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1.
Ann Rheum Dis ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969328

RESUMO

OBJECTIVES: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.

2.
Autoimmun Rev ; : 102458, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31927087

RESUMO

Capillaroscopy is a non-invasive and safe tool which allows the evaluation of the morphology of the microcirculation. Since its recent incorporation in the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for systemic sclerosis together with its assessed role to monitor disease progression, capillaroscopy became a 'mainstream' investigation for rheumatologists. Given its increasing use by a variety of physicians internationally both in daily practice to differentiate primary from secondary Raynaud's phenomenon, as well as in research context to predict disease progression and monitor treatment effects, standardisation in capillaroscopic image acquisition and analysis seems paramount. To step forward to this need, experts in the field of capillaroscopy/microcirculation provide in this very consensus paper their view on image acquisition and analysis, different capillaroscopic techniques, normal and abnormal capillaroscopic characteristics and their meaning, scoring systems and reliability of image acquisition and interpretation.

3.
Clin Rheumatol ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31916106

RESUMO

OBJECTIVES: Multimodal rheumatologic complex treatment (MRCT) is a specific concept of German inpatient care focusing on physical therapy for patients with rheumatic diseases suffering from exacerbated pain and functional impairment. As physical therapy is a key concept in the treatment of spondyloarthritis (SpA), we conducted a monocentric retrospective analysis of the effects of MRCT on pain and functional status in patients with SpA including patients with axial spondyloarthritis (axSpA), non-radiographic axial spondyloarthritis (nr-axSpA) and psoriatic arthritis with axial involvement (axPsA). METHODS: 134 treatment episodes provided to 100 patients with SpA between 2014 and 2017 were analysed. We evaluated changes in pain intensity, in functional status and in disease activity before and after a treatment episode. In addition, we assessed potential influences of various patient characteristics, the course of the disease and comorbidities. RESULTS: Overall, MRCT resulted in significant amelioration of pain (NRS: p < 0.001), significant improvement of functional capacity (FFbH: p = 0.03; HAQ: p = 0.02; BASFI: p < 0.001) and significant reduction of disease activity (BASDAI p < 0.001; DAS28: p = 0.009). In general, treatment effects on axSpA, nr-axSpA and axPsA were comparable. Different aspects of the disease and its previous course did not have a significant effect on the outcome parameters. Comorbidities (e.g. fibromyalgia) did not significantly influence treatment response. CONCLUSION: MRCT not only decreases pain and improves function but also reduces disease activity in patients with axSpA, nr-axSpA and axPsA irrespective of the course of disease and comorbidities (e.g. fibromyalgia), thus underlining the importance of non-pharmacological and physical treatment in the treatment of SpA.Key Points• Physical treatment is a key component in treating SpA.• Multimodal rheumatologic complex treatment (MRCT) is a specific concept of German inpatient care focusing on physical therapy for patients with rheumatic diseases suffering from exacerbated pain and functional impairment.• MRCT not only decreases pain and improves function but also reduces disease activity in patients with axSpA, nr-axSpA and axPsA irrespective of the course of disease and comorbidities (e.g. fibromyalgia).• MRCT could be a role model of treating SpA by means of physical therapy as its effects are not influenced by therapy, disease duration or comorbidities and as it has no side effects.

4.
Ann Rheum Dis ; 79(1): 39-52, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31413005

RESUMO

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31790136

RESUMO

OBJECTIVE: In patients with SSc, peripheral vasculopathy can promote critical ischaemia and gangrene. The aim of this study was to investigate the prevalence, incidence and risk factors for gangrene in the EUSTAR cohort. METHODS: We included patients from the EUSTAR database fulfilling the ACR 1980 or the ACR/EULAR 2013 classification criteria for SSc, with at least one visit recording data on gangrene. Centres were asked for supplementary data on traditional cardiovascular risk factors. We analysed the cross-sectional relationship between gangrene and its potential risk factors by univariable and multivariable logistic regression. Longitudinal data were analysed by Cox proportional hazards regression. RESULTS: 1757 patients were analysed (age 55.9 [14.5] years, disease duration 7.9 [10.3] years, male sex 16.7%, 24.6% diffuse cutaneous subset [dcSSc]). At inclusion, 8.9% of patients had current or previous digital gangrene, 16.1% had current digital ulcers (DUs) and 42.7% had ever had DUs (current or previous). Older age, DUs ever and dcSSc were statistically significant risk factors for gangrene in the cross-sectional multivariable model. During a median follow-up of 13.1 months, 16/771 (0.9%) patients developed gangrene. All 16 patients who developed gangrene had previously had DUs and gangrene. Further risk factors for incident gangrene were the dcSSc subset and longer disease duration. CONCLUSION: In unselected SSc patients, gangrene occurs in about 9% of SSc patients. DUs ever and, to a lesser extent, the dcSSc subset are strongly and independently associated with gangrene, while traditional cardiovascular risk factors could not be identified as risk factors.

