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1.
Curr Rheumatol Rep ; 23(3): 16, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33569681

RESUMO

PURPOSE OF REVIEW: Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis. RECENT FINDINGS: Complement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg/C3 and iC3b/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system. Abnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.


Assuntos
Síndrome Antifosfolipídica , Ativação do Complemento , Lúpus Eritematoso Sistêmico , Biomarcadores , Proteínas do Sistema Complemento , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Nefrite Lúpica
2.
J Clin Rheumatol ; 19(6): 317-23, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23965479

RESUMO

BACKGROUND: In rheumatoid arthritis (RA), there is discordance between patient and physician assessments of disease severity and treatment response. OBJECTIVE: This retrospective analysis of the RADIUS (RA Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) 1 cohort examined specific factors that influence differences in global assessments for therapeutic effectiveness of disease-modifying antirheumatic drugs made by physicians (physician global assessment [PhGA]) and patients (patient global assessment [PtGA]). METHODS: The RADIUS 1 cohort consisted of primarily community-based private practice patients with RA requiring either the addition of or a switch to a new biologic or nonbiologic disease-modifying antirheumatic drug and who were followed for up to 5 years by their rheumatologists. Periodic assessments included PhGA, PtGA, Health Assessment Questionnaire-Disability Index (HAQ-DI), 28-item tender/painful joint count (TJC28), swollen joint count (SJC28), pain Visual Analog Scale (VAS), and acute-phase reactants. RESULTS: Among 4359 patients (mean disease duration, 7.3 years), PhGA most highly correlated with TJC28 (0.6956; 95% confidence interval [CI], 0.6881-0.7030) and SJC28 (0.6757; 95% CI, 0.6678-0.6834). Moderate overall correlations were observed for PtGA with TJC28 (0.5000; 95% CI, 0.4890-0.5108) and less 50 with SJC28 (0.3754; 95% CI, 0.3628-0.3878). Patient global assessment most strongly correlated with pain VAS (0.8349; 95% CI, 0.8305-0.8392) and moderately correlated with HAQ-DI (0.5979; 95% CI, 0.5886-0.6071). Acute-phase reactants poorly correlated with PhGA and PtGA. CONCLUSIONS: Low correlations between PhGA and acute-phase reactants suggest that these measurements have a limited contribution compared with the physical examination when physicians make global assessments. These results also suggest that physicians should consider patients' assessments of their disease activity (HAQ, pain VAS, and PtGA) and put joint counts into proper context.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Avaliação de Resultados da Assistência ao Paciente , Pacientes , Médicos , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Satisfação do Paciente , Estudos Prospectivos , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do Tratamento , Estados Unidos/epidemiologia
3.
Arthritis Rheumatol ; 75(12): 2185-2194, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37459248

RESUMO

OBJECTIVE: Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE). METHODS: During screening, patients with active, non-organ-threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg intravenously or placebo once every 2 weeks until week 32 or loss of improvement (LOI). RESULTS: In this study, 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching week 32 without LOI, used an efficacy-evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment-related toxicity. This endpoint did not reach statistical significance: 21 of 50 obexelimab-treated patients (42.0%) versus 12 of 42 patients (28.6%) treated with a placebo (P = 0.183). Time to LOI was increased in obexelimab-treated patients versus patients treated with a placebo in the EE (hazard ratio [HR] 0.53, P = 0.025) and intention-to-treat (HR 0.59, P = 0.062) populations. In obexelimab-treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well-tolerated. CONCLUSION: Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab-treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation.


