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ID PMID Title PublicationDate abstract
31350812 Sepiapterin Reductase Inhibition Leading to Selective Reduction of Inflammatory Joint Pain 2020 Jan OBJECTIVE: To evaluate the antiinflammatory and analgesic effects of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease, and to determine whether urinary sepiapterin levels, as measured in mice and healthy human volunteers, could be useful as a noninvasive, translational biomarker of SPR inhibition/target engagement. METHODS: The collagen antibody-induced arthritis (CAIA) model was used to induce joint inflammation in mice. The effects of pharmacologic inhibition of SPR on thresholds of heat-, cold-, and mechanical-evoked pain sensitivity and on signs of inflammation were tested in mice with CAIA. In addition, mice and healthy human volunteers were treated with SPR inhibitors, and changes in urinary sepiapterin levels were analyzed by high-performance liquid chromatography. RESULTS: CAIA in mice was characterized by 2 phases: in the acute inflammation (early) phase, joint inflammation and heat-, mechanical-, and cold-induced pain hypersensitivity were present, while in the postinflammation (late) phase, no joint inflammation was observed but heat- and mechanical-induced hypersensitivity, but not cold hypersensitivity, were present. Inhibition of SPR in mice with CAIA significantly attenuated the heat-induced hyperalgesia in both phases, and the mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary tetrahydrobiopterin levels, as a marker of inflammatory pain, were increased during inflammation in mice with CAIA (2-fold increase over controls; P < 0.05) and significantly reduced by SPR inhibition (P < 0.05 versus vehicle-treated mice). Increased urinary sepiapterin levels in the presence of SPR inhibition in both mice and healthy human volunteers were associated with high sensitivity (70-85%) and high specificity (82-88%) for the prediction of SPR inhibition/target engagement. CONCLUSION: SPR inhibition reduces the pain associated with joint inflammation, thus showing its potential utility as an analgesic strategy for inflammatory joint pain. In addition, SPR inhibition increases urinary sepiapterin levels, indicating the potential of this measurement as a noninvasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine, a disease-modifying antirheumatic drug that is currently used as a first-line treatment for rheumatoid arthritis.
31428469 Galectin-1, -4, and -7 Were Associated with High Activity of Disease in Patients with Rheu 2019 BACKGROUND: Due to the variety of functions that galectins (Gal) possess, it is clear that they participate in the pathogenesis of rheumatoid arthritis (RA). Although some studies demonstrate their functions, there is still no correlation with the clinical data of the disease, having the physiological meaning still unknown. OBJECTIVES: To compare serum levels of Gal-1, -4, and -7 in patients with RA and healthy controls and to correlate them with clinical parameters. METHODS: Serum samples were collected from patients with RA and healthy donors to determine the serum levels of Gal-1, -4, and -7. RESULTS: Serum levels of Gal-1, -4, and -7 were significantly higher in RA patients compared to controls. We evaluated disease activity (CDAI) with serum levels of galectins and found that patients who were high in disease activity had high levels of galectin compared to the moderate activity group. Galectin-4 had higher levels in patients who were in high activity when compared to the group in remission or low activity. Evaluating the activity of the individual disease (DAS28), patients in high individual activity had high levels of Gal-4 when compared to the group in remission or low activity. We also found an association between positive rheumatoid factor and Gal-1 and Gal-4 levels. CONCLUSION: Our results show for the first time the relationship between serum levels of galectin and the clinical parameters of patients with RA. Demonstrating their role in pathogenesis, new studies with galectins are needed to assess how they function as a biomarker in RA.
