Quo vadis reactive arthritis?

PURPOSE OF REVIEW: We provide an overview of recent articles which describe new thinking regarding HLA-B27-associated reactive arthritis (ReA), including those additional infection-related arthritides triggered by microbes that often are grouped under the term ReA. RECENT FINDINGS: With the advent and continuation of the pandemic, an increasing number of cases and case series of post-COVID-19 arthritis have been reported and classified as ReA. Further, arthritis after COVID-19 vaccination is a new entity included within the spectrum of ReA. New causative microorganisms identified in case reports include Clostridium difficile, Mycoplasma pneumoniae, Giardia lamblia, Leptospira , and babesiosis. SARS-CoV-2 is emerging as a significant etiologic agent for apparent ReA. SUMMARY: It is now clear that comprehensive clinical and laboratory investigations, synovial fluid analyses, and close follow-up of patients all are essential to differentiate ReA from diseases that may present with similar clinical attributes. Further, and importantly, additional research is required to define the wide diversity in causative agents, epidemiology, and rare case presentations of these arthritides. Finally, new classification and diagnostic criteria, and updated treatment recommendations, are essential to the advancement of our understanding of ReA.

Reactive Arthritis Update: Spotlight on New and Rare Infectious Agents Implicated as Pathogens.

PURPOSE OF REVIEW: This article presents a comprehensive narrative review of reactive arthritis (ReA) with focus on articles published between 2018 and 2020. We discuss the entire spectrum of microbial agents known to be the main causative agents of ReA, those reported to be rare infective agents, and those reported to be new candidates causing the disease. The discussion is set within the context of changing disease terminology, definition, and classification over time. Further, we include reports that present at least a hint of effective antimicrobial therapy for ReA as documented in case reports or in double-blind controlled studies. Additional information is included on microbial products detected in the joint, as well as on the positivity of HLA-B27. RECENT FINDINGS: Recent reports of ReA cover several rare causative microorganism such as Neisseria meningitides, Clostridium difficile, Escherichia coli, Hafnia alvei, Blastocytosis, Giardia lamblia, Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica/dispar, Strongyloides stercoralis, ß-haemolytic Streptococci, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Mycobacterium bovis bacillus Calmette-Guerin, and Rickettsia rickettsii. The most prominent new infectious agents implicated as causative in ReA are Staphylococcus lugdunensis, placenta- and umbilical cord-derived Wharton's jelly, Rothia mucilaginosa, and most importantly the SARS-CoV-2 virus. In view of the increasingly large spectrum of causative agents, diagnostic consideration for the disease must include the entire panel of post-infectious arthritides termed ReA. Diagnostic procedures cannot be restricted to the well-known HLA-B27-associated group of ReA, but must also cover the large number of rare forms of arthritis following infections and vaccinations, as well as those elicited by the newly identified members of the ReA group summarized herein. Inclusion of these newly identified etiologic agents must necessitate increased research into the pathogenic mechanisms variously involved, which will engender important insights for treatment and management of ReA.

Chlamydia-Induced Reactive Arthritis: Disappearing Entity or Lack of Research?

PURPOSE OF REVIEW: Recent studies regarding the frequency of Chlamydia-induced reactive arthritis (ReA) are reviewed, with a focus on the question of whether the entity is in fact disappearing or whether it is simply being underdiagnosed/underreported. Epidemiological reports indicate diversity in the frequency of Chlamydia-associated ReA in various parts of the world, with evidence of declining incidence in some regions. RECENT FINDINGS: The hypothesis that early effective treatment with antibiotics prevents the manifestation of Chlamydia-associated ReA requires further investigation. For clinicians, it is important to remember that ReA secondary to Lymphogranuloma venereum (LGV) serovars L1-L3 of C. trachomatis is probably underestimated due to a limited awareness of this condition, the re-emergence in Western countries of LGV overall, and the present increasingly rare classical inguinal presentation.

Chlamydia pneumoniae: An Etiologic Agent for Late-Onset Dementia.