7.
Int J Rheum Dis ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31808306

RESUMO

BACKGROUND: Despite the great interest in capillaroscopy in systemic sclerosis (SSc), research on the possible combinations of different microvascular phenomena at different fingers in SSc patients have not been performed until now. OBJECTIVE: To assess the diversity of capillaroscopic findings in SSc. METHODS: The study includes analysis of the capillaroscopic findings in 40 SSc patients who were divided into the following categories: "scleroderma", type pattern - "early", "active", "late" phase, normal and/or nonspecific findings. The data were analyzed using descriptive statistics and t test. RESULTS: In 77% of the patients, inhomogeneity of the capillaroscopic findings of the fingers was detected. The most frequent combinations of capillaroscopic patterns were "early + active" (n = 7), "active + late" phase (n = 7), "active" phase + normal and/or nonspecific findings (n = 6), "early + active" phase + normal and/or nonspecific findings (n = 4). Concomitant presence of normal and/or nonspecific findings and "late" phase was detected in only 3 cases. CONCLUSION: Inhomogeneity of the capillaroscopic findings in SSc is a frequent phenomenon. The results indicate that combinations of "scleroderma" type capillaroscopic findings from different phases could be observed as well as concomitant appearance of pathological and normal/or nonspecific findings of different digits. This phenomenon could be a result of the complex action of different factors eg, disease duration, severity of Raynaud's phenomenon, presence of digital ulcers, local action of different angiogenic and angiostatic factors, gradual transition from one phase to another due to the extensive capillary area, therapeutic interventions.

8.
Front Immunol ; 10: 2757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849953

RESUMO

Obesity-in which free fatty acid (FFA) levels are chronically elevated-is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene α, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and ß-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31680161

RESUMO

OBJECTIVES: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. METHODS: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. RESULTS: The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. CONCLUSION: Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.

10.
RMD Open ; 5(2): e001041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673420

RESUMO

Objectives: The aims of this study were to update the evidence on the incidence and prevalence rates of vaccine preventable infections (VPI) in patients with autoimmune inflammatory rheumatic diseases (AIIRD) and compare the data to the general population when available. Methods: A literature search was performed using Medline, Embase and Cochrane library (October 2009 to August 2018). The primary outcome was the incidence or prevalence of VPI in the adult AIIRD population. Meta-analysis was performed when appropriate. Results: Sixty-three publications out of 3876 identified records met the inclusion criteria: influenza (n=4), pneumococcal disease (n=7), hepatitis B (n=10), herpes zoster (HZ) (n=29), human papillomavirus (HPV) infection (n=13). An increased incidence of influenza and pneumococcal disease was reported in patients with AIIRD. HZ infection-pooled incidence rate ratio (IRR) was 2.9 (95% CI 2.4 to 3.3) in patients with AIIRD versus general population. Among AIIRD, inflammatory myositis conferred the highest incidence rate (IR) of HZ (pooled IRR 5.1, 95% CI 4.3 to 5.9), followed by systemic lupus erythematosus (SLE) (pooled IRR 4.0, 95% CI 2.3 to 5.7) and rheumatoid arthritis (pooled IRR 2.3, 95% CI 2.1 to 2.6). HPV infection-pooled prevalence ratio was 1.6, 95% CI 0.7 to 3.4 versus general population, based on studies mainly conducted in the SLE population in Latin America and Asia. Pooled prevalence of hepatitis B surface antigen and hepatitis B core antibody in patients with AIIRD was similar to the general population, 3%, 95% CI 1% to 5% and 15%, 95% CI 7% to 26%, respectively. Conclusion: Current evidence shows an increased risk of VPI in patients with AIIRD, emphasising that prevention of infections is essential in these patients.

