial therapy in early cases.

Rheumatoid arthritis (RA) is a chronic disease, affecting women more than men, especially in those possessing the “shared epitope” (EQK/RRAA) amino acid sequences present in HLA‐DR1/4 molecules. Proteus mirabilis carries sequences showing molecular mimicry to the “shared epitope” and to type XI collagen of hyaline cartilage. Elevated levels of antibodies to P.mirabilis have been reported from 14 different countries involving 1375 RA patients and the microbe has been isolated from urine cultures of such patients. Our working hypothesis is that the disease develops as a result of repeated episodes of Proteus upper urinary tract infections. Prospective studies involving the trial of anti‐Proteus measures in RA patients should be evaluated in the management of this disease. Antibiotics, high fluid intake, and fruit extracts, such as cranberry juice, have all been found to be effective in the treatment of urinary tract infections. Such measures could be used as possible additional adjuncts to the standard therapy with NSAIDs and DMARDs.

Rheumatoid arthritis is caused by a Proteus urinary tract infection

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.

Ankylosing Spondylitis, HLA-B27 and Klebsiella - An Overview: Proposal for Early Diagnosis and Treatment

Ankylosing spondylitis (AS) is a potentially disabling rheumatic disease for which no curative treatment has yet been discovered. An extensive computer-based and manual search was undertaken to evaluate the role of microbes in the pathogenesis of AS. All together 147 papers were scrutinised. A total of 24 studies carried out on 1330 AS patients and 1191 healthy controls involving 15 different countries showed significantly elevated Klebsiella antibodies in AS patients when compared to controls. Molecular analysis has shown that Klebsiella microbes possess antigens, which cross-react with self-antigens, such as HLA-B27 and spinal collagens. Diagnostic criteria have been developed in which a person who is HLA-B27 positive and has clinical and laboratory evidence of an inflammatory backache for at least three months is proposed to have pre-AS. A specific elevation of anti- Klebsiella antibodies would confirm the diagnosis. A proposal for an early treatment using anti-Klebsiella measures is suggested. So far, apart from Klebsiella no other microbes have been shown to have a link with the development of AS. It is suggested that identifying and treating patients with Klebsiella reactive arthritis/pre-AS could involve the use of anti- Klebsiella measures, such as antibiotics and low starch diet together with immunosuppressive drugs in an endeavour to prevent the irreversible sequelae of established AS.

Rheumatoid Arthritis is Caused by Asymptomatic Proteus Urinary Tract Infections

Urinary tract infections (UTI) are considered as one of the most common groups of infections in humans and affecting either the upper (kidneys--pyelonephritis) or the lower (bladder--cystitis) part of the urinary tract (Thomson and Armitage, 2010). The gastrointestinal tract is a reservoir from which uropathogens emerge. Reflecting this, Enterobacteriaceae are the most important cause of UTI in all population groups, accounting for more than 95% of all UTIs. Among these microbes, E. coli is by far the most common invader, causing some 90% of UTIs in outpatients and approximately 50% in hospitalized patients. Whilst, the frequency of P. mirabilis causing outpatient and inpatients UTIs were 3.2% and 12.7% respectively, these value were reversed to 26.6% and 9.3% when all strains of Proteus species were examined (Talkoff-Robin et al, 2008). In a most recent multicentre study involving nine Spanish hospitals, 784 women with uncomplicated cystitis were evaluated for the frequencies of isolated uropathogens and their susceptibility to antibiotics. Among the 650 pathogens isolated, the first group of the most frequent bacterial agents was Escherichia coli (79.2%) followed by Staphylococcus saprophyticus (4.4%), Proteus mirabilis (4.3%), Enterococcus faecalis (3.3%), and Klebsiella pneumoniae (2.3%) (Palou et al, 2011). In contrast to E. coli strains, it appears that all strains of P. mirabilis, regardless of isolate origin, are capable of infecting the urinary tract (Sosa et al, 2006). Proteus is particularly significant as a renal pathogen especially in causing upper UTI because of its propensity to promote struvite renal calculi (Ronald and Nicolle, 2007).

The potential use of antibacterial peptide antibody indices in the diagnosis of rheumatoid arthritis and ankylosing spondylitis.