Assuntos
Anticorpos Monoclonais , Lúpus Eritematoso Sistêmico , Humanos , Anticorpos Monoclonais/uso terapêutico , Método Duplo-Cego , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/induzido quimicamente , Prednisona/uso terapêutico , Resultado do Tratamento
4.
Lancet Rheumatol ; 5(8): e442-e450, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38251576

RESUMO

BACKGROUND: Obexelimab is a bifunctional, non-cytolytic, humanised monoclonal antibody that binds CD19 and Fc gamma receptor IIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease. METHODS: We conducted an open-label, single-arm, single centre, phase 2 pilot trial at the Massachusetts General Hospital in Boston, MA, USA. Eligible patients were aged 18-80 years and had active IgG4-related disease confirmed by an IgG4-related disease responder index score of 3 or more. Patients received 5 mg/kg of obexelimab intravenously every 2 weeks for 24 weeks. Patients on glucocorticoids at baseline were expected to discontinue usage within 2 months following enrolment. The primary endpoint was the proportion of patients with a decrease of 2 or more from baseline in the IgG4-related disease responder index at day 169 (ie, primary responders). Patients who achieved a decrease of 2 or more at any visit were designated as responders. Adverse events were graded on a scale of 1-5 (ie, mild, moderate, severe, life-threatening, or death) according to the Common Terminology Criteria for Adverse Events grading scale (version 4.3). Exploratory analyses were quantification of B-cell CD19 receptor occupancy, plasmablast, total B-cell and CD4+ cytotoxic T-cell count by flow cytometry, and immunoglobulin concentrations by nephelometry. This study is registered with ClinicalTrials.gov, NCT02725476. FINDINGS: Between Feb 24, 2016, and Dec 21, 2016, we enrolled 15 patients. The median age was 63 years (IQR 52-65). Ten (67%) of 15 patients were male, five (33%) were female, and 12 (80%) were White. At baseline, 12 (80%) of 15 patients had an elevated median serum IgG4 concentration of 220 mg/dL (IQR 124-441), and the median IgG4-related disease responder index score was 12 (IQR 7-13). 12 (80%) of 15 patients achieved the primary endpoint (ie, primary responders), 14 (93%) were defined as responders. Reductions from baseline in serum B cells and plasmablasts were observed following treatment with obexelimab. However, in most patients with follow-up data, serum B cells recovered to 75% of baseline concentrations within 42 days of the final obexelimab dose. 13 (87%) of 15 patients reported adverse events, one of which (an infusion reaction) resulted in treatment discontinuation. INTERPRETATION: All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease. FUNDING: Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.


Assuntos
Antineoplásicos , Doença Relacionada a Imunoglobulina G4 , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Anticorpos Monoclonais , Linfócitos B , Plasmócitos , Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD19
5.
Ann Rheum Dis ; 71(6): 836-44, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22128079

RESUMO

OBJECTIVE: To summarise the relationship between joint damage and functional disability in rheumatoid arthritis (RA) patients. METHODS: A systematic review of the literature from 1990 to 2008 was conducted using MEDLINE and EMBASE databases. The search strategy focused on RA, joint damage and disability. Only longitudinal studies or randomised clinical trials with 1 year or more of follow-up containing data correlating joint damage and disability were included. The comparisons were categorised in four ways: baseline damage versus disability at end of follow-up (correlation A); damage versus disability measured cross-sectionally at each of several time points (correlation B); changes in damage versus final disability (correlation C) and changes in damage versus changes in disability (correlation D). RESULTS: From a total of 1902 abstracts, 42 studies met the inclusion/exclusion criteria. More than 50% of the studies that measured baseline damage to later disability (A) reported a statistically significant association. Correlation was significant when measured at multiple time points over time (B; 16/19 studies). Statistically significant associations between changes in damage and either disability at end of follow-up or changes in disability were also found (C and D; 11/13 studies). CONCLUSIONS: While many of the studies did not include multivariate analysis with confounder adjustment, the published evidence indicates a link between joint damage and functional disability and that an increase in joint damage is associated with an increase in disability over time. Treatments to limit progressive joint damage may lead to better joint function and improved patient outcome with less disability.


