Materiały źródłowe

• #1 Reactive Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499831/

  Reactive arthritis (ReA) is inflammatory arthritis that manifests several days to weeks after a gastrointestinal or genitourinary infection. […] It is believed that the disorder is due to an aberrant autoimmune response to a gastrointestinal or genitourinary infection caused by salmonella, shigella, campylobacter, or chlamydia. […] Today, it is believed that the disorder is due to an aberrant autoimmune response to the gastrointestinal infection caused by salmonella, shigella, campylobacter, or chlamydia. […] Reactive arthritis is an immune-mediated syndrome triggered by a recent infection. It is hypothesized that T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids when invasive bacteria reach the systemic circulation. These activated cytotoxic-T cells attack the synovium and other self-antigens through molecular mimicry. The evidence of Chlamydia trachomatis and C pneumoniae ribosomal RNA transcripts, enteric bacterial DNA, and bacterial degradation products in the synovial tissue and fluid supports this. It is believed that anti-bacterial cytokine response is also impaired in reactive arthritis, resulting in decreased bacteria elimination.

• #1 Reactive Arthritis: Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7519381/

  Reactive arthritis is considered to be part of the spectrum of the spondyloarthritis. […] The understanding of pathophysiological models is challenging, but recent studies contribute to elucidate the major factors involved in the development of the disease. […] Recent studies related to ReA pathophysiology have highlighted the contribution of the microbiota in the pathogenesis of this type of arthritis. […] The development of ReA depends on four major factors: infection history (etiological agents), the role of cytokines, the involvement of genetic factor (HLA-B27), and gut microbiota. […] Some bacteria are commonly known to be triggers of ReA. […] Moreover, it has been proven that the synovial tissue or fluid may contain bacterial antigens, and the persistence of these components can turn acute ReA into chronic arthritis.

• #1 Reactive Arthritis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331347-overview

  Reactive arthritis (ReA), formerly termed Reiter syndrome, is an autoimmune condition that develops in response to an infection. It has been associated with gastrointestinal (GI) infections with Shigella, Salmonella, Campylobacter, and other organisms, as well as with genitourinary (GU) infections (especially with Chlamydia trachomatis). […] ReA is usually triggered by a genitourinary or gastrointestinal infection (see Etiology). Less often, respiratory infection with Chlamydia pneumoniae may be implicated. The frequency of ReA after enteric infection averages 1-4% but varies greatly, even among outbreaks of the same organism. Although severely symptomatic gastrointestinal infections are associated with an increased risk of ReA, asymptomatic venereal infections more frequently cause this disease. About 10% of patients have no preceding symptomatic infection.

• #1 Reactive Arthritis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331347-overview

  Molecular evidence of bacterial DNA (obtained via polymerase chain reaction [PCR] assay) in synovial fluids has been found only in Chlamydia-related ReA, and a single placebo-controlled trial of a tetracycline derivative (ie, lymecycline) has shown a reduction in the duration of acute Chlamydia-related, but not enteric-related, ReA. This suggests that persistent infection may play a role, at least in some cases of chlamydial-associated ReA. […] The role of HLA-B27 in this scenario remains to be fully defined. The following theories have been proposed: Molecular mimicry – This hypothesis suggests that a similarity exists at the molecular level between the HLA-B27 molecule and the inciting organisms, allowing the triggering of an immune response and the subsequent development of clinical disease. […] HLA-B27 may share molecular characteristics with bacterial epitopes, facilitating an autoimmune cross-reaction instrumental in pathogenesis. HLA-B27 contributes to the pathogenesis of the disease and reportedly increases the risk of ReA 50-fold.

• #1 Reactive Arthritis: Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7519381/

  The findings assess that HLA-B27 expression can reduce the threshold of endoplasmic reticulum (ER) stress induction and that Salmonella can induce the unfolded protein response. […] The involvement of gut microbial dysbiosis in disease pathogenesis remains unclear; thus, further productive researchers are needed to close these knowledge gaps in the field.

• #1 Of Bugs and Joints: The Relationship Between Infection and Joints | Reumatología Clínica

  http://www.reumatologiaclinica.org/en-of-bugs-joints-relationship-between-articulo-S2173574312001608

  The pathogenesis of reactive arthritis is a complex, multifactorial, with involvement of the environment, genetic factors and the immune system. Environmental factors are represented by infectious agents, particularly gram-negative organisms. In humans, HLA-B27 plays a major role, although the exact mechanism of how it performs its role is unknown. […] The work of Taurog et al. in transgenic rats for HLA-B27 and human 2-microglobulin clearly established the importance of HLA-B27 in the pathogenensis. […] Moreover, the participation of the environment was also clearly established with the second part of the study. If rats were maintained at birth in a sterile environment they did not develop the inflammatory process, indicating that the commensal flora is important in triggering the inflammatory process. These findings are indicative of the role of the commensal flora and are supported by the detection of commensal organisms by PCR in synovial fluid from patients with reactive arthritis.

