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We induced systemic sclerosis (SSc)-like disease in both wild-type and Dnase1l3-deficient mice using two distinct approaches involving bleomycin and hypochlorous acid injections. Our observations revealed that the deficiency in DNASE1L3 did not affect tissue fibrosis or inflammation caused by these treatments. Despite the association of single nucleotide polymorphisms in humans with SSc pathogenesis, our study demonstrates that DNASE1L3 is dispensable in two inducible murine models of SSc-like pathogenesis.
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Bleomicina , Modelos Animales de Enfermedad , Endodesoxirribonucleasas , Ratones Noqueados , Esclerodermia Sistémica , Animales , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Esclerodermia Sistémica/inmunología , Ratones , Endodesoxirribonucleasas/deficiencia , Endodesoxirribonucleasas/genética , Humanos , Ácido Hipocloroso , Fibrosis , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease. METHODS: Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form. RESULTS: Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14. CONCLUSION: This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions.
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Artritis Psoriásica , Inhibidores de las Cinasas Janus , Gammopatía Monoclonal de Relevancia Indeterminada , Enfermedades Reumáticas , Humanos , Anciano , Gammopatía Monoclonal de Relevancia Indeterminada/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Estudios Prospectivos , Anticuerpos Monoclonales , Enfermedades Reumáticas/tratamiento farmacológico , Inmunoglobulina GRESUMEN
OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.
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Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.
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Lupus Eritematoso Sistémico/inmunología , Células Mieloides/inmunología , Ligando OX40/metabolismo , Receptores OX40/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Anciano , Presentación de Antígeno , Linfocitos B/inmunología , Diferenciación Celular , Células Cultivadas , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Memoria Inmunológica , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , ARN/inmunología , Transducción de Señal , Receptor Toll-Like 7/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is associated with NLRP3 pathogenic variants, mostly located in the NACHT (neuronal apoptosis inhibitor protein, MHC class 2 transcription activator, incompatibility locus protein from Podospora anserina, telomerase-associated protein) domain. Cold-induced urticarial rash is among the main clinical features. However, this study identified a series of 14 patients with pathogenic variants of the Y861 residue (p.Tyr861) of the LRR domain of NLRP3 and minimal prevalence of cold-induced urticarial rash. OBJECTIVES: This study aimed to address a possible genotype/phenotype correlation for patients with CAPS and to investigate at the cellular levels the impact of the Y861C substitution (p.Tyr861Cys) on NLRP3 activation. METHODS: Clinical features of 14 patients with CAPS and heterozygous substitution at position 861 in the LRR domain of NLRP3 were compared to clinical features of 48 patients with CAPS and pathogenic variants outside the LRR domain of NLRP3. IL-1ß secretion by PBMCs and purified monocytes from patients and healthy donors was evaluated following LPS and monosodium urate crystal stimulation. RESULTS: Patients with substitution at position 861 of NLRP3 demonstrated a higher prevalence of sensorineural hearing loss while being less prone to skin urticarial. In contrast to patients with classical CAPS, cells from patients with a pathogenic variant at position 861 required an activation signal to secrete IL-1ß but produced more IL-1ß during the early and late phase of secretion than cells from healthy donors. CONCLUSIONS: Pathogenic variants of Y861 of NLRP3 drive a boost-dependent oversecretion of IL-1ß associated with an atypical CAPS phenotype.
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Síndromes Periódicos Asociados a Criopirina , Exantema , Urticaria , Humanos , Síndromes Periódicos Asociados a Criopirina/genética , Exantema/complicaciones , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fenotipo , Urticaria/genéticaRESUMEN
BACKGROUND: Few studies have evaluated mouth opening (MO) in systemic sclerosis (SSc). None have studied MO trajectories. OBJECTIVE: To study MO trajectories in SSc. METHODS: This multicentre study included patients enrolled in the French national SSc cohort with at least one MO assessment, described patients based on MO baseline measure, modeled MO trajectories, and associated MO measures with SSc prognosis. RESULTS: We included 1101 patients. Baseline MO was associated with disease severity. On Kaplan-Meier analysis, MO < 30 mm was associated with worse 30-year-survival (p<0.01) and risk of pulmonary arterial hypertension (p<0.05). Individual MO trajectories were heterogenous among patients. The best model of MO trajectories according to latent-process mixed modeling showed that 88.8% patients had a stable MO trajectory and clustered patients into 3 groups that predicted SSc survival (p<0.05) and interstitial lung disease (ILD) occurrence (p<0.05). The model highlighted a cluster of 9.5% patients with diffuse cutaneous SSc (dcSSc) (p<0.05) and high but decreasing MO over 1 year (p<0.0001) who were at increased risk of poor survival and ILD. CONCLUSION: MO, which is a simple and reliable measure, could be used to predict disease severity and survival in SSc. Although MO remained stable in most SSc patients, dcSSc patients with high but decreasing MO were at risk of poor survival and ILD. This article is protected by copyright. All rights reserved.
