The following research from around the world, carried out over the course of 5-6 decades, focuses on streptococcus as a possible triggering element and causative factor in the progression of rheumatoid arthritis (RA).

Dr. Thomas McPherson Brown placed emphasis on the etiopathogenic role of streptococcal infections in RA, based on rheumatic fever, a classic infectious model of chronic arthritis that he saw frequently during his tenure as a practicing rheumatologist and clinical researcher. In the book, The New Arthritis Breakthrough, by Henry Scammell (p. 150), Dr. Brown describes using an anti-streptococcal approach to treating his rheumatic patients. This approach was administered in combination with mycoplasma treatment until strep titers had been lowered adequately, after which mycoplasma could be targeted more precisely. In these cases, treatment would involve ampicillin or similar penicillin antibiotic, sometimes pulsed with tetracycline antibiotics (spaced well apart or on tetracycline off-days), intermittent IV clindamycin, or just daily penicillin only in some patient cases.

An important clinical observation made by Dr. Brown was that patients with a greater frequency of rheumatoid nodules commonly had a history of streptococcal infection, accompanied by elevated strep antibodies, and that short-term treatment with penicillin derivatives would lead to nodule resolution. He also postulated that rheumatoid nodules are fibrous, skein-like tissue formations that form as a self-protective response to encapsulate and wall-off invading pathogens to prevent their spread.

Migrating Polyarthralgias. NEJM; Physicians-In-Training, Clinical Problem-Solving Review Series; July 5th, 2013.

The New England Journal of Medicine presented the case of an otherwise healthy 28-year old woman with fatigue and migrating joint pain and swelling. Such symptoms typically evolve 2-4 weeks after throat infection with group A streptococcal infection. Minor, early features of rheumatic fever involve fever, elevated CRP and SED rate, joint pain (no swelling) and elevated white blood cell counts (leukocytosis), and sometimes heart block. This report states, however, that these symptoms may be easily misdiagnosed as parvovirus B19, gout, post-infectious or reactive arthritis, gonococcal infection, and systemic rheumatic illnesses, such as, systemic lupus erythematosus, Lyme disease, or rheumatoid arthritis. In addition to migrating joint pain/swelling and fatigue, classic late stage major features of rheumatic fever include carditis, subcutaneous nodules, a skin rash called erythema marginatum, and Sydenham’s chorea (aka St. Vitrus’s Dance), involving rapid, involuntary facial and arm muscle movements, which help to delineate rheumatic fever from other rheumatic presentations. Treatment involves the administration of pencillin in a 10-day course or one intramuscular (IM) injection of penicillin G benzathine, along with anti-inflammatory pain and fever relievers, such as aspirin. Rheumatic fever can result in recurrent episodes if the patient is re-exposed to group A streptococcus. For this reason, rheumatic fever patients will be advised to receive monthly prophylactic IM penicillin G benzathine or twice daily oral penicillin indefinitely to prevent future rheumatic fever occurrences.

RBF Commentary: Strep throat, quickly and efficiently diagnosed today by clinicians with in-office throat swab testing, has resulted in a greatly reduced prevalence of rheumatic fever. Delayed treatment or misdiagnosis, however, can still result in the serious long-term consequences of rheumatic fever. Dr. Brown saw many rheumatic fever patients in the hospital setting, as described in The New Arthritis Breakthrough, by Henry Scammell, and this infection served as a classic model of reactive, infection-induced arthritis. 

Pneumococcal polyarticular septic arthritis after a single infusion of infliximab in a rheumatoid arthritis patient: a case report. J Med Case Rep. 2012 Mar 9;6:81.

Case study of a 38-year old Japanese man with a 5-year history of seronegative rheumatoid arthritis (RA) that was resistant to methotrexate, folic acid, and low dose prednisolone. Eight days after receiving his first Remicade (infliximab) infusion, he became febrile (temp of 105.08f) with chills, polyarthritis (swollen, painful and warm joints), and significantly elevated inflammatory markers, and was diagnosed with bacterial septic arthritis as a result of Streptococcal pneumoniae infection. After surgical intervention due to joint sepsis and a month of intravenous antibiotic therapy, the patient recovered.