• #1 Reactive Arthritis: Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7519381/

  The bacterial antigens are transported from the primary site into the synovial membrane after local bacterial infection, which causes the activation of T-lymphocytes and consequently the release of inflammatory cytokines, resulting in synovial inflammation. […] Studies have shown that the prevalence of positive HLA B27 ranges from 50 to 80% in patients with ReA and 90% of the cases with ankylosing spondylitis. […] It has been suggested that HLA-B27 may influence the host response. […] The altered microbiota may result in aberrant immune responses to gut flora, gut dysbiosis, inflammation, and thus to SpA. […] In a study that compared patients with ReA with those with prior infections who did not go on to develop arthritis, no significant differences were seen in gut bacterial diversity between the groups.

• #1 Reactive Arthritis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331347-overview

  The mechanism by which the interaction of the inciting organism with the host leads to the development of ReA is not known. Possibly, microbial antigens cross-react with self-proteins, stimulating and perpetuating an autoimmune response mediated by type 2 T helper (Th2) cells. Chronicity and joint damage have been associated with a Th2 cytokine profile that leads to decreased bacterial clearance. […] Synovitis in ReA is mediated by proinflammatory cytokines. Native T cells under the influence of transforming growth factor (TGF)- and other cytokines, such as interleukin (IL)-6, differentiate into Th17 effector cells, which then produce IL-17. IL-17 is one of the major cytokines elevated in the synovial fluid of these patients. […] The Toll-like receptors (TLRs) recognize different extracellular antigens as part of the innate immune system. TLR-4 recognizes gram-negative lipopolysaccharide (LPS). Studies in mice and humans showed abnormalities in antigen presentation due to downregulation of TLR-4 costimulatory receptors in patients with ReA.

• #1 Immunopathogenesis of reactive arthritis: Role of the cytokines

  https://www.wjgnet.com/2219-2824/full/v4/i2/78.htm

  In this review, we highlight recent advances on the role of cytokines in ReA. Particularly, we discuss the roles of pro- and anti-inflammatory cytokines, especially interleukin (IL)-17, IL-12, IL-23, IL-6, tumor necrosis factor- (TNF-), interferon- (IFN-) as well as IL-10 in the pathophysiology of the ReA. […] Conflicting data have been reported on the production of cytokines in ReA patients. […] The pathogenic role during the critical stage of the disease supports the idea that TNF- blocking agents could be an effective treatment for patients with ReA who develop severe arthritis that does not respond to conventional lines of treatment.

• #1

  https://journals.lww.com/jclinrheum/fulltext/2022/03000/reactive_arthritis_after_intravesical_bacillus.53.aspx

  Reactive arthritis (ReA) is a sterile arthritis that occurs in genetically predisposed individuals secondary to an extra-articular infection, usually of the gastrointestinal or genitourinary tract. […] Sterile arthritis associated with instillation of intravesical bacillus Calmette-Gurin (iBCG) therapy used for bladder cancer can also be included under ReA based on the pathogenic mechanism. […] Similar to spondyloarthritis, HLA-B27 positivity is a known contributor to the genetic susceptibility underlying iBCG-associated ReA. […] Other genetic factors, such as HLA-B39 and HLA-B51, especially in Japanese patients, can also be involved in the pathophysiology of iBCG-associated ReA. […] After local infection with certain bacteria, the bacteria likely persist at the primary infection sites or their adjacent lymph nodes (incomplete eradication of the infection). Thereafter, the bacteria or their Ags can be transported from these primary sites into the synovium, either directly via the blood or indirectly by phagocytes (monocytes), resulting in an altered local immune response in genetically susceptible individuals. Thus, ReA development depends on a combination of contributors: (1) microbial agents (intracellular Gram-negative bacteria), (2) genetic factors (HLA-B27 positivity and single-nucleotide polymorphisms in TLR2), and (3) an aberrant synovial immune response (unbalanced production of TNF- [decreased in acute ReA and elevated in chronic ReA], IFN- [decreased in acute ReA], IL-6 [elevated in ReA], IL-10 [increased in ReA], IL-17 [elevated in ReA]).

• #1 Metabolomics: An Emerging Approach to Understand the Pathogenesis of Reactive Arthritis. | Scilit

  https://www.scilit.com/publications/94e33c06c204888ddf22aae63d6bd29e

  Reactive arthritis (ReA) is characterized by immune-mediated sterile synovitis brought on by an infection that enters the body through the gastrointestinal or urogenital tracts from a distance. […] Cytokines are crucial in orchestrating an effective immune response to eliminate bacterial infections, such as those seen in ReA (Reactive Arthritis) conditions. The balance between Th1 and Th2 cytokines is particularly important in determining the outcome of infections associated with ReA. TNF-α and IFN-γ are key antibacterial Th1 cytokines that promote cell-mediated immunity, essential for effective cellular responses against intracellular bacteria. In contrast, Th2 cytokines like IL-4, IL-5, IL-9, and IL-13 are more involved in generating humoral immunity and allergic responses. The mechanisms underlying the differentiation of T helper lymphocytes, which lead to a skewed cytokine secretion profile, remain unclear. Several factors, including the local inflammatory environment, IL-12 levels during T cell priming, variations among antigen-presenting cells (APCs), and antigen dose, have been suggested as potential contributors. This review will explore the critical role of metabolomics in cytokine production and its profound impact on the pathogenesis of reactive arthritis.