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OBJECTIVES: To estimate the association between SSc clinical phenotypes and quantitative occupational exposure to crystalline silica, chlorinated solvents, trichloroethylene, and pesticides using job-exposure matrices. METHODS: In the VISS-EXPOSITION transversal study, data on declarative occupational exposure to crystalline silica, solvents, and pesticides were retrieved. In parallel, the Lifetime Occupational History was evaluated using a questionnaire and cursus laboris for SSc patients followed at Bordeaux University Hospital (France). Using job-exposure matrices, we assessed patients' occupational exposure in relation to relevant clinical phenotypic forms of the disease. RESULTS: Toxic exposure to crystalline silica and pesticides is underestimated by patients. Non-biased job-exposure matrices retrieved more exposed patients than the declarative assessment (10.1% of patients by job-exposure matrices versus 6.3% by declaration for crystalline silica and 25.9% versus 12.2% for pesticides). Patients overestimate their solvent exposure (7.9% for chlorinated solvents and 4.8% for trichlorethylene assessed by job-exposure matrices and 24.4% declarative exposure to solvents at large). Clinical form evaluation revealed a nonsignificant trend toward an increased risk of crystalline silica occupational exposure in the pulmonary fibrotic group of SSc patients (OR 3.12 CI 95% [0.80-12.15]). We also observed a nonsignificant trend toward elevated OR (OR 2.89 CI 95% [0.93-8.95]) for chlorinated solvent occupational exposure and the vascular phenotype of SSc. Of note, pesticide occupational exposure evaluation represents one of the largest to date in SSc patients. CONCLUSION: This study emphasizes that many exposed SSc patients are unaware of their occupational exposure. Job-exposure matrices allow better exposure screening for SSc secondary prevention and occupational exposure compensation. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, https://www.clinicaltrials.gov, NCT03543956.
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OBJECTIVE: To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in RA in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar). METHODS: The PubMed, EMBASE and Cochrane databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the ACR 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% CI, pooled using random-effects models and then compared using a meta-regression model. RESULTS: We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95% CI, 66, 74) compared with 59% (95% CI, 55, 62) in the reference-pbo group (P =0.001). A significant difference was also found for ACR 50 [44% (95% CI, 39, 50) vs 35% (95% CI, 31, 39), respectively, P <0.01]. CONCLUSION: The effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the lessebo effect.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adalimumab/uso terapéutico , Productos Biológicos/uso terapéutico , Etanercept/uso terapéutico , Humanos , Infliximab/uso terapéutico , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de InvestigaciónRESUMEN
OBJECTIVES: Evidence shows that dysfunctional SSc keratinocytes contribute to fibrosis by altering dermal homeostasis. Whether IL-25, an IL-17 family member regulating many epidermal functions, takes part in skin fibrosis is unknown. Here we address the role of IL-25 in skin fibrosis. METHODS: The expression of IL-25 was evaluated by immunofluorescence and in situ hybridization in 10 SSc and seven healthy donor (HD) skin biopsies. Epidermal equivalents (EE) reconstituted by primary HD keratinocytes were used as a model to study transcriptomic changes induced by IL-25 in the epidermis. RNA expression profile in EEs was characterized by RNAseq. The conditioned medium (CM) from primary SSc and HD keratinocytes primed with IL-25 was used to stimulate fibroblasts. IL-6, IL-8, MMP-1, type-I collagen (Col-I), and fibronectin production by fibroblasts was assessed by ELISA. RESULTS: SSc epidermis expressed lower levels of IL-25 compared with HDs. In EEs, IL-25 regulated several molecular pathways related to wound healing and extracellular matrix remodelling. Compared with control CM, the CM from IL-25-primed keratinocytes enhanced the fibroblast production of MMP-1, IL-6 and IL-8, but not of Col-I nor fibronectin. However, IL-25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. CONCLUSIONS: These results show that IL-25 participates in skin homeostasis, and its decreased expression in SSc may contribute to skin fibrosis by favouring extracellular matrix deposition over degradation.