30873159 Role of NFAT5 in the Immune System and Pathogenesis of Autoimmune Diseases. 2019 The nuclear factor of activated T cells (NFAT5), also known as a tonicity-responsive enhancer-binding protein, was originally identified as a key transcription factor involved in maintaining cellular homeostasis against hypertonic and hyperosmotic environments. Although NFAT5 has been expressed and studied in various types of hyperosmolar tissues, evidence has emerged that NFAT5 plays a role in the development and activation of immune cells, especially T cells and macrophages. The immune-regulatory function of NFAT5 is achieved by inducing different target genes and different signaling pathways in both tonicity-dependent and -independent manners. Particularly in response to hyperosmotic stress, NFAT5 induces the generation of pathogenic T(H)17 cells and pro-inflammatory macrophages, contributing to autoimmune and inflammatory diseases. Meanwhile, with tonicity-independent stimuli, including activation of the Toll-like receptors and inflammatory cytokines, NFAT5 also can be activated and promotes immune cell survival, proliferation, migration, and angiogenesis. Moreover, under isotonic conditions, NFAT5 has been implicated in the pathogenesis of a variety of inflammatory and autoimmune diseases including rheumatoid arthritis. This review describes the current knowledge of NFAT5, focusing on its immune-regulatory functions, and it highlights the importance of NFAT5 as a novel therapeutic target for chronic inflammatory diseases.
31804308 Reactive arthritis induced by active extra-articular tuberculosis: A case report. 2019 Dec RATIONALE: Rare cases of reactive arthritis induced by active extra-articular tuberculosis (Poncet disease) have been reported. Complete response to antitubercular treatment and evidence of active extra-articular tuberculosis are the most important clinical features of Poncet disease. We report the case of successfully treated a patient with reactive arthritis induced by active extra-articular tuberculosis with a TNF inhibitor after sufficient antitubercular treatment. PATIENT CONCERNS: A 56-year-old Japanese man was admitted to our department with polyarthralgia, low back pain, and high fever. The results of rheumatoid factor, anti-citrullinated protein antibody, human leukocyte antigen B27, and the assays for the detection of infections (with an exception of T-SPOT.TB) were all negative. Fluoro-deoxy-D-glucose-positron emission tomography with CT (PET/CT) showed moderate uptake in the right cervical, right supraclavicular, mediastinal, and abdominal lymph nodes. As magnetic resonance imaging and power Doppler ultrasonography showed peripheral inflammation (tendinitis, tenosynovitis, ligamentitis, and enthesitis in the limbs). DIAGNOSIS: A diagnosis of tuberculous lymphadenitis was eventually established on the basis of lymph node biopsy results. There was no evidence of a bacterial infection including acid-fast bacteria in his joints, and the symptoms of polyarthralgia and low back pain were improved but not completely resolved with NSAID therapy; in addition, a diagnosis of reactive arthritis induced by active extraarticular tuberculosis was made. INTERVENTIONS: The patient experienced persistent peripheral inflammation despite antitubercular treatment for more than nine months and was then successfully treated with a tumor necrosis factor inhibitor (adalimumab 40 mg every 2 weeks). OUTCOMES: Finally, the patient responded to the treatment and has been in remission for over 4 months as of this writing. LESSONS: In patients who present with symptoms associated with spondyloarthritis, it is important to distinguish between classic reactive arthritis and reactive arthritis induced by extra-articular tuberculosis infection. Introduction of biological agents should be carefully considered in settings where reactive arthritis induced by active extra-articular tuberculosis shows progression to chronicity despite sufficient antitubercular treatment.
31727153 iNOS dependent and independent phases of lymph node expansion in mice with TNF-induced inf 2019 Nov 14 INTRODUCTION: A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph node expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS(-/-)) will show delayed draining lymph node expansion, maintained LV contractions, and decreased synovitis and erosions. METHOD: iNOS(-/-)× TNF-Tg female and male mice, and control littermates (iNOS(-/-), TNF-Tg, and WT), were examined with (1) ultrasound to determine popliteal lymph node (PLN) volume and (2) near-infrared imaging (NIR) to assess popliteal LV contraction frequency, and differences between genotypes were assessed at 3, 4, 5, and 6 months of age. Knees and PLN were harvested at 4 months in females and 6 months in males, to assess synovitis, bone erosions, and cellular accumulation in PLN sinuses via histology. RESULTS: Initially, an increase in PLN volume was observed for both female and male iNOS(-/-)× TNF-Tg and TNF-Tg compared to their WT and iNOS(-/-) counterparts at 2 and 3 months, respectively. Subsequently, TNF-Tg PLNs continue to increase in volume, while iNOS(-/-)× TNF-Tg did not increase in volume from the initial timepoints. WT and iNOS(-/-) PLN volume was unchanged throughout the experiment. LV contraction frequency was increased at 4 months in females and 5 months in males, in the iNOS(-/-)× TNF-Tg mice compared to the TNF-Tg. Synovitis and erosions were moderately reduced in iNOS(-/-)× TNF-Tg versus TNF-Tg knees in females, while no differences in knee pathology were observed in males. CONCLUSIONS: Genetic iNOS ablation maintains draining lymph node volume and LV function during TNF-induced inflammatory arthritis and is associated with moderately decreased joint inflammation and damage.
