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1.
Br J Clin Pharmacol ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33822406

RESUMO

AIM: To evaluate pharmacokinetic equivalence and preliminary safety of the adalimumab biosimilar CT-P17 administered via autoinjector (CT-P17 AI) or prefilled syringe (CT-P17 PFS) in healthy subjects. METHODS: This phase I, open-label study (ClinicalTrials.gov: NCT04295356) randomised subjects (1:1) to receive a single 40 mg (100 mg/mL) dose of CT-P17 AI or CT-P17 PFS. Primary endpoint was pharmacokinetic equivalence of CT-P17 AI to CT-P17 PFS for: area under the concentration-time curve from time zero to infinity (AUC0-inf ); area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-last ); maximum serum concentration (Cmax ). Equivalence was determined if the 90% confidence interval (CI) for the geometric least-squares mean ratio was within the 80-125% equivalence margin. Additional pharmacokinetic endpoints, safety, and immunogenicity were evaluated. RESULTS: Of 193 subjects who were randomised (98 CT-P17 AI; 95 CT-P17 PFS), 180 received study drug. Pharmacokinetic equivalence was demonstrated: 90% CIs were within the 80-125% equivalence margin (AUC0-inf : 93.98-114.29; AUC0-last : 91.09-121.86; Cmax : 94.08-111.90). Mean serum CT-P17 concentrations, secondary pharmacokinetic parameters, and numbers of subjects with antidrug antibodies (ADAs) or neutralising ADAs were comparable between groups. AUC0-inf , AUC0-last , and Cmax were numerically lower for ADA-positive than for ADA-negative subjects (both groups); pharmacokinetic equivalence was also demonstrated among ADA-positive subjects. CT-P17 AI and CT-P17 PFS were well tolerated, with comparable overall safety profiles. CONCLUSION: CT-P17 AI and CT-P17 PFS were pharmacokinetically equivalent. Overall safety and immunogenicity were comparable between the two delivery devices.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33644992

RESUMO

OBJECTIVE: Responsive assessment of disease activity in patients with rheumatoid arthritis (RA) is necessary to evaluate therapeutic efficacy and guide treatment. We compared the utility of the multi-biomarker disease activity (MBDA) score in assessing RA disease activity with that of the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) and the Clinical Disease Activity Index (CDAI) in a multicenter, randomized, placebo-controlled trial of repository corticotropin injection (RCI) in patients with persistently active RA. METHODS: Patients received 80 U of RCI twice weekly during a 12-week open-label period; those who achieved low disease activity at week 12 were randomly assigned to receive either 80 U of RCI or placebo twice weekly during a 12-week double-blind period. Changes in disease activity (measured by DAS28-ESR, CDAI, and MBDA) and correlations between MBDA scores and both DAS28-ESR and CDAI scores were assessed. RESULTS: Changes from baseline in DAS28-ESR and CDAI scores suggested that RCI therapy led to clinically meaningful improvements in disease activity, but improvements from baseline in MBDA scores were below the minimally important difference threshold. For the DAS28-ESR and CDAI, correlations with total MBDA and individual component scores were generally low (r≤0.3), occasionally moderate (r>0.3 but <0.5). CONCLUSION: Our results suggest overall MBDA scores are not sufficiently responsive for assessing RA disease activity after RCI therapy. These findings are consistent with those seen with other RA drugs and, although they are from a clinical trial, suggest the MBDA should not be a preferred disease activity measure in clinical practice.

