RESUMO
OBJECTIVE: To investigate the performance and factors of influence of optical spectral transmission (OST) imaging as a new technique for measuring joint inflammation in rheumatoid arthritis (RA). METHOD: OST was performed in 24 RA patients and 37 controls. Mann-Whitney U-test was used to assess differences in OST score between RA patients and controls. Receiver operating characteristics (ROC), linear regression and generalized estimating equations analysis were used to assess the discriminative capability of OST and the association of OST score with clinical disease parameters, ultrasound, radiographic features and cardiovascular risk parameters. RESULTS: Median OST score was higher in RA patients than in controls [16.9 (interquartile range 12.77-19.7) vs 12.11 (10.32-14.93)]. At patient level, OST score was moderately associated with ultrasound [beta 0.38 (95% CI 0.16-0.60), p = 0.001] and clinical disease activity [28-joint Disease Activity Score-C-reactive protein beta 0.30 (95% CI 0.04- 0.57), p = 0.024] in RA patients. In controls, male sex, high body mass index, and hypertension were associated with higher OST scores, while these associations were absent in RA. At joint level, the area under the ROC curve for OST score, with ultrasound or clinical swelling as reference, ranged from 0.63 to 0.70. Joint-space narrowing and malalignment were associated with higher OST joint scores, and subchondral sclerosis with lower scores. CONCLUSION: OST provides an objective measure of synovitis and correlates moderately with other examined disease activity assessment tools. Clinical patient characteristics must be considered when interpreting the results.
Assuntos
Artrite Reumatoide , Sinovite , Humanos , Masculino , Artrite Reumatoide/diagnóstico , Ultrassonografia/métodos , Sinovite/diagnóstico , Curva ROC , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To assess sex differences in response, level of disease activity, and drug survival in tumour necrosis factor inhibitor (TNFi)-naïve ankylosing spondylitis (AS) patients. METHOD: Consecutive AS patients, fulfilling the modified New York criteria, were included in a prospective cohort study at initiation of the first TNFi and followed until this medication was stopped (drug survival). Disease activity scores [AS Disease Activity Score using C-reactive protein (ASDAS-CRP), Bath AS Disease Activity Index (BASDAI), and CRP] were measured at 3, 6, and 12 months, and every subsequent year, up to 5 years. The response was defined by the ASDAS-CRP response criteria (clinically important improvement: ASDAS-CRP decrease ≥ 1.1). Analyses included regression methods for repeated measurements and survival analyses. RESULTS: Overall, 356 patients were included (34% women, mean ± sd age 46 ± 12 years), with a median disease duration of 12 (interquartile range 6;20) years. Women were less likely than men to achieve a clinically important response after 6 months of TNFi treatment (47% vs 64%; relative risk 1.4, 95% confidence interval (CI) 1.1;1.9, p = 0.02], despite a lack of sex differences in mean ASDAS-CRP levels over 5 year follow-up. Adjusted models for BASDAI over 5 years showed that women had a 0.6 point higher BASDAI score than men (ß = 0.6 0.1;1.1 <0.02). Numerically, more women than men discontinued treatment over a period of 5 years (hazard ratio = 1.5, 95% CI 0.9;2.5, p = 0.15). CONCLUSION: Female AS patients show a lower response to TNFi and a higher disease activity compared to men.
Assuntos
Espondilite Anquilosante , Feminino , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Estudos Prospectivos , Fator de Necrose Tumoral alfa , Índice de Gravidade de Doença , Resultado do Tratamento , Proteína C-Reativa/metabolismoRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN-stimulating pathways, but also from decreased activation of type I IFN-inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR-induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired FcγR-mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR-induced interleukin (IL)-1ß production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR-mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL-1ß. This dysregulation may contribute to the development of nephritis in SLE patients.