30706568 Intravoxel incoherent motion MRI for discrimination of synovial proliferation in the hand 2019 Oct BACKGROUND: Postcontrast-enhanced MRI is currently the reference standard for synovial proliferation in rheumatoid arthritis (RA). However, the technique is somewhat invasive due to the use of gadolinium contrast agents, which may cause severe adverse/side effects. Intravoxel incoherent motion (IVIM) simultaneously permits quantification of perfusion as well as diffusion using a single imaging scan. PURPOSE/HYPOTHESIS: To test the capability of IVIM MRI for noninvasive discrimination of synovial proliferation in hand arthritis. STUDY TYPE: Prospective. SUBJECTS: Seven suspected RA patients (three women and four men; mean age, 61 years; range, 26-74 years). FIELD STRENGTH/SEQUENCE: 3 T/short tau inversion recovery (STIR), IVIM, postcontrast-enhanced MRI. ASSESSMENT: Region of interest (ROI) was identified based on STIR. Contrast-enhanced MRI was evaluated using a 5-point grading scale of 0 (water) to 4 (synovial proliferation) according to the degree of contrast enhancement within the ROI. For each ROI, we calculated the apparent diffusion coefficient (ADC) and IVIM parameters (molecular diffusion coefficient [D], perfusion fraction [f], and perfusion-related diffusion coefficient [D*]). These parameters were subsequently compared with ROI contrast enhancement grades. STATISTICAL TESTS: Spearman's rank correlation test and a receiver operating characteristic (ROC) curve. RESULTS: A total of 90 ROIs of suspected synovial proliferation and/or joint effusion were identified. ROI grades were correlated with ADC and D values (r (S) = -0.385, P < 0.001, r (S) = -0.458, P < 0.0001, respectively), but not with the f and D* values (r (S) = -0.010, P = 0.936, r (S) = -0.084, P = 0.505, respectively). The area under the curves (AUCs) of D values (0.708-0.888, P = 0.002-0.0002) were slightly larger than those of ADC values (0.692-0.791, P = 0.013-0.001) when comparing low- vs. high-contrast enhancement grades. DATA CONCLUSION: The IVIM parameter D and ADC may be useful for the noninvasive identification of synovial proliferation in hand arthritis. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1199-1206.
31092410 Chromatin interactions reveal novel gene targets for drug repositioning in rheumatic disea 2019 Aug OBJECTIVES: There is a need to identify effective treatments for rheumatic diseases, and while genetic studies have been successful it is unclear which genes contribute to the disease. Using our existing Capture Hi-C data on three rheumatic diseases, we can identify potential causal genes which are targets for existing drugs and could be repositioned for use in rheumatic diseases. METHODS: High confidence candidate causal genes were identified using Capture Hi-C data from B cells and T cells. These genes were used to interrogate drug target information from DrugBank to identify existing treatments, which could be repositioned to treat these diseases. The approach was refined using Ingenuity Pathway Analysis to identify enriched pathways and therefore further treatments relevant to the disease. RESULTS: Overall, 454 high confidence genes were identified. Of these, 48 were drug targets (108 drugs) and 11 were existing therapies used in the treatment of rheumatic diseases. After pathway analysis refinement, 50 genes remained, 13 of which were drug targets (33 drugs). However considering targets across all enriched pathways, a further 367 drugs were identified for potential repositioning. CONCLUSION: Capture Hi-C has the potential to identify therapies which could be repositioned to treat rheumatic diseases. This was particularly successful for rheumatoid arthritis, where six effective, biologic treatments were identified. This approach may therefore yield new ways to treat patients, enhancing their quality of life and reducing the economic impact on healthcare providers. As additional cell types and other epigenomic data sets are generated, this prospect will improve further.
