scholarly journals Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis

2019 ◽  
Vol 78 (9) ◽  
pp. 1242-1248 ◽  
Author(s):  
Mike Becker ◽  
Nicole Graf ◽  
Rafael Sauter ◽  
Yannick Allanore ◽  
John Curram ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Systemic Sclerosis ◽  
Disease Progression ◽  
Muscle Weakness ◽  
Lung Fibrosis ◽  
Heart Function ◽  
Strong Association ◽  
Organ Damage ◽  
Inclusion Criteria ◽  
Patients At Risk

ObjectivesMortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.MethodsInclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.ResultsOf 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.ConclusionsThe use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.

scholarly journals Assessment of the pathologic inclusion criteria from contemporary adjuvant clinical trials for predicting disease progression after nephrectomy for renal cell carcinoma

Cancer ◽  
2012 ◽  
Vol 118 (18) ◽  
pp. 4412-4420 ◽  
Author(s):  
Simon P. Kim ◽  
Paul L. Crispen ◽  
R. Houston Thompson ◽  
Christopher J. Weight ◽  
Stephen A. Boorjian ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Cell Carcinoma ◽  
Disease Progression ◽  
Renal Cell ◽  
Inclusion Criteria

scholarly journals Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Andrea Sierra-Sepúlveda ◽  
Alexia Esquinca-González ◽  
Sergio A. Benavides-Suárez ◽  
Diego E. Sordo-Lima ◽  
Adrián E. Caballero-Islas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Systemic Sclerosis ◽  
Autoimmune Disease ◽  
State Of The Art ◽  
Therapeutic Targets ◽  
Organ Damage ◽  
The State ◽  
Pathogenic Mechanism ◽  
Emerging Therapies

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far.

scholarly journals FRI0325 IDENTIFYING SYSTEMIC SCLEROSIS PATIENTS AT RISK OF PROGRESSIVE LUNG FIBROSIS – A EUSTAR DATABASE ANALYSIS

2019 ◽  
Author(s):  
Anna-Maria Hoffmann-Vold ◽  
Martina Gahlemann ◽  
Nicole Graf ◽  
Paolo Airò ◽  
Lidia P. Ananyeva ◽  
...  
Keyword(s):  
At Risk ◽  
Systemic Sclerosis ◽  
Lung Fibrosis ◽  
Database Analysis ◽  
Patients At Risk

scholarly journals An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Corrado Campochiaro ◽  
Yannick Allanore
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Systemic Sclerosis ◽  
Targeted Therapies ◽  
Observational Studies ◽  
Phase 1 ◽  
Phase 2 ◽  
Inclusion Criteria ◽  
Phase 3 ◽  
Trial Drug

AbstractNew molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.

scholarly journals Development and validation of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis

2019 ◽  
Vol 78 (6) ◽  
pp. 807-816 ◽  
Author(s):  
Nava Ferdowsi ◽  
Molla Huq ◽  
Wendy Stevens ◽  
Marie Hudson ◽  
Mianbo Wang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Systemic Sclerosis ◽  
Short Form ◽  
Damage Index ◽  
Clinical Importance ◽  
Organ Damage ◽  
Physical Component Summary Score ◽  
Summary Score ◽  
Data Set ◽  
Mortality And Morbidity

ObjectiveWe sought to develop the first Damage Index (DI) in systemic sclerosis (SSc).MethodsThe conceptual definition of ‘damage’ in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with p<0.10 were retained; (3) using multivariable regression analysis, coefficients were used to determine a weighted score for each item. The DI was externally validated in a Canadian cohort.ResultsNinety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort.ConclusionsThrough the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

scholarly journals Defining the optimal disease duration of early diffuse systemic sclerosis for clinical trial design

Rheumatology ◽  
2021 ◽  
Author(s):  
Robyn T Domsic ◽  
Shiyao Gao ◽  
Maureen Laffoon ◽  
Steven Wisniewski ◽  
Yuqing Zhang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Systemic Sclerosis ◽  
Disease Duration ◽  
Disease Onset ◽  
Clinical Trial Design ◽  
Primary Outcome Measure ◽  
Inclusion Criteria ◽  
Regression To The Mean ◽  
The Mean ◽  
Definition Of