3.
Semin Arthritis Rheum ; 51(2): 425-429, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33677309

RESUMO

INTRODUCTION/BACKGROUND: Skin ulcers are a complex array of clinical manifestations of systemic sclerosis (SSc) and are often difficult to treat. However, the definition of SSc-skin ulcers has to date not been promising, demonstrating poor reliability and accuracy. There are emerging data that ultrasound has significant potential to evaluate SSc-skin ulcers. OBJECTIVE: To perform a systematic literature review (SLR) to understand the degree to which ultrasound of SSc skin ulcers has been validated according to OMERACT criteria. METHODS: In a SLR, we investigated the Cochrane Library, Web of Science and Pubmed databases for manuscripts from inception to 1st April 2020. Inclusion and exclusion criteria included manuscripts on SSc patients aged over 16 years, performing SSc-related skin ulcer evaluation with ultrasound machines. Papers on animal model, diseases other than SSc, venous ulcers were excluded. Data extraction used a uniform case report form which collected data on patient demographics, disease activity, description of the ultrasound machine and procedures and the degree to which domains of validity were fulfilled. Manuscript evaluation and extraction was performed by two independent assessors, with a third author being consulted in case of disagreement. RESULTS: amongst 308 manuscripts that were identified, 6 published manuscripts/ posters fulfilled the inclusion/exclusion criteria and were extracted. Face validity was found. Three studies developed an US definition of SSc-ulcers across patients (content validity); one study evaluated the concordance between US image and clinical assessment. Criterion validity was shown by one study and ultrasound detected improvement (sensitivity to change) of SSc-skin ulcer in response to therapy. Feasibility was demonstrated by US use for skin ulcers in multiple settings (the 6 manuuscripts/posters). CONCLUSION: This systematic literature review shows that ultrasound for skin ulcers in SSc has been partially validated. It has face, content, criterion validity, responsiveness and reasonable feasibility. Further validation for construct validity, reliability and discrimination is required.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33560297

RESUMO

OBJECTIVE: The representation of women among authors of peer reviewed scientific papers is gradually increasing. The aims of this study were to examine the trend of the proportion of women among authors in the field of rheumatology during the last two decades. METHODS: Articles published in journals ranked in the top quartile of the field of rheumatology in the years 2002-2019 were analyzed. The authorship positions of all authors, country of the article's source and manuscript type were retrieved by specifically designed software. RESULTS: Overall, 153,856 author names were included in the final analysis. Of them, 55,608 (36.1%) were women. There was a significant rise in the percentage of women authors over time (r = 0.979, P < 0.001) from 30.9% in 2002 to 41.2% in 2018, with a slight decline to 39.8% in 2019. There were significantly fewer women in the senior author positions compared to the first author positions (24.3% in senior position Vs. 40.9% as first author, p < 0.001). CONCLUSION: The proportion of women among authors of rheumatology articles has increased over the years, both in general and as a first or senior author, however, their proportion is still less than 50% and there is still a gap between the proportion of women among first authors and the proportion of women among senior authors.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33560345

RESUMO

OBJECTIVES: The "European League Against Rheumatism" and "American College of Rheumatology" 2019 (EULAR/ACR-19) criteria for the diagnosis of Systemic Lupus Erythematosus (SLE) were recently published, with the stated goal of maintaining the level of sensitivity and raising the level of specificity for classification of SLE in adults. The aim of this study is to examine their application to juvenile SLE (jSLE) patients. METHODS: In this multicenter study the charts of jSLE patients from three tertiary medical centers were reviewed and compared to patients with non-jSLE diagnosis. Pediatric rheumatologists, blinded to the original diagnosis, reviewed and diagnosed all cases. Pediatric patients' clinical and laboratory data were retrospectively extracted and then examined with regard to how they met the new and old criteria. RESULTS: Included were 225 patients (112 jSLE, 113 non-SLE). When applied to juvenile SLE classification, the sensitivity of the new EULAR/ACR-19 criteria was 0.96 (0.9-.0.99) and the specificity was 0.89 (0.82-0.94). These were comparable to the Systemic Lupus International Collaborating Clinics (SLICC) criteria. . The sensitivity of the EULAR/ACR-19 criteria improves over time and was 0.83 twelve months following disease onset, reaching 0.96 after longer than 24 months. CONCLUSION: Among a cohort of jSLE patients, sensitivity of the new EULAR/ACR-19 criteria was found to be high and specificity may have improved slightly compared to the SLICC-12 criteria. We support the use of the new classification criteria for pediatric patients in future jSLE studies, but it should be noted that its specificity is lower than for adults.