30999014 Leaves and stems of Capparis erythrocarpos, more sustainable than roots, show antiarthriti 2019 Jun 28 ETHNOPHARMACOLOGICAL RELEVANCE: Capparis erythrocarpos is a medicinal plant used widely in many parts of Africa for the management of pain and inflammatory conditions such as rheumatoid arthritis. Its wide range of use, popularity and high value, make C. erythrocarpos containing products a target for economically driven adulteration. This is made worse, by the use of roots, which are unsustainable plant parts. In addition, the mechanism of anti-inflammation is not clearly understood. AIM OF THE STUDY: Therefore, this study comparatively evaluated the anti-arthritic and analgesic effects of the leaves, stems and roots of C. erythrocarpos, while elucidating the mechanism of anti-inflammation. MATERIALS AND METHODS: Using the complete Freund's adjuvant arthritis model, the antiathritic effects were evaluated. The analgesic effects were determined by measuring responses to Von Frey filament number 9. Effects of C. erythrocarpos extracts on the levels of Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) were determined using ELISA. Haematological and serum biochemical assays were also carried out. RESULTS: The leaf, stem and root extracts significantly reduced paw volumes with ED(50) values (mg/kg) of 182.5, 181.5 and 36.4 respectively. The leaf extract at a dose of 100 mg/kg showed substantial analgesic activity with a decrease in the percentage response to Von Frey filament 9. However, there was no significant difference in activities of the leaf, stem and root extracts. Results from ELISA assays show that lower doses of the stem extracts reduce levels of IL-6. Lower doses of all extracts also reduce TNF-α levels. Haematological analysis showed extracts reversed elevated WBC and platelet levels. Toxicity evaluation with kidney and liver function tests indicated no significant differences between the treatment and control groups. CONCLUSIONS: The leaves and stems, just as the roots, have antiarthritic and analgesic effects and can be used as more sustainable alternatives to the roots. This will support the continuous growth of the industry that has developed around C. erythrocarpos.
31370858 Therapeutic glucocorticoids prevent bone loss but drive muscle wasting when administered i 2019 Aug 1 BACKGROUND: Patients with rheumatoid arthritis (RA) experience extra-articular manifestations including osteoporosis and muscle wasting, which closely associate with severity of disease. Whilst therapeutic glucocorticoids (GCs) reduce inflammation in RA, their actions on muscle and bone metabolism in the context of chronic inflammation remain unclear. We utilised the TNF-tg model of chronic polyarthritis to ascertain the impact of therapeutic GCs on bone and muscle homeostasis in the context of systemic inflammation. METHODS: TNF-tg and wild-type (WT) animals received either vehicle or the GC corticosterone (100 μg/ml) in drinking water at onset of arthritis. Arthritis severity and clinical parameters were measured, serum collected for ELISA and muscle and bone biopsies collected for μCT, histology and mRNA analysis. In vivo findings were examined in primary cultures of osteoblasts, osteoclasts and myotubes. RESULTS: TNF-tg mice receiving GCs showed protection from inflammatory bone loss, characterised by a reduction in serum markers of bone resorption, osteoclast numbers and osteoclast activity. In contrast, muscle wasting was markedly increased in WT and TNF-tg animals receiving GCs, independently of inflammation. This was characterised by a reduction in muscle weight and fibre size, and an induction in anti-anabolic and catabolic signalling. CONCLUSIONS: This study demonstrates that when given in early onset chronic polyarthritis, oral GCs partially protect against inflammatory bone loss, but induce marked muscle wasting. These results suggest that in patients with inflammatory arthritis receiving GCs, the development of interventions to manage deleterious side effects in muscle should be prioritised.
