RESUMO
Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Etanercepte/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab/efeitos adversos , Adalimumab/uso terapêutico , Adulto , Anticorpos , Antirreumáticos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Etanercepte/efeitos adversos , Feminino , Humanos , Infliximab/efeitos adversos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversosRESUMO
BACKGROUND: Recently, disease activity states were developed for the Disease Activity index for PSoriatic Arthritis (DAPSA). Here, we assess if different DAPSA disease activity states are associated with different degrees of functional impairment and different extents of joint damage progression in patients with psoriatic arthritis (PsA). METHODS: We used data from two pivotal trials of tumour necrosis factor (TNF) inhibitors in PsA (IMPACT II and GO-REVEAL) and identified patients in DAPSA remission (REM, ≤4), and low, moderate or high disease activity (LDA, ≤14; MDA, ≤28; HDA, >28) at 6â months. Across these groups we compared the functional scores (Health Assessment Questionnaire Disability Index, HAQ and physical component scale of the Short Form-36, PCS), and 1-year structural progression (PsA-modified Sharp/van der Heijde Score). RESULTS: We identified 310 from GO-REVEAL and 130 from IMPACT II, with a mean (SD) baseline DAPSA of 48.8 (26.4) and 44.6 (17.9), respectively. HAQ scores increased across patients groups in the four DAPSA disease activity states, while PCS decreased (p<0.001 for both). The mean progression in the combined cohort was -0.47 for REM, -0.28 for LDA, -0.14 for MDA and 0.51 for HDA (p<0.001). This association was also significant in the individual trial cohorts, and in the subgroups of patients treated with TNF inhibitors or placebo. Higher DAPSA scores were significantly and independently associated with probability of structural progression in multiple analyses. CONCLUSIONS: Disease activity states of the PsA specific DAPSA score are highly valid for future use as endpoints in clinical trials or as targets in clinical practice. TRIAL REGISTRATION NUMBERS: IMPACT 2: NCT02152254; GO-REVEAL: NCT00265096.
Assuntos
Atividades Cotidianas , Artrite Psoriásica/fisiopatologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/diagnóstico por imagem , Artrite Psoriásica/tratamento farmacológico , Ensaios Clínicos como Assunto , Progressão da Doença , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Radiografia , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. METHODS: A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. RESULTS: Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. CONCLUSIONS: This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.
Assuntos
Gota/sangue , Gota/tratamento farmacológico , Ácido Úrico/sangue , Doença Crônica , Guias como Assunto , Humanos , Rim/fisiopatologia , Estilo de Vida , Adesão à Medicação , Planejamento de Assistência ao Paciente , Educação de Pacientes como Assunto , Participação do Paciente , Literatura de Revisão como AssuntoRESUMO
BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.
Assuntos
Algoritmos , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Glucocorticoides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Gerenciamento Clínico , Europa (Continente) , Humanos , Reumatologia , Sociedades MédicasRESUMO
BACKGROUND: Sonographic assessment, measuring grey scale (GS) and power Doppler (PD) signals, is a sensitive tool for the evaluation of inflammatory joint activity in patients with rheumatoid arthritis (RA). We evaluated the persistence of PD and GS signals in previously clinically active RA joints that have reached a state of continuous clinical inactivity. METHODS: We performed sonographic imaging of 22 joints of the hands of patients with RA, selected all joints without clinical activity but showing ongoing sonographic signs of inflammation, and evaluated the time from last clinical joint activity. RESULTS: A total of 90 patients with RA with 1980 assessed joints were included in this study. When comparing the mean time from clinical swelling, we found a significantly longer period of clinical inactivity in joints showing low sonographic activity (mean±SD time from swelling of 4.1±3.2 vs 3.1±2.9â years for PD1 vs PD≥2, p=0.031 and 4.5±3.4 vs 3.3±3.2â years for GS1 vs GS≥2, p≤0.0001). CONCLUSIONS: We conclude that subclinical joint activity is long-lasting in RA joints in clinical remission, but attenuates over time. The latter conclusion is based on the observed shorter time duration from last clinical activity for strong compared with weaker sonographic signals.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Articulações dos Dedos/diagnóstico por imagem , Articulação Metacarpofalângica/diagnóstico por imagem , Sinovite/diagnóstico por imagem , Articulação do Punho/diagnóstico por imagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Estudos de Coortes , Feminino , Articulações dos Dedos/irrigação sanguínea , Humanos , Masculino , Articulação Metacarpofalângica/irrigação sanguínea , Pessoa de Meia-Idade , Osteoartrite/complicações , Osteoartrite/diagnóstico por imagem , Indução de Remissão , Índice de Gravidade de Doença , Ultrassonografia Doppler , Articulação do Punho/irrigação sanguíneaRESUMO