6.
Arthritis Rheumatol ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33538094

RESUMO

OBJECTIVE: Tocilizumab has demonstrated lung function preservation in two randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of quantitative radiographic lung involvement. In this post-hoc analysis, we assess tocilizumab's impact on lung function preservation, stratifying treatment arms by the degree of radiographic lung involvement. METHODS: The focuSSced trial was a phase 3, randomized placebo-controlled trial of tocilizumab in patients with SSc and progressive skin disease. Participants had baseline and serial spirometry along with high resolution chest CT at baseline and week 48. Quantitative interstitial lung disease and fibrosis were derived using computer software. We divided quantitative interstitial lung disease in mild (5-10%), moderate (>10-20%), or severe (>20%) categories. RESULTS: Of 210 participants recruited in the trial, 136 [65%] had interstitial lung disease. The majority of these participants had moderate-to-severe involvement defined by >10% lung involvement (77%). The tocilizumab arm demonstrated preservation of forced vital capacity over 48 weeks (least squared mean change in %predicted = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean decline in the %pFVC in the tocilizumab arm at 48 weeks were -4.1, 0.7, and 2.1, and in the placebo group were -10.0, -5.7, and -6.7, respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity. CONCLUSION: Tocilizumab in early SSc- associated interstitial lung disease with progressive skin disease stabilized forced vital capacity over 48 weeks, independent of the extent of quantitative radiographic interstitial lung disease or fibrosis.

7.
Arthritis Res Ther ; 23(1): 51, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546755

RESUMO

BACKGROUND: To demonstrate equivalent efficacy of the proposed high-concentration (100 mg/ml), citrate-free adalimumab biosimilar CT-P17 to European Union-approved adalimumab (EU-adalimumab) in subjects with active rheumatoid arthritis (RA). METHODS: This randomized, double-blind phase III study ( ClinicalTrials.gov , NCT03789292) randomized (1:1) subjects with active RA at 52 centers to receive CT-P17 or EU-adalimumab 40 mg subcutaneously every 2 weeks until week 52. Results to week 24 are reported here. The primary endpoint was 20% improvement by American College of Rheumatology criteria (ACR20) response rate at week 24. Equivalence was concluded if the corresponding confidence intervals (CIs) for the estimate of treatment difference were within predefined equivalence margins: - 15 to 15% (95% CI; European Medicines Agency assumption); - 12 to 15% (90% CI; Food and Drug Administration assumption). Additional efficacy, pharmacokinetic, usability, safety, and immunogenicity endpoints were evaluated. RESULTS: 648 subjects were randomized (324 CT-P17; 324 EU-adalimumab). The ACR20 response rate at week 24 was 82.7% (n = 268/324) in both groups (intention-to-treat population). The 95% CI (- 5.94 to 5.94) and 90% CI (- 4.98 to 4.98) were within predefined equivalence margins for both assumptions and equivalent efficacy was concluded. Additional endpoints and overall safety were comparable between groups. Mean trough serum concentrations of CT-P17 were slightly higher than those of EU-adalimumab. Immunogenicity was slightly lower numerically for the CT-P17 group than for the EU-adalimumab group. CONCLUSIONS: CT-P17 and EU-adalimumab have equivalent efficacy and comparable safety and immunogenicity in subjects with active RA. Overall safety of CT-P17 is consistent with the known safety profile of reference adalimumab. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03789292 . Registered 28 December 2018-retrospectively registered.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33483129