Background:Both rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are potentially disabling arthritic disorders for which as yet no highly sensitive and reliable diagnostic laboratory markers are available. Objective:The objective of this study was to evaluate the levels of antibodies against Proteus and Klebsiella antigenic peptides in an endeavor to develop diagnostic indices for the identification of patients with RA and AS, respectively. Methods:Sera from 50 patients with RA, 34 patients with AS, and 38 healthy subjects were screened for antibodies against “ESRRAL” and “IRRET” synthetic amino acid peptides obtained from Proteus hemolysin and urease (HU) as well as against “QTDRED” and “DRDE” peptides from Klebsiella nitrogenase and pullulanase (NP) proteins, respectively. Multiplication of the 2 antibodies against each organism produced indices for RA-HU and AS-NP. Results:Significantly increased levels of anti-HU antibodies (P < 0.0001) were observed in patients with RA when compared with patients with AS or with healthy control subjects. Patients with AS were found to have significantly elevated levels of anti-NP (P < 0.0001) antibodies when compared with patients with RA or with healthy subjects. Furthermore, all patients with RA were found to have values of anti-HU antibody (RA-HU) index above 95% confidence limit (CL) of the mean of healthy control subjects; meanwhile, all patients with AS were having values of anti-NP antibody (AS-NP) index above the 95% CL of the mean of healthy control subjects (100% sensitivity). However, the specificity of the RA-HU index in RA and the AS-NP index in patients with AS were 92% and 95%, respectively. Conclusion:The use of the RA-HU or AS-NP diagnostic index as a sole marker or in combination with other autoantibody markers could be used in the identification of patients with RA or AS, respectively. Longitudinal investigations starting with patients with early disease will be needed.

The Link Between Klebsiella and Ankylosing Spondylitis in Worldwide Geographical Locations.

Ankylosing spondylitis (AS) is a world-wide chronic inflammatory disease of the axial skeleton most likely caused by a microbial factor in genetically susceptible individuals. Over the last 40 years extensive data has been produced which shows that the majority of patients with AS possess the HLA-B27 genetic marker. Significantly elevated levels of Klebsiella antibodies have been demonstrated in 1556 AS patients in 16 different countries with various geographical locations. Other evidence for the link between Klebsiella and AS include increased fecal isolation rates of Klebsiella microbes in AS patients together with shared molecular and immunological cross-reactivity features existing between Klebsiella antigens and HLA-B27 and collagens I, III and IV. Anti-Klebsiella measures could possibly be included with the currently used medical treatment in the management of patients with AS.

Worldwide Links between Proteus mirabilis and Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic and arthritic autoimmune disease affecting millions of people throughout the world. During the last 4 decades extensive data indicate that subclinical urinary tract infection by Proteus mirabilis has a role in the aetiopathogenesis of RA based on cross-reactivity or molecular mimicry between Proteus haemolysin and RA-associated HLA-DRB1 alleles as well as between Proteus urease and type XI collagen. Studies from 15 countries have shown that antibodies against Proteus microbes were elevated significantly in patients with active RA in comparison to healthy and non-RA disease controls. Proteus microbes could also be isolated more frequently in the urine of patients with RA than in controls. It is suggested that treatment of RA by using antibiotics and increased daily fluid intake in order to eradicate Proteus bacteria from urinary tract could be implemented in conjunction with the currently used immunosuppressant’s and biologicals.

Ankylosing Spondylitis, HLA-B27, Klebsiella and “Popper Sequences”

The cause of ankylosing spondylitis (AS) was investigated through 11 Karl Popper sequences. “Popper sequences” provide a powerful method of investigating a scientific problem. A “Popper sequence” consists of a “problem”, “tentative theory”, “error elimination” which then leads to a “new fact”. The 11 “Popper sequences” establish that: (1) HLA-B27 lymphocytes injected into a rabbit evoke antibodies against Klebsiella, (2) anti-HLA-B27 tissue typing sera bind to Klebsiella antigens, (3) total serum IgA is elevated in AS patients, (4) antibodies to Klebsiella are present in AS patients from 16 different countries, (5) antibodies to Klebsiella in AS patients are disease specific, (6) Klebsiella bacteria can be grown from fecal cultures, (7) the sequence QTDRED found in HLA-B27 resembles a sequence DRDE found in pullulanase-D enzyme of Klebsiella, (8) Klebsiella pullulanase-A contains a sequence which resembles type I, II, and IV collagens, (9) sera from AS patients have cytopathic properties against sheep red cells coated with the crossreacting peptides found in Klebsiella and HLA-B27 sequences, (10) Klebsiella bacteria grow preferentially on carbohydrate substrates, and this could be used to decrease bowel bacteria which may lead to a reduction of inflammatory parameters, (11) post-pubertal hormonally-induced muscle mass leads to increased starch consumption and onset of AS. The use of “Popper Sequences” suggests that Klebsiella microbes are the probable causative agents of AS.