• #1 Reactive Arthritis (Reiter’s Syndrome) | AAFP

  https://www.aafp.org/pubs/afp/issues/1999/0801/p499.html

  Reactive arthritis usually occurs following an infection in a genetically susceptible person. Over two thirds of these patients are HLA-B27 positive. Those who are negative frequently are positive for cross-reacting antigens such as B7, B22, B40 and B42. A recent study found a similarity between some peptides found in gram-negative organisms and peptides that are in the binding site of the B27 molecule. […] Although these gram-negative organisms may trigger the disease, viable organisms have not been cultured from involved tissues. It was recently reported that the organisms may be persistent in synovial tissue but not in a form that is detectable by routine screening methods.

• #1 Immunopathogenesis of reactive arthritis: Role of the cytokines

  https://www.wjgnet.com/2219-2824/full/v4/i2/78.htm

  The immunopathogenic mechanisms involved in reactive arthritis (ReA) development are still unknown. However, in the last years, increased evidence suggests that the immune response in particular certain cytokines could be involved in the pathogenesis of ReA. […] The classical bacteria associated with gastrointestinal ReA are Yersinia, Salmonella, Shigella and Campylobacter, while C. trachomatis is by far the most common cause of ReA associated with genital infection. […] The immunopathogenic mechanisms involved in ReA development are still unknown. Even when bacterial cultures of synovial fluids are negative in ReA, bacterial antigens have been found in the joints of patients. […] Based on these findings, some authors have suggested that the bacteria probably persist outside the joint at sites such as gut mucosa or lymph nodes, and bacterial antigens might then be transported by monocytes to the joints. On the other hand, an altered immune response and the unbalanced production of cytokines have been reported in subjects with ReA. This altered immune response benefits the bacterial persistence and disfavors the elimination of the antigen by the host.

• #1 Sexually Associated Reactive Arthritis (SARA); Post-infectious STI arthritis | Johns Hopkins ABX Guide

  https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540500/all/Sexually_Associated_Reactive_Arthritis__SARA_

  The mechanism of SARA pathogenesis is not wholly known. This appears to be due to an immune response to urogenital organisms or the persistence of the organism or antigenic debris in synovial tissue. […] When CT is the underlying cause, an aberrant form with the repressed synthesis of the major outer membrane protein and active production of heat shock protein appears, contributing to the inflammatory response. […] A causal role for other genital tract pathogens is unclear (there are cases of reactive arthritis due to Shigella).

• #1 Reactive Arthritis | MedUni Vienna

  https://innere-med-3.meduniwien.ac.at/en/unsere-abteilungen/rheumatologie/patientinneninformationen/services/services-4/

  The pathogenesis of joint inflammation is not fully understood. Increased mucosal permeability in the intestine or urinary tract is considered a possible factor. The resulting increased exposure to bacterial or other antigens leads to immune reactions in the joint. Loss of tolerance to the body’s own (intestinal) bacterial flora could also play a role.

• #1 Reactive Arthritis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331347-overview

  ReA is associated with histocompatibility leukocyte antigen B-27 (HLA-B27), a major histocompatibility complex (MHC) class I molecule involved in T-cell antigen presentation. Results for HLA-B27 are positive in 65-96% of patients (average, 75%) with ReA. Patients with HLA-B27, as well as those with a strong family clustering of the disease, tend to develop more severe and long-term disease. […] Sun et al reported that susceptibility to ReA arthritis is affected by the levels of certain killer cell immunoglobulin-like receptors (KIRs), which correspond with specific HLA-C ligand genotypes. In individuals with high levels of activating and low levels of inhibitory KIR signals, pathogens can more easily trigger natural killer cell and T-cell innate and adaptive immune responses, resulting in the overproduction of cytokines that contribute to the pathogenesis of ReA.

• #1 Reactive Arthritis (Reiter’s disease, Reiter’s syndrome, Fiessinger-Leroy disease, venereal arthritis, polyarteritis enterica) – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/reactive-arthritis-reiters-disease-reiters-syndrome-fiessinger-leroy-disease-venereal-arthritis-polyarteritis-enterica/

  Additionally, compared to other HLA molecules, B27 has an increased tendency to misfold due to the location of disulfide bonds, and the misfolded protein could potentially induce a proinflammatory immune response. […] Furthermore, compared to controls, in vitro HLA-B27 positive monocytes kill Salmonella less efficiently and show increased production of proinflammatory cytokines IL-10 and TNF-alpha. This effect on the local cytokine milieu may also be important in the pathogenesis of reactive arthritis and is supported by the success of biologic therapeutics that specifically inhibit these cytokines.

