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Background Activation of the NLRP3 inflammasome in gout amplifies the inflammatory response and mediates further damage. In the current study, we assessed the therapeutic effect of OLT1177, an orally active NLRP3 inflammasome inhibitor that is safe in humans, in murine acute arthritis models. Methods Zymosan or monosodium urate (MSU) crystals were injected intra-articularly (i.a.) into mouse knee joints to induce reactive or gouty arthritis. Joint swelling, articular cell infiltration, and synovial cytokines were evaluated 25 hours and 4 hours following zymosan or MSU challenge, respectively. OLT1177 was administrated intraperitoneally by oral gavage or in the food by an OLT1177-enriched diet. Results OLT1177 reduced zymosan-induced joint swelling ( p  < 0.001), cell influx ( p  < 0.01), and synovial levels of interleukin (IL)-1β, IL-6, and chemokine (C-X-C motif) ligand 1 (CXCL1) ( p  < 0.05), respectively, when compared with vehicle-treated mice. Plasma OLT1177 levels correlated ( p  < 0.001) dose-dependently with reduction in joint inflammation. Treatment of mice with OLT1177 limited MSU crystal articular inflammation ( p  > 0.0001), which was associated with decreased synovial IL-1β, IL-6, myeloperoxidase, and CXCL1 levels ( p  < 0.01) compared with vehicle-treated mice. When administrated orally 1 hour after MSU challenge, OLT1177 reduced joint inflammation, processing of IL-1β, and synovial phosphorylated c-Jun N-terminal kinase compared with the vehicle group. Mice were fed an OLT1177-enriched diet for 3 weeks and then challenged i.a. with MSU crystals. Joint swelling, synovial IL-1β, and expression of Nlrp3 and Il1b were significantly reduced in synovial tissues in mice fed an OLT1177-enriched diet when compared with the standard diet group. Conclusions Oral OLT1177 is highly effective in ameliorating reactive as well as gouty arthritis.

At this time, reactive arthritis (ReA) is considered to be part of the spectrum of the spondyloarthritis, previously known as Reiter’s syndrome, and refers to an infection induced systemic illness, characterized by a sterile synovitis occurring in a genetically predisposed individual, secondary to an infection localized in a distant organ/system, but also accompanied with multiple extra articular manifestations.

Reactive Arthritis (ReA), a rare seronegative inflammatory arthritis, lacks exquisite classification under rheumatic autoimmunity. ReA is solely established using differential clinical diagnosis of the patient cohorts, where pathogenic triggers linked to enteric and urogenital microorganisms e.g. Salmonella , Shigella , Yersinia , Campylobacter , Chlamydia have been reported. Inflammatory Bowel Disease (IBD), an idiopathic enteric disorder co-evolved and attuned to present gut microbiome dysbiosis, can be correlated to the genesis of enteropathic arthropathies like ReA. Gut microbes symbolically modulate immune system homeostasis and are elementary for varied disease patterns in autoimmune disorders. The gut-microbiota axis structured on the core host-microbe interactions execute an imperative role in discerning the etiopathogenesis of ReA and IBD. This study predicts the molecular signatures for ReA with co-evolved IBD through the enveloped host-microbe interactions and microbe-microbe ‘interspecies communication’, using synonymous gene expression data for selective microbes. We have utilized a combinatorial approach that have concomitant in-silico work-pipeline and experimental validation to corroborate the findings. In-silico analysis involving text mining, metabolic network reconstruction, simulation, filtering, host-microbe interaction, docking and molecular mimicry studies results in robust drug target/s and biomarker/s for co-evolved IBD and ReA. Cross validation of the target/s or biomarker/s was done by targeted gene expression analysis following a non-probabilistic convenience sampling. Studies were performed to substantiate the host-microbe disease network consisting of protein-marker-symptom/disease-pathway-drug associations resulting in possible identification of vital drug targets, biomarkers, pathways and inhibitors for IBD and ReA. Our study identified Na (+) /H (+) anti-porter (NHAA) and Kynureninase (KYNU) to be robust early and essential host-microbe interacting targets for IBD co-evolved ReA. Other vital host-microbe interacting genes, proteins, pathways and drugs include Adenosine Deaminase (ADA), Superoxide Dismutase 2 (SOD2), Catalase (CAT), Angiotensin I Converting Enzyme (ACE), carbon metabolism (folate biosynthesis) and methotrexate. These can serve as potential prognostic/theranostic biomarkers and signatures that can be extrapolated to stratify ReA and related autoimmunity patient cohorts for further pilot studies.

