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1.
Artigo em Inglês | MEDLINE | ID: mdl-33807952

RESUMO

The global COVID-19 pandemic has led to drastic changes in the management of patients with rheumatic diseases. Due to the imminent risk of infection, monitoring intervals of rheumatic patients have prolonged. The aim of this study is to present insights from patients, rheumatologists, and digital product developers on the ongoing digital health transition in rheumatology. A qualitative and participatory semi-structured fishbowl approach was conducted to gain detailed insights from a total of 476 participants. The main findings show that digital health and remote care are generally welcomed by the participants. Five key themes emerged from the qualitative content analysis: (1) digital rheumatology use cases, (2) user descriptions, (3) adaptation to different environments of rheumatology care, and (4) potentials of and (5) barriers to digital rheumatology implementation. Codes were scaled by positive and negative ratings as well as on micro, meso, and macro levels. A main recommendation resulting from the insights is that both patients and rheumatologists need more information and education to successfully implement digital health tools into clinical routine.


Assuntos
Reumatologia , Telemedicina , Transição Epidemiológica , Humanos , Pandemias , Pesquisa Qualitativa
2.
Artigo em Inglês | MEDLINE | ID: mdl-33822898

RESUMO

OBJECTIVE: To further characterize the effect of guselkumab, a selective interleukin-23p19-subunit inhibitor approved for psoriatic arthritis (PsA), on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. METHODS: Adults with active PsA despite standard therapies in the Phase-3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every-4-weeks (Q4W); guselkumab 100 mg at Week0, Week4, Q8W; or placebo through Week20 followed by guselkumab 100 mg Q4W (Placebo→Q4W). Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0-6). Enthesitis findings through Week24 were prespecified to be pooled across studies; post hoc and Week52 analyses also employed pooled data. RESULTS: Among 1,118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation, and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at Week24 (45% and 50% vs 29%; both adjusted p= 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at Week52, including patients with mild (LEI = 1; 70-75%), moderate (LEI = 2; 69-73%), or severe (LEI = 3-6; 42-44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at Week24, 42% achieved minimal disease activity at Week52, vs 17% of patients with unresolved enthesitis. CONCLUSION: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by Week24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. CLINICAL TRIAL REGISTRATION: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285).

3.
Artigo em Inglês | MEDLINE | ID: mdl-33831144

RESUMO

OBJECTIVES: Efficacy evaluation of giant cell arteritis (GCA) treatment is primarily based on non-specific symptoms and laboratory markers. We aimed to assess the change in vascular inflammation in patients with large vessel (LV)-GCA under different treatments using [18F]FDG PET/CT. METHODS: Observational study on patients with new-onset, active LV-GCA starting treatment with either prednisolone monotherapy (PRED) or combination with methotrexate (MTX) or tocilizumab (TOC). All patients underwent baseline and follow-up PET/CT. The aorta and its major branches were assessed using PET vascular activity score (PETVAS) by independent readers. Cumulative glucocorticoid doses and cessation of glucocorticoid treatment were documented in all patients. RESULTS: We included 88 LV-GCA patients, 27 were treated with PRED, 42 with MTX, and 19 with TOC. PETVAS decreased from 18.9-8.0 units at follow-up in the overall population (p< 0.001). PETVAS changes were numerically higher in patients receiving MTX (-12.3 units) or TOC (-11.7 units) compared with PRED (-8.7). Mean cumulative prednisolone dosages were 5637, 4418, and 2984 mg in patients treated with PRED, MTX, and TOC (p= 0.002). Risk ratios for glucocorticoid discontinuation at the time of follow-up PET/CT were 6.77 (95%CI 1.01-45.29; p= 0.049) and 16.25 (95%CI 2.60-101.73; p= 0.003) for MTX and TOC users compared with PRED users. CONCLUSION: Treatment of LV-GCA inhibits vascular inflammation in the aorta and its major branches. While similar control of vascular inflammation was achieved with PRED, MTX, and TOC treatments, TOC showed a strong glucocorticoid sparing effect, supporting the concept of initial combination therapy.

