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The progress observed over the last 30 years in the field of axial spondyloarthritis (axSpA) has not made it possible to answer all the current questions. This manuscript represents the proceedings of the meeting of the French spondyloArthitiS Task force (FAST) in Besançon on September 28 and 29, 2023. Different points of discussion were thus individualized as unmet needs: biomarkers for early diagnosis and disease activity, a common electronic file dedicated to SpA nationwide, a better comprehension of dysbiosis in the disease, a check-list for addressing to the rheumatologist, adapt patient reported outcomes thresholds for female gender, implementation of comorbidities screening programs, new imaging tools, in research cellular and multi omics approaches, grouping, at a nationwide level, different cohorts and registries, therapeutic strategy studies, consensual definition of difficult to treat disease and management, preclinical stage of the disease, mastering AI as a tool in the various aspects of research. These elements may represent a framework for the research agenda in axSpA for the years to come.
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INTRODUCTION: National and international scientific societies advocate for a regular, systematic, and standardized global evaluation of axial spondyloarthritis (axSpA) patients. However, there are no recommendations specifying the content of this global evaluation. This initiative aimed to propose a standardized reporting framework, using evidence-based and consensus approaches, to collect data on all domains of axSpA. METHODS: A literature review and consensus process involved a steering committee and an expert panel of 37 rheumatologists and health professionals. The first steering committee took place in March 2022 and identified the main domains for inclusion in the standardized report. A hierarchical literature review was conducted to identify items within these domains and tools for assessment. The items and tools for assessment were discussed and consensus was reached through a vote session during an expert meeting that took place in March 2023. RESULTS: The steering committee identified four main domains to include in the standardized reporting framework: disease assessment, comorbidities, lifestyle, and quality of life. Items and tools for assessment were adopted after the expert meeting. Additionally, recommendations regarding digital tools (websites, apps, social media) were provided. CONCLUSION: This initiative led to a consensus, based on evidence and expertise, on a reporting framework for use during periodic systematic global evaluations of axSpa in daily practice.
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OBJECTIVE: We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission. METHODS: This multicenter open-label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M-arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S-arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2-year follow-up analyzed per protocol with a linear mixed-effects model, evaluated by an NI test based on the one-sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression. RESULTS: Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S-arm and 112 in M-arm). At the end of follow-up, 16.2% of the patients in the S-arm could discontinue their biologic disease-modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10-0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0-55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI -6.7 to 34.4). CONCLUSION: The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy.
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Anticuerpos Monoclonales Humanizados , Antirreumáticos , Artritis Reumatoide , Humanos , Abatacept/uso terapéutico , Resultado del Tratamiento , Artritis Reumatoide/tratamiento farmacológico , Antirreumáticos/uso terapéuticoRESUMEN
OBJECTIVES: Tropheryma whipplei infection can manifest as inflammatory joint symptoms, which can lead to misdiagnosis of inflammatory rheumatic disease and the use of disease-modifying antirheumatic drugs. We investigated the impact of diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease. METHODS: We initiated a registry including patients with disease-modifying antirheumatic drugs-treated inflammatory rheumatic disease who were subsequently diagnosed with Tropheryma whipplei infection. We collected clinical, biological, treatment data of the inflammatory rheumatic disease, of Tropheryma whipplei infection, and impact of antibiotics on the evolution of inflammatory rheumatic disease. RESULTS: Among 73 inflammatory rheumatic disease patients, disease-modifying antirheumatic drugs initiation triggered extra-articular manifestations in 27% and resulted in stabilisation (51%), worsening (34%), or improvement (15%) of inflammatory rheumatic disease. At the diagnosis of Tropheryma whipplei infection, all patients had rheumatological symptoms (mean age 58 years, median inflammatory rheumatic disease duration 79 months), 84% had extra-rheumatological manifestations, 93% had elevated C-reactive protein, and 86% had hypoalbuminemia. Treatment of Tropheryma whipplei infection consisted mainly of doxycycline plus hydroxychloroquine, leading to remission of Tropheryma whipplei infection in 79% of cases. Antibiotic treatment of Tropheryma whipplei infection was associated with remission of inflammatory rheumatic disease in 93% of cases and enabled disease-modifying antirheumatic drugs and glucocorticoid discontinuation in most cases. CONCLUSIONS: Tropheryma whipplei infection should be considered in inflammatory rheumatic disease patients with extra-articular manifestations, elevated C-reactive protein, and/or hypoalbuminemia before disease-modifying antirheumatic drugs initiation or in inflammatory rheumatic disease patients with an inadequate response to one or more disease-modifying antirheumatic drugs. Positive results of screening and diagnostic tests for Tropheryma whipplei infection involve antibiotic treatment, which is associated with complete recovery of Tropheryma whipplei infection and rapid remission of inflammatory rheumatic disease, allowing disease-modifying antirheumatic drugs and glucocorticoid discontinuation.