Abstract Objectives Clinical trials in early diffuse cutaneous systemic sclerosis (SSc) using the modified Rodnan skin score (mRSS) as the primary outcome measure have most often been negative. We wanted to assess how the definition of disease onset (first SSc manifestation vs first non-Raynaud manifestation), and varying lengths of disease duration at trial entry as an inclusion criteria functioned. Our objective was to optimize trial inclusion criteria Methods We used the prospective, observational University of Pittsburgh Scleroderma Cohort to identify early diffuse SSc patients first evaluated between 1980 and 2015. All had &lt;3 years from first SSc (n = 481) or first non-Raynaud manifestation (n = 514) and 3 or more mRSS scores. We used descriptive, survival and group-based trajectory analyses to compare the different definitions of disease onset and disease duration as inclusion criteria for clinical trials. Results There was no appreciable difference between using first SSc manifestation compared with first non-Raynaud manifestation as the definition of disease onset. Compared with other disease durations, &lt;18 months of disease had &gt;70% of patients fitting into trajectories with worsening cutaneous disease over six months of follow-up. Longer disease durations demonstrated the majority of patients with trajectories showing an improvement in mRSS (regression to the mean) over six months. Conclusions Regardless of whether the first SSc or first non-Raynaud manifestation is used to define disease onset, duration of &lt; 18 months at enrolment is preferable. Longer disease duration criteria more frequently results in regression to the mean of the mRSS score, and likely contributes to negative trial outcomes.

Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study

2012 ◽  
Vol 72 (7) ◽  
pp. 1217-1220 ◽  
Author(s):  
Muriel Elhai ◽  
Marine Meunier ◽  
Marco Matucci-Cerinic ◽  
Britta Maurer ◽  
Gabriela Riemekasten ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Observational Study ◽  
Disease Activity ◽  
Lung Fibrosis ◽  
Disease Activity Score ◽  
Research Network ◽  
Inclusion Criteria ◽  
Joint Parameters ◽  
Biological Assessments

ObjectiveTo evaluate the safety and effectiveness of tocilizumab and abatacept in systemic sclerosis (SSc)-polyarthritis or SSc-myopathy.Methods20 patients with SSc with refractory polyarthritis and seven with refractory myopathy from the EUSTAR (EULAR Scleroderma Trials and Research) network were included: 15 patients received tocilizumab and 12 patients abatacept. All patients with SSc-myopathy received abatacept. Clinical and biological assessments were made at the start of treatment and at the last infusion.ResultsAfter 5 months, tocilizumab induced a significant improvement in the 28-joint count Disease Activity Score and its components, with 10/15 patients achieving a EULAR good response. Treatment was stopped in two patients because of inefficacy. After 11 months’ treatment of patients with abatacept, joint parameters improved significantly, with 6/11 patients fulfilling EULAR good-response criteria. Abatacept did not improve muscle outcome measures in SSc-myopathy. No significant change was seen for skin or lung fibrosis in the different groups. Both treatments were well tolerated.ConclusionsIn this observational study, tocilizumab and abatacept appeared to be safe and effective on joints, in patients with refractory SSc. No trend for any change of fibrotic lesions was seen but this may relate to the exposure time and inclusion criteria. Larger studies with longer follow-up are warranted to further determine the safety and effectiveness of these drugs in SSc.

An enrichment strategy for clinical trials in SPMS

2021 ◽  
pp. 135245852098358
Author(s):  
Marcus W Koch ◽  
Luanne Metz ◽  
Gary Cutter
Keyword(s):  
Clinical Trials ◽  
Strong Association ◽  
Data Sets ◽  
Inclusion Criteria ◽  
Disability Status ◽  
Data Source ◽  
Baseline Characteristics ◽  
The Impact ◽  
Enrichment Strategy ◽  
Selection Of

Background: We recently compared clinical outcomes in secondary progressive MS (SPMS) clinical trials and found an association of timed 25 foot walk (T25FW) worsening events and baseline disability scores. It is unclear whether disability worsening in clinical trials is comparable to that seen in clinical practice. Objective: The objective of this study is to compare disability worsening between the IMPACT and ASCEND data sets and data from the Calgary MS clinic and to characterize the association of baseline T25FW and expanded disability status scale (EDSS) scores with disability worsening. Methods: We combined the three data sets and investigated the impact of baseline characteristics on disability worsening with a logistic regression model. We calculated T25FW, EDSS, and ‘EDSS or T25FW’ worsening events as a function of ascending cut-off baseline disability scores. Results: Data source was not associated with T25FW worsening at 12 months. There was a strong association of baseline T25FW and EDSS cut-off scores with T25FW worsening. No such association was present for the EDSS and ‘EDSS or T25FW’. Conclusion: Our results suggest that it is possible to ‘enrich’ a trial cohort for expected T25FW worsening events using specific baseline T25FW and EDSS cut-off scores. These analyses inform the selection of inclusion criteria for clinical trials in SPMS.