4.
Arthritis Res Ther ; 23(1): 112, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849654

RESUMO

BACKGROUND: Timely diagnosis and treatment are essential in the effective management of inflammatory rheumatic diseases (IRDs). Symptom checkers (SCs) promise to accelerate diagnosis, reduce misdiagnoses, and guide patients more effectively through the health care system. Although SCs are increasingly used, there exists little supporting evidence. OBJECTIVE: To assess the diagnostic accuracy, patient-perceived usability, and acceptance of two SCs: (1) Ada and (2) Rheport. METHODS: Patients newly presenting to a German secondary rheumatology outpatient clinic were randomly assigned in a 1:1 ratio to complete Ada or Rheport and consecutively the respective other SCs in a prospective non-blinded controlled randomized crossover trial. The primary outcome was the accuracy of the SCs regarding the diagnosis of an IRD compared to the physicians' diagnosis as the gold standard. The secondary outcomes were patient-perceived usability, acceptance, and time to complete the SC. RESULTS: In this interim analysis, the first 164 patients who completed the study were analyzed. 32.9% (54/164) of the study subjects were diagnosed with an IRD. Rheport showed a sensitivity of 53.7% and a specificity of 51.8% for IRDs. Ada's top 1 (D1) and top 5 disease suggestions (D5) showed a sensitivity of 42.6% and 53.7% and a specificity of 63.6% and 54.5% concerning IRDs, respectively. The correct diagnosis of the IRD patients was within the Ada D1 and D5 suggestions in 16.7% (9/54) and 25.9% (14/54), respectively. The median System Usability Scale (SUS) score of Ada and Rheport was 75.0/100 and 77.5/100, respectively. The median completion time for both Ada and Rheport was 7.0 and 8.5 min, respectively. Sixty-four percent and 67.1% would recommend using Ada and Rheport to friends and other patients, respectively. CONCLUSIONS: While SCs are well accepted among patients, their diagnostic accuracy is limited to date. TRIAL REGISTRATION: DRKS.de, DRKS00017642 . Registered on 23 July 2019.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33788924

RESUMO

BACKGROUND: Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts and modulated by inflammatory cytokines. Apremilast (a selective phosphodiesterase 4 inhibitor) is efficacious in PsA and acts by inhibiting cytokine production. However, there are no direct data informing whether and how apremilast affects osteoclast formation in humans. METHODS: Osteoclastogenic cytokine production by activated human peripheral blood mononuclear cells (PBMCs) was measured in the presence and absence of apremilast. Effects of apremilast on osteoclast differentiation were tested (i) in co-cultures of activated PBMCs and human CD14+ blood monocytes as well as (ii) in CD14+ blood monocytes stimulated with activated-PBMCs supernatant, TNF or IL-17A. Bone resorption was measured on OsteoAssay plates. Effects of apremilast on ex vivo osteoclast differentiation were compared in PsA, pre-PsA and psoriasis patients as well as in healthy controls. RESULTS: Apremilast significantly impaired the expression of key osteoclastogenic cytokines in activated PBMCs. Furthermore, apremilast dose-dependently and significantly inhibited activated PBMC-driven osteoclast differentiation, and ex-vivo osteoclast differentiation of PBMCs derived from PsA and pre-PsA patients, but not from psoriasis patients or healthy controls. TNF and IL-17A-enhanced osteoclastogenesis and osteolytic activity of CD14+ blood monocytes from PsA patients was also significantly inhibited by apremilast. Finally, apremilast inhibited expression of the key osteoclast fusion protein DC-STAMP. CONCLUSION: Phosphodiesterase-4 targeting by apremilast not only inhibits osteoclastogenic cytokine production, but also directly suppresses inflammation-driven osteoclastogenesis. These data provide initial evidence that apremilast has the potential to provide a direct bone protective effect in PsA.

6.
Nat Rev Rheumatol ; 17(4): 224-237, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33674813

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA.

