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1.
RMD Open ; 5(2): e001040, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673419

RESUMO

Objective: To provide the first direct comparison of patient-reported outcomes (PROs) following treatment with tofacitinib monotherapy versus tofacitinib or adalimumab (ADA) in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR). Methods: ORAL Strategy (NCT02187055), a phase IIIB/IV, head-to-head, randomised controlled trial, assessed non-inferiority between tofacitinib 5 mg two times per day monotherapy, tofacitinib 5 mg two times per day+MTX and ADA 40 mg every other week+MTX. PROs assessed included the following: Patient Global Assessment of disease activity (PtGA), Pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and 36-Item Short-Form Health Survey (SF-36) summary and domain scores. Results: Substantial improvements from baseline were reported across all PROs in all treatment arms, which, in the majority, met or exceeded minimum clinically important differences. Compared with tofacitinib monotherapy, tofacitinib+MTX combination treatment conferred significantly greater improvements in PtGA, Pain and SF-36 physical component summary scores at month 6. Statistically or numerically greater improvements were often, but not uniformly, reported for combination treatments compared with tofacitinib monotherapy at other time points. Conclusion: Treatment with tofacitinib+MTX, ADA+MTX and tofacitinib monotherapy resulted in clinically meaningful improvements in PROs in MTX-IR patients with RA. These were comparatively greater with combination treatments versus tofacitinib monotherapy, although differences between treatment arms were small, limiting our ability to confer clinical meaning. Trial registration number: NCT02187055.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31722413

RESUMO

OBJECTIVE: In early RA, some patients exhibit rapid radiographic progression (RRP) after one year, associated with poor functional prognosis. Matrices predicting this risk have been proposed, lacking precision or inadequately calibrated. We developed a matrix to predict RRP with high precision and adequate calibration. METHODS: Post-hoc analysis by pooling individual data from cohorts (ESPOIR and Leuven cohorts) and clinical trials (ASPIRE, BeSt and SWEFOT trials). Adult DMARD-naïve patients with active early RA for which the first therapeutic strategy after inclusion was to prescribe methotrexate or leflunomide were included. A logistic regression model to predict RRP was built. The best model was selected by 10-fold stratified cross-validation by maximizing the Area Under the Curve. Calibration and discriminatory power of the model were checked. The probabilities of RRP for each combination of levels of baseline characteristics were estimated. RESULTS: 1306 patients were pooled. 20.6% exhibited RRP. Four predictors were retained: rheumatoid factor positivity, presence of at least one RA erosion on X-rays, CRP > 30mg/l, number of swollen joints. The matrix estimates RRP probability for 36 combinations of level of baseline characteristics with a greatly enhanced precision compared with previously published matrices (95% CI: from ± 0.02 minimum to ± 0.08 maximum) and model calibration is excellent (P = 0.79). CONCLUSION: A matrix proposing RRP probability with high precision and excellent calibration in early RA was built. Although the matrix has moderate sensitivity and specificity, it is easily usable and may help physicians and patients to make treatment decisions in daily clinical practice.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31590930

RESUMO

OBJECTIVES: In patients with rheumatoid arthritis (RA), remission may be assessed by various composite measures. We assessed achievement of remission as defined by Boolean criteria, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) and determined the components that limit patients in SDAI, CDAI, or DAS28(CRP) remission from achieving Boolean remission. METHODS: The proportions of patients achieving Boolean, SDAI, CDAI, or DAS28(CRP) remission were calculated for 3 trials: PREMIER and OPTIMA in patients with early RA and DE019 in patients with established RA. At the first visit that remission was recorded during the first 52 weeks of the trial, the following were assessed: swollen/tender joint count at 28 and 66/68 joints, CRP, Patient's/Physician's Global Assessment (PGA/PhGA), SDAI, DAS28(CRP), and Health Assessment Questionnaire-Disability Index. RESULTS: The majority of patients (61-66%) who achieved SDAI or CDAI remission also attained Boolean remission. Although DAS28(CRP) remission was most frequently attained, 74-77% of patients in DAS28(CRP) remission did not achieve Boolean remission. Compared with patients in Boolean remission, patients in SDAI or CDAI remission but not Boolean remission had higher PGA scores, while patients with DAS28(CRP) remission but not Boolean remission had higher joint counts, and PGA and PhGA scores. CONCLUSIONS: Differences in PGA limit patients in SDAI/CDAI remission from meeting the Boolean remission criteria, suggesting that these criteria otherwise can be used interchangeably. In contrast, patients in DAS28(CRP) remission are limited by differences in multiple disease activity measures from achieving Boolean remission.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31609525