Assuntos
Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Interleucina-1beta/imunologia , Nefrite Lúpica/imunologia , Receptores de IgG/imunologia , Adulto , Células Dendríticas/patologia , Feminino , Humanos , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Objectives: Inadequate response to adalimumab can be caused by insufficient blockade of the target tumour necrosis factor (TNF) at low serum concentrations. In such cases, patients may respond to another TNF inhibitor. We investigated whether the serum adalimumab concentration is related to the efficacy of a second TNF inhibitor, etanercept, in rheumatoid arthritis (RA). Methods: Patients with RA starting etanercept treatment were prospectively observed in the Reade Rheumatology Registry. In patients previously on adalimumab, serum concentrations were determined before treatment discontinuation. According to this concentration, three subgroups were formed: < 0.5 µg/mL, 0.5-5.0 µg/mL, and ≥ 5.0 µg/mL. The European League Against Rheumatism (EULAR) good/moderate response rate after 52 weeks of etanercept was compared between the switcher subgroups and biologic-naive patients. Results: In total, 449 consecutive patients were included, of whom 69 switched from adalimumab (15%) and 380 were biologic naive (85%). EULAR good or moderate response was achieved by 74% of the biologic-naive patients and by 72%, 50%, and 52% of switchers with adalimumab concentration < 0.5 µg/mL, 0.5-5.0 µg/mL, and ≥ 5.0 µg/mL, respectively (p = 0.15). Patients with an adalimumab concentration ≥ 0.5 µg/mL were significantly less likely to achieve EULAR good/moderate response on etanercept compared to biologic-naive patients, whereas patients with a concentration < 0.5 µg/mL did not significantly differ from patients starting etanercept without prior biologic treatment. Conclusion: RA patients with an inadequate response to adalimumab, in the presence of sufficient drug concentrations, benefit less from switching to another TNF inhibitor, etanercept.
Assuntos
Adalimumab , Artrite Reumatoide , Substituição de Medicamentos/métodos , Etanercepte , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adalimumab/sangue , Adulto , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Monitoramento de Medicamentos/métodos , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Etanercepte/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Seleção de Pacientes , Sistema de Registros/estatística & dados numéricos , Resultado do TratamentoRESUMO
Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 µg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 µg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 µg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into < 0.2, 0.2-2.9, 3.0-7.0, and > 7.0 µg/mL showed a dose-response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 µg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 µg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 µg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 ( https://clinicaltrials.gov/ct2/show/NCT00764725 ).
Assuntos
Anticorpos/sangue , Artrite Reumatoide/tratamento farmacológico , Infliximab/farmacocinética , Fator Reumatoide/sangue , Anticorpos/imunologia , Antirreumáticos/imunologia , Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Infliximab/imunologia , Masculino , Metotrexato/uso terapêutico , Falha de TratamentoRESUMO
OBJECTIVES: To investigate whether smoking habits predict response to rituximab (RTX) in rheumatoid arthritis (RA). METHOD: We included patients from the CERERRA international cohort receiving the first treatment cycle with available smoking status (n = 2481, smokers n = 528, non-current smokers n = 1953) and at least one follow-up visit. Outcome measures were change in Disease Activity Score based on 28-joint count (ΔDAS28) and European League Against Rheumatism (EULAR) good response at 6 months, with non-current smokers as the referent group. RESULTS: Compared with non-smokers at baseline, smokers were more often rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) positive and males, had shorter disease duration, lower DAS28 and Health Assessment Questionnaire (HAQ) score, a higher number of prior biological disease-modifying anti-rheumatic drugs, and were more likely to receive concomitant conventional synthetic disease-modifying anti-rheumatic drug (csDMARDs). Disease activity had decreased less in smokers at 6 months (ΔDAS28 = 1.5 vs 1.7, p = 0.006), although the difference was no longer significant after correction for baseline DAS28 (p = 0.41). EULAR good response rates did not differ between smokers and non-smokers overall or stratified by RF/ACPA status, although smokers had lower good response rates among seronegative patients (ACPA-negative: 6% vs 14%, RF-negative: 11% vs 18%). Smoking did not predict good response [odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.76-1.41], while ACPA, DAS28, HAQ, and concomitant csDMARDs were significant predictors for good response. However, when stratified by country, smokers were less likely to achieve good response in Sweden (unadjusted OR = 0.24, 95% CI = 0.07-0.89), and a trend was seen in the Czech Republic (OR = 0.45, 95% CI = 0.16-1.02). CONCLUSION: In this large, observational, multinational RA cohort, smokers starting RTX differed from non-smokers by having shorter disease duration and lower disease activity, but more previous treatments. The overall results do not support smoking as an important predictor for response to RTX in patients with RA.