OBJECTIVES: This 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with low to moderate disease activity, and stopping therapy in patients in sustained remission. METHODS: Patients were randomised 1:1 to CZP (400â mg at weeks 0, 2 and 4, then 200â mg every 2â weeks) or placebo (every 2â weeks) plus current non-biologic DMARDs. At week 24, patients who achieved the primary endpoint of Clinical Disease Activity Index (CDAI) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52. RESULTS: Of 194 patients (CZP=96; placebo=98), >90% had moderate disease activity at baseline. Significantly more CZP patients met the primary endpoint than placebo patients (week 20 and 24 CDAI remission rates: 18.8% vs 6.1%; p≤0.05). At week 24, 63.0% vs 29.7% of CZP versus placebo patients (p<0.001) achieved LDA. Disease activity score (ESR) based on 28-joint count and Simplified Disease Activity Index remission rates were also significantly higher with CZP versus placebo (19.8% vs 3.1%; p≤0.01 and 14.6% vs 4.1%; p≤0.05). CZP patients reported improvements in physical function versus placebo (mean Health Assessment Questionnaire-Disability-Index change from baseline: CZP, -0.25 vs placebo, -0.03; p≤0.01). During the period following withdrawal of CZP or placebo, only 3/17 prior CZP patients and 2/6 prior placebo patients maintained CDAI remission until week 52, but CZP reinstitution allowed renewed improvement. Adverse and serious adverse event rates were comparable between CZP and placebo groups. CONCLUSIONS: Addition of CZP to non-biologic DMARDs is an effective treatment in RA patients with predominantly moderate disease activity, allowing low-disease activity or remission to be reached in a majority of the patients. However, the data suggest that CZP cannot be withdrawn in patients achieving remission. TRIAL REGISTRATION NUMBER: NCT00674362.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Idoso , Certolizumab Pegol , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To validate ultrasound (US) for measuring metacarpal cartilage thickness (MCT), by comparing it with anatomical measurement using cadaver specimens. To correlate US MCT with radiographic joint space narrowing (JSN) or width (JSW) in patients with rheumatoid arthritis (RA). METHODS: Bilateral metacarpophalangeal (MCP) joints of 35 consecutive outpatients, with recent hand X-rays, were included in the analysis. Metacarpal and phalangeal cartilage of MCP 2-5 was assessed bilaterally by US. JSW and JSN were evaluated on X-rays by the van der Heijde modified Sharp method (vdHS). In addition, cadaver specimens of MCP 2-5 joints (n=19) were evaluated by anatomical measurement and US. RESULTS: The agreement (intraclass correlation coefficient) between sonographic and anatomical MCT on cadaver specimens of MCP joints was 0.61. MCT of individual MCP joints correlated with individual MCP JSN (r=-0.32, p<0.001) and individual MCP JSW (r=0.72, p<0.001). No correlation was found between phalangeal cartilage thickness and JSN in individual MCP joints. The US MCT summary score for MCP joints 2-5 correlated with summary scores for JSW (r=0.78, p<0.001), JSN (r=-0.5, p<0.001), erosion score of the vdHS (r=-0.39, p<0.001) and total vdHS (r=-0.47, p<0.001). CONCLUSIONS: Sonographic cartilage assessment in MCPs is closely related to anatomical cartilage thickness. Both JSW and JSN by radiography represent cartilage thickness in the MCP joints of patients with RA quite well. Thus, US is a valid tool for measuring MCT if radiographs are not available or in case of joint malalignment.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Cartilagem Articular/diagnóstico por imagem , Articulação Metacarpofalângica/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/patologia , Cartilagem Articular/patologia , Estudos de Casos e Controles , Feminino , Articulação da Mão/diagnóstico por imagem , Articulação da Mão/patologia , Humanos , Masculino , Articulação Metacarpofalângica/patologia , Pessoa de Meia-Idade , Tamanho do Órgão , Radiografia , Reprodutibilidade dos Testes , UltrassonografiaRESUMO
No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.