RBF Commentary: S. pneumoniae is a community-acquired form of pneumonia and resides in asymptomatic, healthy carriers, but can become pathogenic in immune-compromised individuals, spreading from the nasal cavity, sinuses, and respiratory tract to other locations in the body, such as the joints (septic arthritis), bones (osteomyelitis), heart (endocarditis), gut (peritonitis), skin (cellulitis), brain (abscess or meningitis), ears (otitis media), and eyes (conjunctivitis). Antistreptolysin O (ASO) titer is a blood test to measure antibodies against streptolysin O, a substance produced by Group A streptococcus bacteria. ASO testing of rheumatic patients should be routine and a reading of >200 units is considered significant. Dr. Brown would treat all rheumatic patients who had a history of strep with IV clindamycin followed by penicillin therapy until ASO titers and symptoms normalized.

Streptococcal cell wall induced arthritis: leukocyte activation in extra-articular lymphoid tissue. Inflammation. 2003 Apr;27(2):59-70.

Seeking better understanding of rheumatoid arthritis (RA) and the roles played by leukocytes and their subsets in this rheumatic disease, researchers in Louisiana used a streptococcal cell wall-induced arthritis model.

RBF Commentary: This study was included here to exemplify the universal acceptance that streptococcal antigens can induce arthritis for the purpose of studying various aspects of arthritis. By using this method of arthritis induction in the laboratory setting, these researchers were then able to confirm evidence of leukocyte activation in spleen, lymph node, and myeloid lineages, resulting in the production of specific antibodies, B cells, monocytes, T cells, and myeloid cells that are consistent with RA pathogenesis.

Tranilast suppresses the disease development of the adjuvant- and streptococcal cell wall-induced arthritis in rats. J Pharmacol Sci. 2007 Sep;105(1):48-56. Epub 2007 Sep 8.

Japanese researchers studied the effectiveness of Tranilast, an anti-allergy and anti-fibrotic medication used in the treatment of allergic disorders (e.g. asthma, allergic rhinitis, atopic dermatitis) in rats with streptococcal cell wall-induced arthritis. Results of this study concluded that Tranilast was superior to methotrexate in treating streptococcal cell wall-induced arthritis as compared to adjuvant-induced arthritis.

RBF Commentary: Dr. Brown described rheumatoid arthritis as a rheumatic disease that had all the characteristics of bacterial hypersensitivity (aka bacterial allergy) and, as a part of his antibiotic protocol treatment regimen, he would add an anti-histamine, such as Benedryl or Ateldrinspansule, to reduce the effects of bacterial die-off and the resulting tissue hypersensitivity caused by these antigenic endotoxins. The above Japanese study provides further evidence of the effectiveness of this approach.

[Molecular mimicry of bacteria as a factor in bacterial pathogenicity]. Postepy Hig Med Dosw. 1999;53(4):545-59. Inflammation. 2003 Apr;27(2):59-70.

A Polish researcher describes how bacterial proteins and host antigens are structurally and functionally similar, leading to molecular mimicry and self-directed immune system attacks in rheumatic fever (group A streptococcus), rheumatoid arthritis (Escherichia coli), and reactive arthritides, such as ankylosing spondylitis and Reiter’s Syndrome (Klebsiella pneumoniae), as well as Grave’s disease (Yersinia enterocolitica).

Streptococcal cell wall arthritis. Curr Protoc Immunol. 2001 May;Chapter 15:Unit 15.10.

A researcher at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a division of the National Institutes of Health, in Bethesda, Maryland, describes how inflammatory forms of arthritis, similar to rheumatoid arthritis, is induced in the rat model by using Group A streptococcal cell wall peptidoglycan-polysaccharide polymers. Described as “biphasic,” acute phase arthritis occurs within 24 hours and, after 10-21 days, chronic phase arthritis develops and persists for months.

Pneumococcal polyarticular septic arthritis in a patient with rheumatoid arthritis. Rev Rhum Engl Ed. 1999 Jun;66(6):344-6.