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Sistema de Registros , Fator Reumatoide/sangue , Rituximab/uso terapêutico , Fumar/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/epidemiologia , Biomarcadores/sangue , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Fumar/epidemiologiaRESUMO
The autoimmune rheumatological diseases rheumatoid arthritis (RA), spondyloarthritis (SpA) and systemic lupus erythematosus (SLE) are treated with conventional immunosuppressive agents and with modern biological immunomodulators. The latter group of medications have brought about a major change in our ability to control RA and SpA, with more modest results for SLE. The biologicals are very specific in their mechanisms of action, targeting one specific cytokine or one particular cellular marker. Because of this, their efficacy can readily be linked to a single immunomodulatory mechanism. This observation has fuelled hopes that the efficacy of these agents can be predicted at the individual level based on the patient's genetic predisposition, immunological profile or disease phenotype. Whilst the biologic therapies have improved the prospects for patients with these diseases very significantly, the hope that they could be targeted to the patient in an individualized manner has not completely born fruit. In this review, I will argue that we are witnessing important progress in this field, and that justified hope exists for true advances in precision medicine in the autoimmune diseases in the coming years.
Assuntos
Genótipo , Fatores Imunológicos/uso terapêutico , Fenótipo , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/genética , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Biomarcadores/sangue , Predisposição Genética para Doença/genética , Humanos , Fatores Imunológicos/efeitos adversos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Doenças Reumáticas/diagnóstico , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/genética , Resultado do TratamentoRESUMO
Objective Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/µl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1-15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.
Assuntos
Antirreumáticos/efeitos adversos , Nefrite Lúpica/tratamento farmacológico , Neutropenia/induzido quimicamente , Rituximab/efeitos adversos , Adulto , Fator Ativador de Células B/sangue , Feminino , Humanos , Nefrite Lúpica/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangueRESUMO
PURPOSE OF REVIEW: Ankylosing spondylitis (AS) was historically seen as a predominantly male disease. However, more recent data showed a more homogenous sex prevalence. Unfortunately, in many studies in axial spondyloarthritis (axSpA), the number of women included is low and the analyses are often not stratified for gender distribution. The purpose of this review is to aggregate the existing data on gender differences in axSpA in order to increase the awareness that female axSpA patients are still under-recognized. RECENT FINDINGS: Several studies considering gender differences revealed that female axSpA patients had different disease manifestations due to different immunological, hormonal, and genetic responses. For instance, allelic frequencies of the AHNK-gene and tissue non-specific alkaline phosphatase (TNAP) haplotypes differed between men and women with ankylosing spondylitis (AS). In addition, different levels of tumor necrosis factor (TNF), interleukins IL-6, IL-17, and IL-18, were found between the two sexes. Furthermore, female patients show a higher diagnostic delay compared to males. Several studies indicate a higher frequency of extra-articular manifestations (EAM) in female axSpA patients, such as enthesitis, psoriasis, and inflammatory bowel disease (IBD), whereas acute anterior uveitis is more prevalent in male patients. Male AS patients more frequently show a higher Bath Ankylosing Spondylitis Radiology Index (BASRI) scores and modified Stoke Ankylosing Spondylitis Spine Scores (mSASSS) than females, which indicates that males have higher radiological damage and radiographic progression. However, disease activity (BASDAI) and quality of life (AsQol) scores are significantly higher in women, and more importantly, they have significantly lower response rates to treatment with TNF inhibitors (TNFi) and a significantly lower drug adherence. Despite the fact that men with axial SpA have a worse radiologic prognosis, women have a high disease burden, in part because they have a longer delay in diagnosis, higher disease activity, and significantly less responsiveness to treatment with TNFi.
