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1.
Artigo em Inglês | MEDLINE | ID: mdl-33738492

RESUMO

OBJECTIVE: To investigate the efficacy and safety of rituximab + LEF in patients with RA. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators' control. RESULTS: Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders. CONCLUSION: The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring. TRIAL REGISTRATION: EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958.

3.
Front Med (Lausanne) ; 7: 468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984365

RESUMO

Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations (e.g., oligo- or polyarthritis, enthesitis, dactylitis, and axial inflammation), early diagnosis of PsA is often difficult and delayed. Approximately 30% of PsO patients will develop PsA. The responsible triggers for the transition from PsO only to PsA are currently unclear, and the impacts of different factors (e.g., genetic, environmental) on disease development are currently discussed. There is a high medical need, recently unmet, to specifically detect those patients with an increased risk for the development of clinically evident PsA early to initiate sufficient treatment to inhibit disease progression and avoid structural damage and loss of function or even intercept disease development. Increased neoangiogenesis and enthesial inflammation are hypothesized to be early pathological findings in PsO patients with PsA development. Different disease states describe the transition from PsO to PsA. Two of those phases are of value for early detection of PsA at-risk patients to prevent later development of PsA as changes in biomarker profiles are detectable: the subclinical phase (soluble and imaging biomarkers detectable, no clinical symptoms) and the prodromal phase (imaging biomarkers detectable, unspecific musculoskeletal symptoms such as arthralgia and fatigue). To target the unmet need for early detection of this at-risk population and to identify the subgroup of patients who will transition from PsO to PsA, imaging plays an important role in characterizing patients precisely. Imaging techniques such as ultrasound (US), magnetic resonance imaging (MRI), and computerized tomography (CT) are advanced techniques to detect sensitively inflammatory changes or changes in bone structure. With the use of these techniques, anatomic structures involved in inflammatory processes can be identified. These techniques are complemented by fluorescence optical imaging as a sensitive method for detection of changes in vascularization, especially in longitudinal measures. Moreover, high-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) may give the advantage to identify PsA-related early characteristics in PsO patients reflecting transition phases of the disease.

4.
Cells ; 9(7)2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32640727

RESUMO

Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the "sneaking ligand" approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The prototype SLC1 binds specifically to the activated endothelium and blocks canonical NF-kappaB activation. In vivo, SLC1 attenuated clinical and histological signs of experimental arthritides. The SLFP architecture allows an easy exchange of binding and effector domains and represents an attractive approach to study disease-relevant biological targets in a broad range of diseases. In vivo, SLFP treatment might increase therapeutic efficacy while minimizing adverse effects.

5.
Dtsch Med Wochenschr ; 145(11): 773-780, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32492748

RESUMO

Psoriatic arthritis is a heterogeneous immune-mediated disease that usually involves skin and joints but can also affect entheses and extraarticular structures in the disease course. In addition, associated diseases must be considered when choosing the appropriate therapeutic strategy. Different recommendations for treatment of psoriatic arthritis are available for clinical use. The recommendations of the European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) are the two internationally accepted guidelines frequently used to assist therapeutic decisions in clinical practice. New targeted treatment options developed based on a better knowledge of critical pathogenic pathways, will enlarge our armamentarium for optimized pharmacotherapy of psoriatic arthritis and improve personalized patient care.

6.
Clin Rheumatol ; 39(8): 2491, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32474886

RESUMO

The original version of this article was published without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed.].