11.
Bone Rep ; 11: 100226, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31709277

RESUMO

Progressive bone loss is a predominant symptom of aging and osteoporosis. Therefore, the effects of sex steroids (i.e. testosterone and 17ß-estradiol) on the differentiation capacity of human bone-derived mesenchymal stromal cells (hMSCs), as progenitors of osteoblasts and adipocytes, are of particular interest. The objectives of the present study were, thus, to elucidate whether bone-derived hMSCs of postmenopausal women produce aromatase (CYP19A1) and, whether they modulate their differentiation behaviour in response to testosterone and 17ß-estradiol (E2), in relation to their steroid receptor expression. Supplementation of testosterone resulted in a considerable formation of E2 under osteogenic and adipogenic culture conditions, whereas E2 synthesis remained minimal in the cells cultured in basal medium. Concomitant with high aromatase expression and 17ß-estradiol formation of the cells cultured in osteogenic medium supplemented with testosterone, a distinct promotion of late-stage osteogenesis was found, as shown by significant matrix mineralization and a notable increase in osteogenic markers. These effects were abrogated by the aromatase inhibitor anastrozole. Under adipogenic conditions, testosterone reduced the occurrence of lipid droplets and led to a decrease in PPARγ and AR expression, independent of anastrozole. Regardless of the culture conditions, ERα was detectable whilst ERß was not. In conclusion, aromatase activity is limited to differentiated hMSCs and the resulting 17ß-estradiol enhances late osteogenic differentiation stages via ERα. Adipogenic differentiation, on the other hand, is reduced by both sex steroids: testosterone via AR and 17ß-estradiol.

12.
RMD Open ; 5(2): e001035, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565247

RESUMO

Aim: To present a systematic literature review (SLR) on efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD), aiming to provide a basis for updating the EULAR evidence-based recommendations. Methods: An SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Outcome was determined by efficacy, immunogenicity and safety of vaccination in adult patients with AIIRD, including those receiving immunomodulating therapy. Furthermore, a search was performed on the effect of vaccinating household members of patients with AIIRD on the occurrence of vaccine-preventable infections in patients and their household members (including newborns). The literature search was performed using Medline, Embase and the Cochrane Library (October 2009 to August 2018). Results: While most investigated vaccines were efficacious and/or immunogenic in patients with AIIRD, some were less efficacious than in healthy control subjects, and/or in patients receiving immunosuppressive agents. Adverse events of vaccination were generally mild and the rates were comparable to those in healthy persons. Vaccination did not seem to lead to an increase in activity of the underlying AIIRD, but insufficient power of most studies precluded arriving at definite conclusions. The number of studies investigating clinical efficacy of vaccination is still limited. No studies on the effect of vaccinating household members of patients with AIIRD were retrieved. Conclusion: Evidence on efficacy, immunogenicity and safety of vaccination in patients with AIIRD was systematically reviewed to provide a basis for updated recommendations.

13.
Autoimmun Rev ; 18(11): 102394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520797

RESUMO

OBJECTIVES: This study was designed to propose a simple "Fast Track algorithm" for capillaroscopists of any level of experience to differentiate "scleroderma patterns" from "non-scleroderma patterns" on capillaroscopy and to assess its inter-rater reliability. METHODS: Based on existing definitions to categorise capillaroscopic images as "scleroderma patterns" and taking into account the real life variability of capillaroscopic images described standardly according to the European League Against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases, a fast track decision tree, the "Fast Track algorithm" was created by the principal expert (VS) to facilitate swift categorisation of an image as "non-scleroderma pattern (category 1)" or "scleroderma pattern (category 2)". Mean inter-rater reliability between all raters (experts/attendees) of the 8th EULAR course on capillaroscopy in Rheumatic Diseases (Genoa, 2018) and, as external validation, of the 8th European Scleroderma Trials and Research group (EUSTAR) course on systemic sclerosis (SSc) (Nijmegen, 2019) versus the principal expert, as well as reliability between the rater pairs themselves was assessed by mean Cohen's and Light's kappa coefficients. RESULTS: Mean Cohen's kappa was 1/0.96 (95% CI 0.95-0.98) for the 6 experts/135 attendees of the 8th EULAR capillaroscopy course and 1/0.94 (95% CI 0.92-0.96) for the 3 experts/85 attendees of the 8th EUSTAR SSc course. Light's kappa was 1/0.92 at the 8th EULAR capillaroscopy course, and 1/0.87 at the 8th EUSTAR SSc course. CONCLUSION: For the first time, a clinical expert based fast track decision algorithm has been developed to differentiate a "non-scleroderma" from a "scleroderma pattern" on capillaroscopic images, demonstrating excellent reliability when applied by capillaroscopists with varying levels of expertise versus the principal expert and corroborated with external validation.