Assuntos
Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Avaliação da Deficiência , Articulações/patologia , Articulações/fisiopatologia , Atividades Cotidianas , Artrite Reumatoide/terapia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Ann Rheum Dis ; 71(7): 1143-50, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22258482

RESUMO

OBJECTIVES: To compare health-related quality of life (HRQoL) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis using spydergram representations. METHODS: Data from randomised, controlled trials of etanercept in patients with RA, PsA and psoriasis were analysed. HRQoL was assessed by the medical outcomes survey short form 36 (SF-36) physical (PCS) and mental (MCS) component summary and domain scores. Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure. RESULTS: Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA, but near normative values in patients with psoriasis; MCS scores at baseline were near normal in PsA and psoriasis but low in RA. Treatment with etanercept resulted in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications. Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA; clinically meaningful improvements in SF-6D were observed in all three patient populations following treatment with etanercept. CONCLUSIONS: Patients with RA, PsA and psoriasis demonstrated unique HRQoL profiles at baseline. Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA, PsA and psoriasis.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica , Artrite Reumatoide , Imunoglobulina G/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida/psicologia , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/fisiopatologia , Artrite Psoriásica/psicologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/psicologia , Etanercepte , Feminino , Nível de Saúde , Humanos , Articulações/patologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Resultado do Tratamento , Adulto Jovem
7.
Clin Exp Rheumatol ; 30(2): 197-201, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22325420

RESUMO

OBJECTIVES: AMG623, also known as A-623, is an antagonist of B-cell activating factor (BAFF). The present study was to evaluate the effects of AMG623 on murine models of autoimmune diseases. METHODS: AMG623 was generated through phage library. Inhibitory activities of AMG623 against human and murine BAFF were measured by biacore binding and BAFF-mediated B-cell proliferation assay. Pharmacological effects of AMG623 were studied in BALB/c mice, collagen-induced arthritis model (CIA) and in the NZBxNZW F1 lupus model. RESULTS: AMG623 binds to both soluble and cell surface BAFF. AMG623 blocks both human murine BAFF binding to the receptors. Treatment of AMG623 resulted in B-cell number reduction, and improvement of arthritis and lupus development in mice. CONCLUSIONS: AMG623 is a novel modality of BAFF antagonist. AMG623 is a potential therapeutic agent for the treatment of SLE, rheumatoid arthritis, and other B-cell-mediated autoimmune diseases.


Assuntos
Artrite Experimental/tratamento farmacológico , Fator Ativador de Células B/antagonistas & inibidores , Linfócitos B/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Animais , Artrite Experimental/imunologia , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Fatores de Tempo , Transfecção
8.
J Manag Care Spec Pharm ; 28(9): 1021-1032, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35775579