7.
Medicine (Baltimore) ; 99(19): e20201, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384515

RESUMO

Most studies of methotrexate (MTX) in combination with tumor necrosis factor (TNF) inhibitors have focused on treatment-naive patients with early disease. The goal of this study was to evaluate whether previous biologic therapy influenced the impact of concomitant MTX in patients initiating treatment with adalimumab.We retrospectively analyzed data from 2 large noninterventional studies of German patients with active rheumatoid arthritis (RA) who initiated adalimumab therapy during routine clinical practice. Patients were seen between April 2004 and February 2013 for study 1 and between April 2003 and March 2013 for study 2. Key outcomes were Disease Activity Score-28 joints (DAS28), patient global assessment of health (PGA), and pain. Subgroup analyses by prior biologic treatment were performed on patients treated with continuous adalimumab monotherapy or adalimumab plus MTX for 12 months and 2-sample t tests were used to evaluate differences. We also assessed outcomes in subgroups in which MTX had been added or removed at 6 months and compared outcomes with 1-sample t tests.Of 2654 patients, 1911 (72%) were biologic naive and 743 (28%) had received prior biologic therapy, usually with a TNF inhibitor. All subgroups showed improvements following initiation of adalimumab therapy. In patients with no previous biologic treatment, continuous adalimumab plus MTX was associated with greater improvements in DAS28, PGA, and pain at month 12 compared with continuous adalimumab monotherapy (P = .0006, .0031, and .0032, respectively). In patients with previous biologic treatment, concomitant MTX was associated with statistically significant benefits in pain only. Adding MTX at month 6 resulted in additional benefits in patients with no prior biologic therapy, but not those with previous biologics.We conclude that concomitant MTX resulted in additional improvements in DAS28 and PGA vs adalimumab monotherapy in patients with no previous biologic therapy, but changes were not statistically significant in patients treated with prior biologics. These findings may help inform the patient/provider treatment decision during routine clinical care.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Adalimumab/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/complicações , Produtos Biológicos , Progressão da Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Nível de Saúde , Humanos , Masculino , Metotrexato/administração & dosagem , Dor/etiologia , Estudos Retrospectivos , Índice de Gravidade de Doença
8.
BMC Med Genet ; 21(1): 102, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32397996

RESUMO

BACKGROUND: Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene. METHODS: Clinical data of all patients were collected and assessed for different combinations of clinical symptoms. SAPHO patients were grouped into categories according to the acronym; disease-contribution by pathogens was evaluated. We sequenced coding exons of FBLIM1. RESULTS: Palmoplantar pustular psoriasis (PPP) was the most common skin manifestation in CRMO/CNO and SAPHO patients; most SAPHO patients had sterno-costo-clavicular hyperostosis. The most common clinical category of the acronym was S_PHO (n = 26). Lack of pathogen detection from bone biopsies was more common than microbial isolation. We did not identify autosomal-recessive FBLIM1 variants. CONCLUSIONS: S_PHO is the most common combination of symptoms of its acronym. Genetic analyses of FBLIM1 did not provide evidence that this gene is relevant in our patient group. Our study indicates the need to elucidate SAPHO's and CRMO/CNO's pathogenesis.


Assuntos
Síndrome de Hiperostose Adquirida/genética , Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Osteomielite/genética , Síndrome de Hiperostose Adquirida/fisiopatologia , Adolescente , Adulto , Criança , Feminino , Humanos , Hiperostose/genética , Hiperostose/fisiopatologia , Masculino , Osteomielite/fisiopatologia , Psoríase/genética , Psoríase/fisiopatologia , Fatores de Risco
9.
Clin Rheumatol ; 39(9): 2583-2592, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32206973

RESUMO

OBJECTIVE: The goal of this study was to evaluate the long-term impact of adalimumab therapy on work-related outcomes in employed patients with rheumatoid arthritis (RA). METHOD: We utilized data from an observational cohort of German patients who initiated adalimumab treatment during routine clinical care. Analyses were based on employed patients (part-time or full-time) who continued adalimumab treatment for 24 months. Major outcomes were self-reported sick leave days in the previous 6 months, absenteeism, presenteeism, and total work productivity impairment as assessed by the Work Productivity and Activity Impairment (WPAI) questionnaire and disease activity assessments. The normal number of sick leave days was based on data from the German Federal Statistical Office. RESULTS: Of 783 patients, 72.3% were women, mean age was 47.9 years, and mean disease duration was 7.8 years. At baseline (before adalimumab initiation), 42.9% of patients had higher than normal sick leave days (> 5) in the previous 6 months. During 24 months of adalimumab treatment, 61% of patients with higher than normal sick leave days at baseline returned to normal sick leave values (≤ 5 days/6 months). Overall, mean sick leave days/6 months decreased from 14.8 days at baseline to 7.4 days at month 24. Improvements were observed in WPAI assessments and disease activity measures, although presenteeism levels remained high (32.2% at month 24). CONCLUSIONS: Adalimumab treatment was associated with strong and sustained improvements in work-related outcomes in employed patients who continued on adalimumab for 24 months. Presenteeism appears to be the work outcome most resistant to improvement during RA treatment. TRIAL REGISTRATION: NCT01076205 Key Points • Long-term adalimumab therapy was associated with sustained improvements in work outcomes in patients with rheumatoid arthritis. • Despite improvements in sick leave days and work absenteeism, presenteeism (impairment while at work) remained relatively high.