RESUMO

BACKGROUND: Underreporting of harms in randomized controlled trials (RCTs) may lead to incomplete or erroneous assessments of the perceived benefit-to-harm profile of an intervention. To compare benefit with harm in clinical practice and future clinical studies, adverse event (AE) profiles including severity need to be understood. Even though patients report harm symptoms earlier and more frequently than clinicians, rheumatology RCTs currently do not provide a reporting framework from the patient's perspective regarding harms. Our objective for this meta-research project was to identify AEs in order to determine harm clusters and whether these could be self-reported by patients. Our other objective was to examine reported severity grading of the reported harms. METHODS: We considered primary publications of RCTs eligible if they were published between 2008 and 2018 evaluating pharmacological interventions in patients with a rheumatic or musculoskeletal condition and if they were included in Cochrane reviews. We extracted data on harms such as reported AE terms together with severity (if described), and categorized AE- and severity-terms into overall groups. We deemed all AEs with felt components appropriate for patient self-reporting. RESULTS: The literature search identified 187 possible Cochrane reviews, of which 94 were eligible for evaluation, comprising 1,297 articles on individual RCTs. Of these RCTs, 93 pharmacological trials met our inclusion criteria (including 31,023 patients; representing 20,844 accumulated patient years), which reported a total of 21,498 AEs, corresponding to 693 unique reported terms for AEs. We further sub-categorized these terms into 280 harm clusters (i.e., themes). AEs appropriate for patient self-reporting accounted for 58% of the AEs reported. Among the reported AEs, we identified medical terms for all of the 117 harm clusters appropriate for patient reporting and lay language terms for 86%. We intended to include severity grades of the reported AEs, but there was no evidence for systematic reporting of clinician- or patient-reported severity in the primary articles of the 93 trials. However, we identified 33 terms suggesting severity, but severity grading was discernible in only 9%, precluding a breakdown by severity in this systematic review. CONCLUSIONS: Our results support the need for a standardized framework for patients' reporting of harms in rheumatology trials. Reporting of AEs with severity should be included in future reporting of harms, both from the patients' and investigators' perspectives. REGISTRATION: PROSPERO: CRD42018108393.

9.
Clin Transl Sci ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33503313

RESUMO

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT-P17 to United States-licensed adalimumab (US-adalimumab) and European Union-approved adalimumab (EU-adalimumab). This double-blind, parallel-group, phase I trial (clinicaltrials.gov NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT-P17, US-adalimumab, or EU-adalimumab. Primary end points were PK equivalence in terms of: area under the concentration-time curve from time zero to infinity (AUC0-inf ); AUC from time zero to the last quantifiable concentration (AUC0-last ); and maximum serum concentration (Cmax ). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80-125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT-P17; 103 US-adalimumab; 106 EU-adalimumab), 308 subjects received study drug. AUC0-inf , AUC0-last , and Cmax were equivalent among CT-P17, US-adalimumab, and EU-adalimumab, because 90% CIs for the ratios of GLSMs were within the 80-125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single-dose administration of CT-P17, EU-adalimumab, and US-adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

10.
ACR Open Rheumatol ; 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33277978

RESUMO

OBJECTIVE: To evaluate short- and long-term outcomes of African American (AA) participants of Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomized 158 participants with systemic sclerosis-interstitial lung disease (SSc-ILD) to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 participants with SSc-ILD to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF). Joint models compared the course of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) between AA and non-AA, and Cox proportional hazard models assessed long-term morbidity and mortality outcomes. RESULTS: In SLS I, there was no difference in the course of the FVC or DLCO between AA and non-AA in either treatment arm. In SLS II, AA had an improved course of the FVC compared with non-AA in the CYC arm; in the MMF arm, there was no difference in FVC course. There was no difference in DLCO course in either arm. Time to death and respiratory failure were similar for AA and non-AA in SLS I. There was a trend for improved survival and time to respiratory failure in AA compared with non-AA in SLS II. AA race was not independently associated with mortality in the SLS I or II in the Cox models. CONCLUSION: Data from two randomized controlled trials demonstrated that AA patients with SSc-ILD have similar morbidity and mortality outcomes compared with non-AA patients. These findings contrast with the racial disparities described in prior observational studies and warrant further investigation.