This French study asserts that clinical presentation of extraarticular symptoms of joint infection in long-standing rheumatoid arthritis (RA) patients is often atypical, leading to misdiagnoses during flares. Staphylococcus aureus is the most common causative organism, but in 5% of cases, the infectious agent is Streptococcus pneumoniae, leading to polyarticular septic arthritis, bearing a high degree of risk (a 50% mortality rate) in patients with RA.

[Infectious origin of rheumatoid arthritis]. Rev Rhum Ed Fr. 1993 May;60(5 Pt 2):30S-35S.

French researchers present 3 hypotheses for how infections, such as streptococcus, proteus, mycobacteria, and viruses, may perpetuate rheumatoid arthritis (RA). They state that either the microbe is present in the body and is either still accessible or becomes cloaked and hidden. The third alternative theory is that the microbe is absent and the original infection has perpetuated ongoing immune system stimulation.

RBF Commentary: Dr. Brown treated patients who had a history of strep with long-term ampicillin and IV clindamycin until all clinical signs and symptoms of RA resolved. 

The role of infections in the rheumatic diseases: molecular mimicry between bacterial and human stress proteins? Am J Med Sci. 1991 Feb;301(2):138-49.

Researchers in Texas, using the established rheumatic fever model, caused by group A streptococcal infection, point to other rheumatic diseases, such as rheumatoid arthritis, lupus, scleroderma, Sjogren’s syndrome, polymyositis, and ankylosing spondylitis, having an infectious cause. They state that genetic susceptibility and the interplay of infectious agents may both cause and exacerbate rheumatic diseases in different ways, including molecular mimicry, whereby bacterial heat shock proteins may cross-react with similar human tissue proteins.

The clinical significance of immune reactions with some streptococcal antigens in rheumatoid arthritis. J Rheumatol. 1990 Jul;17(7):874-9.

Russian researchers conducted a controlled study of 247 rheumatoid arthritis (RA) patients and found these patients to have an increased immune response to group B streptococcus antigens. Higher levels of seropositivity correlated with greater disease activity of short duration and swift onset, progressive disease. In early RA, antibodies to group B streptococcus polysaccharides were found in high titers in synovial fluid. Rheumatoid factor, immune complexes, and immunologlobulin levels were also directly correlated with immune response values. They conclude that group B streptococcus was more commonly found in RA urogenital tracts than in healthy individuals and discuss the immunopathology of this infection and its role as a disease trigger.

RBF Commentary: Group B streptococcus, otherwise known as Streptococcus agalactiae, is considered to be a harmless commensal bacterium that colonizes the human gastrointestinal and urogenital tracts of up to 30% of healthy human adults (asymptomatic carriers), but can cause serious consequences in the elderly, the newborn and young, and in the immune-incompetent.

[Group-specific antigens of streptococci in the make-up of circulating immune complexes in rheumatism and rheumatoid arthritis]. Vestn Akad Med Nauk SSSR. 1989;(6):51-6.

Russian researchers studied the structure and level of antibodies and circulating immune complexes in patients with rheumatoid arthritis (RA) and rheumatism to determine if there was a correlation with the level of group A and B streptococcal antigens to group-specific polysaccharides. It was determined that RA patients had higher concentrations of both strep types in comparison to healthy control subjects and tonsillitis patients and that high titers of antibodies to group B streptococcal polysaccharides were found in synovial fluid. These findings led to conjecture that streptococcal antigens and antibodies are involved in disease pathogenesis for both early RA and mild rheumatism.

Mechanisms of bone and cartilage destruction in rheumatoid arthritis: lessons from the streptococcal cell wall arthritis model in LEW/N rats. Clin Exp Rheumatol. 1989 Sep-Oct;7 Suppl 3:S123-7.

Russian researchers focused on synovial connective tissue cells and the role of cytokines in regulating destructive actions in the joints. They describe rheumatoid arthritis (RA) as tumor-like and that its mechanism of progression, the erosive nature of bone and cartilage destruction, and immune-pathology is similar to streptococcal cell wall-induced arthritis in the rat model.