31681333 A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunology. 2019 Glucocorticoids (GCs) are known to have a strong impact on the immune system, metabolism, and bone homeostasis. While these functions have been long investigated separately in immunology, metabolism, or bone biology, the understanding of how GCs regulate the cellular cross-talk between innate immune cells, mesenchymal cells, and other stromal cells has been garnering attention rather recently. Here we review the recent findings of GC action in osteoporosis, inflammatory bone diseases (rheumatoid and osteoarthritis), and bone regeneration during fracture healing. We focus on studies of pre-clinical animal models that enable dissecting the role of GC actions in innate immune cells, stromal cells, and bone cells using conditional and function-selective mutant mice of the GC receptor (GR), or mice with impaired GC signaling. Importantly, GCs do not only directly affect cellular functions, but also influence the cross-talk between mesenchymal and immune cells, contributing to both beneficial and adverse effects of GCs. Given the importance of endogenous GCs as stress hormones and the wide prescription of pharmaceutical GCs, an improved understanding of GC action is decisive for tackling inflammatory bone diseases, osteoporosis, and aging.
31754394 Mesenchymal stem cell transplantation alleviates experimental Sjögren's syndrome through 2019 Rationale: Although mesenchymal stem cell (MSC) transplantation has been proved to be an effective therapeutic approach to treat experimental Sjögren's syndrome (SS), the detailed underlying mechanisms remains unknown. IL-27 has diverse influences on the regulation of T cell differentiation and was involved in SS through modulating immune response. Here we aimed to explore whether IL-27-mediated regulation of immune cells was responsible for the beneficial effects of MSC transplantation on SS. Methods: The SS-like symptoms were evaluated in IL-27 deficient and recombinant IL-27-treated NOD mice. The MSCs were infused into NOD mice via the tail vein. The histological features of submandibular glands, saliva flow rate and serum IL-27 were examined. The effects of MSCs on the IL-27 production and Th17/Treg cell in SS patients and mice in vitro and in vivo were determined for the mechanistic study. Results: This study showed that SS patients had decreased IL-27 level and increased ratio of Th17/Treg cells. Consistently, exacerbated SS-like symptoms were observed in IL-27 deficient NOD mice, along with increased ratio of Th17/Treg cells. Importantly, MSC transplantation alleviated SS-like symptoms by elevating the level of IL-27 to restore Th17/Treg balance in NOD mice. Mechanistically, MSC-secreted interferon-β (IFN-β) promote dendritic cells to produce IL-27. Conclusions: Thus, we have revealed a previously unrecognized function of MSC-mediated IL-27 production by DCs in suppressing SS-like syndrome, which provided evidences for clinical application of MSC in patients with SS.
30826774 Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF 2019 May OBJECTIVES: To evaluate the efficacy and safety of ianalumab (VAY736), a B cell-depleting, B cell activating factor receptor-blocking, monoclonal antibody, in patients with active primary Sjögren's syndrome (pSS) in a double-blind, placebo-controlled, phase II, single-centre study. METHODS: Patients with pSS, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥6, were randomised to ianalumab single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12) or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B cell numbers had recovered. Clinical outcomes included ESSDAI, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity. RESULTS: A similar trend showing positive therapeutic effect by ianalumab was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, Multidimensional Fatigue Inventory, Short Form-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B cell depletion of long-lasting duration occurred after a single infusion of ianalumab at either dose. Serum Ig light chains decreased, with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild to moderate infusion reactions within 24 hours of ianalumab administration. CONCLUSIONS: Overall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.
30886639 Shexiang-Wulong Pills Attenuate Rheumatoid Arthritis by Alleviating Inflammation in a Mous 2019 Shexiang-Wulong Pill (SWP) is derived from "Moschus Yuan," first formulated during the Song Dynasty for the treatment of joint pain. The aim of this study was to evaluate the therapeutic effect of SWP in a mouse model of collagen-induced arthritis (CIA). Forty-five DBA/1 mice were randomly divided into control group, model group, and SWP-treated group. SWP was administered by oral gavage for 22 days after the booster immunization. The clinical arthritic scores and joint histopathology, including synovial hyperplasia and hypoxic regions, cartilage erosion, and bone destruction, were evaluated. Microcomputed tomography (micro-CT) was used to assess microstructural changes in the bone. Serum levels of TNF-a, IL-6, and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA). The results showed a statistically significant improvement in joint pathological changes in the SWP-treated group. Imaging assessment confirmed that SWP protected the bone tissue from CIA-induced erosion and increased the bone density. In addition, the serum levels of TNF-a, IL-6, and IFN-γ in SWP-treated mice were significantly lower than those in the model group (P<0.05). Taken together, Shexiang-Wulong Pill can effectively alleviate joint swelling in CIA mice, inhibit synovial tissue hyperplasia, reduce inflammatory cell infiltration, and delay bone destruction. These results indicate that Shexiang-Wulong Pills could be an efficient medication for the treatment of RA.