Assuntos
Terapia Biológica/métodos , Consenso , Imunossupressores/uso terapêutico , Infecções Oportunistas , Vigilância de Produtos Comercializados/métodos , Ensaios Clínicos como Assunto , Saúde Global , Humanos , Morbidade/tendências , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/terapia , Fatores de RiscoRESUMO
BACKGROUND: Current recommendations for the management of axial spondyloarthritis (SpA) and psoriatic arthritis are to monitor disease activity and adjust therapy accordingly. However, treatment targets and timeframes of change have not been defined. An international expert panel has been convened to develop 'treat-to-target' recommendations, based on published evidence and expert opinion. OBJECTIVE: To review evidence on targeted treatment for axial and peripheral SpA, as well as for psoriatic skin disease. METHODS: We performed a systematic literature search covering Medline, Embase and Cochrane, conference abstracts and studies in http://www.clinicaltrials.gov. RESULTS: Randomised comparisons of targeted versus routine treatment are lacking. Some studies implemented treatment targets before escalating therapy: in ankylosing spondylitis, most trials used a decrease in Bath Ankylosing Spondylitis Disease Activity Index; in psoriatic arthritis, protocols primarily considered a reduction in swollen and tender joints; in psoriasis, the Modified Psoriasis Severity Score and the Psoriasis Area and Severity Index were used. Complementary evidence correlating these factors with function and radiographic damage at follow-up is sparse and equivocal. CONCLUSIONS: There is a need for randomised trials that investigate the value of treat-to-target recommendations in SpA and psoriasis. Several trials have used thresholds of disease activity measures to guide treatment decisions. However, evidence on the effect of these data on long-term outcome is scarce. The search data informed the expert committee regarding the formulation of recommendations and a research agenda.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Medicina Baseada em Evidências , Espondilartrite/tratamento farmacológico , Humanos , Internacionalidade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVES: Nailfold capillaroscopy (NC) and laboratory tests for antinuclear antibodies (ANA) are routinely used in parallel for detection of emerging connective tissue disease (CTD) in patients with Raynaud's phenomenon (RP). The aim of this study was to assess the associations between distinct nailfold capillary abnormalities and concomitant autoantibodies in patients with incipient RP without previously known CTD. METHOD: Patients with incipient RP without previously known CTD were included in this retrospective analysis. We analysed the association of particular capillary abnormalities (reduced density, avascular fields, dilations, giant capillaries, haemorrhages, tortuosity, ramifications, oedema) with ANA and ANA subsets (anti-Scl-70, anti-CENP-B, anti-U1-RNP, anti-dsDNA, anti-SSA(Ro), anti-SSB(La), anti-Sm, and anti-Jo-1 antibodies). We also developed a score that allows the estimation of each patient's individual probability for the presence of an ANA titre ≥ 1:160. RESULTS: The final analysis comprised 2971 patients. Avascular fields, giant capillaries, reduced capillary density, and capillary oedema were closely related to an ANA titre ≥ 1:160. Both giant capillaries and avascular fields were associated with anti-Scl-70 and anti-CENP-B antibodies. Only a weak association was found between giant capillaries and anti-U1-RNP antibodies. Each patient's individual probability for the presence of an ANA titre ≥ 1:160 can be represented by a sum score comprising giant capillaries, reduced density, avascular fields, ramifications, and oedema as well as patients' sex and age. CONCLUSION: In patients with incipient RP, anti-Scl-70 and anti-CENP-B antibodies are related most specifically to distinct capillary alterations. Although a sum score can represent the patient's probability for elevated ANA titres, NC cannot substitute for immunological tests in patients with incipient RP.
Assuntos
Anticorpos Antinucleares/imunologia , Capilares/anormalidades , Doenças da Unha/diagnóstico , Doenças da Unha/epidemiologia , Unhas/irrigação sanguínea , Doença de Raynaud/epidemiologia , Doença de Raynaud/imunologia , Adulto , Fatores Etários , Área Sob a Curva , Biomarcadores/análise , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Masculino , Angioscopia Microscópica/métodos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Doença de Raynaud/diagnóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
Disease activity assessment is one of the most pivotal aspects in the care of RA patients. Composite measures of disease activity are superior to individual measures, since they capture the multiple facets of the disease. Since swollen joint counts correlate with joint damage progression and tender joint counts with physical function, composite scores that include joint counts are preferable. The simplified and clinical disease activity indices (SDAI, CDAI) are easy to calculate and correlate well with joint damage and physical function. Cutpoints for disease activity states have been established and improvement criteria likewise. The SDAI and CDAI remission criteria (ACR-EULAR index-based remission) are stringent, usually associated with a halt of progression of damage and optimisation of physical function and can still be achieved in 1 of 4 clinic patients and up to one third of patients in trials of early arthritis.