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Antirreumáticos , Hipoalbuminemia , Enfermedades Reumáticas , Enfermedad de Whipple , Humanos , Persona de Mediana Edad , Tropheryma/fisiología , Glucocorticoides/uso terapéutico , Proteína C-Reactiva , Hipoalbuminemia/tratamiento farmacológico , Antibacterianos/uso terapéutico , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Enfermedad de Whipple/diagnóstico , Enfermedad de Whipple/tratamiento farmacológico , Enfermedad de Whipple/epidemiologíaRESUMEN
Aging is associated with detrimental bone loss leading to fragility fractures in both men and women. Notably, a majority of bone loss with aging is cortical, as well as a large number of fractures are non-vertebral and at the non-hip sites. Nacre is a product of mollusks composed of calcium carbonate embedded in organic components. As our previous study demonstrated the protective effect of nacre supplementation on trabecular bone loss in ovariectomized rats, we sought to evaluate the effect of dietary nacre on bone loss related to aging in female mice which do not suffer true menopause as observed in women. The current study compared the effect of a 90-day long nacre-supplemented diet to that of Standard or CaCO3 diets on both bone mass and strength in 16-month-old C57BL/6 female mice. Multiple approaches were performed to assess the microarchitecture and mechanical properties of long bones, analyze trabecular histomorphometry, and measure bone cell-related gene expressions, and bone turnover markers. In the cortex, dietary nacre improved cortical bone strength in line with lower expression levels of genes reflecting osteoclasts activity compared to Standard or CaCO3 diets (p < 0.05). In the trabeculae, nacre-fed mice were characterized by a bone remodeling process more active than the other groups as shown by greater histomorphometric parameters and osteoblast-related gene expressions (p < 0.05). But these differences were not exhibited at the level of the trabecular microarchitecture at this age. Collectively, these data suggest that dietary nacre should be a potential candidate for reducing aging-associated cortical bone loss in the elderly.
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Enfermedades Óseas Metabólicas , Nácar , Humanos , Masculino , Anciano , Femenino , Ratones , Ratas , Animales , Ratones Endogámicos C57BL , Huesos , Densidad Ósea , Hueso Cortical , Suplementos DietéticosRESUMEN
The patent expiry of Humira® in 2018 opened up the current European market to eight adalimumab biosimilars - (in alphabetical order) Amgevita®, Amsparity®, Hulio®, Hukyndra®, Hyrimoz®, Idacio®, Imraldi® and Yuflyma® - for the treatment of various immune and inflammatory conditions. Amjevita, Hadlima®, Hyrimoz and Yuflyma have recently become available in the USA, with others expected to reach this market in 2023 as the US patent protection for Humira ends. Although adalimumab biosimilars demonstrate efficacy, safety and immunogenicity similar to the originator, they may differ in product excipient(s) and preservatives, along with their device type(s). Physicians may find it both difficult and time consuming to navigate their way among the array of available adalimumab biosimilars when they need to make a treatment decision. This article explores the characteristics of various adalimumab biosimilars to help clinicians navigate the various options available across Europe and the USA. In addition to drug selection, effective patient-physician communication is needed to nurture realistic patient expectations and minimise potential nocebo effects when prescribing biosimilars.