30169446 Patient and Practice Trends in Total Ankle Replacement and Tibiotalar Arthrodesis in the U 2019 Jan 15 INTRODUCTION: Both total ankle replacement (TAR) and tibiotalar arthrodesis (TTA) are used in the surgical management of ankle arthritis. Over the past decade, TAR instrumentation, techniques, and implants have improved, making the procedure more reliable and reproducible, thus making TAR more common. METHODS: The Nationwide Inpatient Sample database from 2007 to 2013 was used to obtain data on patients elder than 50 years who underwent either TAR or TTA. Differences in temporal, demographic, and diagnosis trends between TAR and TTA were analyzed. RESULTS: Between 2007 and 2013, 15,060 patients underwent TAR and 35,096 underwent TTA. Patients undergoing TTA had significantly more comorbidities (2.17 versus 1.55; P < 0.001). The share of TAR performed increased significantly from 2007 (14%) to 2013 (45%) (P < 0.001). From 2007 to 2013, we found a 12-fold increase in the odds of having a TAR for patients with posttraumatic osteoarthritis (P < 0.001), a 4.9-fold increase for those with primary osteoarthritis, and a 3.1-fold increase for patients with rheumatoid arthritis (P < 0.001). CONCLUSIONS: Over the past decade, the frequency of TAR has increased, particularly in patients with posttraumatic arthritis and osteoarthritis. Surgeons still perform TAR in healthier patients compared with TTA; however, because surgeons become more experienced with the technique, patients are undergoing TAR at a markedly higher rate. LEVEL OF EVIDENCE: Level III: retrospective comparative study.
31583354 Are painDETECT scores in musculoskeletal disorders associated with duration of daily pain 2019 May OBJECTIVES: We aimed to compare painDETECT scores in outpatients seen in a rheumatology department over a 1-month period and search for correlations between painDETECT scores and the estimated duration of daily pain and time elapsed since the onset of current pain. PATIENTS AND METHODS: A total of 529 of 738 outpatients agreed to complete a set of questionnaires, including painDETECT. RESULTS: The mean painDETECT score was 14.14 ± 7.59, and 31% of the patients had painDETECT scores of >18. Fibromyalgia ranked first (21.2 ± 6.0), followed by osteoarthritis of the lower limbs (17.8 ± 8.2), back pain and radiculopathies (16.1 ± 6.8), osteoarthritis of the upper limbs (15.7 ± 8.1), spondylarthrosis (15.1 ± 7.2), entrapment neuropathies (14.1 ± 2.4), rheumatoid arthritis (13.8 ± 7.1), miscellaneous conditions (13.8 ± 8.2), tendinitis (13.4 ± 7.9), connectivitis (11.5 ± 6.7), and osteoporosis (8.5 ± 6.9). The duration of daily pain was much longer in patients with painDETECT scores of >18 (12.41 ± 8.45 vs 6.53 ± 7.45 hours) (t = 0.0000), but very similar painDETECT scores were observed for patients suffering from pain for less than 1 week (13.7 ± 8.2; 38% > 18), for 1 month (14.5 ± 8.2; 25% > 18), several months (12.7 ± 7.3; 23% > 18), 1 year (13.8 ± 7.7; 29% > 18), or several years (14.7 ± 7.4; 33% > 18). CONCLUSION: PainDETECT scores differed little depending on the musculoskeletal condition, strongly correlated with the duration of daily pain, and appeared to be as high in patients with recent pain as in those suffering for years.