7.
Immunity ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33761330

RESUMO

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

9.
J Rheumatol ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722947

RESUMO

OBJECTIVE: To assess the efficacy of secukinumab on axial and peripheral enthesitis in patients with ankylosing spondylitis (AS) using pooled data from randomized controlled phase 3 studies. METHODS: In this post-hoc analysis, data were pooled from patients originally randomized to secukinumab 150 mg, 300 mg, or placebo from phase 3 MEASURE 1-4 studies (ClinicalTrials.gov identifiers: NCT01358175, NCT01649375, NCT02008916 and NCT02159053). Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was used for assessments of enthesitis through Week 52. Efficacy outcomes were mean change in MASES score and complete resolution (MASES=0) of enthesitis in patients with baseline MASES>0. RESULTS: A total of 693 (71.5%) patients had enthesitis at baseline in secukinumab 300 mg, 150 mg and placebo groups (58 [76.3%], 355 [70.4%] and 280 [72%]), respectively, out of 969 patients pooled in this analysis. At Week 16, mean change from baseline for overall MASES and enthesitis at axial MASES-sites was: secukinumab 300 mg (-2.9 [P<0.01] and -2.9 [P<0.01]); 150 mg (-2.4 [P<0.015] and -2.3 [P<0.05]), and placebo (-1.9 and -1.8), with improvements seen through Week 52. More than a third of secukinumab-treated patients (300 mg, 36.2% and 150 mg, 40.8%) achieved complete resolution of enthesitis at Week 16. CONCLUSION: Secukinumab improved enthesitis at overall MASES and axial sites in patients with ankylosing spondylitis.

10.
Eur J Immunol ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594693

RESUMO

To avoid autoimmunity, it is essential to keep the balance between the defence against pathogens and the maintenance of tolerance to self-antigens. Mucosal inflammation may lead to breakdown of tolerance and activation of autoreactive cells. Growing evidence suggests a major contribution of gut microbiota to the onset of chronic, autoimmune inflammatory diseases including rheumatoid arthritis (RA). RA patients show significant differences in the composition of gut microbiota compared to healthy controls, and in murine arthritis models certain bacteria can induce inflammatory Th17 responses or autoantibody production. The gut microbiota plays an important role in regulating the balance between immunogenic and tolerogenic immune responses. The intestinal barrier is the site of the body where most host-microbiota interaction takes place. Certain microbiota or their metabolites can cause a break in homeostasis by affecting the intestinal barrier integrity and permeability. However, an intact intestinal barrier is essential to separate the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. This review will focus on the correlation between a leaky gut and the onset of arthritis. Furthermore, it will be discussed how targeting the intestinal barrier function by dietary changes might provide an opportunity to modulate the development of RA.

11.
Blood ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33529322

RESUMO

Chronic graft-versus-host disease (cGvHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGvHD remain poorly understood and targeted therapies are not well established for clinical use. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGvHD (sclGvHD). WNT signaling was activated in human sclGvHD with increased nuclear accumulation of the transcription factor ß-catenin and WNT-biased gene expression signature in lesional skin. Treatment with highly selective tankryase inhibitor G007-LK, CK1α agonist pyrvinium or LRP6 inhibitor salinomycin, abrogated the activation of WNT signaling and protected against experimental cGvHD, without significant impact on graft-versus-leukemia effect (GvL). Treatment with G007-LK, pyrvinium or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d)→BALB/c (H-2d) and in the LP/J (H-2b)→C57BL/6 (H-2b) model of sclGvHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect, inflammation-dependent effects in sclGvHD. Our findings may have direct translational potential, as pyrvinium is in clinical use and tankyrase inhibitors are in clinical trials for other implications.

12.
Nat Commun ; 12(1): 1112, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602937

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.


Assuntos
/diagnóstico , Interleucina-3/sangue , Animais , Quimiocina CXCL12/imunologia , Células Dendríticas/citologia , Modelos Animais de Doenças , Feminino , Alemanha , Humanos , Imunidade Inata , Interferons/sangue , Pulmão/imunologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estudos Prospectivos , Índice de Gravidade de Doença , Linfócitos T/citologia , Carga Viral
13.
Arthritis Res Ther ; 23(1): 67, 2021 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-33640008