Idiotypic interactions between rheumatoid factors and other antibodies.

British researchers at the University of Liverpool comment that rheumatoid factor (RF), a marker for rheumatoid arthritis (RA) is associated with bacterial infections, such as streptococcus, in which antibodies occur frequently. When injecting experimental mice with streptococcal cell wall peptidoglycan-polysaccharide (PG-PS), the resulting immune complexes produce RF-like antibodies. Conversely, when mice are immunized with IgM- or IgG-RF, an anti-PG-PS response is initiated, leading these researchers to conclude that RF may act as an anti-idiotype to anti-PG-PS.

RBF Commentary: An “anti-idiotype” in immunology is described as an antibody that can either suppress or enhance immune response by binding to the antigen-combining site of another antibody and, as such, this study seems to be indicating that a form of molecular mimicry is occurring with infections that promote RF seropositivity in RA.

Reaction of bacterium-primed murine T cells to cartilage components: a clue for the pathogenesis of arthritis? Clin Exp Immunol. 1988 Apr;72(1):9-14.

Dutch researchers in The Netherlands studied the cross-reactive nature of bacterial components and the cartilage in rheumatoid arthritis (RA), supported by previous clinical and experimental studies. These researchers were able to provide evidence of cellular and humoral anti-cartilage responses by immunizing mice with cell wall fragments of group A streptococcus (Streptococcal pyogenes) and Escherichia coli (E. coli). They conclude that they were able to identify a possible mechanism for RA pathology using various bacteria as stimuli for triggering chronic arthritis.

RBF Commentary: Streptococcus pyogenes is one of the most common pathogens in humans as a part of the skin flora. This bacterium can cause a wide variety of diseases (noninvasive and invasive) ranging from minor skin rashes to severe systemic infections.

A monoclonal antibody raised by immunising mice with group A streptococci binds to agalactosyl IgG from rheumatoid arthritis. Ann Rheum Dis. 1988 Mar;47(3):247-50.

Researchers at the Department of Medical Microbiology, University College, in London, comment that the causative microbe of rheumatic fever, group A streptococcus, appears to evoke antibodies that bind to an abnormality of IgG in rheumatoid arthritis. This was demonstrated in mice immunized with a peptidoglycan/ polysaccharide complex of this microbe.

Molecular interactions between human IgG, IgM rheumatoid factor and streptococcal IgG Fc receptors. Int Arch Allergy Appl Immunol. 1988;86(1):92-6.

Swedish researchers describe their observations of the complex molecular binding site patterns of group A streptococcus to rheumatoid factor (RF) and how these may play a role in rheumatoid arthritis pathogenesis.

Pneumococcal septic arthritis in rheumatoid arthritis. Ann Rheum Dis. 1987 Jun;46(6):482-4.

British study authors present three cases of rheumatoid arthritis (RA) in which the patients had a recent history of chest infection, caused by Streptococcus pneumoniae, which spread from the lungs to cause joint sepsis.

RBF Commentary: Although S. pneumoniae represents less than 5% of RA septic arthritis cases, delayed diagnosis can have fatal consequences as described in the following previously summarized study (above).

Pneumococcal polyarticular septic arthritis in a patient with rheumatoid arthritis. Rev Rhum Engl Ed. 1999 Jun;66(6):344-6.

T15 group A streptococcal Fc receptor binds to the same location on IgG as staphylococcal protein A and IgG rheumatoid factors. J Immunol. 1987 Feb 1;138(3):922-6.

Swedish researchers studied the receptor binding sites of group A streptococcus finding similarities with IgG rheumatoid factor (RF) and this infection’s bacterial cell wall Fc receptors.

[Immune reactions with streptococcal antigens and homologous myocardial tropomyosin in rheumatoid arthritis with visceritis]. Ter Arkh. 1987;59(5):66-9.

Russian researchers studied humoral and cellular immune responses to streptococcal cell wall polysaccharides and protein antigens and the similar heart protein, myocardial tropomyosin in rheumatoid arthritis (RA) patients as compared to healthy subjects, finding higher reactive responses in the RA group with articular disease. They conclude that group B streptococcal cell wall antigens and myocardial tropomyosin antibodies may play a role in heart disease in RA patients.