31531116 Effects of Qingluo Tongbi Decoction on Gut Flora of Rats with Adjuvant-Induced Arthritis a 2019 Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease. Recent studies show that gut flora plays an important role in regulating the systemic immune response, and gut dysbacteria are linked with systemic chronic inflammation in the development of RA. Our previous results found that Qingluo Tongbi decoction (QLT) can treat RA effectively. The present study explored the effect of QLT on gut flora in an adjuvant-induced arthritis (AA) rat model. Thirty rats were divided randomly into three groups: a control group, a model group, and a treatment group (n = 10 per group). The rats in the model group were injected with complete Freund's adjuvant (FCA), while the treatment group received FCA combined with QLT treatment. After 27 days, the gut flora was profiled by 16S rRNA gene sequencing. The levels of cadherin-11, IL-17α, TLR2, and TLR4 proteins in the synovial tissues were detected by western blotting (WB). The results showed that QLT treatment significantly inhibited raw swelling during the 15-27 d period compared with the model group. QLT treatment reversed the ten altered bacterial genera in the model group, and three families (Lachnospiraceae, Eubacteriaceae, and Leuconostocaceae) were closely related to QLT treatment based on linear discriminant analysis (LDA). Functional prediction showed seven types of predicted functions were related to the QLT treatment, and WB results showed that QLT treatment reversed the increased expression levels of cadherin-11, IL-17α, TLR2, and TLR4 in synovial tissues significantly. The expression levels of cadherin-11, IL-17α, and TLR2 correlated negatively with the abundance of Staphylococcus and Candidatus_Saccharimonas. Therefore, RA development was related to gut dysbiosis, and QLT effectively ameliorated RA with decreased inflammatory responses regulated by the gut flora.
31108549 Testosterone Influence on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren S 2019 May 1 PURPOSE: Sjögren syndrome is an autoimmune disorder that occurs almost exclusively in women and is associated with extensive inflammation in lacrimal tissue, an immune-mediated destruction and/or dysfunction of glandular epithelial cells, and a significant decrease in aqueous tear secretion. We discovered that androgens suppress the inflammation in, and enhance the function of, lacrimal glands in female mouse models (e.g., MRL/MpJ-Tnfrsf6lpr [MRL/lpr]) of Sjögren syndrome. In contrast, others have reported that androgens induce an anomalous immunopathology in lacrimal glands of nonobese diabetic/LtJ (NOD) mice. We tested our hypothesis that these hormone actions reflect unique, strain- and tissue-specific effects, which involve significant changes in the expression of immune-related glandular genes. METHODS: Lacrimal glands were obtained from age-matched, adult, female MRL/lpr and NOD mice after treatment with vehicle or testosterone for up to 3 weeks. Tissues were processed for analysis of differentially expressed mRNAs using CodeLink Bioarrays and Affymetrix GeneChips. Data were analyzed with bioinformatics and statistical software. RESULTS: Testosterone significantly influenced the expression of numerous immune-related genes, ontologies, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in lacrimal glands of MRL/lpr and NOD mice. The nature of this hormone-induced immune response was dependent upon the autoimmune strain, and was not duplicated within lacrimal tissues of nonautoimmune BALB/c mice. The majority of immune-response genes regulated by testosterone were of the inflammatory type. CONCLUSIONS: Our findings support our hypothesis and indicate a major role for the lacrimal gland microenvironment in mediating androgen effects on immune gene expression.
31036626 Video clip assessment of a salivary gland ultrasound scoring system in Sjögren's syndrome 2019 Jul OBJECTIVE: To develop ultrasound (US) definitions and a US novel scoring system for major salivary gland (SG) lesions in patients with primary Sjögren's syndrome (pSS) and to test their intrareader and inter-reader reliability using US video clips. METHODS: Twenty-five rheumatologists were subjected to a three-round, web-based Delphi process in order to agree on (1) definitions and scanning procedure of salivary gland ultrasonography (SGUS): parotid, submandibular and sublingual glands (PG, SMG and SLG); (2) definitions for the elementary SGUS lesions in patients with Sjögren's syndrome; (3) scoring system for grading changes. The experts rated the statements on a 1-5 Likert scale. In the second step, SGUS video clips of patients with pSS and non-pSS sicca cases were collected containing various spectrums of disease severity followed by an intrareader and inter-reader reliability exercise. Each video clip was evaluated according to the agreed definitions. RESULTS: Consensual definitions were developed after three Delphi rounds. Among the three selected SGs, US assessment of PGs and SMGs was agreed on. Agreement was reached to score only greyscale lesions and to focus on anechoic/hypoechoic foci in a semiquantitative matter or, if not possible on a qualitatively (present/absent) evaluation of fatty or fibrous lesions. Intrareader reliability for detecting and scoring these lesions was excellent (Cohen's kappa 0.81) and inter-reader reliability was good (Light's kappa 0.66). CONCLUSION: New definitions for developing a novel semiquantitative US score in patients with pSS were developed and tested on video clips. Inter-reader and intrareader reliabilities were good and excellent, respectively.