RESUMO

BACKGROUND: Biological disease-modifying anti-rheumatic drugs (bDMARDs) can be tapered in some rheumatoid arthritis (RA) patients in sustained remission. The purpose of this study was to assess the feasibility of building a model to estimate the individual flare probability in RA patients tapering bDMARDs using machine learning methods. METHODS: Longitudinal clinical data of RA patients on bDMARDs from a randomized controlled trial of treatment withdrawal (RETRO) were used to build a predictive model to estimate the probability of a flare. Four basic machine learning models were trained, and their predictions were additionally combined to train an ensemble learning method, a stacking meta-classifier model to predict the individual flare probability within 14 weeks after each visit. Prediction performance was estimated using nested cross-validation as the area under the receiver operating curve (AUROC). Predictor importance was estimated using the permutation importance approach. RESULTS: Data of 135 visits from 41 patients were included. A model selection approach based on nested cross-validation was implemented to find the most suitable modeling formalism for the flare prediction task as well as the optimal model hyper-parameters. Moreover, an approach based on stacking different classifiers was successfully applied to create a powerful and flexible prediction model with the final measured AUROC of 0.81 (95%CI 0.73-0.89). The percent dose change of bDMARDs, clinical disease activity (DAS-28 ESR), disease duration, and inflammatory markers were the most important predictors of a flare. CONCLUSION: Machine learning methods were deemed feasible to predict flares after tapering bDMARDs in RA patients in sustained remission.

14.
Sensors (Basel) ; 21(4)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572273

RESUMO

In light of the state-of-the-art treatment options for patients with rheumatoid arthritis (RA), a detailed and early quantification and detection of impaired hand function is desirable to allow personalized treatment regiments and amend currently used subjective patient reported outcome measures. This is the motivation to apply and adapt modern measurement technologies to quantify, assess and analyze human hand movement using a marker-based optoelectronic measurement system (OMS), which has been widely used to measure human motion. We complement these recordings with data from markerless (Doppler radar) sensors and data from both sensor technologies are integrated with clinical outcomes of hand function. The technologies are leveraged to identify hand movement characteristics in RA affected patients in comparison to healthy control subjects, while performing functional tests, such as the Moberg-Picking-Up Test. The results presented discuss the experimental framework and present the limiting factors imposed by the use of marker-based measurements on hand function. The comparison of simple finger motion data, collected by the OMS, to data recorded by a simple continuous wave radar suggests that radar is a promising option for the objective assessment of hand function. Overall, the broad scope of integrating two measurement technologies with traditional clinical tests shows promising potential for developing new pathways in understanding of the role of functional outcomes for the RA pathology.


Assuntos
Artrite Reumatoide , Movimento , Radar , Artrite Reumatoide/diagnóstico , Mãos , Humanos , Projetos Piloto
16.
Ocul Surf ; 20: 1-12, 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401018

RESUMO

PURPOSE: Obstructive Meibomian gland dysfunction (MGD) is one of the leading causes of evaporative dry eye disease. Meibomian glands at the eyelid secrete lipids that prevent evaporation of the aqueous tear film. The pathogenesis of obstructive MGD is incompletely understood to date. Herein, we aim to investigate the pathogenesis of obstructive MGD using murine and human samples with various forms of ocular surface inflammation. METHOD: The presence of Neutrophil extracellular Traps (NETs) was detected with immunofluorescence analysis of ocular surface discharge and biopsy samples from patients with blepharitis. Tear fluid from patients with MGD and blepharitis were evaluated for the presence of inflammatory mediators using bead based immunoassay. Murine model of allergic eye disease (AED) was performed to investigate the role of NETs in MG occlusion. RESULTS: we show that the ocular discharge from patients with blepharitis contains aggregated neutrophil extracellular traps (aggNETs). Furthermore, the ducts of human Meibomian glands affected by blepharitis were largely congested by aggNETs. Tear fluid from patients with MGD showed elevated neutrophil chemoattractants (C5a, IL6, IL8 and IL18). C5a and IL8 correlated with the degree of deficiency of tear fluid. In the murine model of allergic eye disease (AED), aggNETs accumulated in the MG leading to occlusion of their ducts and the retrograde pent-up of the fluid followed by acinar atrophy. Constraining aggNET formation by genetic or pharmacological inhibition of peptidyl arginine deiminase type 4 (PADI4) effectively reduced MG damage. CONCLUSION: We conclude that aggNETs occlude MG causing MGD after ocular surface inflammation.

