Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan-induced SKG mice.

Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogens have an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor modulator (SERM) lasofoxifene (Laso) on disease activity of SpA. Mice were randomized into zymosan-treated, zymosan + 17ß-estradiol (E2)-treated, and zymosan + Laso-treated groups. Arthritis was assessed by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography and bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from SERM treatment.

Patients' and rheumatologists' perceptions on preventive intervention in rheumatoid arthritis and axial spondyloarthritis.

BACKGROUND: Individuals at risk of developing rheumatoid arthritis (RA) may benefit from lifestyle or pharmacological interventions aimed at primary prevention. The same may apply to individuals at risk of axial spondyloarthritis (axSpA). Our aim was to investigate and compare the willingness of individuals at risk of RA or axSpA and rheumatologists to initiate preventive intervention. METHODS: Individuals at risk of RA (arthralgia and anti-citrullinated protein antibodies and/or rheumatoid factor positivity without arthritis (RA-risk cohort; n = 100)), axSpA (first-degree relatives of HLA-B27-positive axSpA patients (SpA-risk cohort; n = 38)), and Dutch rheumatologists (n = 49) completed a survey on preventive intervention which included questions about disease perception, lifestyle intervention, and preventive medication. RESULTS: At-risk individuals reported willingness to change median 7 of 13 lifestyle components in the areas of smoking, diet, and exercise. In contrast, 35% of rheumatologists gave lifestyle advice to ≥ 50% of at-risk patients. The willingness to use 100% effective preventive medication without side effects was 53% (RA-risk), 55% (SpA-risk), and 74% (rheumatologists) at 30% disease risk which increased to 69% (RA-risk) and 92% (SpA-risk and rheumatologists) at 70% risk. With minor side effects, willingness was 26%, 29%, and 31% (at 30% risk) versus 40%, 66%, and 76% (at 70% risk), respectively. CONCLUSIONS: Risk perception and willingness to start preventive intervention were largely similar between individuals at risk of RA and axSpA. Although the willingness to change lifestyle is high among at-risk individuals, most rheumatologists do not advise them to change their lifestyle. In contrast, rheumatologists are more willing than at-risk patients to start preventive medication.

Baseline severity of sacroiliitis can predict acute inflammatory status of sacroiliac joint in early axial spondyloarthritis of male patients: a cross sectional study.

BACKGROUND: This study compared clinical, laboratory and radiographic features of axial spondyloarthritis (axSpA) between ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nrAxSpA) of young male patients. Additionally, we sought factors which can predict the baseline inflammatory status of sacroiliac joint (SIJ) in axSpA. METHODS: We retrospectively reviewed the medical records of 322 patients who visited our hospital due to inflammatory back pain, and 159 male patients with axSpA were enrolled. Enrolled patients were divided into two groups, AS group and nrAxSpA group, and medical records, laboratory data, radiologic findings were collected and analyzed. RESULTS: Alternating buttock pain and CRP elevation were significantly frequent in AS patients than nrAxSpA patients (68.8% vs 41.3%, P = 0.001, 63.5% vs 37.1%, P = 0.002), and SPondyloArthritis Research Consortium of Canada (SPARCC) score of SIJ was higher in AS patients than nrAxSpA patients (14.0 vs 5.0, P < 0.0001). Baseline sacroiliitis severity, psoriasis, and CRP elevation had positive association in univariate and multivariate regression analysis for SIJ inflammatory SPARCC score. CONCLUSION: AS patients were more frequently in acute inflammatory state than nrAxSpA patients according to laboratory and MRI finding. Baseline sacroiliitis grade was significantly associated with baseline inflammatory SPARCC score of SIJ. AS patients might need more intense initial treatment to resolve active inflammatory lesion of SIJ and prevent further radiologic progression.

Estrogen attenuates the spondyloarthritis manifestations of the SKG arthritis model.

BACKGROUND: Ankylosing spondylitis (AS) is a male-predominant disease, and radiographic evidence of damage is also more severe in males. Estrogen modulates immune-related processes such as T cell differentiation and cytokine production. This study aimed to evaluate the effect of estrogen on the disease activity of spondyloarthritis (SpA). METHODS: The effects of estrogen on the development of arthritis were evaluated by performing ovariectomy and 17ß-estradiol (E2) pellet implantation in zymosan-treated SKG mice. Clinical arthritis scores were measured, and 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography performed to quantify joint inflammation. The expression of inflammatory cytokines in joint tissue was measured. RESULTS: E2-treated mice showed remarkable suppression of arthritis clinically and little infiltration of inflammatory cells in the Achilles tendon and intervertebral disc. 18F-FDG uptake was significantly lower in E2-treated mice than in sham-operated (sham) and ovariectomized mice. Expression of TNF, interferon-γ, and IL-17A was significantly reduced in E2-treated mice, whereas expression of sclerostin and Dickkopf-1 was increased in E2-treated mice compared with sham and ovariectomized mice. CONCLUSIONS: Estrogen suppressed arthritis development in SKG mice, a model of SpA. Results of this study suggest that estrogen has an anti-inflammatory effect on the spondyloarthritis manifestations of the SKG arthritis model.