Assuntos
Qualidade de Vida , Caracteres Sexuais , Espondilartrite/diagnóstico , Diagnóstico Tardio , Feminino , Humanos , Masculino , Prevalência , Índice de Gravidade de Doença , Espondilartrite/epidemiologiaRESUMO
BACKGROUND: An important goal in medicine is to provide patients with individualised and personalised treatment. Personalised medicine is making an important contribution. AIM: To summarise developments in the field of personalised medicine in rheumatology. METHOD: We review the results so far and discuss what developments we can expect in the future. RESULTS: In rheumatology there have been advances in three main areas: 1. therapeutic drug monitoring (measuring medication levels and using the results as a guide for further treatment); 2. the use of biomarkers to determine which drugs should be selected or which should be stopped; 3. involvement of the patient's own observations concerning treatment options. CONCLUSION: Personalised medicine is being used increasingly in rheumatology.
Assuntos
Medicina de Precisão , Reumatologia , Biomarcadores , Monitoramento de Medicamentos , Humanos , Participação do Paciente , Resultado do TratamentoRESUMO
Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fatores de Transcrição/imunologia , beta 2-Glicoproteína I/imunologia , Adulto , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , PrevalênciaRESUMO
OBJECTIVES: To explore the relationship between antinuclear antibody (ANA) overuse and rheumatologist-related factors before and after an intervention aimed at reducing ANA overuse. METHOD: In this mixed methods study we performed surveys among rheumatologists (n = 20) before and after the ANA intervention (education and feedback). We identified clinician-related determinants of ANA overuse (demographic characteristics, cognitive bias, numeracy, personality, thinking styles, and knowledge) by multivariate analysis. Two focus group meetings with rheumatologists were held 6 months after the intervention to explore self-reported determinants. RESULTS: Questionnaires were completed by all rheumatologists and eight participated in the focus groups. Rheumatologists with more work experience and a less extravert personality ordered more ANA tests before the intervention [ß = 0.01, 95% confidence interval (CI) 0.003 to 0.02, p = 0.01 and ß = -0.11, 95% CI -0.21 to -0.01, p = 0.04, respectively; R2 = 47%]. After the intervention, female rheumatologists changed less than their male colleagues with regard to the number of ANA tests ordered (ß = 0.15, 95% CI 0.03-0.26, p = 0.02; R2 = 25%). During the focus groups, seven themes were identified that influenced improvement in ANA overuse: determinants related to the intervention and the study, individual health professionals, patients, professional interactions, incentives and resources, capacity for organizational change, and social, political, and legal factors. CONCLUSIONS: We identified several determinants that together explained a sizable part of the variance observed in the ANA outcomes at baseline and in the change in ANA outcomes afterwards. Furthermore, the focus groups yielded additional factors suggesting a complex interplay of determinants influencing rheumatologists' ANA ordering behaviour.
Assuntos
Anticorpos Antinucleares , Competência Clínica , Uso Excessivo dos Serviços de Saúde/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Reumatologistas/estatística & dados numéricos , Testes Sorológicos/estatística & dados numéricos , Adulto , Cognição , Estudos Controlados Antes e Depois , Educação Médica Continuada , Extroversão Psicológica , Retroalimentação , Feminino , Grupos Focais , Humanos , Masculino , Uso Excessivo dos Serviços de Saúde/prevenção & controle , Pessoa de Meia-Idade , Análise Multivariada , Personalidade , Pesquisa Qualitativa , Reumatologistas/psicologia , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: To assess the effects of education, guideline development, and individualized treatment advice on rheumatologist adherence to tight control-based treatment and biological dose optimization in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthropathy (SpA) patients. METHOD: This pilot study, among two rheumatologists and two specialized nurses in a general hospital, combined education, feedback, local guideline development, and individualized treatment