• #1 Pathogenesis of Ankylosing Spondylitis and Reactive Arthritis | Musculoskeletal Key

  https://musculoskeletalkey.com/pathogenesis-of-ankylosing-spondylitis-and-reactive-arthritis/

  Genetics plays a major role in the etiology of ankylosing spondylitis. […] Reactive arthritis is initiated by infection outside the joints. […] At least in the case of Chlamydia-induced arthritis, a modified form of the pathogen can be detected in the joints of some patients. […] The process of bone formation in this disease has become a major research frontier. […] TNF is a major player in causing the symptoms of ankylosing spondylitis. […] The arthritogenic peptide hypothesis postulates that in the case of ankylosing spondylitis, there is a breakdown of tolerance to certain self-peptides, and this breakdown is a consequence of mimicry between the self-peptides and certain pathogen-derived and arthritis-causing peptides. […] The free heavy chain hypothesis postulates that engagement of these receptors will generate arthritis-causing events. […] The unfolded protein hypothesis postulates that HLA-B27 induces an unfolded protein response, which, in conjunction with activation by pattern recognition receptors (PRRs) such as those for lipopolysaccharide, would generate proinflammatory cytokines to such a degree as to cause arthritis.

• #1 Reactive Arthritis – The Rheumatologist

  https://www.the-rheumatologist.org/article/reactive-arthritis-2/?singlepage=1

  Recent studies in CD have supported the role of defective host immune response to foreign organisms in immunopathogenesis. […] The recognition that Chlamydia trachomatis and Chlamydia pneumoniae species may exist in a persistent metabolically active infection state in the synovium suggests that persistent Chlamydiae may be susceptible to antimicrobial agents. […] This raises a very pertinent clinical question: How many patients currently classified as undifferentiated SpA might be effectively treated with antibiotics? […] What would transpire if the mitochondrial DNA were released systemically, as might occur following trauma? […] As our thinking of self/nonself proved in retrospect to be simplistic, and the gap between infection and trauma begins to narrow, potential new scenarios arise in the pathogenesis of inflammatory joint disease.

• #1 Of Bugs and Joints: The Relationship Between Infection and Joints | Reumatología Clínica

  http://www.reumatologiaclinica.org/en-of-bugs-joints-relationship-between-articulo-S2173574312001608

  The evidence discussed supports the notion that the prolonged use of combinations of antibiotics and antimicrobial activity to inhibit the production capacity of the Chlamydia HSP-60 could cure chronic reactive arthritis induced by Chlamydia, somewhat similar to what happens with other persistent intracellular organisms, such as Mycoplasma tuberculosis.

• #1 Reactive Arthritis – The Rheumatologist

  https://www.the-rheumatologist.org/article/reactive-arthritis-2/?singlepage=1

  The discovery of the complex tango of receptor-ligand interactions involving TLRs led to the recognition that the inflammation arising as a consequence of infection requires neither a viable pathogen nor even of the intact organism. […] The notion that TLRs are specific only for foreign determinants has been replaced with the recognition that mammalian nucleic acids, among other molecules, are ligands for certain TLRs; indeed, this concept has proved to be pivotal in current concepts of lupus pathogenesis. […] The underlying assumption in the molecular mimicry theories, exemplified by the studies of rheumatic fever, is that the host immune response to infection is overactive in nonseptic sequelae like ReA. […] The cytokine profiles of ReA patients suggest down-regulation of proinflammatory cytokines rather than upregulation.

• #1 Elucidating potential molecular signatures through host-microbe interactions for reactive arthritis and inflammatory bowel disease using combinatorial approach | Scientific Reports

  https://www.nature.com/articles/s41598-020-71674-8

  The gut derived core host-microbe and microbe-microbe interspecies communication would enhance the existing knowledge of such co-existent disorders IBD and ReA. […] The most closely associated common protein observed in all the selected common microbial species involved in both IBD and ReA is Na(+)/H(+) antiporter (NHAA), microbial integral membrane protein, catalyzing the exchange of 2 H(+) per Na(+) and involved in processes crucial for cell viability. […] Similarly, the common host interacting protein with NHAA is Kynureninase (KYNU), involved in tryptophan metabolism and whose differential expression (upregulation and downregulation based on the control samples) have been followed in IBD patient cohorts. […] It is suggested that in host-microbe interactions, bacterial proteins entering host cells interact with host proteins and inject their effector components, but has not been proven in ReA and IBD.

• #1 Elucidating potential molecular signatures through host-microbe interactions for reactive arthritis and inflammatory bowel disease using combinatorial approach | Scientific Reports

  https://www.nature.com/articles/s41598-020-71674-8

  This could assist to comprehend the very few reports indicated in the rare autoimmune ReA, where gene expression datasets of the co-evolved disorder IBD can serve to incorporate the larger theme of gut-microbiome associations. […] The theme of gut-microbiome paradigm shifts thus contemplates the vital cues in triggering autoimmunity with indirect linkages to diet and environmental triggers. […] This mechanism has been observed in ReA where reports have predicted microorganism peptides such as chlamydial proteins and Yersinia pseudotuberculosis peptides showing homology with human HLA-B27 via bioinformatic analysis. […] We state that the initial host-microbe triggers for IBD associated ReA is when pathogenic microbial protein NHAA interacts with host protein KYNU that further interacts with human proteins ADA, SOD2, CAT and ACE and carbon metabolism involving the above host proteins is hampered.