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex clinical diagnosis historically aided by imperfect biomarkers. The advent of a multianalyte assay panel incorporating innovative cell-bound complement activation markers necessitates a comparison of its clinical utility to conventional autoantibodies for the diagnosis and treatment of SLE. OBJECTIVES: To compare the likelihood of SLE diagnosis, SLE treatment initiation, and the downstream impact on health care utilization among patients tested with AVISE Lupus (AVISE) vs standard-of-care laboratory testing with the traditional antinuclear antibody (ANA) testing strategy cohort (tANA). METHODS: An observational retrospective cohort study was conducted using electronic health record (EHR) data from the Illumination Health registry, which integrates EHR records from more than 300 rheumatologists across the US. Health records from January 2016 to December 2020 and administrative claims with cost data for a subset of patients linkable to the HealthCore Integrated Research Database and Medicare data were analyzed. The AVISE and tANA test results were classified as positive, negative, or indeterminate, and outcomes were stratified based on test results. Two cohorts were established: AVISE testing strategy and the tANA approach. Analyses included test impact on SLE diagnosis, treatment initiation, patterns of repeat testing, and downstream health care utilization. Multivariable logistic regression was used to estimate odds ratios (ORs) comparing the likelihood of SLE medication initiation and SLE diagnosis between the AVISE and tANA cohorts. RESULTS: The main cohort included 21,827 AVISE testing episodes and 22,778 tANA testing episodes. A total of 2,437 (11.2%) patients tested positive by AVISE compared with 5,364 (23.6%) of tANA positive patients. Among patients with no baseline prescription for SLE medication(s), patients with a positive AVISE test result were more likely to initiate SLE medications compared with tANA positive patients (43% vs 32%; OR = 1.57; 95% CI = 1.41-1.76). The treatment effect was larger in patients new to the practice within the preceding year (55% vs 33%; adjusted OR = 2.77; 95% CI = 2.31-3.32). AVISE positive patients were more than 5-fold more likely to be diagnosed with SLE, as compared with the tANA patients (31% vs 8%; OR = 5.11; 95% CI = 4.43-5.89), and similar in the new patient cohort (30% vs 6%; OR = 6.34; 95% CI = 5.12-7.86). Linked EHR-Medicare data revealed a greater decrease in posttest vs pretest mean annualized outpatient laboratory testing in AVISE negative (-$985; P < 0.0001) vs tANA negative (-$356; P < 0.0001) patients. A similar analysis in the EHR-HealthCore linked data revealed similar numerical trends as the Medicare data for outpatient laboratory testing but did not reach significance (P > 0.05). Cost comparisons in the categories of hospitalization, emergency department, outpatient imaging, and pharmacy costs did not yield significant differences. CONCLUSIONS: The significantly greater likelihood of SLE diagnosis and SLE medication initiation in AVISE positive vs tANA positive patients is consistent with improved clinical actionability, potentially shortening time to diagnosis. AVISE negative patients experienced a greater decrease in outpatient laboratory testing posttest relative to tANA negative patients, supporting the improved negative predictive value of AVISE vs tANA. DISCLOSURES: Mr O'Malley and Dr Zack are employed by Exagen Inc. Drs Curtis and Xie, Ms Su, and Ms Clinton are affiliated with the University of Alabama at Birmingham. Mr Haechung and Dr Grabner are employees of HealthCore, Inc., which received funding from Bendcare (owner of the Illumination Health Registry) for the conduct of parts of the study on which this manuscript is based. Exagen Inc. provided funding to Bendcare for the conduct of the study. Dr Grabner is also a shareholder of Anthem, Inc.


Assuntos
Lúpus Eritematoso Sistêmico , Medicare , Idoso , Ativação do Complemento , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos
9.
Biomarkers ; 13(7): 692-712, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19096963

RESUMO

Rats with collagen-induced arthritis (CIA) were necropsied on 14 occasions from 4 days after induction to 27 days after disease onset to evaluate the kinetics of local (joint protein extracts) and systemic (serum) levels of inflammatory and pro-erosive factors. Systemic increases in alpha1 acid glycoprotein and KC/GRO together with systemic and local enrichment of interleukin (IL)-1beta, IL-6, CCL2, transforming growth factor (TGF)-beta and elevated IL-1alpha and IL-18 in joint extracts preceded the onset of clinical disease. Systemic upregulation of IL-1beta, IL-6, TGF-beta CCL2, RANKL and prostaglandin E(2) (PGE(2)) during acute and/or chronic CIA coincided with systemic leukocytosis and a CD4+ T-cell increase in blood and spleen. In contrast, progression of joint erosions during clinical CIA was associated with intra-articular increases in IL-1alpha/beta, IL-6, IL-18, CCL2, KC/GRO and RANKL, and a dramatic decline in osteoprotegerin (OPG). These data indicate that systemic and local events in inflammatory arthritis can be discrete processes, driven by multiple cellular and humoral mediators with distinct temporospatial profiles.