30844839 The Use of Conjunctival Staining to Measure Ocular Surface Inflammation in Patients With D 2019 Jun PURPOSE: To investigate the expression levels of inflammatory cytokines in the conjunctival epithelium and correlations with clinical parameters in dry eye disease (DED). METHODS: This study evaluated 28 patients with Sjögren syndrome (SS) DED, 28 patients with non-SS DED, and 10 controls. The messenger ribonucleic acid (mRNA) expression of inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ, IL-17, and matrix metalloproteinase 9 (MMP9) from conjunctival epithelium was investigated by real-time polymerase chain reaction. Protein expression was confirmed by immunofluorescence staining. Correlations were evaluated between the mRNA expression of inflammatory cytokines and clinical DED parameters such as ocular surface disease index score, Schirmer I value, tear film breakup time, and corneal and conjunctival staining scores. RESULTS: Patients with non-SS DED expressed significantly more IFN-γ, IL-6, and MMP9 genes in the conjunctival epithelium than the controls (P < 0.05), and all cytokine gene expression was significantly higher in patients with SS DED than in the controls (P < 0.01). Tumor necrosis factor-α, IL-1β, IL-6, and IL-17 gene expression was higher in patients with SS DED than in the non-SS DED group (P < 0.05). Immunofluorescence staining of conjunctival epithelium demonstrated that positive cells with IL-6 or MMP9 were significantly higher in non-SS DED than in controls (P < 0.01) and much higher in SS DED than in non-SS DED (P < 0.05). Conjunctival staining scores significantly correlated with the expression of IFN-γ, IL-6, IL-17, and MMP9 in both DED groups (P < 0.05 in non-SS DED and P < 0.01 in SS-DED). Interestingly, correlation coefficients of all cytokines were much higher in SS DED compared to non-SS DED. Corneal staining scores showed positive correlations with IFN-γ, IL-17, and MMP9 (P < 0.05), and correlation coefficients were lower than those of conjunctival staining scores. CONCLUSIONS: Conjunctival staining scores may be useful to measure ocular surface inflammation in SS and non-SS DED.
30902822 Blockade of CD40-CD154 pathway interactions suppresses ectopic lymphoid structures and inh 2019 Jul OBJECTIVE: To examine the role of CD40-CD154 costimulation and effects of therapeutic pathway blockade in the non-obese diabetic (NOD/ShiLtJ) model of Sjögren's syndrome (SS). METHODS: We assessed leucocyte infiltration in salivary glands (SGs) from NOD/ShiLtJ mice by immunohistochemistry and examined transcriptomics data of SG tissue from these animals for evidence of a CD40 pathway gene signature. Additionally, we dosed MR1 (anti-CD154 antibody) in NOD mice after the onset of SS-like disease and examined the effects of MR1 treatment on sialadenitis, autoantibody production, SG leucocyte infiltration, gene expression downstream of CD40 and acquaporin 5 (AQP5) expression. RESULTS: We could detect evidence of CD40 expression and pathway activation in SG tissue from NOD mice. Additionally, therapeutic treatment with MR1 suppressed CD40 pathway genes and sialadenitis, inhibited ectopic lymphoid structure formation and autoantibody production, as well as decreased the frequency of antibody-secreting cells in SGs but had minimal effects on AQP5 expression in NOD/ShiLtJ SGs. CONCLUSION: CD40-CD154 interactions play an important role in key pathological processes in a mouse model of SS, suggesting that blockade of this costimulatory pathway in the clinic may have beneficial therapeutic effects in patients suffering from this autoimmune exocrinopathy.