• #1 Mechanism of lysine oxidase-like 1 promoting synovial inflammation mediating rheumatoid arthritis development | Aging

  https://www.aging-us.com/article/205429/text

  LOXL1 expression was significantly elevated in the synovium of patients with rheumatoid arthritis, and LOXL1 mRNA and protein levels were elevated in tumor necrosis factor -stimulated human synovial sarcoma cells (SW982). […] Knockdown of LOXL1 inhibited tumor necrosis factor -induced inhibition in SW982 cells expression of inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX2), and interleukin-6 (IL-6). […] Interestingly, knockdown of LOXL1 inhibited the phosphorylation of PI3K and AKT. […] In summary, LOXL1 may become a novel diagnostic gene for RA, and knockdown of LoxL1 may inhibit synovial inflammation by affecting PI3K/AKT pathway. […] The results of KEGG enrichment analysis showed that the presence of PI3K/AKT signaling pathway in the disease process. […] We concluded from the study of basement membrane-associated gene LOXL1 that LOXL1 may decelerate RA synovial inflammation by inhibiting the activation of PI3K/AKT signaling pathway, and LOXL1 may be a potential diagnostic biomarker and therapeutic target for rheumatoid arthritis.

• #1

  https://journals.lww.com/jclinrheum/fulltext/2022/03000/reactive_arthritis_after_intravesical_bacillus.53.aspx

  The arthritogenic peptide hypothesis is among the potential mechanisms linking HLA-B27 to ReA. This hypothesis explains that HLA-B27+ APCs initially present a bacterial-derived peptide to CD8+ T cells in primary infection sites. The activated CD8+ T cells then translocate to joints, where they respond to self-peptides presented by HLA-B27 on synovium cells due to molecular mimicry. […] With regard to the immunopathogenesis of ReA after iBCG therapy, it has been shown that iBCG therapy can provoke a systemic hypersensitivity reaction (both CD4+ and CD8+ T cells) in addition to the previously discussed local immunity. Therefore, activated and memory immune cells may translocate to joints, resulting in the development of arthritis. […] A BCG-induced cytotoxic immune response has been suggested to be triggered in the synovium via cross-reactivity with an endogenous heat shock protein presented by HLA-B27. […] However, prior studies have reported that the prevalence of HLA-B27 positivity is lower in Japan. […] Therefore, other genetic factors might also be involved in the pathophysiology of iBCG-associated ReA.

• #1 Aetiology and pathogenesis of reactive arthritis: role of non-antigen-presenting effects of HLA-B27 | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar1762

  Spondyloarthropathies are inflammatory diseases closely associated with human leukocyte antigen (HLA)-B27 by unknown mechanisms. One of these diseases is reactive arthritis (ReA), which is typically triggered by Gram-negative bacteria, which have lipopolysaccharide as an integral component of their outer membrane. Several findings in vivo and in vitro obtained from patients with ReA and from different model systems suggest that HLA-B27 modulates the interaction between ReA-triggering bacteria and immune cells by a mechanism unrelated to the antigen presentation function of HLA-B27. […] Recent studies suggest that in addition to its function as an antigen-presenting molecule, HLA-B27 might also have other functions that could modulate the inflammatory response and thus might cause susceptibility to SpA. Results from these experiments have offered new information about the abnormal host-microbe interaction between ReA-triggering bacteria and an HLA-B27-positive host.

• #1 Reactive Arthritis Caused by Blastocistys hominis | Reumatología Clínica

  https://www.reumatologiaclinica.org/en-reactive-arthritis-caused-by-blastocistys-articulo-S2173574312000032

  Reactive arthritis is defined as an acute arthritis caused by enteric or genitourinary infection. This infection usually precedes arthritis by a month. The most frequent reactive arthritis due to Salmonella, Shigella, Chlamydia, Yersinia and Campylobacter. However, there are cases described in the literature of reactive arthritis caused by other microorganisms, such as protozoa. […] The mechanisms by which different parasites can cause joint disease are multiple. For example, local invasion from neighboring bones or muscles, via the blood or lymphatic with the presence of adult individuals, larvae or eggs in the joint cavity. They could also trigger a reactive inflammatory reaction to the presence of the parasite in the surrounding tissue, without an actual joint invasion. In our case, we assume that the latter was the most likely mechanism of action of B. hominis. […] On the other hand, some authors use the term parasitic rheumatism in the case of inflammatory conditions without the presence of the parasite in the joint or in its vicinity, probably triggered by an immune mechanism.

• #2 Reactive Arthritis: Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7519381/

  Reactive arthritis is considered to be part of the spectrum of the spondyloarthritis. […] The understanding of pathophysiological models is challenging, but recent studies contribute to elucidate the major factors involved in the development of the disease. […] Recent studies related to ReA pathophysiology have highlighted the contribution of the microbiota in the pathogenesis of this type of arthritis. […] The development of ReA depends on four major factors: infection history (etiological agents), the role of cytokines, the involvement of genetic factor (HLA-B27), and gut microbiota. […] Some bacteria are commonly known to be triggers of ReA. […] Moreover, it has been proven that the synovial tissue or fluid may contain bacterial antigens, and the persistence of these components can turn acute ReA into chronic arthritis.