Assuntos
Artrite Experimental/patologia , Biomarcadores/análise , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Linfócitos T CD4-Positivos , Colágeno , Citocinas/análise , Progressão da Doença , Sistema Imunitário , Inflamação , Mediadores da Inflamação/análise , Cinética , Leucocitose , Ratos , Fatores de Tempo
10.
Adv Exp Med Biol ; 602: 143-50, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17966399

RESUMO

RANKL, the primary mediator of osteoclast formation, function and survival, is implicated in bone loss across a broad range of conditions. RANK and RANKL are expressed by cells involved in bone remodeling, by cells of the immune system, and by cells in other tissues. Preclinical and clinical data support the following conclusions: (1) The immune and skeletal phenotypes associated with RANKL inhibition differ in important ways from those associated with the complete absence or ablation of RANK or RANKL. (2) Immune challenge performed in animals in the presence of RANKL inhibition demonstrates normal immune function, consistent with the interpretation that RANKL inhibition does not impair the ability of animals to mount an effective immune response. (3) In animal models of inflammatory disease, inhibition of RANKL prevents bone loss but does not show a detectable effect on immune mediators or inflammation. (4) A phase 2 study in postmenopausal women with low BMD using the RANKL inhibitor denosumab showed an increase in BMD with an incidence of adverse events that was similar to placebo and to open-label alendronate. In addition, in a subset of patients tested for immunological markers, there were no clinically meaningful differences in T, B, or NK cell numbers or in immunoglobulin levels across dose or treatment groups.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Inflamação/tratamento farmacológico , Osteoporose/tratamento farmacológico , Ligante RANK/antagonistas & inibidores , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Denosumab , Feminino , Humanos , Inflamação/imunologia , Masculino , Osteoporose/imunologia , Ligante RANK/imunologia , Ligante RANK/metabolismo
11.
Mol Immunol ; 39(13): 783-9, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12617993

RESUMO

Methods for cell type specific targeted intracellular delivery of proteins in vivo remain limited. A murine monoclonal anti-dsDNA antibody, mAb 3E10, was selectively transported into skeletal muscle cells in vivo. The antibody bound a 200 kDa protein only found in lysates of skeletal muscle by Western blotting. The 200 kDa protein was purified from muscle lysate by antibody affinity chromatography and identified as the skeletal muscle specific heavy chain of myosin IIb by electrospray mass spectrometry. Antibody binding specificity for myosin IIb was demonstrated in Western blots by binding myosin in skeletal muscle lysates from mice null for myosin IId but not in mice null for myosin IIb. Myosin IIb is implicated in the specific targeting of mAb 3E10 to skeletal muscle.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Músculo Esquelético/imunologia , Miosina não Muscular Tipo IIB/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Antinucleares/administração & dosagem , Anticorpos Antinucleares/metabolismo , Anticorpos Monoclonais/farmacocinética , Especificidade de Anticorpos , Feminino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Miosina não Muscular Tipo IIB/deficiência , Miosina não Muscular Tipo IIB/genética , Miosina não Muscular Tipo IIB/metabolismo , Ratos , Distribuição Tecidual
12.
Arthritis Res Ther ; 17: 215, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26290435

RESUMO

INTRODUCTION: Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE). METHODS: SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed. RESULTS: All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for ≥ 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naïve B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects. CONCLUSIONS: Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.


Assuntos
Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Proteínas Recombinantes de Fusão/farmacocinética , Adulto , Área Sob a Curva , Fator Ativador de Células B/antagonistas & inibidores , Subpopulações de Linfócitos B/efeitos dos fármacos , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Cefaleia/induzido quimicamente , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Contagem de Linfócitos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Resultado do Tratamento , Adulto Jovem
13.
J Int Med Res ; 41(4): 1150-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23803306