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Biosimilares Farmacéuticos , Humanos , Adalimumab/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Testimonio de Experto , Europa (Continente)RESUMEN
In this article, we review published literature on "telerheumatology", a term describing the use of telemedicine in rheumatology. This field has received considerable recent attention through the development of efficient digital technologies, resulting in a good level of satisfaction among patients and health care professionals. In 2020, the social distancing constraints during the COVID-19 pandemic accelerated more widespread adoption worldwide. Telerheumatology is particularly suited for patients with rheumatoid arthritis who have achieved a sustained therapeutic target of remission or low disease activity. To facilitate remote consultations and meet expectations of rheumatologists and patients, international and national guidelines have recently been proposed and existing tools, such as Patient-Reported Outcomes questionnaires, have had to be digitally adapted. In addition, telerheumatology toolkits are proposed by the Arab League of Associations for Rheumatology (ArLAR), the Association of American Medical College (AAMC), and the American College of Rheumatology (ACR) for all learners, from medical students to practicing clinicians, encouraging the acquisition of telehealth skills and facilitating their integration into their routine clinical practice. The main benefits reported for this mode of health care are greater access to specialty care, flexibility, reduced rates of missed appointments, as well as improved patient engagement and autonomy. Limitations include the absence of physical examination. However, to implement telerheumatology effectively and widely in daily clinical practice, some barriers still need to be addressed. These include training of health care professionals, technological restrictions and reimbursement mechanisms. Despite the advantages of telerheumatology, it is not intended to replace face-to-face visits, but rather as a way to enhance access to care, service delivery and health care support for patients.
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Consulta Remota , Reumatología , Telemedicina , Humanos , Consulta Remota/métodos , Reumatología/métodos , Pandemias , Telemedicina/métodos , Atención a la SaludRESUMEN
OBJECTIVES: To assess differentially expressed blood proteins between patients with active rheumatoid arthritis (RA) and patients in remission after methotrexate (MTX) treatment, with the aim of identifying a biomarker of methotrexate resistance (MTXR). METHODS: Two populations of RA patients treated with a stable dose of subcutaneous MTX for at least 3 months were constituted according to the DAS28: remission (DAS28 < 2.6; n = 24) and active disease (DAS28 > 3.2; n = 32). The two groups of RA patients were homogeneous regarding their epidemiological characteristics, except for the duration of treatment which was longer in the remission group. After collection of a blood sample, plasma protein digestion was performed, followed by untargeted proteomics analysis. Then, a targeted analysis was performed to confirm the results of the untargeted approach. RESULTS: Untargeted proteomics analysis revealed 8 plasma proteins differentially expressed between the two groups of patients. Among them, triosephosphate isomerase (TPI-1) and glucose-6-phosphate isomerase (GPI), which are main actors of glycolysis, were found down-regulated in the active group. This result was confirmed for TPI-1 in the targeted proteomics analysis. CONCLUSIONS: A first step was achieved in the search for biomarker of MTXR with identification of two actors of glycolysis (TPI-1 and GPI). The next step will be to confirm these results in a larger cohort, including samples from treatment-naive patients, to assess the predictive potential of these protein markers.
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OBJECTIVES: The aim was to evaluate the ability of baseline multi-biomarker disease activity (MBDA) score to discriminate between patients with rheumatoid arthritis (RA) in remission who are at high risk versus low risk of relapse after TNF-inhibitor (TNFi) tapering. METHODS: The study is a post-hoc analysis of patients who completed the Spacing of TNFi injections in Rheumatoid ArthritiS Study (STRASS), a multicentre 18-month equivalence randomised controlled study, of TNFi tapering in RA patients in remission, and had baseline serum samples available for MBDA testing. The primary endpoint of this study was the ability of the baseline MBDA score to predict relapse at any time during the 18 months following initiation of TNFi tapering. Secondary endpoints were the ability of baseline MBDA score to predict TNFi discontinuation at Month 18, and structural damage progression on x-rays assessed by the change in total van der Heijde-modified Sharp score from baseline to month 18. RESULTS: 64 and 73 patients were included in the spacing (S)-arm and maintenance (M)-arm, respectively. In the M-arm, the mean MBDA score at baseline was higher among patients who relapsed during the 18-month follow-up than those who did not relapse: 32.5 compared to 27.2 (p=0.053) whereas no difference in the MBDA score was observed in the S-arm between patients who relapsed or not 27 compared to 26.2 (p=0.57) 13 patients (21.3%) of the S-arm were able to discontinue TNFi, for which the predictive value of the MBDA score was low (AUC=0.560). Radiographic progression in both arms, although low (n=9) was not correlated with the MBDA score at baseline with a poor discriminative value in both arms (AUC=0.558). CONCLUSIONS: In our study MBDA score in baseline was not predictive of relapse, discontinuation of TNFi in patients with long-standing RA patients tapering TNFi.