Rebamipide prevents peripheral arthritis and intestinal inflammation by reciprocally regulating Th17/Treg cell imbalance in mice with curdlan-induced spondyloarthritis.

BACKGROUND: Spondyloarthritis (SpA) usually manifests as arthritis of the axial and peripheral joints but can also result in extra-articular manifestations such as inflammatory bowel disease. Proinflammatory cytokine interleukin-17 (IL-17) plays a crucial role in the pathogenesis of SpA. Rebamipide inhibits signal transducer and activator of transcription 3 that controls IL-17 production and Th17 cell differentiation. This study examined the effect of rebamipide on SpA development. METHODS: SKG ZAP-70(W163C) mice were immunized with curdlan to induce SpA features. The mice were then intraperitoneally injected with rebamipide or vehicle 3 times a week for 14 weeks and their clinical scores were evaluated. Histological scores of the paw and spine and the length of the gut were measured at sacrifice. Immunohistochemical staining of IL-17 and tumor necrosis factor-α (TNF-α) was performed using tissue samples isolated from the axial joints, peripheral joints, and gut. Spleen tissue samples were isolated from both rebamipide- or vehicle-treated mice with SpA at 14 weeks after curdlan injection to determine the effect of rebamipide on Th17 and regulatory T (Treg) cell differentiation. RESULTS: Rebamipide decreased the clinical and histological scores of the peripheral joints. The total length of the gut was preserved in rebamipide-treated mice. IL-17 and TNF-α expression in the spine, peripheral joints, and gut was lower in rebamipide-treated mice than in control mice. Th17 cell differentiation was suppressed whereas Treg cell differentiation was upregulated in the spleen of rebamipide-treated mice. CONCLUSION: Rebamipide exerted beneficial effects in mice with SpA by preventing peripheral arthritis and intestinal inflammation and by regulating Th17/Treg cell imbalance, suggesting that it can be used as a potential therapeutic agent for treating arthritis to SpA patients.

Spondylarthritis in HLA-B27/human beta2-microglobulin-transgenic rats is not prevented by lack of CD8.

OBJECTIVE: HLA-B27 predisposes to spondylarthritis by an unknown mechanism. A logical candidate mechanism is through recognition of B27 by CD8+ T cells. The purpose of this study was to examine the effects of a lack of CD8 on the spondylarthritis that develops in B27/human beta(2)-microglobulin (Hubeta(2)m)-transgenic rats. METHODS: A missense mutation in the CD8a gene that causes a loss of CD8alpha expression was identified in offspring of a male Sprague-Dawley rat that had been treated with the mutagen N-ethyl-N-nitrosourea. The mutation was crossed into B27/Hubeta(2)m-transgenic lines on the Lewis background. CD8a(-/-) and CD8a(+/-) progeny were compared on a mixed SD-LEW background as well as after at least 10 backcrosses to LEW rats. CD8 function was assessed by generating cytolytic T lymphocytes (CTLs) against allogeneic DA strain antigens. RESULTS: Homozygous mutant rats showed normal CD8a and CD8b messenger RNA levels but no detectable expression of either protein and an almost complete abrogation of the allogeneic CTL response. Two disease phenotypes previously observed in different B27/Hubeta(2)m-transgenic lines also occurred in the respective CD8a(-/-)-transgenic rat lines. There was no significant difference in disease prevalence or severity between CD8a(-/-) rats and CD8a(+/-) rats. CONCLUSION: All of the previously described disease manifestations in HLA-B27/Hubeta(2)m-transgenic rats arise in the absence of any functional CD8+ T cells. It thus seems unlikely that classic T cell recognition of HLA-B27 is of primary importance in this animal model. The possibility of a secondary role of a CD8-dependent mechanism cannot be entirely excluded.

[Criteria to notify to the authorities the occupational lumbar trait diseases]. / Criteri per la denuncia ex D.M. 27/4/04 delle spondilodiscopatie del tratto lombare e dell'ernia discale lombare.

To carry out the requirement of notification according to the Italian law D.M. 27/4/04 in relation to the item "Manual handling of loads made continuously during working shift" it is necessary to clarify some quantitative and chronological aspects regarding the exposure and to precise the nature of the diseases to be notified. To fulfil their choices doctors at the moment can not rely on quantitative referrings based on the evidence and wide spread accepted, but they basically have operative indications partly taken from literature and stil under validation. However, to carry out the requirement of the law and to avoid choices not based on considered criteria, we propose some operative criteria deriving from the knowledge that at the moment seems more consolidated and accepted in the occupational and previdential medicine.