RESUMO

OBJECTIVES: To investigate the relationships between inflammation, nocturnal back pain and fatigue in ankylosing spondylitis (AS) and the impact of 12 weeks' etanercept treatment versus sulfasalazine or placebo. METHODS: Data were combined from four clinical trials for patients with AS who received at least one dose of etanercept, sulfasalazine or placebo and had at least one postbaseline assessment value. Linear regression was performed (controlling for site, protocol and demographics), to explore the relationship between inflammation (C-reactive protein [CRP]), nocturnal back pain (visual analog scale [VAS] 0-100 mm) and fatigue (VAS 0-100 mm Bath AS Disease Activity Index fatigue item). RESULTS: Out of 1283 patients (etanercept, n = 867; sulfasalazine, n = 187; placebo, n = 229), improvement in nocturnal back pain was a significant predictor of improvement in fatigue. Significant correlations were found between nocturnal back pain and fatigue, but not CRP levels. Etanercept provided significantly greater pain/fatigue improvement than sulfasalazine or placebo. Improvements in nocturnal back pain and fatigue had weak relationships with improvement in inflammation (CRP level). CONCLUSIONS: AS patients treated with etanercept demonstrated superior improvement in nocturnal back pain and fatigue versus sulfasalazine or placebo. Decrease in nocturnal back pain can improve fatigue. Assessing treatment response using CRP levels alone may be misleading without also examining patient-reported outcomes such as back pain and fatigue.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Dor nas Costas/tratamento farmacológico , Fadiga/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Adulto , Dor nas Costas/sangue , Dor nas Costas/complicações , Dor nas Costas/fisiopatologia , Proteína C-Reativa/metabolismo , Etanercepte , Fadiga/sangue , Fadiga/complicações , Fadiga/fisiopatologia , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Medição da Dor , Periodicidade , Índice de Gravidade de Doença , Espondilite Anquilosante/sangue , Espondilite Anquilosante/complicações , Espondilite Anquilosante/fisiopatologia , Sulfassalazina/uso terapêutico , Resultado do Tratamento
14.
Arthritis Res Ther ; 13(4): R125, 2011 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-21801403

RESUMO

INTRODUCTION: AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee. METHODS: In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score. RESULTS: In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively). CONCLUSIONS: The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov with the identifier NCT00110942.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Antirreumáticos/administração & dosagem , Antirreumáticos/farmacocinética , Osteoartrite do Joelho/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Receptores de Interleucina-1/antagonistas & inibidores
15.
Pediatr Rheumatol Online J ; 8: 18, 2010 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-20546618

RESUMO

BACKGROUND: Concerns have been raised about a potential link between the use of TNF inhibitors and development of malignancy in the pediatric population. We examined the worldwide experience of etanercept use in pediatric patients and the occurrence of malignancies as reported from clinical trials, registry studies, post-marketing surveillance, and published scientific literature. METHODS: All reports of "malignancy" in pediatric patients (including subjects who received etanercept before age 18 and developed a malignancy before age 22) were collected from the etanercept clinical trials database and global safety database using the Medical Dictionary for Regulatory Activities (MedDRA; v12.0) standardized MedDRA query "Malignancies" from 1998 to August 2009. Cases were collected irrespective of treatment indication. All cases were included regardless of exposure to other TNF blockers or other biologics and whether the other exposure was before or after etanercept. RESULTS: A total of 18 potential malignancies were identified: 4 leukemias, 7 lymphomas, and 7 solid tumors. Three of the 18 malignancies remain unconfirmed. No malignancies were reported from clinical trials or the open-label extension studies in any indication in children. CONCLUSION: The data suggest that there does not appear to be an increased risk of malignancy overall with the use of etanercept. Among etanercept-exposed patients aged 4 to 17 years, the estimated worldwide and US reporting rates for lymphoma were approximately 0.01 per 100 patient-years (1 in 10,000 pt-yrs). While the reported rate of lymphoma is higher in pediatric patients treated with etanercept than in normal children, the expected rate of lymphoma in biologic naïve JIA patients is currently unknown. The risk of TNF inhibitors in the development of malignancies in children and adolescents is difficult to assess because of the rarity of malignant events, the absence of knowledge of underlying frequency of leukemia and lymphoma in JIA, and the confounding use of concomitant immunosuppressive medications.

