Arthritis

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Like many of the conditions and diseases on this site, the body of evidence on infection in various forms of arthritis has done little to impact standard of care or innovative discovery.  Here are a few quotes from the pioneers who have published extensively in this field.

Dr. John Carter et al. “Persistent, metabolically active, Chlamydiae have been observed in the synovial tissue of these patients years after their initial exposure. Trials with lymecycline and rifampin have shown benefit in early/acute Chlamydia-induced arthritis. In vitro data suggest that persistent Chlamydia become resistant to chronic monotherapy of tetracyclines or rifampin, whereas no such resistance is noted when rifampin is added to antimicrobials that are active against Chlamydia. Rifampin and doxycycline also show synergistic effect against Chlamydia. In addition, rifampin inhibits chlamydial production of heat shock proteins (HSP). HSP60 plays a key role in the chronic persistent state of Chlamydia. ”

Dr.’s Zeidler and Hudson “Our intention is for these insights to be translated rapidly into clinical practice to overcome misdiagnosis and underdiagnosis of the disease, and for them to stimulate the continued development of a cure.”

As you review the research studies and review papers below it will become clear that there are some patients who could be benefiting from combination antibiotic therapy.  In general, the treatment was well-tolerated.  Regardless, Dr.’s Zeidler and Hudson’s plea remains unaddressed.  Physicians continue to treat the symptoms with a cocktail aimed at blocking the inflammatory pathways of what is likely to be underlying, active infection in a subset of patients.


Research Studies

Combination Antibiotics as a Treatment for Chronic Chlamydia-Induced
Reactive Arthritis

Double-blind, triple-dummy prospective trial, n=42, Arthritis and Rheumatology, 2010.
Methods- 9 months total duration.  Patients met disease criteria for 6 months prior to initiation of treatment and were PCR positive for either CpN or Ct (Chlamydia trachomatis). Treatment was for 6 months; the 3 groups included doxycycline 100mg twice daily and rifampin 300mg daily, azithromycin 500mg daily × 5 days then twice weekly and rifampin 300mg daily, or matching placebos. Responders were defined as improving in 4 of 6 variables without worsening in any one variable.
Results- “At month 6, 17/27 subjects (63%) randomized to combination antibiotics were responders compared to 3/15 (20%) on placebo (P-value = 0.01). Secondary efficacy endpoints showed similar results with significant improvement in the modified swollen joint count, tender joint count, physician global assessment (P-values 0.0007, 0.002, and 0.0009, respectively), and a trend with the erythrocyte sedimentation rate (P-value = 0.07) in those patients on combination antibiotics compared to placebo. 6/27 (22%) subjects on combination antibiotics experienced complete resolution of their symptoms whereas 0/15 subjects on placebo achieved this endpoint. There were significantly more subjects who became PCR negative at month 6 in the active therapy group than in the placebo group (P-Value = 0.03). Adverse events (AE’s) were mild; there were no significant differences between the groups.
Conclusions- 6 months of antibiotics is an effective therapy for Chlamydia-induced reactive arthritis.


Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison
n=30, prospective open-label trial, blinded joint examination, Journal of Rheumatology, 2004.
Methods- Patients with an average of chronic inflammatory arthritis (undifferentiated spondyloarthropathy) with disease duration average of 10 years.  “Patients received doxycycline 100 mg PO twice daily or a combination of doxycycline 100 mg PO twice daily and rifampin 600 mg PO daily. They received a 4-question self-questionnaire and a blinded joint examination at each visit. The questions include a visual analog scale (VAS) for their current amount of back pain, duration of morning stiffness, back pain at night, and peripheral joint pain. The blinded joint examination consisted of a swollen joint count (SJC) and a tender joint count (TJC). These 6 variables were assessed at baseline and at 1, 3, 6, and 9 months. Responders were defined as those who improved > or = 20% in at least 4 of the 6 variables at 9 months of therapy.”
Results- At 9 months of therapy, all 6 variables improved more in doxy + rifampin arm versus doxy alone, 4 of which were statistically significant.
Conclusion-“The combination of doxycycline and rifampin for 9 months seemed to be effective in treatment of chronic uSpA. This is the first study to demonstrate therapeutic benefit with antimicrobials to a chronic inflammatory arthritis possibly secondary to persistent Chlamydia.”