The disease known as late-onset Alzheimer's disease is a neurodegenerative condition recognized as the single most commonform of senile dementia. The condition is sporadic and has been attributed to neuronal damage and loss, both of which have been linked to the accumulation of protein deposits in the brain. Significant progress has been made over the past two decades regarding our overall understanding of the apparently pathogenic entities that arise in the affected brain, both for early-onset disease, which constitutes approximately 5% of all cases, as well as late-onset disease, which constitutes the remainder of cases. Observable neuropathology includes: neurofibrillary tangles, neuropil threads, neuritic senile plaques and often deposits of amyloid around the cerebrovasculature. Although many studies have provided a relatively detailed knowledge of these putatively pathogenic entities, understanding of the events that initiate and support the biological processes generating them and the subsequent observable neuropathology and neurodegeneration remain limited. This is especially true in the case of late-onset disease. Although early-onset Alzheimer's disease has been shown conclusively to have genetic roots, the detailed etiologic initiation of late-onset disease without such genetic origins has remained elusive. Over the last 15 years, current and ongoing work has implicated infection in the etiology and pathogenesis of late-onset dementia. Infectious agents reported to be associated with disease initiation are various, including several viruses and pathogenic bacterial species. We have reported extensively regarding an association between late-onset disease and infection with the intracellular bacterial pathogen Chlamydia pneumoniae. In this article, we review previously published data and recent results that support involvement of this unusual respiratory pathogen in disease induction and development. We further suggest several areas for future research that should elucidate details relating to those processes, and we argue for a change in the designation of the disease based on increased understanding of its clinical attributes.

Recent advances and future directions in understanding and treating Chlamydia-induced reactive arthritis.

INTRODUCTION: 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.

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.

Causality of Chlamydiae in Arthritis and Spondyloarthritis: a Plea for Increased Translational Research.

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.

Etiology and pathogenesis of late-onset Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative condition that occurs in two forms, an early-onset form that is genetically determined and a far more common late-onset form that is not. In both cases, the disease results in severe cognitive dysfunction, among other problems, and the late-onset form of the disease is now considered to be the most common cause of dementia among the elderly. While a good deal of research has been focused on elucidating the etiology of the late-onset form for more than two decades, results to date have been modest and have not yet engendered useful therapeutic strategies for cure of the disease. In this review, we discuss the prevalent ideas that have governed this research for several years, and we challenge these ideas with alternative findings suggesting a multifactorial etiology. We review promising newer ideas that may prove effective as therapeutic interventions for late-onset AD, as well as providing reliable means of earlier and more specific diagnosis of the disease process. In the discussions included here, we reference relevant clinical and basic science literature underlying research into disease etiology and pathogenesis, and we highlight current reviews on the various topics addressed.

New insights into Chlamydia and arthritis. Promise of a cure?

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.

Dendrimer-enabled transformation of Chlamydia trachomatis.

Lack of a system for genetic manipulation of Chlamydia trachomatis has been a key challenge to advancing understanding the molecular genetic basis of virulence for this bacterial pathogen. We developed a non-viral, dendrimer-enabled system for transformation of this organism and used it to characterize the effects of inserting the common 7.5 kbp chlamydial plasmid into strain L2(25667R), a C. trachomatis isolate lacking it. The plasmid was cloned in pUC19 and the clone complexed to polyamidoamine dendrimers, producing ∼83 nm spherical particles. Nearly confluent McCoy cell cultures were infected with L2(25667R) and reference strain L2(434). At 16 h post-infection, medium was replaced with dendrimer-plasmid complexes in medium lacking additives (L2(25667R)) or with additive-free medium alone (L2(434)). Three h later complexes/buffer were removed, and medium was replaced; cultures were harvested at various times post-transformation for analyses. Real time PCR and RT-PCR of nucleic acids from transformed cultures demonstrated plasmid replication and gene expression. A previous report indicated that one or more plasmid-encoded product govern(s) transcription of the glycogen synthase gene (glgA) in standard strains. In L2(25667R) the gene is not expressed, but transformants of that strain given the cloned chlamydial plasmid increase glgA expression, as does L2(434). The cloned plasmid is retained, replicated, and expressed in transformants over at least 5 passages, and GFP is expressed when transformed into growing L2(25667R). This transformation system will allow study of chlamydial gene function in pathogenesis.

Attack rate of Chlamydia-induced reactive arthritis and effect of the CCR5-Delta-32 mutation: a prospective analysis.

OBJECTIVE: Factors that predispose patients to Chlamydia-induced reactive arthritis (CiReA) are poorly defined. Data indirectly suggest chemokine receptor-5 (CCR5)-delta-32 mutation might play a role in CiReA. We investigated the attack rate of CiReA and we hypothesized that the CCR5-delta-32 allele may modulate disease susceptibility. METHODS: Patients who tested positive for Chlamydia trachomatis after either (1) symptoms of an acute venereal disease or (2) sexual contact with an individual known to be positive for the same organism were followed in a prospective fashion. All patients were contacted at Week 6 after their acute infection and queried for symptoms of CiReA. Patients who had new-onset symptoms suggestive of CiReA were followed at Weeks 12, 26, and 52. All subjects were tested for CCR5-delta-32 mutation. RESULTS: A total of 365 study participants were enrolled, with average age 24.4 years, 201 men (55%) and 164 women (45%). We followed up with 149 patients (41%) at Week 6. Twelve of 149 participants (8.1%) had symptoms suggestive of CiReA at Week 6. None of these 12 patients was positive for the CCR5-delta-32 mutation. Of the 12 patients that had symptoms at Week 6, we were able to follow up with 7 through Week 52. All 7 had complete resolution of their symptoms by Week 26. Overall, 25/365 (6.8%) subjects were positive for the CCR5-delta-32 mutation. CONCLUSION: The attack rate of CiReA in our study was higher than previously reported, but the CCR5-delta-32 mutation does not seem to play a role in CiReA disease susceptibility.