11.
Arthritis Rheumatol ; 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33350170

RESUMO

OBJECTIVE: Response to immunosuppression is highly variable in systemic sclerosis (SSc) related interstitial lung disease (ILD). We hypothesized that a composite serum Interferon Inducible Serum Protein Score would exhibit predictive significance for the response to immunosuppression in SSc-ILD. METHODS: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate versus cyclophosphamide, were examined. Results were validated in an independent observational cohort on active treatment. A composite score of 6 interferon inducible proteins (IP-10, MIG, MCP-2, B2M, TNFR2, and MIP-3 beta) was calculated and its predictive significance for longitudinal forced vital capacity % predicted measurements was examined. RESULTS: Higher baseline Interferon Inducible Protein Score predicted better response over 3 to 12-month visits in the mycophenolate (b=0.41, p=0.001) and cyclophosphamide (b=0.91, p=0.009) arms. In contrast, higher baseline c-reactive protein (CRP) levels predicted worse ILD course in both treatment arms. The predictive significance of Interferon Inducible Protein Score and CRP remained after adjustment for baseline demographic/clinical predictors. During the second-year placebo treatment period of the cyclophosphamide arm, higher Interferon Inducible Protein Score at 12 months showed a trend for predicting worse ILD course (b=-0.61, p=0.068) while it continued predicting better response to active immunosuppression in the mycophenolate arm (b=0.28, p=0.029). The predictive significance of baseline Interferon Inducible Protein Score was replicated in the independent cohort (rs =0.43; p=0.028). CONCLUSIONS: Higher Interferon Inducible Protein Score in SSc-ILD predicts better response to immunosuppression and could be potentially used for identifying patients who may derive the most benefit from these two treatments.

12.
Clin Rheumatol ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33231773

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disorder and commonly presents with vascular system involvement and motility disorders in the gastrointestinal (GI) tract. Vinculin is a cytoskeletal protein that plays major roles in cell-cell adhesion and is expressed in the neuromuscular apparatus of the gut. Antibodies to vinculin have been identified as a biomarker of irritable bowel syndrome (IBS). Our aim was to evaluate serum anti-vinculin antibodies in patients with SSc. METHODS: Patients were recruited from two SSc centers: group I (GI-enriched group), University of Leeds, UK, and Group II (vascular predominant), University of California, Los Angeles. Serum samples of patients recruited from two SSc centres, Group I ( GI enriched group), University of Leeds, UK and Group II (Vascular predominant), University of California, Los Angeles) were collected. Samples from age- and sex-matched healthy volunteers (N = 88) were used as controls. RESULTS: Group I (GI-enriched group, N = 83) patients were 58 [50-67] years old; 83% were females with a median body mass index (BMI) of 20.3 (21.2 ± 4.5) [18-23]. Group II (vascular-enriched group, N = 72) patients were 58 [50-67] years old; 80% were female, and BMI was 23.9 (21.3-26.9). More subjects in group I had prominent GI involvement (N = 55, 66%) than group II (12, 16%), p ˂ 0.0001. Anti-vinculin antibody levels in SSc group I (1.3 [0.9]) were significantly higher than in HC (0.7 [0.8]; p = 0.002). When pooled, circulating anti-vinculin levels in both SSc groups remained significantly higher than in the HC group (p = 0.02). Higher anti-vinculin levels were associated with higher GI-visual analogue scale (GI-VAS) scores and specifically with GI-VAS scores of ≥ 4 (p < 0.0001). CONCLUSION: This study demonstrates that elevated anti-vinculin antibody levels are common in SSc and suggests a potential link between increased anti-vinculin levels and GI tract symptoms. KEY POINTS: • Anti-vinculin antibodies are elevated in systemic sclerosis and are relatively common. • In these SSc patients, anti-vinculin antibodies are associated with higher levels of GI symptoms in SSc. • A potential link between anti-vinculin antibodies and vascular system involvement was shown.

13.
Eur J Rheumatol ; 7(Suppl 3): S237-S241, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33164737

RESUMO

Fibrosis, inflammation, and vasculopathy are the main determinants of systemic sclerosis (SSc) pathogenesis. Cyclophosphamide (CYC), an alkylating agent, has been used to treat skin fibrosis and interstitial lung diseases in SSc for many years and still represents a mainstay in hematopoietic stem cell transplantation. Despite significant effect in reducing lung functional impairment and skin tightness, CYC has a significant safety burden, including infection risk and bone marrow and bladder toxicity. Moreover, it can affect fertility and also cause a predisposition for cancer development in the future, particularly in the bladder. This review summarizes the current evidences regarding the use of CYC to treat SSc, its efficacy and safety profile, and currently available or tested alternative drugs for lung and skin involvement in SSc.