10.
Rheumatol Int ; 40(5): 747-755, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32040761

RESUMO

Assessment of individual therapeutic responses provides valuable information concerning treatment benefits in individual patients. We evaluated individual therapeutic responses as determined by the Disease Activity Score-28 joints critical difference for improvement (DAS28-dcrit) in rheumatoid arthritis (RA) patients treated with intravenous tocilizumab or comparator anti-tumor necrosis factor (TNF) agents. The previously published DAS28-dcrit value [DAS28 decrease (improvement) ≥ 1.8] was retrospectively applied to data from two studies of tocilizumab in RA, the 52-week ACT-iON observational study and the 24-week ADACTA randomized study. Data were compared within (not between) studies. DAS28 was calculated with erythrocyte sedimentation rate as the inflammatory marker. Stability of DAS28-dcrit responses and European League Against Rheumatism (EULAR) good responses was determined by evaluating repeated responses at subsequent timepoints. A logistic regression model was used to calculate p values for differences in response rates between active agents. Patient-reported outcomes (PROs; pain, global health, function, and fatigue) in DAS28-dcrit responder versus non-responder groups were compared with an ANCOVA model. DAS28-dcrit individual response rates were 78.2% in tocilizumab-treated patients and 58.2% in anti-TNF-treated patients at week 52 in the ACT-ion study (p = 0.0001) and 90.1% versus 59.1% at week 24 in the ADACTA study (p < 0.0001). DAS28-dcrit responses showed greater stability over time (up to 52 weeks) than EULAR good responses. For both active treatments, DAS28-dcrit responses were associated with statistically significant improvements in mean PRO values compared with non-responders. The DAS28-dcrit response criterion provides robust assessments of individual responses to RA therapy and may be useful for discriminating between active agents in clinical studies and guiding treat-to-target decisions in daily practice.

12.
BMC Rheumatol ; 3: 51, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867564

RESUMO

Background: The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functional status in rheumatoid arthritis (RA), but the change required for meaningful improvements remains unclear. A minimum clinically important difference (MCID) of 0.22 is frequently used in RA trials. The aim of this study was to determine a statistically defined critical difference for HAQ-DI (HAQ-DI-dcrit) and evaluate its association with therapeutic outcomes. Methods: We retrospectively analyzed data from adult German patients with RA enrolled in a multicenter observational trial in which they received adalimumab therapy at the decision of the treating clinician during routine clinical care. The HAQ-DI-dcrit, defined as the minimum change that can be reliably discriminated from random long-term variations in patients on stable therapy, was determined by evaluating intra-individual variation in patient scores. Other outcomes of interest included Disease Activity Score-28 joints and patient-reported pain and fatigue. Results: The HAQ-DI-dcrit was calculated as an improvement (decrease) from baseline of 0.68 in a discovery cohort (N = 1645) of RA patients on stable therapy and with moderate disease activity (mean DAS28 [standard deviation] of 4.4 [1.6]). In the full patient cohort (N = 2740), 22.1% of patients achieved a HAQ-DI-dcrit improvement at month 6. Compared with patients with a small improvement in HAQ-DI (decrease of ≥0.22 to < 0.68) or no improvement (< 0.22), patients achieving a HAQ-DI-dcrit at month 6 had better therapeutic outcomes at months 12 and 24, including stable functional improvements. Change in pain was the most important predictor of HAQ-DI improvement during the first 6 months of therapy. Conclusions: A HAQ-DI-dcrit of 0.68 is a reliable measure of functional improvement. This measure may be useful in routine clinical care and clinical trials. Trial registration: ClinicalTrials.gov NCT01076205. Registered on February 26, 2010 (retrospectively registered).

13.
PLoS One ; 14(5): e0217412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31136632

RESUMO

OBJECTIVES: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. METHODS: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. RESULTS: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. CONCLUSIONS: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. CLINICAL TRIAL REGISTRATION NUMBER: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).


Assuntos
Artrite Reumatoide/psicologia , Depressão/epidemiologia , Idoso , Artrite Reumatoide/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
14.
Cell Rep ; 27(3): 835-846.e5, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995480

RESUMO

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.