Assuntos
Artrite Reumatoide/diagnóstico , Indicadores Básicos de Saúde , Articulações , Reumatologia/métodos , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/terapia , Avaliação da Deficiência , Progressão da Doença , Nível de Saúde , Humanos , Articulações/patologia , Articulações/fisiopatologia , Valor Preditivo dos Testes , Indução de Remissão , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVES: We aimed to describe patterns of disease activity during infliximab plus methotrexate (MTX) treatment and explore C-reactive protein (CRP) as a potential marker of early response. METHODS: REMARK was a phase IV, open-label, observational study of infliximab-naïve adults with rheumatoid arthritis (RA) who received infliximab 3 mg/kg plus MTX for 14 weeks. Treatment response was evaluated in 3 subgroups: patients with <1 year disease duration who were TNF-inhibitor (TNFi)-naïve, patients with ≥ 1 year disease duration who were TNFi-naïve, and patients who had previous TNFi failure or intolerance. In post hoc analyses, CRP kinetic profiles were analysed by EULAR response (good, moderate, non-response) in REMARK and in an independent replication with data from the ASPIRE study. RESULTS: In the efficacy-evaluable population (n=662), median 28-joint disease activity score (DAS28) improved from baseline to Week 14 (5.2 vs. 3.6, p<0.0001). Regardless of disease history subgroup, most patients had good or moderate EULAR responses at Weeks 2 (64.9%), 6 (74.1%), and 14 (73.6%). DAS28 and its components did not differ across patient subgroups. Disease flare occurred in 16.2% of patients. CRP levels declined markedly at Week 2, but patients who were EULAR non-responders at Week 14 showed a CRP rebound at Weeks 6 and 14. This CRP pattern was independently replicated in data from ASPIRE. Adverse events were consistent with the known risk profile of infliximab. CONCLUSIONS: Infliximab plus MTX treatment in patients with RA rapidly diminished disease activity. A unique pattern of CRP rebound was found in non-responders early in treatment.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/metabolismo , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Quimioterapia Combinada , Feminino , Humanos , Infliximab , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , TerapêuticaRESUMO
OBJECTIVE: The binding of abatacept (CTLA-4Ig) to the B7 ligands CD80 and CD86 prevents the engagement of CD28 on T cells and thereby prevents effector T cell activation. In addition, a direct effect of CTLA-4Ig on antigen-presenting cells (APCs) could contribute to the therapeutic effect. To further elucidate the mechanism of CTLA-4Ig, we performed phenotype and functional analyses of APCs in patients with rheumatoid arthritis (RA) before and after the initiation of CTLA-4Ig therapy. METHODS: Peripheral blood mononuclear cells were analyzed before and at 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of APCs were determined by flow cytometry. CD14+ monocytes were further analyzed for the expression of costimulatory and adhesion molecules and for their transendothelial migratory capacity in vitro. In addition, CD14+ monocytes from healthy controls were analyzed for their migratory and spreading capacity. RESULTS: Proportions and absolute numbers of monocytes were significantly increased in RA patients treated with CTLA-4Ig. The expression of several adhesion molecules was significantly diminished. In addition, monocytes displayed a significant reduction in their endothelial adhesion and transendothelial migratory capacity upon treatment with CTLA-4Ig. Likewise, isolated monocytes from healthy controls revealed a significant reduction in their migratory and spreading activity after preincubation with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. CONCLUSION: We describe direct effects of CTLA-4Ig therapy on phenotype and functional characteristics of monocytes in RA patients that might interfere with the migration of monocytes to the synovial tissue. This additional mechanism of CTLA-4Ig might contribute to the beneficial effects of CTLA-4Ig treatment in RA patients.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Movimento Celular/efeitos dos fármacos , Imunoconjugados/uso terapêutico , Monócitos/efeitos dos fármacos , Monócitos/patologia , Abatacepte , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/patologia , Antirreumáticos/uso terapêutico , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Moléculas de Adesão Celular/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismoRESUMO
Little is known about how health insurance contributes to the prevalence of chronic disease in the overlooked population of low-income urban whites. This study uses cross-sectional data on 491 low-income urban non-elderly non-Hispanic whites from the Exploring Health Disparities in Integrated Communities-Southwest Baltimore (EHDIC-SWB) study to examine the relationship between insurance status and chronic conditions (defined as participant report of ever being told by a doctor they had hypertension, diabetes, stroke, heart attack, anxiety or depression, asthma or emphysema, or cancer). In this sample, 45.8 % were uninsured, 28.3 % were publicly insured, and 25.9 % had private insurance. Insured participants had similar odds of having any chronic condition (odds ratios (OR) 1.06; 95 % confidence intervals (CI) 0.70-1.62) compared to uninsured participants. However, those who had public insurance had a higher odds of reporting any chronic condition compared to the privately insured (OR 2.29; 95 % CI 1.21-4.35). In low-income urban areas, the health of whites is not often considered. However, this is a significant population whose reported prevalence of chronic conditions has implications for the Medicaid expansion and the implementation of health insurance exchanges.