16.
Arthritis Res Ther ; 12(5): R192, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20950476

RESUMO

INTRODUCTION: Preclinical work has suggested that IL-1 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The objective of the present study was to determine the effect of a long-acting IL-1 receptor inhibitor, AMG 108, in a double-blind, placebo-controlled, parallel-dosing study in patients with active RA who were receiving stable methotrexate (15 to 25 mg/week). METHODS: Patients were randomized equally to receive placebo or 50, 125, or 250 mg AMG 108 subcutaneously every 4 weeks for 6 months. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response (ACR20) at week 24; other efficacy endpoints included the ACR50, the ACR70, and the RA disease activity score (28-joint count Disease Activity Score) responses, patient-reported outcomes, and pharmacokinetic parameters. Safety endpoints included treatment-emergent adverse events (AEs), infectious AEs, serious AEs, serious infections, injection site reactions, laboratory abnormalities, and antibodies to AMG 108. RESULTS: Of 813 patients enrolled in the study, 204 patients were randomized to the 50 mg group, 203 to the 125 mg group, 203 to the 250 mg group, and 203 to placebo. At week 24, 40.4% of the 250 mg group, 36% of the 125 mg group, 30.9% of the 50 mg group, and 29.1% of the placebo group achieved an ACR20 (P = 0.022, 250 mg vs. placebo). Of the individual ACR components, numerical dose-dependent improvements were only seen in tender joint counts, pain (visual analog scale), and the acute phase reactants, erythrocyte sedimentation rate and C-reactive protein. No dose-related increase was observed in the incidence of treatment-emergent AEs. No deaths were reported, and the incidence of AEs and infections, serious AEs and infections, and withdrawals from study for safety were similar in the AMG 108 and placebo groups. CONCLUSIONS: This large double-blind randomized trial with a long-acting IL-1 receptor blocker, AMG 108, is consistent with the experience of other IL-1 blockers, represents a definitive experiment showing that IL-1 inhibition provides only moderate symptomatic amelioration of arthritis activity in the majority of RA patients, and provides an answer to a question that has been discussed for many years in the rheumatologic community. TRIAL REGISTRATION: ClinicalTrials.gov NCT00293826.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Receptores de Interleucina-1/imunologia , Anticorpos Monoclonais/farmacocinética , Antirreumáticos/farmacocinética , Artrite Reumatoide/imunologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor
17.
J Immunol ; 179(11): 7497-505, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18025194

RESUMO

Receptor activator of NF-kappaB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The effects of RANKL are inhibited by a soluble decoy receptor called osteoprotegerin (OPG). Total ablation of RANKL in knockout mice leads to high bone mass, lymph node agenesis, and altered lymphocyte differentiation. In contrast, RANKL inhibition via OPG suppresses bone resorption but not inflammation in animal models of inflammatory bone loss. This suggests that the immune phenotype of RANKL knockout mice is related to total RANKL ablation. We hypothesized that prenatal RANKL inhibition via OPG overexpression would suppress bone resorption without influencing lymph node formation or subsequent immune responses. Transgenic rats were created, wherein soluble OPG was overexpressed by 100-fold vs wild type (WT) controls, by gestational day 11 (i.e., before lymph node formation). The structure of lymph nodes, spleen, and thymus of OPG-transgenic (OPG-Tg) animals were comparable to those of age-matched WT rats at gestational day 19 and in adulthood. The OPG-Tg neonates had elevated bone mass, confirming the prenatal inhibition of RANKL. Adult OPG-Tg rats and OPG-Tg mice exhibited no significant functional alterations relative to WT controls when subjected to immune challenges to test for altered innate and humoral responses (e.g., contact hypersensitivity to oxazolone, IgM response to Pneumovax, IgG response to keyhole limpet hemocyanin, or cytokine response to LPS). In summary, prenatal RANKL inhibition did not impair lymph node development, nor did continuous life-long RANKL inhibition cause obvious changes in innate or humoral immune responses in mice or rats.