Chlamydia trachomatis Is Present and Metabolically Active During the Remitting Phase in Synovial Tissues From Patients With Chronic Chlamydia-induced Reactive Arthritis
n=4, American Journal of Medical Sciences, 2014.
Methods- “Synovial biopsies were procured from the knees of 4 patients with quiescent Reactive Arthritis (ReA) by the Parker-Pearson technique. Nucleic acids prepared from them were analyzed by real time PCR and RT-PCR and results compared with data averaged from the knee synovial tissue samples of 10 patients with active ReA.”
Results- “Real time PCR indicated that bacterial load in remitting samples was ~20% of that in active disease samples. Transcripts from the HSP60 gene were equal to or higher than those seen in active disease. mRNA from the paralog HSP60 genes were equal to/lower than those of active disease. Host mRNA encoding IL-10, TNFα, IFNγ were 4-fold lower than those in active disease samples, while MCP-1, RANTES mRNA levels were equal to or higher.”
Conclusions- “Bacterial load in synovial tissue of patients with remitting disease is lower than that of active disease, but messengers encoding pro-inflammatory proteins are equal to/higher than those of active disease. Transcription in the host is attenuated for cytokines and chemokines. These initial results demonstrate that organism is present and metabolically active in synovium during the remitting phase of chronic Chlamydia-induced ReA, and that the genetic events characterizing quiescence are complex.”


Chlamydia pneumoniae present in the human synovium are viable and metabolically active
n=10, Microbial Pathogenesis, 2000.
Methods- Reverse transcription-polymerase chain reaction (RT-PCR) study of synovial tissue in patients with Reactive Arthritis/Reiter’s Syndrome and other arthritides targeting primary transcripts from the chlamydial rRNA operons, and mRNA from several C. pneumoniae genes (hsp60, ompA, KDO transferase, Mr=76000 protein).
Results- “In the 10 patients PCR-positive for C. pneumoniae DNA, RT-PCR assays targeting primary transcripts from the rRNA operons of the organism showed that these molecules were present in each sample, as were transcripts from the bacterial hsp60 gene.”
Conclusion- “These results indicate that in patients infected with the organism, synovial C. pneumoniae are viable and metabolically active, as are C. trachomatis cells in the same context. Such viability is consistent with a role in long-term contribution to pathogenesis in joint disease.”


Review Papers

The role of Chlamydia in connective tissue diseases
Elsevier Antimicrobics and Infectious Diseases Newsletter, 1999.
Introduction- “Among chronic illnesses that Chlamydia species have been associated with are connective tissue diseases. Connective tissue diseases are defined as those involving joints and related structures of the skeleton. This brief review will address this association and discuss the diagnostic and therapeutic implications.”


New insights into Chlamydia and arthritis. Promise of a cure?
Annals of Rheumatic Diseases, 2014.
Abstract- 
“Chlamydia trachomatis and Chlamydia pneumoniae together comprise the most frequent causative pathogens that elicit reactive arthritis (ReA). Advances in our understanding of the molecular biology/molecular genetics of these organisms have improved significantly the ability to detect chlamydiae in the joint for diagnostic purposes, as well as extending our current understanding of the pathogenic processes they elicit in the joint and elsewhere. An important aspect of the latter is that synovial chlamydiae infect the joint in an unusual but metabolically active state. While some standard treatments can provide a palliative effect on the ReA disease phenotype, many reports have indicated that standard antibiotic treatment does not provide a cure. Of critical importance, however, two recent reports of controlled clinical trials demonstrated that Chlamydia-ReA can be treated successfully using combination antibiotic therapy. These observations offer the opportunity of a cure for this disease, thereby increasing the practical importance of awareness and diagnosis of the spondyloarthritis caused by Chlamydia. In this viewpoint, we provide an overview of recent key findings in the epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of Chlamydia-induced arthritis. Our intention is for these insights to be translated rapidly into clinical practice to overcome misdiagnosis and underdiagnosis of the disease, and for them to stimulate the continued development of a cure.”


Combination antibiotics for the treatment of Chlamydia-induced reactive arthritis: is a cure in sight?
International Journal of Clinical Rheumatology, 2011.
Abstract- “The inflammatory arthritis that develops in some patients subsequent to urogenital infection by the obligate intracellular bacterial pathogen Chlamydia trachomatis, and that induced subsequent to pulmonary infection with C. pneumoniae, both have proved difficult to treat in either their acute or chronic forms. Over the last two decades, molecular genetic and other studies of these pathogens have provided a good deal of information regarding their metabolic and genetic structures, as well as the detailed means by which they interact with their host cells. In turn, these insights have provided for the first time a window into the bases for treatment failures for the inflammatory arthritis. In this article we discuss the biological bases for those treatment failures, provide suggestions as to research directions that should allow improvement in treatment modalities, and speculate on how treatment regimens that currently show promise might be significantly improved over the near future using nanotechnological means.”