RESUMO

OBJECTIVES: Gender differences may modify symptoms, disease expression, and treatment effects. The objective was to evaluate the link between life impact and gender in psoriatic arthritis (PsA). METHODS: ReFlaP (NCT03119805) was a study in 14 countries of consecutive adult patients with definite PsA. Participants underwent comprehensive PsA assessment: Disease Activity in PSoriatic Arthritis (DAPSA), Minimal Disease Activity (MDA), and Psoriatic Arthritis Impact of Disease (PsAID). Disease activity was compared by gender using t-tests or Wilcoxon tests. The association of PsAID with gender was analyzed using hierarchical generalized linear models. RESULTS: Of 458 participants 50.2% were male, mean age (SD) 53.1 (12.6) years, PsA duration 11 (8.2) years, and 51.5% taking bDMARDs. Women versus men had worse Leeds enthesitis index: 0.8 (1.7) / 0.3 (0.9), pain [numerical rating scale 0-10 (NRS)]: 4.7 (2.7) / 3.5 (2.7), HAQ-DI: 0.9 (0.7) / 0.5 (0.6), fatigue NRS: 5.2 (3) / 3.3 (2.8), PsAID: 4.1 (2.4) / 2.8 (2.3), p<0.001 for all, and were less frequently at treatment target (T2T): DAPSA (DAPSA cut-offs ≤4 remission, >4 and ≤14 low disease activity): 16.9 (14.9) / 12.6 (16.6), MDA: 25.7% / 50.0%, p<0.001 for all. High life impact (PsAID≥4) was associated with female gender [odds ratio (OR) 2.3], enthesitis (OR 1.34), tender joints (OR 1.10) p<0.001 for all, and comorbidities (OR 1.22, p=0.002). CONCLUSIONS: High life impact was independently associated with female gender, enthesitis, comorbidities, and tender joints. At T2T, women vs men had higher life impact. Life impact needs to become part of PsA T2T strategies.

5.
Ann Rheum Dis ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31662322

RESUMO

OBJECTIVES: To detail the greatest areas of unmet scientific and clinical needs in rheumatology. METHODS: The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20-30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area. RESULTS: Overarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases. CONCLUSIONS: Unmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.

6.
Rheum Dis Clin North Am ; 45(4): 477-485, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31564291

RESUMO

Chronic immune-mediated rheumatic diseases are characterized by inflammatory signs and symptoms, damage to joints, or spine and physical disability. In all these diseases the adverse outcomes are related to the degree of the inflammatory response and the duration of the high inflammatory situation. A state in which inflammation is minimized or eliminated is the therapeutic goal, but the time to reach such a state is also essential. Repeated treatment adaptations in the course of regular clinical assessments of disease activity are essential until the desired, predefined state is achieved. This approach constitutes the treat-to-target concept.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31471012

RESUMO

OBJECTIVES: To assess the influence of rheumatoid arthritis (RA) disease activity (DA) on the risk of aseptic loosening after total hip/knee arthroplasty (THA/TKA). METHODS: We identified RA patients who underwent THA/TKA and determined their DA using the simplified disease activity index (SDAI). The risk of aseptic loosening was estimated using radiographic signs of component loosening (RCL). We performed Cox regression to estimate RCL based on SDAI, adjusting for therapy. We also investigated a cohort of 2:1 matched osteoarthritis (OA) patients as a control group without systemic inflammation. RESULTS: We identified 49 RA patients with a history of THA/TKA, of whom 18 (36.7%) showed RCL. SDAI over time was significantly higher in patients with RCL (median; 25th and 75th percentile: 10.8 months; 8.6 and 15.8; vs 7.0 months; 2.7 and 15.5;p = 0.043). In the regression model, each unit of mean SDAI over time significantly increased the risk of RCL (HR 1.125, 95% CI 1.021-1.241;p = 0.018). Patients treated with biological had a lower risk of RCL than those treated with traditional DMARDs (HR 0.192, 95% CI 0.042-0.891;p = 0.035). In the 88 matched OA patients, the RCL rate was significantly lower than in the RA group (13.6%;p = 0.002). CONCLUSION: Higher inflammatory DA increases the risk for radiographic loosening after THA/TKA in patients with RA. The significantly lower risk in patients with OA further underlines the potential role of inflammatory DA. In the context of treating RA to target, the presence of an arthroplasty might be considered as an indication for more stringent control of DA.