• #2 Reactive Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499831/

  Reactive arthritis (ReA) is inflammatory arthritis that manifests several days to weeks after a gastrointestinal or genitourinary infection. […] It is believed that the disorder is due to an aberrant autoimmune response to a gastrointestinal or genitourinary infection caused by salmonella, shigella, campylobacter, or chlamydia. […] Today, it is believed that the disorder is due to an aberrant autoimmune response to the gastrointestinal infection caused by salmonella, shigella, campylobacter, or chlamydia. […] Reactive arthritis is an immune-mediated syndrome triggered by a recent infection. It is hypothesized that T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids when invasive bacteria reach the systemic circulation. These activated cytotoxic-T cells attack the synovium and other self-antigens through molecular mimicry. The evidence of Chlamydia trachomatis and C pneumoniae ribosomal RNA transcripts, enteric bacterial DNA, and bacterial degradation products in the synovial tissue and fluid supports this. It is believed that anti-bacterial cytokine response is also impaired in reactive arthritis, resulting in decreased bacteria elimination.

• #2 Reactive Arthritis (Reiter’s disease, Reiter’s syndrome, Fiessinger-Leroy disease, venereal arthritis, polyarteritis enterica) – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/reactive-arthritis-reiters-disease-reiters-syndrome-fiessinger-leroy-disease-venereal-arthritis-polyarteritis-enterica/

  Reactive arthritis, the currently accepted term, is a systemic, seronegative spondyloarthropathy defined by a temporal relationship to a precipitating infection with manifestations not limited to the classic triad. […] While the exact pathophysiologic mechanism has not been elucidated, it has been shown that an aberrant, exaggerated cell-mediated and humoral immune response to particular antigens leads to inflammation at target organs in genetically susceptible individuals, with Chlamydia, Salmonella, Campylobacter, Shigella, and Yersinia infections as the most commonly reported triggering bacteria. […] It is unclear whether the pathogenic mechanism is the same for each organism, but common features amongst them include an ability to invade mucosal surfaces, the presence of lipopolysaccharide (LPS) in their outer membrane, and an ability to invade host cells and survive intracellularly, particularly in macrophage endosomes.

• #2 Reactive Arthritis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331347-overview

  ReA is associated with histocompatibility leukocyte antigen B-27 (HLA-B27), a major histocompatibility complex (MHC) class I molecule involved in T-cell antigen presentation. Results for HLA-B27 are positive in 65-96% of patients (average, 75%) with ReA. Patients with HLA-B27, as well as those with a strong family clustering of the disease, tend to develop more severe and long-term disease. […] Sun et al reported that susceptibility to ReA arthritis is affected by the levels of certain killer cell immunoglobulin-like receptors (KIRs), which correspond with specific HLA-C ligand genotypes. In individuals with high levels of activating and low levels of inhibitory KIR signals, pathogens can more easily trigger natural killer cell and T-cell innate and adaptive immune responses, resulting in the overproduction of cytokines that contribute to the pathogenesis of ReA.

• #2

  https://journals.lww.com/jclinrheum/fulltext/2022/03000/reactive_arthritis_after_intravesical_bacillus.53.aspx

  The arthritogenic peptide hypothesis is among the potential mechanisms linking HLA-B27 to ReA. This hypothesis explains that HLA-B27+ APCs initially present a bacterial-derived peptide to CD8+ T cells in primary infection sites. The activated CD8+ T cells then translocate to joints, where they respond to self-peptides presented by HLA-B27 on synovium cells due to molecular mimicry. […] With regard to the immunopathogenesis of ReA after iBCG therapy, it has been shown that iBCG therapy can provoke a systemic hypersensitivity reaction (both CD4+ and CD8+ T cells) in addition to the previously discussed local immunity. Therefore, activated and memory immune cells may translocate to joints, resulting in the development of arthritis. […] A BCG-induced cytotoxic immune response has been suggested to be triggered in the synovium via cross-reactivity with an endogenous heat shock protein presented by HLA-B27. […] However, prior studies have reported that the prevalence of HLA-B27 positivity is lower in Japan. […] Therefore, other genetic factors might also be involved in the pathophysiology of iBCG-associated ReA.

• #2 Reactive Arthritis: Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7519381/

  The bacterial antigens are transported from the primary site into the synovial membrane after local bacterial infection, which causes the activation of T-lymphocytes and consequently the release of inflammatory cytokines, resulting in synovial inflammation. […] Studies have shown that the prevalence of positive HLA B27 ranges from 50 to 80% in patients with ReA and 90% of the cases with ankylosing spondylitis. […] It has been suggested that HLA-B27 may influence the host response. […] The altered microbiota may result in aberrant immune responses to gut flora, gut dysbiosis, inflammation, and thus to SpA. […] In a study that compared patients with ReA with those with prior infections who did not go on to develop arthritis, no significant differences were seen in gut bacterial diversity between the groups.