advice. Outcomes (baseline and 1 year post-intervention) were the percentage of patients with a Disease Activity Score in 28 joints (DAS28) or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) measured during the visit, mean DAS28/BASDAI, and the percentage of patients using a reduced biological dose. DAS28 outcomes only applied to RA and PsA patients, BASDAI outcomes only applied to SpA patients whereas outcomes on biological dose applied to all patients. RESULTS: A total of 232 patients (67% RA, 15% PsA, 18% SpA; 58% female, mean age 56 ± 15 years) were included in the study. The percentage of DAS28 and BASDAI measurements performed increased after the intervention [DAS28 15-51%, odds ratio (OR) 3.3, 95% confidence interval (CI) 2.1-5.5; BASDAI 23-50%, OR 2.2, 95% CI 1.0-5.5], with mean DAS28 and BASDAI scores remaining similar (DAS28: mean difference 0.1, 95% CI -0.3 to 0.5; BASDAI: mean difference 0.03, 95% CI -1.8 to 1.9). Use of a reduced biological dose increased from 10% to 61% (OR 3.9, 95% CI 2.4-6.5). CONCLUSIONS: A multicomponent intervention strategy aimed at rheumatologists can lead to improved adherence to tight control-based treatment and a reduction in the use of biologicals in RA, SpA, and PsA patients.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Espondiloartropatias/tratamento farmacológico , Adulto , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
OBJECTIVES: To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). METHODS: This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240â mg) at week 0 and followed by 120â mg every 2â weeks (120 Q2W), 120â mg every 4â weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. RESULTS: Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. CONCLUSION: SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. TRIAL REGISTRATION NUMBER: NCT01205438.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Fator Ativador de Células B/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Antinucleares/sangue , Anticorpos Monoclonais Humanizados , Autoanticorpos/sangue , Fator Ativador de Células B/administração & dosagem , Linfócitos B/metabolismo , Biomarcadores/sangue , População Negra , Complemento C3/metabolismo , Complemento C4/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral GSK2586184 50-400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes in Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index score, and number/severity of adverse events. A pre-specified interim analysis was performed when ≥ 5 patients per group completed 2 weeks of treatment. In total, 84-92% of patients were high baseline expressors of the interferon transcriptional biomarkers evaluated. At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients. Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index scores were not analysed due to the small number of patients completing the study. The study futility and safety data described for GSK2586184 do not support further evaluation in patients with SLE. Study identifiers: GSK Study JAK115919; ClinicalTrials.gov identifier: NCT01777256.
Assuntos
Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Janus Quinase 1/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Administração Oral , Adulto , Azetidinas/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Interferons/genética , Lúpus Eritematoso Sistêmico/enzimologia , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Resultado do Tratamento , Triazóis/farmacologia , Adulto JovemRESUMO
OBJECTIVE: Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. METHODS: Information and blood samples were obtained in a cross-sectional study from patients with SLE (n = 308) and other rheumatologic diseases (n = 389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA. RESULTS: Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR = 2.7, 95% CI: 1.8-4, p < 0.001). Anti-C1q was associated with proteinuria (OR = 3.0, 95% CI: 1.7-5.1, p < 0.001), red cell casts (OR = 2.6, 95% CI: 1.2-5.4, p = 0.015), anti-dsDNA (OR = 3.4, 95% CI: 1.9-6.1, p < 0.001) and anti-Smith (OR = 2.8, 95% CI: 1.5-5.0, p = 0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR = 2.3, 95% CI: 1.3-4.2, p < 0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR = 14.9, 95% CI: 5.8-38.4, p < 0.01). CONCLUSIONS: Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis.