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Antirreumáticos , Artritis Reumatoide , Humanos , Antirreumáticos/efectos adversos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Biomarcadores , Enfermedad Crónica , Recurrencia , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: The objective of the current study was to evaluate the severity of COVID-19 and identify factors associated with severe disease outcomes in patients with spondyloarthritis (SpA), a chronic inflammatory rheumatic and musculoskeletal disease (RMD). METHODS: We utilized patient data from the French national multicenter RMD COVID-19 cohort (NCT04353609). The primary outcome was to describe COVID-19 characteristics in patients with SpA based on disease severity of COVID-19 (mild, moderate or severe) with serious infection including moderate and severe cases. The secondary outcome was to identify the factors associated with serious COVID-19 classification. RESULTS: Among the 626 patients with SpA (56% female, mean age 49±14 years) from the French RMD cohort, COVID-19 severity was mild in 508 (81%), moderate in 93 (15%), and severe in 25 (4%) patients. Clinical signs and symptoms of COVID-19 were reported in 587 (94%) patients, with the most frequent presented symptom of fever (63%) and cough (62%), followed by flu-like symptoms (53%), agueusia (39%), anosmia (37%), dyspnea (32%) and diarrhea (19.9%). COVID-19 severity was associated with corticosteroid therapy (OR=3.08 [95% CI: 1.44-6.58], P=0.004) and age (OR=1.06 [95% CI: 1.04-1.08], P<0.001) while use of tumor necrosis factor inhibitor (TNFi, OR=0.27 [95% CI: 0.09-0.78], P=0.01) was associated with less severe disease. We did not identify an association between NSAID use and COVID-19 severity. CONCLUSIONS: In this study, the majority of patients with SpA had a favorable COVID-19 outcome. We confirmed age and corticosteroids therapy had a negative impact on disease outcomes while TNFi use was protective.
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COVID-19 , Espondiloartritis , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , COVID-19/complicaciones , Espondiloartritis/diagnóstico , Espondiloartritis/tratamiento farmacológico , Espondiloartritis/epidemiología , Factor de Necrosis Tumoral alfaRESUMEN
For a better understanding of the pathophysiology of spondyloarthropathy (SpA), a detailed anatomical description of the sacroiliac joint is required because sacroiliitis is the earliest and most common sign of SpA and an essential feature for the diagnosis of ankylosing spondylitis. Beyond the anatomy, the histopathology of sacroiliac entheses and immunological mechanisms involved in sacroiliitis are crucial for a better understanding of disease causation. In this narrative review, we discuss the core anatomical, histological, and immunohistological observations involved in the development of sacroiliitis, focusing particularly on imaging-based information associated with sacroiliitis. Finally, we try to answer the question of whether at the sacroiliac joint, enthesitis precedes synovitis and subchondral bone changes in SpA.
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Introduction: Autoimmune/inflammatory rheumatic diseases (AIRDs) patients might be at-risk of severe COVID-19. However, whether this is linked to the disease or to its treatment is difficult to determine. This study aimed to identify factors associated with occurrence of severe COVID-19 in AIRD patients and to evaluate whether having an AIRD was associated with increased risk of severe COVID-19 or death. Materials and methods: Two databases were analyzed: the EDS (Entrepôt des Données de Santé, Clinical Data Warehouse), including all patients followed in Paris university hospitals and the French multi-center COVID-19 cohort [French rheumatic and musculoskeletal diseases (RMD)]. First, in a combined analysis we compared patients with severe and non-severe COVID-19 to identify factors associated with severity. Then, we performed a propensity matched score case-control study within the EDS database to compare AIRD cases and non-AIRD controls. Results: Among 1,213 patients, 195 (16.1%) experienced severe COVID-19. In multivariate analysis, older age, interstitial lung disease (ILD), arterial hypertension, obesity, sarcoidosis, vasculitis, auto-inflammatory diseases, and treatment with corticosteroids or rituximab were associated with increased risk of severe COVID-19. Among 35,741 COVID-19 patients in EDS, 316 having AIRDs were compared to 1,264 Propensity score-matched controls. AIRD patients had a higher risk of severe COVID-19 [aOR = 1.43 (1.08-1.87), p = 0.01] but analysis restricted to rheumatoid arthritis and spondyloarthritis found no increased risk of severe COVID-19 [aOR = 1.11 (0.68-1.81)]. Conclusion: In this multicenter study, we confirmed that AIRD patients treated with rituximab or corticosteroids and/or having vasculitis, auto-inflammatory disease, and sarcoidosis had increased risk of severe COVID-19. Also, AIRD patients had, overall, an increased risk of severe COVID-19 compares general population.