Mosquito-borne alphaviruses such as chikungunya virus and Ross River virus (RRV) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. The pathology of RRV-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. In this study, we have used a mouse model of RRV-induced disease to identify and characterize which complement activation pathways mediate disease progression after infection, and we have identified the mannose binding lectin (MBL) pathway, but not the classical or alternative complement activation pathways, as essential for development of RRV-induced disease. MBL deposition was enhanced in RRV infected muscle tissue from wild type mice and RRV infected MBL deficient mice exhibited reduced disease, tissue damage, and complement deposition compared to wild-type mice. In contrast, mice deficient for key components of the classical or alternative complement activation pathways still developed severe RRV-induced disease. Further characterization of MBL deficient mice demonstrated that similar to C3(-/-) mice, viral replication and inflammatory cell recruitment were equivalent to wild type animals, suggesting that RRV-mediated induction of complement dependent immune pathology is largely MBL dependent. Consistent with these findings, human patients diagnosed with RRV disease had elevated serum MBL levels compared to healthy controls, and MBL levels in the serum and synovial fluid correlated with severity of disease. These findings demonstrate a role for MBL in promoting RRV-induced disease in both mice and humans and suggest that the MBL pathway of complement activation may be an effective target for therapeutic intervention for humans suffering from RRV-induced arthritis and myositis.

The aim of this study was to assess the ability of MRI determined synovial volumes and bone marrow oedema to predict progressions in bone erosions after 1 year in patients with different types of inflammatory joint diseases. Eighty-four patients underwent MRI, laboratory and clinical examination at baseline and 1 year later. Magnetic resonance imaging of the wrist and finger joints was performed in 22 patients with rheumatoid arthritis less than 3 years (group 1) who fulfilled the American College of Rheumatology (ACR) criteria for rheumatoid arthritis, 18 patients with reactive arthritis or psoriatic arthritis (group 2), 22 patients with more than 3 years duration of rheumatoid arthritis, who fulfilled the ACR criteria for rheumatoid arthritis (group 3), and 20 patients with arthralgia (group 4). The volume of the synovial membrane was outlined manually before and after gadodiamide injection on the T1-weighted sequences in the finger joints. Bones with marrow oedema were summed up in the wrist and fingers on short-tau inversion recovery sequences. These MRI features was compared with the number of bone erosions 1 year later. The MR images were scored independently under masked conditions. The synovial volumes in the finger joints assessed on pre-contrast images was highly predictive of bone erosions 1 year later in patients with rheumatoid arthritis (groups 1 and 3). The strongest individual predictor of bone erosions at 1-year follow-up was bone marrow oedema, if present at the wrist at baseline. Bone erosions on baseline MRI were in few cases reversible at follow-up MRI. The total synovial volume in the finger joints, and the presence of bone oedema in the wrist bones, seems to be predictive for the number of bone erosions 1 year later and may be used in screening. The importance of very early bone changes on MRI and the importance of the reversibility of these findings remain to be clarified.

Reactive arthritis is a form of inflammatory arthritis associated with bacterial infection. In this article, the authors describe the current state of our knowledge regarding Chlamydia -induced reactive arthritis, including chlamydial persistence in joints, susceptibility factors and host and pathogen biology, and discuss future research priorities in this disease. Reactive arthritis (ReA), an inflammatory arthritic condition that is commonly associated with Chlamydia infections, represents a significant health burden, yet is poorly understood. The enigma of this disease is reflected in its problematic name and in its ill-defined pathogenesis. The existence of persistent pathogens in the arthritic joint is acknowledged, but their relevance remains elusive. Progress is being made in understanding the underlying mechanisms of ReA, whereby an imbalance between type 1 and type 2 immune responses seems to be critical in determining susceptibility to disease. Such an imbalance occurs prior to the initiation of an adaptive immune response, suggesting that innate cellular and molecular mechanisms in ReA should be prioritized as fruitful areas for investigation.

