Vamorolone, a dissociative steroidal compound, reduces collagen antibody-induced joint damage and inflammation when administered after disease onset

Abstract Background Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. Methods C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. Results Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host’s ability to clear the infection. Conclusions Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.

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Adipokines as Potential Biomarkers in Rheumatoid Arthritis

Mediators of Inflammation ◽

10.1155/2014/425068 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Annalisa Del Prete ◽

Valentina Salvi ◽

Silvano Sozzani

Keyword(s):

Rheumatoid Arthritis ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Therapeutic Response ◽

Wide Spectrum ◽

Disease Onset ◽

Joint Damage ◽

Joint Injury ◽

Potential Biomarkers

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease characterized by severe joint injury. Recently, research has been focusing on the possible identification of predictor markers of disease onset and/or progression, of joint damage, and of therapeutic response. Recent findings have uncovered the role of white adipose tissue as a pleiotropic organ not only specialized in endocrine functions but also able to control multiple physiopathological processes, including inflammation. Adipokines are a family of soluble mediators secreted by white adipose tissue endowed with a wide spectrum of actions. This review will focus on the recent advances on the role of the adipokine network in the pathogenesis of RA. A particular attention will be devoted to the action of these proteins on RA effector cells, and on the possibility to use circulating levels of adipokines as potential biomarkers of disease activity and therapeutic response.

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Short-term low-magnesium diet reduces autoimmune arthritis severity and synovial tissue gene expression

Physiological Genomics ◽

10.1152/physiolgenomics.00003.2017 ◽

2017 ◽

Vol 49 (4) ◽

pp. 238-242 ◽

Cited By ~ 4

Author(s):

Max Brenner ◽

Teresina Laragione ◽

Pércio S. Gulko

Keyword(s):

Synovial Tissue ◽

Disease Onset ◽

Joint Damage ◽

Normal Diet ◽

Autoimmune Arthritis ◽

Short Term ◽

Erosive Disease ◽

Arthritis Severity ◽

Low Magnesium ◽

Dietary Magnesium

Magnesium has been suggested to have anti-inflammatory properties in short-term, mostly in vitro studies. To examine the effect of dietary magnesium modifications in arthritis severity and joint damage DA rats were placed on one of three diet regimens before the induction of autoimmune pristane-induced arthritis (PIA): a 4 wk low-magnesium diet, normal diet, and a magnesium-supplemented diet. The diets were switched to a normal diet 14 days after the induction of PIA (typical time of disease onset). Arthritis severity was scored for 38 days, and joints were examined by histology and quantitative PCR for proinflammatory genes. Rats on the low-magnesium diet were significantly and reproducibly protected and had 70% lower median arthritis severity score, with preservation of normal joint histology without erosive changes. Rats on the normal or magnesium-supplemented diets were not protected and developed equally severe and erosive disease. While the dietary modifications were at disease onset ( day 14 postinduction), the protective effect of the short-term low-magnesium diet persisted, suggesting a lasting effect on a critical pathogenic pathway. Rats on the low-magnesium diet had significant reduction in synovial tissue expression of IL-6, RORA, and RORC, which are genes required for the development of Th17 T cells. This study revealed a novel role for dietary magnesium in the regulation of autoimmune arthritis and opens new possibilities for the treatment of autoimmune diseases such as rheumatoid arthritis and psoriatic arthritis with short courses of dietary or drug-induced modulations of magnesium levels.

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Cost Effectiveness Analysis of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. A Systematic Review Literature

International Journal of Rheumatology ◽

10.1155/2011/845496 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 23

Author(s):

Maurizio Benucci ◽

Gianantonio Saviola ◽

Mariangela Manfredi ◽

Piercarlo Sarzi-Puttini ◽

Fabiola Atzeni

Keyword(s):

Rheumatoid Arthritis ◽

Cost Effectiveness ◽

Disease Activity ◽

Disease Onset ◽

Critical Evaluation ◽

Joint Damage ◽

Review Literature ◽

Disease Modifying Antirheumatic Drugs ◽

Antirheumatic Drugs ◽

Disease Modifying

The cost effectiveness of treatments that have changed the “natural history” of a chronic progressive disease needs to be evaluated over the long term. Disease-modifying antirheumatic drugs (DMARDs) are the standard treatment of rheumatoid arthritis (RA) and should be started as early as possible. A number of studies have shown that they are effective in improving disease activity and function, and in joint damage. Our review was focused on revision and critical evaluation of the studies including the literature on cost effectiveness of DMARDs (cyclosporine A, sulphasalazine, leflunomide, and methotrexate). The European League Against Rheumatism (EULAR) recommendations showed that traditional DMARDs are cost effective at the time of disease onset. They are less expensive than biological DMARDs and can be useful in controlling disease activity in early RA.