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The objective of this study was to develop a serum biochemical marker of the degradation of type III and IV collagens, as an index of synovium turnover, and evaluate its performance in patients with rheumatoid arthritis (RA). An enzyme-linked immunosorbent assay for serum synovial collagen fragments (Col3-4) was developed using an antibody recognizing a specific sequence from human type III collagen, which shares 70% homology with type IV collagen. Immunohistochemistry was performed to localize Col3-4 and the matrix metalloprotease MMP-9 which is upregulated in RA synovial fibroblasts in the synovial tissue from a RA patient. Serum Col3-4 was measured in patients with RA (n = 66, 73% women, mean age 62 years, median disease activity score 28 with erythrocyte sedimentation rate (DAS28-ESR) 2.6) and in sex and age matched healthy controls (n = 70, 76% women, mean age 59 years). Col3-4 immunoassay demonstrated adequate analytical performances and recognized a circulating neoepitope resulting from the cleavage of type III and IV collagens. In RA synovium tissue, Col3-4 fragments were localized in the lining layer where destructive fibroblasts are present and around blood vessels rich in type IV collagen. MMP-9 colocalized with Col3-4 staining and efficiently released Col3-4 fragments from type III and type IV collagen digestion. Serum Col3-4 was markedly increased in patients with RA (+240% vs controls, p < 0.0001) and correlated with DAS28-ESR (r = 0.53, p < 0.0001). Patients with RA and active disease (DAS28-ESR > 3.2, n = 20) had 896% (p < 0.0001) higher levels than subjects with low activity (n = 46). Serum Col3-4 is a specific and sensitive biochemical marker reflecting MMP- mediated type III and IV collagen degradation from synovial tissue. Serum Col3-4 levels are markedly increased in patients with RA, particularly in those with active disease, suggesting that it may be useful for the clinical investigation of RA.
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Artritis Reumatoide , Metaloproteinasa 9 de la Matriz , Humanos , Femenino , Persona de Mediana Edad , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Colágeno Tipo IV/metabolismo , Artritis Reumatoide/metabolismo , Membrana Sinovial/metabolismo , BiomarcadoresRESUMEN
PURPOSE: Analysis of cochlear structures and postoperative temporal bone (TB) imaging are gaining importance in the evaluation of cochlear implantation (CI°). Our aims were to explore the microarchitecture of human cochlea using micro-computed tomography (µCT), analyze electrode's placement inside cochlea after CI°, and compare pre-/post-implantation µCT scans with cone-beam CT (CBCT) scans of same TBs. METHODS: Cadaveric TBs were scanned using µCT and CBCT then underwent CI° using straight electrodes. Thereafter, they underwent again µCT and CBCT-imaging. RESULTS: Ten TBs were studied. µCT allowed visualization of scala tympani, scala vestibuli, basilar membrane, osseous spiral lamina, crista fenestrae, and spiral ligament. CBCT showed same structures except spiral ligament and crista fenestrae. After CI°, µCT and CBCT displayed the scalar location and course of electrode array within the cochlea. There were 7 cases of atraumatic electrode insertion and 3 cases of insertion trauma: basilar membrane elevation, electrode foldover with limited migration into scala vestibuli, and electrode kinking with limited migration into scala vestibuli. Insertion trauma was not correlated with cochlea's size or crista's maximal height but with round window membrane diameter. Resolution of µCT was higher than CBCT but electrode artifacts were similar. CONCLUSIONS: µCT was accurate in visualizing cochlear structures, and course and scalar position of electrode array inside cochlea with any possible trauma to cochlea or array. CBCT offers a good alternative to µCT in clinical practice for cochlear imaging and evaluation of CI°, with lower radiation and higher resolution than multi-slice CT. Difficulties related to non-traumatic CI° are multifactorial.