Assuntos
Interleucina-17/metabolismo , Interleucina-1/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Pele/patologia , Linfócitos T/metabolismo , Animais , Anticorpos/imunologia , Anticorpos/uso terapêutico , Diferenciação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imiquimode/toxicidade , Inflamação/prevenção & controle , Interleucina-1/genética , Interleucina-1/farmacologia , Proteína Acessória do Receptor de Interleucina-1/deficiência , Proteína Acessória do Receptor de Interleucina-1/genética , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/patologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Regeneração/efeitos dos fármacos , Pele/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia
16.
Arthritis Rheumatol ; 71(1): 63-72, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30003689

RESUMO

OBJECTIVE: To investigate mechanisms underlying the capability of ADAM15 to transform FasL-mediated death-inducing signals into prosurvival activation of Src and focal adhesion kinase (FAK) in rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Caspase 3/7 activity and apoptosis rate were determined in RASFs and ADAM15-transfected T/C28a4 cells upon Fas/CD95 triggering using enzyme assays and annexin V staining. Phosphorylated Src and FAK were analyzed by immunoblotting. Interactions of ADAM15 and CD95 with calmodulin (CaM), Src, or FAK were analyzed by pull-downs using CaM-Sepharose and coimmunoprecipitations with specific antibodies. Protein binding assays were performed using recombinant CaM and ADAM15. Immunofluorescence was performed to investigate subcellular colocalization of ADAM15, Fas/CD95, and CaM. RESULTS: The antiapoptotic effect of ADAM15 in FasL-stimulated cells was demonstrated either by increased apoptosis of cells transfected with an ADAM15 construct lacking the cytoplasmic domain compared to cells transfected with full-length ADAM15 or by reduced apoptosis resistance of RASFs upon RNA interference silencing of ADAM15. Fas ligation triggered a Ca2+  release-activated Ca2+ /calcium release-activated calcium channel protein 1 (CRAC/Orai1) channel-dependent CaM recruitment to Fas/CD95 and ADAM15 in the cell membrane. Simultaneously, Src associated with CaM was shown to become engaged in the ADAM15 complex also containing cytoplasmic-bound FAK. Accordingly, Fas ligation in RASFs led to ADAM15-dependent phosphorylation of Src and FAK, which was associated with increased survival. Pharmacologic interference with either the CaM inhibitor trifluoperazine or the CRAC/Orai inhibitor BTP-2 simultaneously applied with FasL synergistically enhanced Fas-mediated apoptosis in RASFs. CONCLUSION: ADAM15 provides a scaffold for formation of CaM-dependent prosurvival signaling complexes upon CRAC/Orai coactivation by FasL-induced death signals and a potential therapeutic target to break apoptosis resistance in RASFs.


Assuntos
Proteínas ADAM/genética , Apoptose/genética , Artrite Reumatoide/metabolismo , Calmodulina/metabolismo , Condrócitos/metabolismo , Proteína Ligante Fas/metabolismo , Fibroblastos/metabolismo , Proteínas de Membrana/genética , Proteínas ADAM/metabolismo , Anilidas/farmacologia , Apoptose/efeitos dos fármacos , Calmodulina/antagonistas & inibidores , Linhagem Celular , Quinase 1 de Adesão Focal/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Proteína ORAI1/antagonistas & inibidores , Proteína ORAI1/metabolismo , Fosforilação , Interferência de RNA , Membrana Sinovial/citologia , Tiadiazóis/farmacologia , Trifluoperazina/farmacologia , Receptor fas/metabolismo , Quinases da Família src/metabolismo
17.
PLoS One ; 13(9): e0203847, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30265671

RESUMO

The regulation of temporo-spatial compartmentalization of protein synthesis is of crucial importance for a variety of physiologic cellular functions. Here, we demonstrate that the cell membrane-anchored disintegrin metalloproteinase ADAM15, upregulated in a variety of aggressively growing tumor cells, in the hyperproliferative synovial membrane of inflamed joints as well as in osteoarthritic chondrocytes, transiently binds to poly(A) binding protein 1 (PABP) in cells undergoing adhesion. The cytoplasmic domain of ADAM15 was shown to selectively interact with the proline-rich linker of PABP. Immunostainings of adhesion-triggered cells demonstrate an ADAM15-dependent recruitment of PABP to cell membrane foci coinciding with ongoing mRNA translation as visualized by the detection of puromycin-terminated polypeptides. Moreover, the increase in cell membrane-associated neosynthesis of puromycylated proteins upon induction of cell adhesion was proven linked to ADAM15 expression in HeLa and ADAM15-transfected chondrocytic cells. Thus, down regulation of ADAM15 by siRNA and/or the use of a cell line transfected with a mutant ADAM15-construct lacking the cytoplasmic tail resulted in a considerable reduction in the amount of cell membrane-associated puromycylated proteins formed during induced cell adhesion. These results provide first direct evidence for a regulatory role of ADAM15 on mRNA translation at the cell membrane that transiently emerges in response to triggering cell adhesion and might have potential implications under pathologic conditions of matrix remodeling associated with ADAM15 upregulation.