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Interleucina-17 , Queratinocitos , Esclerodermia Sistémica , Humanos , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Epidermis/metabolismo , Epidermis/patología , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Fibrosis , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Queratinocitos/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Esclerodermia Sistémica/patología , Piel/patologíaRESUMEN
OBJECTIVE: Digital pitting scars (DPS) are frequent, but little studied in SSc to date. METHODS: An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. RESULTS: A total of 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P ≤ 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P ≤ 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51-24.87), active digital ischaemia: 6.30 (5.34-7.42) and death: 1.86 (1.48-2.36). CONCLUSION: DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.
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Cicatriz/etiología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/mortalidad , Úlcera Cutánea/etiología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Treatments for SSc-associated interstitial lung disease (SSc-ILD) differ in attributes, i.e. mode of administration, adverse events (AEs) and efficacy. As physicians and patients may perceive treatments differently, shared decision-making can be essential for optimal treatment provision. We therefore aimed to quantify patient preferences for different treatment attributes. METHODS: Seven SSc-ILD attributes were identified from mixed-methods research and clinician input: mode of administration, shortness of breath, skin tightness, cough, tiredness, risk of gastrointestinal AEs (GI-AEs) and risk of serious and non-serious infections. Patients with SSc-ILD completed an online discrete choice experiment (DCE) in which they were asked to repeatedly choose between two alternatives characterized by varying severity levels of the included attributes. The data were analysed using a multinomial logit model; relative attribute importance and maximum acceptable risk measures were calculated. RESULTS: Overall, 231 patients with SSc-ILD completed the DCE. Patients preferred twice-daily oral treatments and 6-12 monthly infusions. Patients' choices were mostly influenced by the risk of GI-AEs or infections. Improvement was more important in respiratory symptoms than in skin tightness. Concerning trade-offs, patients accepted different levels of increase in GI-AE risk: +21% if it reduced the infusions' frequency; +15% if changing to an oral treatment; up to +37% if it improved breathlessness; and up to +36% if it reduced the risk of infections. CONCLUSIONS: This is the first study to quantitatively elicit patients' preferences for treatment attributes in SSc-ILD. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in clinical practice.
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Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Conducta de Elección , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Prioridad del Paciente , Esclerodermia Sistémica/complicaciones , Encuestas y CuestionariosRESUMEN
Systemic sclerosis may be complicated by digital ulcers. Nailfold capillaroscopy on one finger might reflect an increased risk of digital ulcer (DU). In the present study we studied the correlations between a history of ulcer and capillary findings on the finger. METHOD: This study is part of Sclerocap, a multicenter study aiming at validating prospectively the prognostic value of Maricq's and Cutolo's capillaroscopic classifications during a three-year longitudinal follow-up. A history of past or present digital ulcer was recorded at inclusion and nailfold capillaroscopy was performed. Elementary findings as well as Cutolo and Maricq's classifications were assessed. RESULTS: 387 patients were included in Sclerocap (327 females, 60 males) and 3096 fingers were examined by capillaroscopy at inclusion: 316 fingers (10%) belonging to 113 patients had a history of DU. Late Cutolo's stage was statistically correlated with a history of DU, both by univariate: OR 2.08 [1.09-3.96] and multivariate analysis: OR 1.97 [1.06-3.63]. Among the elemental abnormalities, only edema and decreased capillary density were correlated with a history of DU by multivariate analysis: respectively OR 1.92 [1.17-3.16] and 0.65 [0.49-0.85]. CONCLUSION: This cross-sectional study in a large cohort of patients with systemic sclerosis shows a correlation between a history of digital ulcer and edema, a decrease in capillary density and the late stage in Cutolo's classification. The extent of capillary abnormalities on one finger is associated with a history of local digital ulcer. Capillaroscopy might be used to predict the risk of DU but these results need first to be confirmed by prospective studies.