In addition to its well‐known pro‐inflammatory effects, tumor necrosis factor (TNF) displays anti‐inflammatory activities through mechanisms poorly understood. Previously, we reported the development of severe chronic Yersinia enterocolitica‐induced reactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. As regulatory T (Treg) cells limit chronic inflammation, here we aim to investigate the expansion and function of CD4+CD25+FoxP3+ Treg cells in the ReA animal model. The number of Treg cells as well as the FoxP3 mRNA expression and interleukin (IL)‐10 levels were significantly decreased in joint regional lymph nodes (RLNs) of TNFRp55−/− mice vs wild‐type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, the number of Treg cell in TNFRp55−/− was similar to WT mice. To explore the in vivo function of Treg cells at this chronic phase in WT and TNFRp55‐deficient mice, we adoptively transferred CD4+ T cells from TNFRp55‐deficient mice of day 21, into naïve WT or TNFRp55−/− mice. When knockout mice were used as recipients we observed higher delayed‐type hypersensitivity (DTH) responses and joint inflammation after heat‐killed Yersinia (HKY) stimulation. Accordingly, we found higher levels of IL‐17, interferon (IFN)‐γ, IL‐6, transforming growth factor (TGF)‐β1 and IL‐12/23p40 and lower IL‐10 levels in RLN of paws challenged with HKY in TNFRp55−/− recipient mice. In addition, we found that CD4+ T cells from TNFRp55−/− mice controlled antigen‐specific IL‐12/23(p40) production in recipient WT mice. Our results show that TNFRp55 controls the induction and function of Treg cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.

Rarely, tumour necrosis factor (TNF)α antagonist therapy has been associated with de novo psoriasiform eruptions. This is unusual in that these same drugs are used to treat psoriasis. Most of these cases involve the palms and soles, yet palmoplantar pustular psoriasis represents only 1.7% of all cases of psoriasis. Keratoderma blenorrhagicum is a psoriasiform rash that occurs primarily on the palms and soles of some patients with reactive arthritis. It is grossly and histologically indistinguishable from pustular psoriasis. Chlamydia trachomatis is a common aetiological agent for reactive arthritis, and in vitro studies have shown that chlamydial replication is inversely proportional to TNFα levels. Three patients taking TNFα antagonists are presented who developed such lesions and who were found to be positive for C trachomatis DNA in the affected skin. It is proposed that these psoriasiform lesions may not be psoriasis, but rather keratoderma blenorrhagicum.

A 1.5-year-old female Mississippi sandhill crane (Grus canadensis pulla) was presented and managed for a polyarthritis of the intertarsal and tarsophalangeal articulations. Results of aerobic bacterial cultures, Mycoplasma species culture, and polymerase chain reaction testing of articular fluid did not identify any causative organisms. Results of radiographs and cytologic examination of articular fluid were consistent with an inflammatory, nonerosive polyarthritis. The arthritis did not improve with systemic anti-inflammatory and antibiotic treatment and with joint lavage. A large necrotic granulomatous mass was detected on the right shoulder area from which Staphylococcus aureus and Enterococcus species were isolated as opportunistic pathogens. Two days after surgical resection of the mass, the distal polyarthritis resolved. Histopathologic examination of the mass was consistent with granulomatous vasculitis with abscess formation of unknown origin. In this crane, the unresponsiveness to standard therapy, the presence of an infected and inflammatory mass, and the resolution of the polyarthritis after the resection of the mass strongly supported a diagnosis of reactive immune-mediated nonerosive polyarthritis. Analysis of this case suggests that immune-mediated idiopathic arthritis should be a differential diagnosis of distal polyarthritis in cranes and that an inciting source remote from the joints should be investigated in case of lack of response to standard therapy.

Reiter’s syndrome is one of the reactive forms of seronegative spondyloarthropathies. Various therapies used in the management of Reiter’s syndrome are nonsteroidal antiinflammatory drugs (NSAIDs), antibiotics, and disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine (SSZ) or methotrexate (MTX). There is only one case report of successful treatment of Reiter’s syndrome with tumor necrosis factor-α (TNF-α) blockers in human immunodeficiency virus (HIV) patient (Gaylis N, 2003, J Rheumatol 30(2):407–411 Feb). We hereby report a case of Reiter’s syndrome treated successfully with infliximab, an anti-TNF-α chimeric monoclonal antibody. A 28-year-old white male presented with painful swelling of right elbow and ankle joints, urethritis. and lesions involving skin of soles of feet and penis. Detailed work-up of sexually transmitted diseases (STDs), HIV, and systemic etiology were negative. Despite aggressive treatment with antibiotics, NSAIDS, prednisone, and MTX for 3 months, he had persistent synovitis and worsening of skin lesions. He was then treated with infliximab 200 mg intravenously at weeks 0, 2, 6, and 14 weeks which resulted in complete resolution of arthritis and skin lesions within 6 weeks of infliximab therapy.