Assuntos
Algoritmos , Esclerodermia Localizada/diagnóstico , Escleroderma Sistêmico/diagnóstico , Humanos , Angioscopia Microscópica/métodos , Reprodutibilidade dos Testes
14.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443349

RESUMO

Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of many rheumatic conditions remain unknown, it is generally accepted that immune mechanisms and/or uncontrolled inflammatory responses are involved in their etiology and symptomatology. In this regard, the bidirectional communication between neuroendocrine and immune system has been demonstrated to provide a homeostatic network that is involved in several pathological conditions. Adipokines represent a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes that act as signal molecules in the neuroendocrine-immune interactions. Adipokines can also be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the joint microenvironment, showing potent modulatory properties on different effector cells in OA and RA pathogenesis. Effects of adiponectin, leptin, resistin and visfatin on local and systemic inflammation are broadly described. However, more recently, other adipokines, such as progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin, have been recognized to display immunomodulatory actions in rheumatic diseases. This review highlights the latest relevant findings on the role of the adipokine network in the pathophysiology of OA and RA.


Assuntos
Adipocinas/metabolismo , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Adipocinas/genética , Animais , Artrite Reumatoide/patologia , Biomarcadores , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Leptina/genética , Leptina/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Resistina/genética , Resistina/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
15.
Dtsch Arztebl Int ; 116(23-24): 412, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31366434
16.
Arthritis Res Ther ; 21(1): 144, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182152

RESUMO

BACKGROUND: Activin A and follistatin exhibit immunomodulatory functions, thus affecting autoinflammatory processes as found in rheumatoid arthritis (RA). The impact of both proteins on the behavior of synovial fibroblasts (SF) in RA as well as in osteoarthritis (OA) is unknown. METHODS: Immunohistochemical analyses of synovial tissue for expression of activin A and follistatin were performed. The influence of RASF overexpressing activin A on cartilage invasion in a SCID mouse model was examined. RASF and OASF were stimulated with either IL-1ß or TNFα in combination with or solely with activin A, activin AB, or follistatin. Protein secretion was measured by ELISA and mRNA expression by RT-PCR. Smad signaling was confirmed by western blot. RESULTS: In human RA synovial tissue, the number of activin A-positive cells as well as its extracellular presence was higher than in the OA synovium. Single cells within the tissue expressed follistatin in RA and OA synovial tissue. In the SCID mouse model, activin A overexpression reduced RASF invasion. In human RASF, activin A was induced by IL-1ß and TNFα. Activin A slightly increased IL-6 release by unstimulated RASF, but decreased protein and mRNA levels of follistatin. CONCLUSION: The observed decrease of cartilage invasion by RASF overexpressing activin A in the SCID mouse model appears to be mediated by an interaction between activin/follistatin and other local cells indirectly affecting RASF because activin A displayed certain pro-inflammatory effects on RASF. Activin A even inhibits production and release of follistatin in RASF and therefore prevents itself from being blocked by its inhibitory binding protein follistatin in the local inflammatory joint environment.

18.
Sci Transl Med ; 11(489)2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31019027

RESUMO

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

20.
Front Immunol ; 10: 541, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984167

RESUMO

Background: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the effect of JAK inhibitors on activated RASF. The aim of the study was to examine the effects of JAK inhibitors on activated RASF. Methods: Synovium of RA patients was obtained during knee replacement surgeries. Synoviocytes were isolated and pretreated with JAK inhibitors. Pro-inflammatory cytokines and matrix degrading proteinases were measured by ELISA in supernatant after stimulation with oncostatin M or IL-1ß. The proliferation of RASF was measured by BrdU incorporation. Cell culture inserts were used to evaluate cell migration. For adhesion assays, RASF were seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified. Cell viability, cytotoxicity and apoptosis were measured using the ApoTox-Glo™ Triplex and the CellTox™ Green Cytotoxicity Assay. Results: Tofacitinib and baricitinib decreased the IL-6 release of RASF stimulated with oncostatin M. JAK inhibition attenuated the IL-6 release of IL-1ß activated and with soluble IL-6 receptor treated RASF. In contrast, only peficitinib and filgotinib decreased the IL-6 release of RASF activated with IL-1ß. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 µM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 µM. Peficitinib further decreased the migration of RASF without being cytotoxic or pro-apoptotic and without altering cell adhesion. Conclusions: JAK inhibitors effectively suppress the inflammatory response induced by oncostatin M and by transsignaling of IL-6 in RASF. Only peficitinib modulated the IL-1ß-induced response of RASF and their proliferation in vitro at concentrations close to reported Cmax values of well tolerated doses in vivo. In contrast to filgotinib, peficitinib also highly suppressed RASF migration showing the potential of peficitinib to target RASF.

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