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Esclerodermia Sistémica , Úlcera Cutánea , Capilares/diagnóstico por imagen , Estudios Transversales , Femenino , Dedos/irrigación sanguínea , Humanos , Masculino , Angioscopía Microscópica/métodos , Uñas , Estudios Prospectivos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Úlcera Cutánea/diagnóstico , Úlcera Cutánea/etiología , Úlcera/complicacionesRESUMEN
OBJECTIVES: To evaluate MRI performance on both initial and long-term rheumatologic diagnosis of spondyloarthritis (SpA), taking into account clinical evolution and treatment response, and the impact of gadolinium injection. METHODS: In this single-center study, patients who underwent both spinal and sacroiliac (SI) joint MRI were prospectively recruited between May 2013 and January 2014 and followed for 7 years until 2020. Clinical, biological, and radiologic parameters were collected. At 7-year follow-up (2020), two independent readers reevaluated the initial MRI datasets for specific radiological features of SpA with a 5-point Likert scale to record the estimation of confidence. The centralized MRI interpretations were compared to the established rheumatologic diagnoses in 2013 and 2020. RESULTS: In total, 145 patients (52 men and 93 women) were included. During the 7-year follow-up, the number of patients with positive SpA diagnosis decreased from 93 to 58. Mean sensitivity, specificity, and accuracy of non-contrast MRI were 18, 97, and 49% and 27, 97, and 69% considering 2013 and 2020 rheumatologic diagnoses, respectively. Mean sensitivity, specificity, and accuracy values of gadolinium-enhanced MRI were 26, 97, and 54% and 38, 97, and 73% considering 2013 and 2020 diagnoses, respectively. Post-contrast MRI enabled identification of a subgroup of enthesis-only lesions, without any bone lesions, corresponding to 14% of the pathological cohort. It confirmed uncertain diagnoses in an additional 8.5% of pathological cases. CONCLUSIONS: MRI performance for SpA diagnosis is higher when long-term clinical follow-up is considered than when compared to initial diagnosis. Gadolinium injection increases MRI diagnostic performance and may demonstrate a pure enthesic form of the disease, without bone abnormality. KEY POINTS: ⢠Compared to the rheumatologist's diagnosis over long-term clinical follow-up, MRI performance for SpA is higher than usually estimated. ⢠Gadolinium injection increases diagnostic performance of MRI as it may identify a purely enthesis form of the disease. ⢠Gadolinium injection should be discussed in patients for whom the diagnostic suspicion is strong and whose initial non-injected examination is normal or doubtful.
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Espondiloartritis , Espondiloartropatías , Femenino , Estudios de Seguimiento , Gadolinio , Humanos , Imagen por Resonancia Magnética , Masculino , Articulación Sacroiliaca , Sensibilidad y Especificidad , Espondiloartritis/diagnóstico por imagen , Espondiloartropatías/diagnóstico por imagenRESUMEN
PURPOSE: JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE. METHODS: A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized. RESULTS: Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1-75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5-9.2] for VTE and 6.1 months [IQR: 3.0-8.5] for ATE. An IRR of 8.27 (95% CI 3.41-20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02-21.11]). An IRR of 9.27 (3.68-23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27-31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE. CONCLUSIONS: This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib.
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Azetidinas , Inhibidores de las Cinasas Janus , Tromboembolia Venosa , Humanos , Femenino , Masculino , Inhibidores de las Cinasas Janus/efectos adversos , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/epidemiología , Azetidinas/efectos adversos , Pirazoles/efectos adversosRESUMEN
Robustness, understood as the maintenance of specific functionalities of a given system against internal and external perturbations, is pervasive in today's biology. Yet precise applications of this notion to the immune system have been scarce. Here we show that the concept of robustness sheds light on tissue repair, and particularly on the crucial role the immune system plays in this process. We describe the specific mechanisms, including plasticity and redundancy, by which robustness is achieved in the tissue reconstruction system (TRS). In turn, tissue repair offers a very important test case for assessing the usefulness of the concept of robustness, and identifying different varieties of robustness.