Assuntos
Proteínas ADAM/metabolismo , Proteínas ADAM/fisiologia , Adesão Celular/fisiologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Comunicação Celular , Linhagem Celular , Membrana Celular/metabolismo , Condrócitos/metabolismo , Humanos , Osteoartrite/genética , Osteoartrite/fisiopatologia , Proteínas de Ligação a Poli(A)/metabolismo , Biossíntese de Proteínas/fisiologia , RNA Mensageiro/metabolismo , Transdução de Sinais/fisiologia , Membrana Sinovial/metabolismo , Transfecção
18.
Ann Rheum Dis ; 77(11): 1590-1598, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077990

RESUMO

BACKGROUND: Cardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR). METHODS AND RESULTS: This is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p<0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ2 0.462, p<0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement. CONCLUSIONS: Patients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement. TRIAL REGISTRATION NUMER: NCT02407197; Results.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Miocardite/diagnóstico , Miocardite/etiologia , Troponina T/sangue , Adulto , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Endocárdio/patologia , Feminino , Coração/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Miocardite/diagnóstico por imagem , Miocardite/patologia
19.
Rheumatology (Oxford) ; 57(11): 1938-1946, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010891

RESUMO

Objective: The aim of this study was to evaluate minimal disease activity (MDA) assessments in patients with PsA during routine clinical care. Methods: We used data from a multicentre observational study of patients with active PsA who initiated treatment with adalimumab during routine clinical practice and continued treatment for at least 6 months to evaluate achievement of MDA, individual MDA criteria (modified to conform to study assessments) and ACR responses during 24 months of therapy. Pearson correlation coefficients were used to evaluate the association between MDA and individual criteria at month 6; regression models were used to determine the influence of baseline MDA criteria on achievement of MDA at month 6. Results: A total of 1684 patients were included in these analyses; most had long-standing disease. MDA was achieved by 597 patients (35.5%) at month 6. This proportion increased to 45.5% at month 24 in patients remaining on therapy. MDA status was stable over time; >75% of patients with MDA at month 6 recorded MDA at subsequent visits. Pain was the most difficult individual criterion to achieve, and enthesitis was the least difficult. Higher functional status and fewer tender joints at baseline predicted achievement of MDA at month 6. About half of patients (51.5%) with an ACR20 response at month 6 achieved MDA. Conclusion: In this observational cohort of patients with long-standing disease, MDA provided a stable and valid assessment of clinical status over 24 months. Trial registration: Clinicaltrials.gov, https://clinicaltrials.gov, NCT01111240.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Adulto , Artrite Psoriásica/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Sci Adv ; 4(5): eaas9864, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29774240

RESUMO

Previous identification of the inducible nitric oxide synthase (NOS2) gene as a risk allele for psoriasis (Ps) and psoriatic arthritis (PsA) suggests a possible pathogenic role of nitric oxide (NO). Using a mouse model of mannan-induced Ps and PsA (MIP), where macrophages play a regulatory role by releasing reactive oxygen species (ROS), we found that NO was detectable before disease onset in mice, independent of a functional nicotinamide adenine dinucleotide phosphate oxidase 2 complex. MIP was suppressed by either deletion of Nos2 or inhibition of NO synthases with NG-nitro-l-arginine methyl ester, demonstrating that Nos2-derived NO is pathogenic. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-γ-stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1α (IL-1α) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS.


Assuntos
Artrite Psoriásica/etiologia , Artrite Psoriásica/metabolismo , Imunidade Inata , Interleucina-17/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Mananas/imunologia , Óxido Nítrico Sintase Tipo II/genética , Alelos , Animais , Artrite Psoriásica/patologia , Modelos Animais de Doenças , Expressão Gênica , Humanos , Interleucina-1alfa/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Transgênicos , Óxido Nítrico/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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