Causality of Chlamydiae in Arthritis and Spondyloarthritis: a Plea for Increased Translational Research
Current Rheumatology Reports, 2016.
Abstract- “Current molecular genetic understanding of the metabolically active persistent infection state of Chlamydia trachomatis and Chlamydia pneumoniae in the synovium in patients with arthritis and spondyloarthritis favors a causal relationship. Here, we examine how adequately the accepted criteria for that etiologic relationship are fulfilled, emphasizing the situation in which these microorganisms cannot be cultivated by standard or other means. We suggest that this unusual situation of causality by chlamydiae in rheumatic disease requires establishment of a consensus regarding microorganism-specific terminology as well as the development of new diagnostic and classification criteria. Recent studies demonstrate the value of molecular testing for diagnosis of reactive arthritis, undifferentiated spondyloarthritis, and undifferentiated arthritis caused by C. trachomatis and C. pneumoniae in clinical practice. Data regarding combination antibiotic therapy is consistent with the causative role of chlamydiae for these diseases. Observations of multiple intra-articular coinfections require more research to understand the implications and to respond to them.”


Recent advances and future directions in understanding and treating Chlamydia-induced reactive arthritis
Expert Review of Clinical Immunology, 2017.
Abstract- “Reactive arthritis (ReA) is an inflammatory disease that can follow gastrointestinal or genitourinary infections. The primary etiologic agent for post-venereal ReA is the bacterium Chlamydia trachomatis; its relative, C. pneumoniae, has also been implicated in disease induction although to a lesser degree. Studies have indicated that the arthritis is elicited by chlamydiae infecting synovial tissue in an unusual biologic state designated persistence. We review clinical aspects, host-pathogen interactions, and treatments for the disease. Areas covered: We briefly discuss both the historic and, more extensively, the current medical literature describing ReA, and we provide a discussion of the biology of the chlamydiae as it relates to elicitation of the disease. A summary of clinical aspects of Chlamydia-induced ReA is included to give context for approaches to treatment of the arthritis. Expert commentary: Basic research into the biology and host-pathogen interactions characteristic of C. trachomatis has provided a wealth of information that underlies our current understanding of the pathogenic processes occurring in the ReA synovium. Importantly, a promising approach to cure of the disease is at hand. However, both basic and clinical research into Chlamydia-induced ReA has lagged over the last 5 years, including required studies relating to cure of the disease.”


Coinfection of Chlamydiae and other Bacteria in Reactive Arthritis and Spondyloarthritis: Need for Future Research
Microorganisms, 2016.
Abstract- “Reactive (inflammatory) arthritis has been known for many years to follow genital infection with the intracellular bacterial pathogen Chlamydia trachomatis in some individuals. Recent studies from several groups have demonstrated that a related bacterium, the respiratory pathogen Chlamydia pneumoniae, can elicit a similar arthritis. Studies of these organisms, and of a set of gastrointestinal pathogens also associated with engendering inflammatory arthritis, have been relatively extensive. However, reports focusing on coinfections with these and/or other organisms, and the effects of such coinfections on the host immune and other systems, have been rare. In this article, we review the extant data regarding infections by multiple pathogens in the joint as they relate to engendering arthritis, and we suggest a number of research areas that must be given a high priority if we are to understand, and therefore to treat in an effective manner, such arthritides.”


Letter to the Editor on Single versus Combination Therapy
Annals of Rheumatic Diseases, 2005.
Excerpt- “We have recently completed a trial assessing a 9 month course of a combination of doxycycline and rifampin versus doxycycline monotherapy.  The results showed a rather dramatic response in the patients who received the combination. The chlamydial resistance that has been documented in vitro, was overcome when a combination of antibiotics were used.  Ours was the first trial to assess a combination of antibiotics in this setting. Do antibiotics work in ReA, specifically Chlamydia induced ReA? In our opinion, this question has not been answered. We believe studies of large groups of patients, with the appropriate antibiotics, in the right dose, used for the proper length of time, need to be conducted before this question can be answered.”


Chlamydia-induced reactive arthritis: Hidden in plain sight?
Best Practice & Research Clinical Rheumatology, 2011.
Abstract- “Reactive arthritis belongs to the group of arthritidies known as the spondyloarthritides. There are two main types of reactive arthritis: post-venereal and post-enteric. Chlamydia trachomatis is felt to be the most common cause of reactive arthritis, in general. Until recently, even the terminology for the condition itself was unclear as multiple eponyms and names have been associated with reactive arthritis. In recent years, a great deal has been learnt about the epidemiology, pathophysiology and treatment of reactive arthritis and Chlamydia-induced reactive arthritis, specifically. Prospective epidemiologic data suggest that Chlamydia-induced reactive arthritis is underdiagnosed. Other truths being actively revealed include data suggesting that the pathogen itself (i.e., Chlamydia) might play an equally important role, or perhaps even more important, than the host with disease susceptibility; asymptomatic chlamydial infections might be a common cause of ReA and the two variants of reactive arthritis might respond differently to treatment in spite of the congruent clinical presentation. However, much about this syndrome remains shrouded in mystery. Data covered in this review suggest that Chlamydia-induced reactive arthritis might be a common condition that clinicians fail to recognize. An emphasis is placed on disease awareness since viable treatment options are emerging.”