17.
Autoimmun Rev ; 20(3): 102760, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33485992

RESUMO

Spondyloarthritis (SpA) is an umbrella term describing a family of chronic inflammatory rheumatic diseases. These diseases are characterised by inflammation of the axial skeleton, peripheral joints, and entheseal insertion sites throughout the body which can lead to structural joint damage including formation of axial syndesmophytes and peripheral osteophytes. Genetic evidence, preclinical and clinical studies indicate a clear role of interleukin (IL)- 23 and IL-17 as mediators in SpA pathogenesis. Targeting the IL-23/-17 pathways seems an efficient strategy for treatment of SpA patients, and despite the remaining challenges the pathway holds great promise for further advances and improved therapeutic opportunities. Much research is focusing on serological markers and imaging strategies to correctly diagnose patients in the early stages of SpA. Biomarkers may facilitate personalised medicine tailored to each patient's specific disease to optimise treatment efficacy and to monitor therapeutic response. This narrative review focuses on the IL-17 pathway in SpA-related diseases with emphasis on its role in pathogenesis, current approved IL-17 inhibitors, and the need for biomarkers reflecting core disease pathways for early diagnosis and measurement of disease activity, prognosis, and response to therapy.


Assuntos
Interleucina-17 , Espondilartrite , Biomarcadores , Humanos , Inflamação , Interleucina-23 , Espondilartrite/diagnóstico , Espondilartrite/terapia
18.
J Clin Endocrinol Metab ; 106(4): 1062-1073, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33382877

RESUMO

CONTEXT: Type 2 diabetes is associated with a greater risk for musculoskeletal disorders, yet its impact on joint function remains unclear. OBJECTIVE: We hypothesized that patients with type 2 diabetes and osteoarthritis would exhibit musculoskeletal impairment, which would associate with insulin resistance and distinct microRNA profiles. METHODS: Participants of the German Diabetes Study with type 2 diabetes (T2D, n = 39) or normal glucose tolerance (CON, n = 27), both with (+OA) or without osteoarthritis (-OA) underwent intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp tests. Musculoskeletal function was assessed by isometric knee extension strength (KES), grip strength, range of motion (ROM), and balance skills, while neural function was measured by nerve conductance velocity (NCV). Arthritis-related symptoms were quantified using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, serum arthritis-related microRNA using quantitative polymerase chain reaction. RESULTS: Insulin sensitivity was lower in T2D+OA vs T2D-OA (4.4 ±â€…2.0 vs 5.7 ±â€…3.0 mg* kg-1*min-1) and in CON+OA vs CON-OA (8.1 ±â€…2.0 vs 12.0 ±â€…2.6 mg*kg-1,*min-1, both P < .05). In T2D+OA, KES and ROM were 60% and 22% lower than in CON+OA, respectively (both P < .05). Insulin sensitivity correlated positively with KES (r = 0.41, P < .05) among T2D, and negatively with symptom severity in CON and T2D (r = -0.60 and r = -0.46, respectively, P < .05). CON+OA and T2D+OA had inferior balance skills than CON-OA, whereas NCV was comparable in T2D+OA and T2D-OA. Expression of arthritis-related microRNAs was upregulated in T2D compared to CON, but downregulated in CON+OA compared to CON-OA (P < .05), and did not differ between T2D+OA and T2D-OA. CONCLUSION: Musculoskeletal impairment and osteoarthritis-related symptoms are associated with insulin resistance. Type 2 diabetes can mask changes in arthritis-related microRNA profiles.

19.
J Exp Med ; 218(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32930709

RESUMO

Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.

20.
Sci Rep ; 10(1): 21020, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273570

RESUMO

Osteoclasts are specialised bone resorbing cells that control both physiological and pathological bone turnover. Functional changes in the differentiation and activity of osteoclasts are accompanied by active metabolic reprogramming. However, the biological significance and the in vivo relevance of these events has remained unclear. Here we show that bone resorption of differentiated osteoclasts heavily relies on increased aerobic glycolysis and glycolysis-derived lactate production. While pharmacological inhibition of glycolysis did not affect osteoclast differentiation or viability, it efficiently blocked bone resorption in vitro and in vivo and consequently ameliorated ovariectomy-induced bone loss. Our experiments thus highlight the therapeutic potential of interfering with osteoclast-intrinsic metabolic pathways as possible strategy for the treatment of diseases characterized by accelerated bone loss.

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