8.
Ann Rheum Dis ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31563894

RESUMO

OBJECTIVES: To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs). METHODS: Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24. RESULTS: The primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients. CONCLUSIONS: IXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.

10.
Ann Rheum Dis ; 78(9): 1151-1159, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383717

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.

11.
Arthritis Rheumatol ; 71(9): 1400-1412, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385462

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

12.
Ann Rheum Dis ; 78(12): 1609-1615, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31434637

RESUMO

OBJECTIVES: To determine if disease duration and number of prior disease-modifying antirheumatic drugs (DMARDs) affect response to therapy in patients with established rheumatoid arthritis (RA). METHODS: Associations between disease duration or number of prior DMARDs and response to therapy were assessed using data from two randomised controlled trials in patients with established RA (mean duration, 11 years) receiving adalimumab+methotrexate. Response to therapy was assessed at week 24 using disease activity outcomes, including 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)), Simplified Disease Activity Index (SDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI), and proportions of patients with 20%/50%/70% improvement in American College of Rheumatology (ACR) responses. RESULTS: In the larger study (N=207), a greater number of prior DMARDs (>2 vs 0-1) was associated with smaller improvements in DAS28(CRP) (-1.8 vs -2.2), SDAI (-22.1 vs -26.9) and HAQ-DI (-0.43 vs -0.64) from baseline to week 24. RA duration of >10 years versus <1 year was associated with higher HAQ-DI scores (1.1 vs 0.7) at week 24, but results on DAS28(CRP) and SDAI were mixed. A greater number of prior DMARDs and longer RA duration were associated with lower ACR response rates at week 24. Data from the second trial (N=67) generally confirmed these findings. CONCLUSIONS: Number of prior DMARDs and disease duration affect responses to therapy in patients with established RA. Furthermore, number of prior DMARDs, regardless of disease duration, has a limiting effect on the potential response to adalimumab therapy.

13.
PLoS One ; 14(7): e0219698, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31344123

RESUMO

The era of next-generation sequencing has mounted the foundation of many gene expression studies. In rheumatoid arthritis research, this has led to the discovery of important candidate genes which offered novel insights into mechanisms and their possible roles in the cure of the disease. In the last years, data generation has outstripped data analysis and while many studies focused on specific aspects of the disease, a global picture of the disease is not yet accomplished. Here, we analyzed and compared a collection of gene expression information from healthy individuals and from patients suffering under different arthritis conditions from published studies containing the following clinical conditions: early and established rheumatoid arthritis, osteoarthritis and arthralgia. We show comprehensive overviews of this data collection and give new insights specifically on gene expression in the early stage, into sex-dependent gene expression, and we describe general differences in expression of different biotypes of genes. Many genes that are related to cytoskeleton changes (actin filament related genes) are differently expressed in early rheumatoid arthritis in comparison to healthy subjects; interestingly, eight of these genes reverse their expression ratio significantly between men and women compared early rheumatoid arthritis and healthy subjects. There are some slighter changes between men and woman between the conditions early and established rheumatoid arthritis. Another aspect are miRNAs and other gene biotypes which are not only promising candidates for diagnoses but also change their expression grossly in average at rheumatoid arthritis and arthralgia compared to the healthy condition. With a selection of intersecting genes, we were able to generate simple classification models to distinguish between healthy and rheumatoid arthritis as well as between early rheumatoid arthritis to other arthritides based on gene expression.

14.
Rheum Dis Clin North Am ; 45(3): 315-324, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31277746

RESUMO

Although many treatment options exist for the initial management of rheumatoid arthritis, there has long been discussion about whether initial treatment should be with methotrexate (MTX) as monotherapy or in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Although studies initially showed additional benefit from combining MTX with other csDMARDs, this benefit disappears when glucocorticoids are added to MTX, a strategy recommended in current guidelines as a short-term bridging approach until MTX therapy exhibits its full efficacy. Also concomitant use of glucocorticoids, with MTX may not be inferior to combination therapy of MTX with TNF-inhibitors.