scholarly journals OP0273 THE SCLERODERMA CLINICAL TRIALS CONSORTIUM DAMAGE INDEX (SCTC-DI) IN A SYSTEMIC SCLEROSIS COHORT WITH 10-YEARS FOLLOW-UP

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 166.2-166
Author(s):  
M. G. Lazzaroni ◽  
M. Breda ◽  
F. Franceschini ◽  
P. Airò
Keyword(s):  
Clinical Trials ◽  
Systemic Sclerosis ◽  
Multivariable Analysis ◽  
Damage Index ◽  
Organ Damage ◽  
Severe Damage ◽  
Time Points ◽  
Cutaneous Involvement ◽  
Male Sex

Background:Systemic Sclerosis (SSc) is characterized by increased mortality and organ damage accrual. A composite SSc Damage Index was recently developed by the Scleroderma Clinical Trials Consortium (SCTC-DI) and was demonstrated as a predictor of mortality both in the Australian derivation cohort and in the Canadian validation cohort.Objectives:To evaluate in a single centre cohort of SSc patients with 10-years follow-up: (1) the evolution of organ damage over time; (2) factors associated with the development and accrual of organ damage.Methods:A retrospective analysis was performed on patients prospectively followed in our centre from 1989 to 2019. Organ damage was evaluated with SCTC-DI (0-55 scale; moderate damage >5, severe damage>12) and comorbidities with Charlson Comorbidity Index (CCI, which includes the age of the patient). Patients were included when a follow-up of at least 10 years was available together with SCTC-DI at the diagnosis (baseline, T0), 1 year (T1), 5 years (T5) and 10 years (T10) after the diagnosis. Univariable and multivariable analysis (logistic regression) were performed when appropriated.Results:253 SSc patients were included (female 93%; Caucasians: 99%; median age at diagnosis: 52 years (IQR: 43-60); diffuse cutaneous subset: 15%; anti-centromere (ACA)+ 55%; anti-Topoisomerase 1 + 20%; anti-RNA polymerase III+: 4%; ever smokers: 28%). Median interval between the first SSc symptom other than Raynaud’s phenomenon and the diagnosis was 1 year. SCTC-DI progressively increased from diagnosis to T10 (p<0.0001; Kruskal-Wallis test).Moderate damage (score:6-12) was observed in 22 patients at T0 (8.7%), in 30 at T1 (11.9%), in 45 at T5 (17.7%) and in 73 at T10 (28.9%). None of the patients had severe damage (score:13-55) at T0 and T1, while it was present in 6 at T5 (2.4%) and in 13 at T10 (5.1%).At T0 no difference in SCTC-DI scores was observed when comparing different subgroups according to gender (female vs. male), disease subsets (diffuse vs. limited) and autoantibodies (ACA- vs. ACA+). At T1, SCTC-DI score was higher in patients with diffuse vs. limited cutaneous subset, and ACA- vs ACA+ (p<0.0001 for both).Multivariable analysis demonstrated that a moderate or severe organ damage (SCTC-DI score >5) at 5 years was positively associated with diffuse cutaneous involvement (p:0.009, OR 4.55, 1.46-14.1), SCTC-DI at T0 (p:0.015, OR 1.34, 1.06-1.70) and at T1 (p:<0.0001, OR 1.65, 1.30-2.07), and negatively associated with ACA+ (p:0.024, OR 0.32, 0.12-0.86), while CCI and male sex showed no association. At 10 years SCTC-DI>5 was associated with diffuse cutaneous involvement (p:0.013, OR 4.30, 1.36-13.7), SCTC-DI at T5 (p:<0.0001, OR 1.67, 1.38-2.01), while SCTC-DI at T0, CCI, male sex and ACA+ had no association.Among 253 patients, 90 (36%) died after >10 years of follow-up. In non-survivors, as compared to survivors, SCTC-DI score was significantly higher at the baseline (T0) and during the entire follow-up (p<0.0001 for every timepoint).Conclusion:At the end of 10-years follow-up (T10), 35% of patients in our cohort had moderate or severe organ damage (SCTC-DI score>5). Diffuse cutaneous involvement was associated with higher SCTC-DI scores at different time points (T5 and T10). Organ damage, quantified by SCTC-DI at different time points, was confirmed as a factor associated with mortality in patients who reached more than 10 years of follow-up.References:[1]Ferdowsi N, et al. Ann Rheum Dis. 2019;78:807-16.Disclosure of Interests:None declared

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