Assuntos
Anticorpos Antinucleares/sangue , Complemento C1q/imunologia , DNA/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Estudos de Casos e Controles , Proteínas do Sistema Complemento/deficiência , Estudos Transversais , Feminino , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Nefrite Lúpica/etnologia , Nefrite Lúpica/imunologia , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Doenças Reumáticas/imunologia , Sensibilidade e Especificidade , Adulto JovemRESUMO
OBJECTIVES: The aim of this study was to apply a previously published method for evaluating radiographic progression, namely, predicted vs. observed radiographic progression in early rheumatoid arthritis (POPeRA), to the Swedish pharmacotherapy (SWEFOT) trial. METHOD: In SWEFOT, 487 patients with eRA were given methotrexate (MTX), and non-responders were randomized to group A [triple therapy: MTX+sulfasalazine (SSZ)+hydroxychloroquine (HCQ)] and group B [anti-tumour necrosis factor (anti-TNF) therapy: MTX+infliximab]. Responders continued on MTX. Predicted progression for 343 eligible patients was calculated based on the baseline total Sharp/van der Heijde score (SHS) divided by symptom duration, compared to observed progression at 12 and 24 months. RESULTS: Observed radiographic progression was reduced from predicted by a mean of 50.1% (A), 72.3% (B), and 73.9% (MTX) at 12 months and by 87.2, 89.8, and 87.8% at 24 months, respectively. Among completers, reductions of 56.7% (A) and 76.5% (B) at 12 months and of 91.0% and 96.0% at 24 months, respectively, were observed. At 12 months, there were no significant between-group differences. At 24 months, progression was reduced more in group B than in group A (first quartile difference 8.5% favouring group B) and in MTX [n=316, 89.8% (sd±32.0) vs. 87.2% (±32.2), p=0.021; vs. 87.8% (±27.8), p=0.013, respectively]. CONCLUSIONS: The POPeRA method confirms the original SWEFOT finding in that anti-TNF therapy was statistically marginally superior (2.6%) to triple therapy in preventing radiographic progression at 24 months among initial MTX non-responders. The simulation provided through POPeRA may facilitate comparisons of the relative efficacy of various treatments in preventing radiographic progression.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Progressão da Doença , Hidroxicloroquina/uso terapêutico , Infliximab/uso terapêutico , Metotrexato/uso terapêutico , Sulfassalazina/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Radiografia , Índice de Gravidade de Doença , Suécia , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVES: Tocilizumab is effective in the treatment of rheumatoid arthritis (RA). A proportion of patients achieve low disease activity using a lower than registered starting dose. We investigated the feasibility of dose reduction to 4 mg/kg in patients who reached low disease activity at the registered dose of 8 mg/kg. METHODS: In this retrospective study, data were collected of 22 patients successfully treated with tocilizumab 8 mg/kg for about 6 months and tapered to 4 mg/kg because of low disease activity. In case of loss of disease control, the dose could be increased again to 8 mg/kg. The percentage of patients with successful dose reduction and difference in DAS28 was described. RESULTS: Mean DAS28 at time of dose reduction was 2.3 (SD 0.9). After 3 and 6 months follow-up, 77% (95% CI 54-91) and 55% (95% CI 32-76) of patients had successfully reduced the dose without losing disease control, respectively. DAS28 at 3 and 6 months was somewhat higher than baseline, 2.7 (SD 1.2) and 2.5 (SD 1.0) respectively. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose escalation. CONCLUSIONS: Dose reduction of tocilizumab seems feasible in a substantial proportion of patients. Dose escalation after flare was effective in all patients.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Idoso , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , 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
An independent cross-sectional survey assessed systemic lupus erythematosus (SLE) disease and treatment burden. Variables included medication classes prescribed, disease activity, flare occurrences, treatment satisfaction, and validated measures of health-related quality of life (HRQoL), fatigue and work productivity. Of 886 eligible patients (mean age 41.3 years, 89% female), 515 completed the survey. One-third reported moderate-to-severe disease activity, and 31% had flared in the last 12 months. Higher severity of disease activity (moderate-to-severe) was associated with ≥ 2 medication classes prescribed and treatment regimens that included corticosteroids (CS) (both p<0.0001). Patients receiving CS reported lower EQ-5D scores (p=0.0019) and higher fatigue levels (p<0.001), and both patients (p=0.0019) and physicians (p=0.0001) were less likely to report satisfaction with treatment regimens including CS. Among responders eligible for work (n=456), severity of disease activity (moderate-to-severe vs. mild) was associated with unemployment (52.9% vs. 40.8%; p=0.0189), greater impairment in work productivity (36% vs. 21%; p=0.0003) and participation in daily activities (41% vs. 21%; p<0.0001). This survey confirms that SLE and current treatment options substantially impair patients' health status and work productivity. Physician- and patient-reported satisfaction with current treatment regimens, despite poorly controlled disease activity, indicate they are resigned to the limitations of available SLE treatment regimens.