15.
Exp Mol Med ; 51(7): 75, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285419

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNß, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31257453

RESUMO

OBJECTIVES: The structural consequences of flare after dose reduction/discontinuation of biologic DMARDs in patients with RA who achieve remission are unclear. We compared the incidence of radiographic progression in patients with RA who did and did not experience flare after etanercept (ETN) reduction/withdrawal. METHODS: Eligible adults with moderately active RA despite MTX received ETN 50 mg plus MTX weekly in a 36-week, open-label induction period; patients achieving sustained low disease activity by week 36 were randomized to ETN 50 mg plus MTX, ETN 25 mg plus MTX, or placebo plus MTX in a 52-week, double-blind maintenance period. In post hoc analyses, radiographic progression (Δ modified total Sharp score ⩾0.5 units/year) was compared in patients with and without flare [based on DAS28 relapse (main analysis), and clinical disease activity index and simplified disease activity index relapse (sensitivity analyses)]. Findings from patients receiving full- and reduced-dose combination therapy were pooled for comparison with those from patients receiving MTX only. RESULTS: Significantly more patients receiving MTX monotherapy experienced flare, defined as DAS28 relapse (62% vs 21%; P < 0.0001) and radiographic progression (17% vs 9%; P < 0.001), than patients receiving full-/reduced-dose combination therapy in the double-blind period. Patients with flare defined as clinical disease activity index and simplified disease activity index relapse had higher rates of radiographic progression than those without flare in the full-/reduced-dose combination therapy group (P < 0.01). CONCLUSION: Radiographic progression may be a consequence of flare after biologic DMARD dose reduction/withdrawal in patients with RA. If these approaches are taken, careful monitoring for signs/symptoms of relapse is needed. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00565409.

17.
Arthritis Res Ther ; 21(1): 164, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277720

RESUMO

BACKGROUND: Biologic disease-modifying antirheumatic drugs (bDMARDs) are important options for managing rheumatoid arthritis (RA). Once patients achieve disease control, clinicians may consider dose reduction or withdrawal of the bDMARD. Results from published studies indicate that some patients will maintain remission; however, others will flare. We analyzed data from three etanercept down-titration studies in patients with RA to determine what extent of remission provides the greatest predictability of maintaining remission following dose reduction or discontinuation. METHODS: Patients with moderate to severe RA from the PRESERVE, PRIZE, and Treat-to-Target (T2T) randomized controlled trials were included. We determined the proportion of patients achieving remission with etanercept at the last time point in the induction period, and sustained remission (last two time points), according to the Disease Activity Score 28-joints (DAS28), the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean criteria, and the clinical disease activity index (CDAI). We also calculated the proportion achieving DAS28 deep remission (DAS28 ≤ 1.98), sustained deep remission (last two time points), and low disease activity (LDA), and LDA according to the CDAI. Then, we evaluated whether they maintained remission or LDA following etanercept dose reduction or withdrawal. RESULTS: Patients achieving sustained and/or deep remission were more likely than patients achieving remission or LDA to maintain remission/LDA after etanercept dose reduction or withdrawal. In PRESERVE, the proportions of patients with DAS28 sustained deep remission, deep remission, sustained remission, remission, and LDA who maintained remission following etanercept dose reduction were 81%, 67%, 58%, 56%, and 36%, respectively, P < 0.001 for trend. In PRESERVE, this trend was significant when etanercept was discontinued and when ACR/EULAR Boolean and CDAI remission criteria were used. Although some sample sizes were small, the PRIZE and T2T studies also demonstrated response trends according to ACR/EULAR Boolean and CDAI remission criteria, and T2T demonstrated response trends according to DAS28. CONCLUSIONS: These results suggest that patients achieving disease control according to a stringent definition, such as sustained ACR/EULAR Boolean or CDAI remission, or a new definition of sustained deep remission by DAS28, have a higher probability of remaining in remission or LDA following etanercept dose reduction or withdrawal. TRIAL REGISTRATION: PRESERVE: ClinicalTrials.gov identifier: NCT00565409 , registered 30 November 2007; PRIZE: ClinicalTrials.gov identifier: NCT00913458 , registered 4 June 2009; T2T: ClinicalTrials.gov identifier: NCT01578850 , registered 17 April 2012.