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Implantación Coclear , Implantes Cocleares , Humanos , Implantación Coclear/métodos , Microtomografía por Rayos X , Cóclea/diagnóstico por imagen , Cóclea/cirugía , Tomografía Computarizada de Haz Cónico , Hueso Temporal/diagnóstico por imagen , Hueso Temporal/cirugíaRESUMEN
OBJECTIVES: MTX is the recommended first-line treatment for RA associated with folic acid (FA) to reduce side effects related to MTX. Here, we proposed to test a co-administration of MTX with FA in the rat adjuvant-induced arthritis (AIA) on efficacy. MATERIAL AND METHODS: AIA was induced in female Lewis rats and treated with MTX in three groups. The first group of rats received only MTX (n = 13), whereas the second received MTX and FA on the same day (n = 14). The third group received FA one day after MTX (n = 14). Arthritic index (AI), ankle circumference (AC), ankle microcomputed tomography, and blood tests assessed arthritis severity and MTX tolerance. RESULTS: AI and AC were similar in MTX groups at various time points. Bone erosion and bone loss parameters were similar in all groups. MTX-PG1 was found at similar levels in various MTX groups and correlated negatively with arthritis severity. Finally, haematology and metabolic parameters were found at a similar level in MTX groups. CONCLUSION: Co-administration of MTX with FA on the same day did not reduce efficacy compared with FA application one day after MTX. Thus, co-administration of MTX and FA could be more convenient and improve compliance in patients.
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Artritis Experimental , Metotrexato , Femenino , Ratas , Animales , Metotrexato/uso terapéutico , Ácido Fólico/uso terapéutico , Microtomografía por Rayos X , Ratas Endogámicas Lew , Artritis Experimental/metabolismoRESUMEN
BACKGROUND: Use of a combination of targeted therapies (COMBIO) in patients with refractory/overlapping immune-mediated inflammatory diseases (IMIDs) has increased, but reported data remain scarce. We aimed to assess effectiveness and safety of COMBIO in patients with IMIDs. METHODS: We conducted a French ambispective multicenter cohort study from September 2020 to May 2021, including adults' patients with 1 or 2 IMIDs and treated at least 3-month with COMBIO. RESULTS: Overall, 143 patients were included. The most common IMIDs were Crohn's disease (63.6%), axial spondyloarthritis (37.7%), and ulcerative colitis (14%). Half of patients had only one IMID, of which 60% were Crohn's disease. Mean duration of COMBIO was 274.5±59.3 weeks, and COMBIO persistence at 104 weeks was estimated at 64.1%. The most frequent COMBIOs combined anti-TNF agents with vedolizumab (30%) or ustekinumab (28.7%). Overall, 50% of patients achieved significant and 27% mild-to-moderate improvement in patient-reported outcomes. Extended duration of COMBIO (aOR=1.09; 95% CI: 1.03-1.14; p=0.002) and diagnoses of two IMIDs (aOR=3.46; 95%CI: 1.29-9.26; p=0.013) were associated with significant improvement in patient-reported outcomes. Incidence of serious infection during COMBIO was 4.51 per 100 person-years (95% CI 2.20-8.27) and 5 COMBIOs were discontinued due to adverse events. CONCLUSIONS: COMBIO can be effective and safe in patients with refractory/overlapping IMIDs.
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Enfermedad de Crohn , Adulto , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Estudios de Cohortes , Agentes Inmunomoduladores , Inhibidores del Factor de Necrosis Tumoral , Ustekinumab/efectos adversosRESUMEN
Transcriptional cofactors YAP/TAZ have recently been found to support autophagy and inflammation, which are part of cell-autonomous immunity and are critical in antibacterial defense. Here, we studied the role of YAP against Staphylococcus aureus using CRISPR/Cas9-mutated HEK293 cells and a primary cell-based organoid model. We found that S. aureus infection increases YAP transcriptional activity, which is required to reduce intracellular S. aureus replication. A 770-gene targeted transcriptomic analysis revealed that YAP upregulates genes involved in autophagy/lysosome and inflammation pathways in both infected and uninfected conditions. The YAP-TEAD transcriptional activity promotes autophagic flux and lysosomal acidification, which are then important for defense against intracellular S. aureus. Furthermore, the staphylococcal toxin C3 exoenzyme EDIN-B was found effective in preventing YAP-mediated cell-autonomous immune response. This study provides key insights on the anti-S. aureus activity of YAP, which could be conserved for defense against other intracellular bacteria.