Chlamydia trachomatis is present and metabolically active during the remitting phase in synovial tissues from patients with chronic Chlamydia-induced reactive arthritis.

BACKGROUND: Patients with chronic Chlamydia-induced reactive arthritis (ReA) often show a remitting-relapsing disease phenotype. Some information regarding bacterial and host responses to one another during active disease is available but no information for quiescence. This article presents the first molecular genetic insight into the behavior of bacterium and host during remitting ReA. METHODS: Synovial biopsies were procured from the knees of 4 patients with quiescent ReA by the Parker-Pearson technique. Nucleic acids prepared from them were analyzed by real-time polymerase chain reaction (PCR) and reverse transcription-PCR, and results were 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 approximately 20% of that in active disease samples. Transcripts from the p60-encoding gene were equal to or higher than those seen in active disease. Messenger RNAs (mRNAs) from the paralog p60-encoding genes were equal to or lower than those of active disease. Host mRNAs encoding interleukin-10, tumor necrosis factor-α and interferon-γ were 4-fold lower than those in active disease samples, whereas monocyte chemotactic protein 1 and regulated upon activation, normal t-cell expressed, and secreted 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 mRNAs encoding proinflammatory proteins are equal to or 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.

Dendrimer-enabled DNA delivery and transformation of Chlamydia pneumoniae.

The chlamydiae are important human pathogens. Lack of a genetic manipulation system has impeded understanding of the molecular bases of virulence for these bacteria. We developed a dendrimer-enabled system for transformation of chlamydiae and used it to characterize the effects of inserting the C. trachomatis plasmid into C. pneumoniae, which lacks any plasmids. The plasmid was cloned into modified yeast vector pEG(KG) and the clone complexed to polyamidoamine dendrimers, producing 50-100 nm spherical particles. HEp-2 cell cultures were infected with C. pneumoniae strain AR-39. Twenty-four hours later, medium was replaced for 3 hours with dendrimer-plasmid complexes, then removed and the medium replaced. Cultures were harvested at various times post-transformation. Real-time PCR and RT-PCR of nucleic acids from transformed cultures demonstrated plasmid replication and gene expression. The cloned plasmid was replicated and expressed in transformants over 5 passages. This system will allow study of chlamydial gene function, allowing development of novel dendrimer-based therapies. FROM THE CLINICAL EDITOR: This team of investigators developed a dendrimer-enabled system for transformation of chlamydiae and successfully utilized it to characterize the effects of inserting the C. trachomatis plasmid into C. pneumonia. This system will allow study of chlamydial gene function, allowing development of novel dendrimer-based therapies.

Dendrimer-enabled modulation of gene expression in Chlamydia trachomatis.

The obligate intracellular bacterium Chlamydia trachomatis is an important human pathogen. The genome of this organism is small but encodes many genes of currently unknown function that are thought to be involved in virulence. Lack of a system for genetic manipulation has been a key challenge to advancing the understanding of molecular genetics underlying virulence for this bacterium. We developed a dendrimer-enabled system for transformation of C. trachomatis, and used it to demonstrate the efficient and highly specific knockdown of transcript levels from targeted genes. Antisense, sense, and other control oligonucleotides targeting two sets of duplicated genes on the chlamydial chromosome were designed, commercially synthesized, and complexed with generation-4 polyamidoamine (PAMAM) dendrimers. The complexes were given to HEp-2 cell cultures infected for 16 h with C. trachomatis serovar K and then removed three hours later. Infected cultures were harvested 6 h after pulsing, and DNA and RNA/cDNA were prepared for assessment of transcript levels compared to those for the same genes in infected cultures, without dendrimer complexation. In all cases, the targeted gene complexed to dendrimer, but not its duplicate, showed up to 90% transcript attenuation. The duration of attenuation can be extended by repeated pulsing, and in some cases transcript levels from multiple genes can be attenuated in the same organism. This system will allow study of chlamydial gene function in pathogenesis, leading to more effective therapies to treat Chlamydia-induced diseases in a targeted manner.