14.
Arthritis Rheumatol ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131208

RESUMO

OBJECTIVE: To provide a large-scale assessment of serum protein dysregulations in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: Baseline serum protein profile of 66 participants with dcSSc enrolled in the Scleroderma: Cyclophosphamide Or Transplant trial and 66 healthy, age- and gender-matched controls was investigated. A panel of 230 proteins, including several cytokines and chemokines was determined. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Mean disease duration was 2.3 years, all had interstitial lung disease (ILD), and none were treated with immunosuppressive agents at baseline visit. Ninety proteins were differentially expressed compared to controls. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion and diapedesis were the top over-represented pathways. Eighteen proteins correlated with modified Rodnan Skin Score (mRSS). Soluble EGFR was significantly down-regulated in dcSSc and showed the strongest negative correlation with mRSS and predicted its course, whereas Alpha 1 Antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with mRSS. Furthermore, higher CA15.3 correlated with more severe ILD, based on lower forced vital capacity and higher high-resolution CT scores. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSIONS: dcSSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33002337

RESUMO

OBJECTIVE: To use unbiased, data-driven, principal component (PC) and cluster analysis to identify patient phenotypes of rheumatoid arthritis (RA) that might exhibit distinct trajectories of disease progression, response to treatment, and risk for adverse events. METHODS: Patient demographic, socioeconomic, health, and disease characteristics recorded at entry into a large, single-center, prospective observational registry cohort, the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS; NCT01793103), were harmonized using PC analysis to reduce dimensionality and collinearity. The number of PCs was established by eigenvalue >1, cumulative variance, and interpretability. The resulting PCs were used to cluster patients using a k-means approach. Longitudinal clinical outcomes were compared between the clusters over 2 years. RESULTS: Analysis of 142 variables from 1443 patients identified 41 PCs that accounted for 77% of the cumulative variance in the dataset. Cluster analysis distinguished five patient clusters: (1) less RA disease activity/multimorbidity, shorter RA duration, lower incidence of comorbidities; (2) less RA disease activity/multimorbidity, longer RA duration, more infections, psychiatric comorbidities, healthcare utilization; (3) moderate RA disease activity/multimorbidity, more neurologic comorbidity; (4) more RA disease activity/multimorbidity, shorter RA duration, more metabolic comorbidity, higher BMI; (5) more RA disease activity/multimorbidity, longer RA duration, more hepatic, orthopedic comorbidity and RA-related surgeries. The clusters exhibited differences in clinical outcomes over 2 years of follow-up. CONCLUSION: Data-driven analysis of the BRASS registry identified five distinct phenotypes of RA. These results illustrate the potential of data-driven patient profiling as a tool to support personalized medicine in RA. Validation in an independent dataset is ongoing.

16.
Ann Rheum Dis ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33055082

RESUMO

OBJECTIVES: The Outcome Measures in Rheumatology Initiative established the Contextual Factors Working Group to guide the understanding, identification and handling of contextual factors for clinical trials. In clinical research, different uses of the term 'contextual factors' exist. This study explores the perspectives of researchers (including clinicians) and patients in defining 'contextual factor' and its related terminology, identifying such factors and accounting for them in trials across rheumatology. METHODS: We conducted individual semistructured interviews with researchers (including clinicians) who have experience within the field of contextual factors in clinical trials or other potentially relevant areas, and small focus group interviews with patients with rheumatic conditions. We transcribed the interviews and applied qualitative content analysis. RESULTS: We interviewed 12 researchers and 7 patients. Researcher's and patient's descriptions of contextual factors were categorised into two broad themes, each comprising two contextual factors types. The 'treatment effect' theme focused on factors explaining variations in treatment effects (A) among patients and (B) among studies. The 'outcome measurement' theme focused on factors that explain (C) variations in the measurement result itself (apart from actual changes/differences in the outcome) and (D) variations in the outcome itself (beside treatment of interest). Methods for identifying and handling contextual factors differed among these themes and types. CONCLUSIONS: Two main themes for contextual factors with four types of contextual factors were identified based on input from researchers and patients. This will guide operationalisation of contextual factors. Further research should refine our findings and establish consensus among relevant stakeholders.