18.
Front Immunol ; 10: 1367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275315

RESUMO

MicroRNA (miR) 155 has been implicated in the regulation of innate and adaptive immunity as well as autoimmune processes. Importantly, it has been shown to regulate several antiviral responses, but its contribution to the immune response against cytopathic viruses such as vesicular stomatitis virus (VSV) infections is not known. Using transgenic/recombinant VSV expressing ovalbumin, we show that miR-155 is crucially involved in regulating the T helper cell response against this virus. Our experiments indicate that miR-155 in CD4+ T cells controls their activation, proliferation, and cytokine production in vitro and in vivo upon immunization with OVA as well as during VSV viral infection. Using intravital multiphoton microscopy we analyzed the interaction of antigen presenting cells (APCs) and T cells after OVA immunization and found impaired complex formation when using miR-155 deficient CD4+ T cells compared to wildtype CD4+ T cells ex vivo. In contrast, miR-155 was dispensable for the maturation of myeloid APCs and for their T cell stimulatory capacity. Our data provide the first evidence that miR-155 is required for efficient CD4+ T cell activation during anti-viral defense by allowing robust APC-T cell interaction required for activation and cytokine production of virus specific T cells.

19.
RMD Open ; 5(1): e000900, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31245050

RESUMO

Compared with the original approved biological drug on which it is based, a biosimilar has highly similar physicochemical characteristics and biological activity, as well as equivalent efficacy and no clinically meaningful differences in safety and immunogenicity. Before they are approved, biosimilars must undergo a rigorous development process using state-of-the-art technologies to establish biosimilarity to the reference biological product. After approval, biosimilars must comply with good pharmacological practices for biological drugs. Several biosimilar disease-modifying antirheumatic drugs (bsDMARDs) based on the tumour necrosis factor inhibitors adalimumab, etanercept and infliximab have been approved for use in patients with rheumatic diseases. Substantial cost savings can be made if biological-naive patients begin treatment with bsDMARDs, and patients receiving original biological DMARDs (bDMARDs) are switched to bsDMARDs. Despite the consistently similar efficacy, safety and immunogenicity of bsDMARDs relative to their respective original bDMARDs, switching from a reference bDMARD to a bsDMARD can result in nocebo responses, such as subjective increase of disease activity and pain-related adverse events. This may have a negative impact on adherence to bsDMARDs in clinical trials and clinical practice. To ensure optimal and rational integration of bsDMARDs into rheumatology practice and realise the full cost-saving efficacy of these drugs, rheumatologists must be aware that careful communication of the cost-saving efficacy and safety of bsDMARDs to their patients is the key to a successful long-term switch to bsDMARD therapy.

20.
Rheumatol Ther ; 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31228100

RESUMO

INTRODUCTION: To explore the relationship of pain and fatigue with daily activity and work productivity in rheumatoid arthritis (RA) patients from the baricitinib clinical trial, RA-BEAM. METHODS: In RA-BEAM, a double-blind phase 3 study, patients were randomized 3:3:2 to placebo (n = 488), baricitinib 4 mg once daily (n = 487), or adalimumab 40 mg biweekly (n = 330) with background methotrexate. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) measured fatigue and the pain visual analog scale (0-100 mm) assessed pain. Work Productivity and Activity Impairment Questionnaire-RA measured daily activity and work productivity. At weeks 12 and 24, pain was assessed using pain reduction (< 30%, 30% to < 50%, ≥ 50%) and overall pain score; clinically relevant FACIT-F changes were assessed by values < 3.56 and ≥ 3.56 and the FACIT-F normative value score (< 40.1, ≥ 40.1). Pairwise comparisons between pain/fatigue reduction groups were assessed using ANCOVA with pooled data on daily activity and work productivity. A mediator analysis with pain, fatigue, and disease activity measured their contribution to daily activity and work productivity. Data were pooled from all patients for most analyses, and baricitinib-treated patients were assessed as a sensitivity analysis. RESULTS: Reductions in pain (≥ 50%) and fatigue (≥ 3.56) had significant (p ≤ 0.001) effects on daily activity and work productivity improvement at weeks 12 and 24. Reductions in pain, fatigue, and disease activity accounted for most of the improvements in daily activity and work productivity. At the lowest levels of remaining pain (≤ 10 mm) at weeks 12 and 24, however, fatigue did not appear to impact work productivity. Similar trends were observed with baricitinib-treated patients. CONCLUSIONS: Reductions in pain and fatigue were associated with improved daily activity and work productivity for all RA patients and for baricitinib-treated patients in RA-BEAM. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01710358. FUNDING: Incyte Corporation and Eli Lilly and Company.

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