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Infecciones Estafilocócicas , Staphylococcus aureus , Humanos , Staphylococcus aureus/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transactivadores/metabolismo , Células HEK293 , Proteínas Señalizadoras YAP , Inmunidad Celular , InflamaciónRESUMEN
(1) Background: The link between periodontal disease and rheumatoid arthritis (RA) is now widely reported. Several studies suggest the role of Porphyromonas gingivalis (P. gingivalis) in the pathophysiology of RA and some observations highlight the improvement of the disease activity induced by therapies against P. gingivalis. We have very little data on the prevalence of P. gingivalis carriage in patients with juvenile idiopathic arthritis (JIA) and its possible involvement in the pathophysiology of inflammatory joint diseases in children. (2) Methods: The specific IgG responses against P. gingivalis and Prevotella intermedia (P. intermedia) were determined in a cohort of 101 patients with JIA and 19 patients with other autoimmune diseases (inflammatory bowel disease and type 1 diabetes). (3) Results: Specific anti-P. gingivalis and anti-P. intermedia IgG titers were higher in JIA group than in control groups. These differences were mainly observed in the oligoarthritis group. The same pattern was observed in enthesitis-related arthritis (ERA). (4) Conclusions: Children with oligoarticular and ERA subsets had higher IgG titers to P. gingivalis and P. intermedia. These results suggest involvement of an oral dysbiosis in the occurrence of JIA in these subgroups.
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Purpose: To evaluate whole-body vibration (WBV) osteogenic potential in physically inactive postmenopausal women using high-frequency and combined amplitude stimuli. Methods: Two-hundred fifty-five physically inactive postmenopausal women (55-75 years) with 10-year major osteoporotic fracture risk (3%-35%) participated in this 18-month study. For the first 12 months, the vibration group experienced progressive 20-min WBV sessions (up to 3 sessions/week) with rest periods (30-60 s) between exercises. Frequencies (30-50 Hz), with low (0.2-0.4 mm) and high (0.6-0.8 mm) amplitude stimuli were delivered via PowerPlate Pro5 platforms producing accelerations of (0.75-7.04 g). The last 6 months for the treatment group were a follow-up period similar to control. Serum bone remodelling markers [C-terminal crosslinked telopeptide of type-1 collagen (CTX), procollagen type-1 N-terminal propeptide (P1NP), bone alkaline phosphatase (BAP) and sclerostin] were measured at fasting. CTX and P1NP were determined by automated chemiluminescence immunoassay, bone alkaline phosphatase (BAP) by automated spectrophotometric immunoassay, and sclerostin by an enzyme-immunoassay. Bone mineral density (BMD) of the whole-body, proximal femur and lumbar vertebrae was measured by dual-energy X-ray absorptiometry (DXA). Bone microarchitecture of the distal non-dominant radius and tibia was measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Results: Femoral neck (p = 0.520) and spine BMD (p = 0.444) failed to improve after 12 months of WBV. Bone macro and microstructural parameters were not impacted by WBV, as well as estimated failure load at the distal radius (p = 0.354) and tibia (p = 0.813). As expected, most DXA and HR-pQCT parameters displayed age-related degradation in this postmenopausal population. BAP and CTX increased over time in both groups, with CTX more marginally elevated in the vibration group when comparing baseline changes to month-12 (480.80 pmol/L; p = 0.039) and month-18 (492.78 pmol/L; p = 0.075). However, no differences were found when comparing group concentrations only at month-12 (506.35 pmol/L; p = 0.415) and month-18 (518.33 pmol/L; p = 0.480), indicating differences below the threshold of clinical significance. Overall, HR-pQCT, DXA bone parameters and bone turnover markers remained unaffected. Conclusion: Combined amplitude and high-frequency training for one year had no ameliorating effect on DXA and HR-pQCT bone parameters in physically inactive postmenopausal women. Serum analysis did not display any significant improvement in formation and resorption markers and also failed to alter sclerostin concentrations between groups.