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Sistema Inmunológico , Inmunidad , Regeneración , Cicatrización de Heridas , Animales , Biodiversidad , Plasticidad de la Célula , Homeostasis , HumanosRESUMEN
Investigate the natural history of urinary incontinence (UI) in systemic sclerosis (SSc) and assess its impact on quality of life (QoL). A longitudinal, international observational study followed 189 patients with SSc for a median duration of 5 years (IQR: 4.8-5.3). Presence, subtype and severity of UI, hospital admission and QoL were assessed using serial self-administered questionnaires. Mortality data came from national death registries. Multilevel mixed-effect logistic regressions explored factors associated with UI. Cox models adjusted the effects of UI on hospitalization and death for age, sex and subtype of SSc. Mean annual rates of new-onset UI and remission were 16.3% (95%CI 8.3%-24.2%) and 20.8% (95%CI 12.6-29.1), respectively. Among UI patients, 57.9% (95%CI 51.8-64.0) changed from one UI subtype to another. Between annual questionnaires, the severity of UI was the same in 51.1% (95%CI 40.8-61.4), milder or resolved in 35.2% (95%CI 25.3-44.9), and worse in 13.8% (95%CI 6.7-20.9). Anti-centromere antibodies, digestive symptoms, sex, age, neurological or urological comorbidities, diuretics and puffy fingers were all associated with UI. The two strongest predictors of UI and UI subtypes were a recent UI episode and the subtype of previous leakage episodes. UI at inclusion was not associated with hospital admission (adjusted HR: 1.86; 95%CI 0.88-3.93), time to death (aHR: 0.84; 95%CI 0.41-1.73) or change in QoL over time. Self-reported UI among SSc patients is highly dynamic: it waxes and wanes, changing from one subtype to another over time.
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Esclerodermia Sistémica , Incontinencia Urinaria , Diuréticos , Humanos , Estudios Prospectivos , Calidad de Vida , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/epidemiología , Encuestas y Cuestionarios , Incontinencia Urinaria/epidemiología , Incontinencia Urinaria/etiología , CerasRESUMEN
Importance: Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica. Objective: To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day. Interventions: Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone. Main Outcomes and Measures: The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone. Results: Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group. Conclusions and Relevance: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms. Trial Registration: ClinicalTrials.gov Identifier: NCT02908217.
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Antiinflamatorios , Anticuerpos Monoclonales Humanizados , Glucocorticoides , Polimialgia Reumática , Prednisona , Administración Intravenosa , Administración Oral , Anciano , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Proteína C-Reactiva/análisis , Método Doble Ciego , Reducción Gradual de Medicamentos , Femenino , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Interleucina-6/antagonistas & inhibidores , Masculino , Polimialgia Reumática/diagnóstico , Polimialgia Reumática/tratamiento farmacológico , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prednisona/uso terapéuticoRESUMEN
QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4â years and 4.0±7.4â years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.
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Antirreumáticos , Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Antirreumáticos/efectos adversos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Estudios de Casos y Controles , Humanos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Metotrexato/efectos adversosRESUMEN
OBJECTIVE: Innate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc). METHODS: Blood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques. The fibrotic role of sorted ILC2 was studied in vitro on dermal fibroblast and further explored by transcriptomic approach. Finally, the efficacy of a new treatment against fibrosis was assessed with a mouse model of SSc. RESULTS: We found that ILC2 numbers were increased in the skin of patients with SSc and correlated with the extent of skin fibrosis. In SSc skin, KLRG1- ILC2 (natural ILC2) were dominating over KLRG1+ ILC2 (inflammatory ILC2). The cytokine transforming growth factor-ß (TGFß), whose activity is increased in SSc, favoured the expansion of KLRG1- ILC2 simultaneously decreasing their production of interleukin 10 (IL10), which regulates negatively collagen production by dermal fibroblasts. TGFß-stimulated ILC2 also increased myofibroblast differentiation. Thus, human KLRG1- ILC2 had an enhanced profibrotic activity. In a mouse model of SSc, therapeutic intervention-combining pirfenidone with the administration of IL10 was required to reduce the numbers of skin infiltrating ILC2, enhancing their expression of KLRG1 and strongly alleviating skin fibrosis. CONCLUSION: Our results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFß and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc.
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Fibroblastos/metabolismo , Linfocitos/inmunología , Esclerodermia Sistémica/inmunología , Piel/patología , Factor de Crecimiento Transformador beta/inmunología , Adulto , Animales , Antiinflamatorios no Esteroideos/farmacología , Biopsia , Diferenciación Celular , Colágeno/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrosis , Perfilación de la Expresión Génica , Humanos , Interleucina-10/inmunología , Interleucina-10/farmacología , Lectinas Tipo C/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Miofibroblastos/citología , Piridonas/farmacología , Receptores Inmunológicos/metabolismo , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Piel/citología , Piel/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.