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P015 Imaging findings in cervical spine in patients with Juvenile Idiopathic Arthritis in Tunisia

Rheumatology ◽

10.1093/rheumatology/keab722.007 ◽

2021 ◽

Vol 60 (Supplement_5) ◽

Author(s):

Hiba Bettaieb ◽

Hanene Ferjani ◽

Kaouther Maatallah ◽

Dorra Ben Nessib ◽

Wafa Triki ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Cervical Spine ◽

Disease Activity ◽

Activity Index ◽

Disease Onset ◽

Clinical Manifestations ◽

Joint Damage ◽

Odontoid Process ◽

P Value ◽

Limited Range Of Motion

Abstract Background Juvenile Idiopathic Arthritis (JIA) is a chronic disease characterized by prolonged synovial inflammation that may cause structural joint damage. However, little is known about cervical spine involvement in JIA. The main objective of this study is to describe radiological findings of the cervical spine in patients with JIA. Methods We conduct a retrospective monocentric study. All JIA patients were included (ILAR criteria). Sociodemographic, JIA subtype, and clinical characteristics were collected. Disease activity at JIA diagnosis was evaluated by JADAS10 (Juvenile Arthritis Disease Activity Score) in poly and oligoarticular subtypes and by BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) in arthritis-related enthesitis form. Cervical spine radiographs including anteroposterior and lateral with flexion views were analyzed. A p-value < 0.05 was considered significant. Results We included 25 patients (16 girls and 9 boys) diagnosed with JIA with a mean age at disease onset of 9.9 ± 3.9 [3–16]. The median disease duration was 36 months (IQR 25–75%; 30–84). The JIA subtypes were in decreasing order of frequency: Enthesitis-related Arthritis (n = 9), Oligoarticular (n = 6), Polyarticular RF- (n = 4), Polyarticular RF + (n = 2), Systemic (n = 2), Psoriatic Arthritis (n = 1), and Undifferentiated (n = 1). Median ESR and CRP were 17 mm/h [2–98] and 15.4 mg/l [0–56] respectively. The Median BASDAI score was 2.8 [1–6.3]. Median JADAS10 score was 5.3 [0–20]. Four patients (16%) were on long-term corticosteroid therapy. Five patients (20 %) have a cervical spine involvement with the following subtypes: Polyarticular (n = 2), enthesitisenthesitis-related arthritis (n = 2), and systemic (n = 1). Clinical manifestations were neck pain (n = 3) and limited range of motion (n = 4). Neurological examination noted brisk deep tendon reflexes (n = 6), positive Babinski reflex (n = 1) and positive Hoffmann reflex (n = 2). No patient had a neurological deficit. The conventional radiographs of the cervical spine showed: loss of cervical lordosis (n = 2), diastasis C1-C2 (n = 3), erosion of the odontoid process (n = 1), and anterior ankylosis (n = 3). Subsequent cervical spine MRI confirmed these findings and showed pannus at the craniocervical junction in one case and block vertebra of C6-C7 in another case. Atlanto-axial subluxation was anteroposterior in 3 patients and rotatory in one. Conclusion Cervical spine involvement is frequent and underestimated in JIA, and its radiological features are various. Hence, regular radiographic monitoring of the cervical spine is required to prevent the development of this complication.

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Accelerating functional gene discovery in osteoarthritis

10.1101/836221 ◽

2019 ◽

Cited By ~ 1

Author(s):

Natalie C. Butterfield ◽

Katherine F. Curry ◽

Julia Steinberg ◽

Hannah Dewhurst ◽

Davide Komla-Ebri ◽

...

Keyword(s):

Imaging Techniques ◽

Disease Onset ◽

Joint Damage ◽

Gene Discovery ◽

Homeobox Gene ◽

Protective Role ◽

Functional Gene ◽

Mutant Mice ◽

Age Related ◽

Functional Involvement

AbstractOsteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox genePitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in theDio2gene byCrispr/Cas9genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

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Accelerating functional gene discovery in osteoarthritis

Nature Communications ◽

10.1038/s41467-020-20761-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Natalie C. Butterfield ◽

Katherine F. Curry ◽

Julia Steinberg ◽

Hannah Dewhurst ◽

Davide Komla-Ebri ◽

...

Keyword(s):

Imaging Techniques ◽

Disease Onset ◽

Joint Damage ◽

Gene Discovery ◽

Homeobox Gene ◽

Protective Role ◽

Functional Gene ◽

Mutant Mice ◽

Age Related ◽

Functional Involvement

AbstractOsteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.

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