Antibody to streptococcal cell wall peptidoglycan-polysaccharide polymers in seropositive and seronegative rheumatic disease. Clin Exp Immunol. 1984 Jan;55(1):115-24.

British researchers at the University of Liverpool, in England, describe an ELISA test that was developed to detect streptococcal cell wall peptidoglycan-polysaccharide polymers (PG-GSP) in blood serum. Strong serum IgG PG-GSP antibody responses to this microbe’s cell wall proteins were found in juvenile rheumatoid arthritis, seronegative and seropositive rheumatoid arthritis, as compared to healthy controls, other rheumatic diseases, and myeloma.

Antibody response to streptococcal cell wall antigens associated with experimental arthritis in rats. Clin Exp Immunol. 1980 Dec;42(3):450-7.

Researchers at the University of North Carolina’s School of Medicine, Chapel Hill, conducted a study to determine antibody responses in rats immunized with group A streptococcal cell wall antigens. No correlation with anti-A polysaccharide antibody titers and disease severity was found and all rats developed moderate and severe chronic arthritis after immunization. These study authors conclude that the role of antibody in this experimental model of arthritis needs to be further understood, surmising that it may play a role in disease pathogenesis.

Can chronic and self-perpetuating arthritis in the human be caused by arthrotropic undegraded microbial cell wall constituents? A working hypothesis. Rheumatol Rehabil. 1977 Aug;16(3):141-9.

The role of mycobacterial and streptococcal cell wall components, persisting within macrophages and activating tissue-destructive lysosomal enzymes, are hypothesized in the pathogenesis of rheumatoid arthritis.

The origin of rheumatoid arthritis.  Rheumatology. 1975;6:322-8.

The author of this study is of the opinion that rheumatoid arthritis (RA) is caused by bacterial infection, providing the examples of experimentally-induced arthritis and rheumatic fever caused by group A streptococcus. The induction of experimental arthritis in rats with streptococci group B, leading to macrophage changes and the release of destructive enzymes, followed by abnormal immune processes in response to a triggering infection agent, are discussed.

Association of experimental chronic arthritis with the persistence of group A streptococcal cell walls in the articular tissue J Bacteriol. 1967 Nov;94(5):1728-35.

Researchers at the University of North Carolina School of Medicine, Chapel Hill, injected the joints of rabbits with group A streptococcal cell wall fragments and, following an acute, initial reaction, a chronic inflammatory process was observed. This chronic inflammatory process was demonstrated to be similar to early rheumatoid arthritis, based on histological examination of synovial tissues and their responses to the cell wall antigen persisting within macrophages.

Beta-haemolytic streptococci and antistreptolysin-O titres in patients with rheumatoid arthritis and a matched control groupAnn Rheum Dis. 1965 Jul; 24(4): 369-377.

A 6-month controlled study of 63 rheumatoid arthritis (RA) patients with varying degrees of disease activity and 60 otherwise healthy subjects at the University Hospital, in Leydon, was conducted to determine if there was any relationship between group A beta-hemolytic Streptococcus pyogenes (GABHS) – the causative organism of strep throat – and antistreptolysin-O (ASO) titers in RA. Of the 95% RA completers of this study, it was found that ASO strep titers were significantly greater (1-6 times higher) and there was a reduced ability to eliminate the infection than in the healthy control group of study completers (93%). The authors postulate that the RA study cohort dealt with compromised immunity due to chronic disease, causing reduced resistance to infections (see RBF Commentary below), and that beta-hemolytic streptococci may be a causative factor in the pathogenesis of RA, or “at least of the rheumatoid factor” (RF).

RBF Commentary: It should be noted that half the patients in the RA group of this study were also taking either gold, a disease-modifying anti-rheumatic drug (DMARD), commonly used at the time of this study, and the other half of the RA cohort were taking either aspirin, anti-malarials, pyramidon, or phenybutazone (2 received short courses of prednisone due to gold-induced dermatitits). 


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