• #2 Immunopathogenesis of reactive arthritis: Role of the cytokines

  https://www.wjgnet.com/2219-2824/full/v4/i2/78.htm

  The immunopathogenic mechanisms involved in reactive arthritis (ReA) development are still unknown. However, in the last years, increased evidence suggests that the immune response in particular certain cytokines could be involved in the pathogenesis of ReA. […] The classical bacteria associated with gastrointestinal ReA are Yersinia, Salmonella, Shigella and Campylobacter, while C. trachomatis is by far the most common cause of ReA associated with genital infection. […] The immunopathogenic mechanisms involved in ReA development are still unknown. Even when bacterial cultures of synovial fluids are negative in ReA, bacterial antigens have been found in the joints of patients. […] Based on these findings, some authors have suggested that the bacteria probably persist outside the joint at sites such as gut mucosa or lymph nodes, and bacterial antigens might then be transported by monocytes to the joints. On the other hand, an altered immune response and the unbalanced production of cytokines have been reported in subjects with ReA. This altered immune response benefits the bacterial persistence and disfavors the elimination of the antigen by the host.

• #2

  https://journals.lww.com/jclinrheum/fulltext/2022/03000/reactive_arthritis_after_intravesical_bacillus.53.aspx

  Reactive arthritis (ReA) is a sterile arthritis that occurs in genetically predisposed individuals secondary to an extra-articular infection, usually of the gastrointestinal or genitourinary tract. […] Sterile arthritis associated with instillation of intravesical bacillus Calmette-Gurin (iBCG) therapy used for bladder cancer can also be included under ReA based on the pathogenic mechanism. […] Similar to spondyloarthritis, HLA-B27 positivity is a known contributor to the genetic susceptibility underlying iBCG-associated ReA. […] Other genetic factors, such as HLA-B39 and HLA-B51, especially in Japanese patients, can also be involved in the pathophysiology of iBCG-associated ReA. […] After local infection with certain bacteria, the bacteria likely persist at the primary infection sites or their adjacent lymph nodes (incomplete eradication of the infection). Thereafter, the bacteria or their Ags can be transported from these primary sites into the synovium, either directly via the blood or indirectly by phagocytes (monocytes), resulting in an altered local immune response in genetically susceptible individuals. Thus, ReA development depends on a combination of contributors: (1) microbial agents (intracellular Gram-negative bacteria), (2) genetic factors (HLA-B27 positivity and single-nucleotide polymorphisms in TLR2), and (3) an aberrant synovial immune response (unbalanced production of TNF- [decreased in acute ReA and elevated in chronic ReA], IFN- [decreased in acute ReA], IL-6 [elevated in ReA], IL-10 [increased in ReA], IL-17 [elevated in ReA]).

• #2 Reactive Arthritis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331347-overview

  The mechanism by which the interaction of the inciting organism with the host leads to the development of ReA is not known. Possibly, microbial antigens cross-react with self-proteins, stimulating and perpetuating an autoimmune response mediated by type 2 T helper (Th2) cells. Chronicity and joint damage have been associated with a Th2 cytokine profile that leads to decreased bacterial clearance. […] Synovitis in ReA is mediated by proinflammatory cytokines. Native T cells under the influence of transforming growth factor (TGF)- and other cytokines, such as interleukin (IL)-6, differentiate into Th17 effector cells, which then produce IL-17. IL-17 is one of the major cytokines elevated in the synovial fluid of these patients. […] The Toll-like receptors (TLRs) recognize different extracellular antigens as part of the innate immune system. TLR-4 recognizes gram-negative lipopolysaccharide (LPS). Studies in mice and humans showed abnormalities in antigen presentation due to downregulation of TLR-4 costimulatory receptors in patients with ReA.

• #3 Immunopathogenesis of reactive arthritis: Role of the cytokines

  https://www.wjgnet.com/2219-2824/full/v4/i2/78.htm

  Reactive arthritis (ReA), also known as sterile postinfectious arthritis, belongs to the group of related arthropathies known as spondyloarthritis (SpA). […] The immunopathogenic mechanisms involved in ReA development are still unknown. A hypothesis suggested that the bacteria probably persist outside the joint, at sites such as gut mucosa or lymph nodes, and bacterial antigens might then be transported to the joints. On the other hand, an altered immune response and the unbalanced production of cytokines have been reported in subjects with ReA. Currently, there is increased evidence to suggest that both mechanisms would operate in the immunopathogenesis of ReA. In this review we highlight recent advances on the role of cytokines in the ReA. Particularly, we discuss the roles of some pro- and anti-inflammatory cytokines involved in the immunopathogenesis of ReA.