Assuntos
Osteoprotegerina/fisiologia , Ligante RANK/antagonistas & inibidores , Animais , Reabsorção Óssea/imunologia , Modelos Animais de Doenças , Imunidade/genética , Lipopolissacarídeos/farmacologia , Linfonodos/crescimento & desenvolvimento , Linfonodos/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Osteoprotegerina/biossíntese , Osteoprotegerina/genética , Fenótipo , Ratos , Ratos Sprague-Dawley
18.
Arthritis Rheum ; 52(10): 3192-201, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16200623

RESUMO

OBJECTIVE: To analyze the kinetics of osteoclastogenesis in 2 models of chronic immune-mediated arthritis and 1 model of acute arthritis. METHODS: Adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in Lewis rats were used as models of chronic arthritis. Acute arthritis was induced in Lewis rats by injecting carrageenan into the hind paw. Osteoclasts were identified by cathepsin K immunohistochemistry at various time points after the onset of arthritis. The location, size, and nucleation of osteoclasts were also analyzed. RESULTS: In both AIA and CIA, multinucleated and cathepsin K-positive osteoclasts first were observed on the day of disease onset. Initially, osteoclasts were localized at the periosteum next to the synovial membrane and in subchondral bone channels. The number, size, and nucleation of osteoclasts rapidly increased, leading to severe bone loss within days after disease onset. In addition, numerous mononucleated cathepsin K-positive osteoclast precursor cells emerged in the synovial membrane. All osteoclasts (cathepsin K-positive, multinucleated, attached to bone) and osteoclast precursors (cathepsin K-positive, mononucleated or multinucleated, within synovial tissue) were also positive for a macrophage-specific marker. Upon induction of acute arthritis with carrageenan, osteoclasts formed transiently in subchondral bone, but regressed 7 days after disease onset. CONCLUSION: Functional osteoclasts are generated at the earliest stage of arthritis, and new precursors are continuously formed in the synovial membrane to replenish the osteoclast pool. These data indicate that anti-resorptive therapies may provide the most effective bone protection, when treatment is started soon after the onset of arthritis.


Assuntos
Artrite Experimental/patologia , Reabsorção Óssea/patologia , Osteoclastos/patologia , Membrana Sinovial/patologia , Doença Aguda , Animais , Artrite Experimental/imunologia , Reabsorção Óssea/imunologia , Carragenina , Catepsina K , Catepsinas/metabolismo , Feminino , Articulações/imunologia , Articulações/patologia , Cinética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Monócitos/metabolismo , Monócitos/patologia , Osteoclastos/imunologia , Ratos , Ratos Endogâmicos Lew , Membrana Sinovial/imunologia
19.
Arthritis Rheum ; 52(5): 1604-11, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15880601

RESUMO

OBJECTIVE: To investigate whether the bone-preserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis. METHODS: Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation. RESULTS: Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (-74% in AIA and -61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (-41% and -29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (-88% in AIA and -73% in CIA, compared with -70% and -55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bone-sparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA. CONCLUSION: The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent.


Assuntos
Artrite/tratamento farmacológico , Doenças Ósseas/prevenção & controle , Proteínas de Transporte/antagonistas & inibidores , Glicoproteínas/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Hormônio Paratireóideo/uso terapêutico , Polietilenoglicóis/uso terapêutico , Receptores Tipo I de Fatores de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Reabsorção Óssea/prevenção & controle , Contagem de Células , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Masculino , Osteoblastos , Osteoprotegerina , Hormônio Paratireóideo/farmacologia , Polietilenoglicóis/farmacologia , Ligante RANK , Ratos , Ratos Endogâmicos Lew , Receptores Citoplasmáticos e Nucleares , Receptores do Fator de Necrose Tumoral
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