17.
Semin Arthritis Rheum ; 50(5): 963-967, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32906032

RESUMO

OBJECTIVE: To investigate the prevalence of the MUC5B promoter variant rs35705950 in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and whether its presence predicts response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF). METHODS: SSc-ILD patients who participated in Scleroderma Lung Study (SLS) II (MMF versus CYC) were included in this study (N = 142). TaqMan Genotyping Assays were used to determine the MUC5B rs35705950 single nucleotide polymorphism. Joint models were created to examine how the presence of this variant affected the course of the forced vital capacity (FVC) over 2 years. Linear regression models were used to investigate the relationship between the presence of this variant and the change in quantitative radiographic fibrosis. RESULTS: Among 128 participants who were tested for this variant, 18% possessed at least one copy of the MUC5B minor allele. Patients with at least one copy of this allele were similar to those without the allele with respect to age, sex, SSc subtype, ILD disease severity; however, this variant was rare among African Americans (3.7%). The presence of the MUC5B variant did not affect the course of the FVC, nor the change in quantitative radiographic fibrosis, ground glass or ILD scores in either treatment arm. CONCLUSION: In the context of a randomized controlled trial for SSc-ILD, the presence of the MUC5B variant did not predict disease severity, nor affect treatment response to MMF or CYC. Future studies are needed to determine whether this variant affects ILD progression in other SSc cohorts and in patients receiving anti-fibrotic therapy.

18.
Ann Rheum Dis ; 79(12): 1608-1615, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32933919

RESUMO

OBJECTIVE: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT. METHODS: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs). RESULTS: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways. CONCLUSIONS: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.

19.
Clin Exp Rheumatol ; 38 Suppl 125(3): 161-168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865169

RESUMO

OBJECTIVES: Both intravenous (IV) and oral (PO) cyclophosphamide (CYC) showed beneficial effects on skin and lung involvement in systemic sclerosis (SSc) in placebo-controlled randomised clinical trials and observational studies. Our goal was to compare the relative efficacy and safety of PO- versus IV-CYC for treating interstitial lung disease and/or skin involvement in SSc. METHODS: Patients were derived from the EUSTAR centres and the Scleroderma Lung Studies I and II. A minimum of 6 months of CYC treatment and 12 months follow-up were required. Serious (SAEs) and non-serious adverse events and efficacy data (change in FVC%, DLCO%, mRSS) were analysed at the end of CYC treatment (EoT) and at follow-up (FU). Analysis included descriptive statistics and linear regressions. RESULTS: Differences in ethnicity, previous DMARD exposure, previous and concomitant steroid exposure/dosage were observed in the PO (n=149) and IV (n=153) CYC groups. Adjusted and unadjusted changes in FVC%, DLCO% and mRSS were similar irrespective of mode of administration. PO patients had more leukopenia (p<0.001), haemorrhagic cystitis (p=0.011) and alopecia (p<0.001) at the EoT visit, while the IV group had more SAEs (p=0.025) and need for oxygen supplementation at FU (p=0.049). CONCLUSIONS: In a comparison of PO- to IV-CYC for SSc, we found no differences in lung function or cutaneous sclerosis after one year. Some differences in side effects were seen. The results need to be considered as preliminary; however, because we needed to use a combination of RCT and registry data, with some differences in demographics and concomitant medications, well-controlled studies are warranted.


Assuntos
Imunossupressores , Escleroderma Sistêmico , Ciclofosfamida , Fibrose , Humanos , Pulmão , Resultado do Tratamento
20.
Lancet Respir Med ; 8(10): 963-974, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32866440

RESUMO

BACKGROUND: A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10-35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with ClinicalTrials.gov (number NCT02453256) and is closed to accrual. FINDINGS: Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was -6·14 for tocilizumab and -4·41 for placebo (adjusted difference -1·73 [95% CI -3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0-6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37-1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events). INTERPRETATION: The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab. FUNDING: F Hoffmann-La Roche Ltd.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
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