• #3 Immunopathogenesis of reactive arthritis: Role of the cytokines

  https://www.wjgnet.com/2219-2824/full/v4/i2/78.htm

  The immunopathogenic mechanisms involved in reactive arthritis (ReA) development are still unknown. However, in the last years, increased evidence suggests that the immune response in particular certain cytokines could be involved in the pathogenesis of ReA. […] The classical bacteria associated with gastrointestinal ReA are Yersinia, Salmonella, Shigella and Campylobacter, while C. trachomatis is by far the most common cause of ReA associated with genital infection. […] The immunopathogenic mechanisms involved in ReA development are still unknown. Even when bacterial cultures of synovial fluids are negative in ReA, bacterial antigens have been found in the joints of patients. […] Based on these findings, some authors have suggested that the bacteria probably persist outside the joint at sites such as gut mucosa or lymph nodes, and bacterial antigens might then be transported by monocytes to the joints. On the other hand, an altered immune response and the unbalanced production of cytokines have been reported in subjects with ReA. This altered immune response benefits the bacterial persistence and disfavors the elimination of the antigen by the host.

• #3 Reactive Arthritis: Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7519381/

  The bacterial antigens are transported from the primary site into the synovial membrane after local bacterial infection, which causes the activation of T-lymphocytes and consequently the release of inflammatory cytokines, resulting in synovial inflammation. […] Studies have shown that the prevalence of positive HLA B27 ranges from 50 to 80% in patients with ReA and 90% of the cases with ankylosing spondylitis. […] It has been suggested that HLA-B27 may influence the host response. […] The altered microbiota may result in aberrant immune responses to gut flora, gut dysbiosis, inflammation, and thus to SpA. […] In a study that compared patients with ReA with those with prior infections who did not go on to develop arthritis, no significant differences were seen in gut bacterial diversity between the groups.

• #3 Pathogenesis of Ankylosing Spondylitis and Reactive Arthritis | Musculoskeletal Key

  https://musculoskeletalkey.com/pathogenesis-of-ankylosing-spondylitis-and-reactive-arthritis/

  Genetics plays a major role in the etiology of ankylosing spondylitis. […] Reactive arthritis is initiated by infection outside the joints. […] At least in the case of Chlamydia-induced arthritis, a modified form of the pathogen can be detected in the joints of some patients. […] The process of bone formation in this disease has become a major research frontier. […] TNF is a major player in causing the symptoms of ankylosing spondylitis. […] The arthritogenic peptide hypothesis postulates that in the case of ankylosing spondylitis, there is a breakdown of tolerance to certain self-peptides, and this breakdown is a consequence of mimicry between the self-peptides and certain pathogen-derived and arthritis-causing peptides. […] The free heavy chain hypothesis postulates that engagement of these receptors will generate arthritis-causing events. […] The unfolded protein hypothesis postulates that HLA-B27 induces an unfolded protein response, which, in conjunction with activation by pattern recognition receptors (PRRs) such as those for lipopolysaccharide, would generate proinflammatory cytokines to such a degree as to cause arthritis.

• #4 Reactive Arthritis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331347-overview

  Molecular evidence of bacterial DNA (obtained via polymerase chain reaction [PCR] assay) in synovial fluids has been found only in Chlamydia-related ReA, and a single placebo-controlled trial of a tetracycline derivative (ie, lymecycline) has shown a reduction in the duration of acute Chlamydia-related, but not enteric-related, ReA. This suggests that persistent infection may play a role, at least in some cases of chlamydial-associated ReA. […] The role of HLA-B27 in this scenario remains to be fully defined. The following theories have been proposed: Molecular mimicry – This hypothesis suggests that a similarity exists at the molecular level between the HLA-B27 molecule and the inciting organisms, allowing the triggering of an immune response and the subsequent development of clinical disease. […] HLA-B27 may share molecular characteristics with bacterial epitopes, facilitating an autoimmune cross-reaction instrumental in pathogenesis. HLA-B27 contributes to the pathogenesis of the disease and reportedly increases the risk of ReA 50-fold.

• #5 Reactive Arthritis: Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7519381/

  The findings assess that HLA-B27 expression can reduce the threshold of endoplasmic reticulum (ER) stress induction and that Salmonella can induce the unfolded protein response. […] The involvement of gut microbial dysbiosis in disease pathogenesis remains unclear; thus, further productive researchers are needed to close these knowledge gaps in the field.

• #6 Of Bugs and Joints: The Relationship Between Infection and Joints | Reumatología Clínica

  http://www.reumatologiaclinica.org/en-of-bugs-joints-relationship-between-articulo-S2173574312001608

  The pathogenesis of reactive arthritis is a complex, multifactorial, with involvement of the environment, genetic factors and the immune system. Environmental factors are represented by infectious agents, particularly gram-negative organisms. In humans, HLA-B27 plays a major role, although the exact mechanism of how it performs its role is unknown. […] The work of Taurog et al. in transgenic rats for HLA-B27 and human 2-microglobulin clearly established the importance of HLA-B27 in the pathogenensis. […] Moreover, the participation of the environment was also clearly established with the second part of the study. If rats were maintained at birth in a sterile environment they did not develop the inflammatory process, indicating that the commensal flora is important in triggering the inflammatory process. These findings are indicative of the role of the commensal flora and are supported by the detection of commensal organisms by PCR in synovial fluid from patients with reactive arthritis.

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