Assuntos
Doença Crônica/economia , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Pobreza/estatística & dados numéricos , População Urbana/estatística & dados numéricos , População Branca/estatística & dados numéricos , Adulto , Baltimore/epidemiologia , Doença Crônica/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Patient Protection and Affordable Care Act/estatística & dados numéricos , Prevalência , Fatores Socioeconômicos , Estados UnidosRESUMO
OBJECTIVE: Arthritis is frequently seen in human lupus, but rarely in lupus models. Pristane-induced lupus (PIL) can be induced in various mouse strains such as BALB/c and C57BL/6. We herein characterize clinical and histological features of arthritis in the context of systemic lupus and provide a prudent comparison with models of rheumatoid arthritis (RA). METHODS: A total of 57 BALB/c mice received pristane (PIL group) and were analyzed for serum autoantibodies (anti-chromatin-, -histone, -Sm, -dsDNA), as well as for clinical features and histopathology of joints, lungs and kidneys. Joint pathology was quantified by image analysis and tissue cytometry. Ten C57BL/6 mice (Bl/6-PIL) and historical groups of two different RA models were analyzed accordingly. RESULTS: In BALB/c PIL, clinical arthritis started at three months, occurred finally in 79% of PIL (but not in controls, p<0.001) and correlated with areas of inflammation, erosion, cartilage damage, osteoclast numbers and total severity score (for all: r>0.7, p<0.001). After eight months, 58% of PIL (but no controls, p<0.001) had mild-erosive arthritis. In contrast to RA, the most frequent inflammatory cell type of the pannus was granulocytes (17.7%), PIL had lower numbers of osteoclasts, erosions rarely affected both layers of the cortical bone and there was no progression to complete joint destruction (even after one year of observation). Serum autoantibodies (auto-abs) preceded arthritis and became significantly elevated in all PIL; affected joints showed increased deposits of IgG (and IgM) within the inflammatory tissue, indicative of an ab-mediated process. PIL mice with arthritis also showed signs of pulmonary (100%) and renal (46%) lupus. In contrast to BALB/c, Bl/6-PIL mice did not develop any signs of arthritis. CONCLUSION: PIL in BALB/c mice is characterized by severe organ involvement, typical autoabs and by a mild-erosive arthritis with similarities to, but also with distinct differences from, RA. PIL may help to study arthritis along with other key features of systemic lupus erythematosus after therapeutic interventions or in knock-out models based on a BALB/c but not on a C57BL/6 background.
Assuntos
Artrite Experimental/fisiopatologia , Artrite Reumatoide/fisiopatologia , Autoanticorpos/sangue , Lúpus Eritematoso Sistêmico/complicações , Animais , Artrite Experimental/etiologia , Artrite Reumatoide/etiologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Granulócitos/metabolismo , Inflamação/etiologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Índice de Gravidade de Doença , Especificidade da Espécie , Terpenos/toxicidade , Fatores de TempoRESUMO
BACKGROUND: Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). METHODS: The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. RESULTS: Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. CONCLUSION: These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Antirreumáticos/efeitos adversos , Comorbidade , Europa (Continente) , Medicina Baseada em Evidências/métodos , Glucocorticoides/uso terapêutico , Humanos , Cooperação Internacional , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.