Madelon Vonk | Radboudumc Nijmegen - The Netherlands (original) (raw)

Papers by Madelon Vonk

Research paper thumbnail of Efficacité du nintédanib chez des patients présentant une pneumopathie interstitielle diffuse associée à la sclérodermie systémique (PID-ScS) avec atteinte des organes internes : données de l’étude SENSCIS

Revue du Rhumatisme, 2021

Research paper thumbnail of Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis

Rheumatology

Objectives The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM ... more Objectives The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. Methods This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint. Results Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated followi...

Research paper thumbnail of AB0441 NAILFOLDCAPILLAROSCOPY and Candidate Biomarker Levels in Systemic Sclerosis- Associated Pulmonary Hypertension; Profiling of Non-Invasive Markers, a Cohort Study

Annals of the Rheumatic Diseases, 2021

Systemic sclerosis (SSc) is characterized by inflammation, vasculopathy and progressive fibrosis.... more Systemic sclerosis (SSc) is characterized by inflammation, vasculopathy and progressive fibrosis. Pulmonary Hypertension (PH) is one of the leading causes of death in SSc (1). Currently, most patients with SSc are screened for the presence of PH, and focus lies on early detection and early treatment. Recent literature describes potential for both nailfoldcapillaroscopy (NCM) and several biomarkers to serve as non-invasive tools to identify SSc patients at risk for developing PH (2). Ideally this could attribute to further improvement of risk stratification in SSc and PH screenings algorithms.To explore NCM characteristics and plasma levels of selected candidate biomarkers in a cross-sectional cohort of SSc patients with and without different forms of PH.From 02-2018 until 02-2019 we included 40 consecutive SSc patients with associated PH (30 (75%) were female, 32 (80%) LcSSc, median age 72 years (IQR 69-77), median SSc duration 10.7 years (IQR 4.3-17.8), median PH duration 3.9 years...

Research paper thumbnail of SAT0313 CORRELATION Between Progression of Skin Fibrosis and Progression of Interstitial Lung Disease (Ild) in Patients with SSC-Ild: Data from the Senscis Trial

Annals of the Rheumatic Diseases, 2020

In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC over... more In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks vs placebo, with no difference between groups in change in mRSS.Analyse correlation between progression of skin fibrosis and progression of SSc-ILD in the SENSCIS trial.Patients with SSc-ILD were randomised to receive nintedanib or placebo until the last patient reached week 52 but for ≤100 weeks. We calculated Spearman correlation coefficients between FVC (mL) at baseline and change from baseline in mRSS, mRSS at baseline and change from baseline in FVC (mL), and changes from baseline in mRSS and FVC at weeks 52 and 100 in all patients. We analysed the rate of decline in FVC (mL/year) in patients who did and did not have progression of skin fibrosis (relative change from baseline in mRSS >25% and absolute change from baseline >5 points) at week 52.In the nintedanib (n=288) and placebo (n=288) groups, respectively, mean (SD) baseline FVC (mL) was 2459 (736) and 2541 (816)...

Research paper thumbnail of Treatment decision-making in diffuse cutaneous systemic sclerosis: a patient’s perspective

Rheumatology, 2019

Objectives To examine the treatment decision-making process of patients with dcSSc in the context... more Objectives To examine the treatment decision-making process of patients with dcSSc in the context of haematopoietic stem cell transplantation (HSCT). Methods A qualitative semi-structured interview study was done in patients before or after HSCT, or patients who chose another treatment than HSCT. Thematic analysis was used. Shared decision-making (SDM) was assessed with the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Results Twenty-five patients [16 male/nine female, median age 47 (range 27–68) years] were interviewed: five pre-HSCT, 16 post-HSCT and four following other treatment. Whereas the SDM-Q-9 showed the decision-making process was perceived as shared [median score 81/100 (range 49–100)], we learned from the interviews that the decision was predominantly made by the rheumatologist, and patients were often steered towards a treatment option. Strong guidance of the rheumatologist was appreciated because of a lack of accessible, reliable and SSc-specific information,...

Research paper thumbnail of Treatment with cyclophosphamide i.v. pulse therapy is an option for effective treatment of skin fibrosis in patients with early systemic sclerosis

Rheumatology, 2019

Objectives SSc is a autoimmune disease characterized by fibrosis of the skin and internal organs.... more Objectives SSc is a autoimmune disease characterized by fibrosis of the skin and internal organs. There is a lack of evidence for the efficacy of i.v. CYC pulse therapy on skin thickening. We aimed to examine the response of i.v. CYC pulse therapy on skin thickening in our cohort of SSc patients and analysed factors that predict this response. Methods We retrospectively evaluated the data for 143 patients with SSc from baseline to 12, 24 and 36 months. All patients were treated with at least 6 i.v. CYC pulses (750 mg/m2/month). We applied the modified Rodnan Skin Score (mRSS) to assess skin thickening. A clinically relevant response was defined as a decrease in mRSS of 5 points and 25% from baseline. Different baseline variables for predicting response on month 12 were tested in logistic regression analyses. Results Baseline characteristics of the patients with dcSSc and lcSSc were collected. Forty-three percent (n = 42) of dcSSc patients had a clinically relevant response on month ...

Research paper thumbnail of SAT0485 What is the effect of cyclophosphamide iv pulse therapy in patients with diffuse cutaneous systemic sclerosis on skin involvement: an observational study

Saturday, 16 JUNE 2018, 2018

SAT0485-Figure 1. mRSS course of all patients during iv CYC Conclusions: This study shows that on... more SAT0485-Figure 1. mRSS course of all patients during iv CYC Conclusions: This study shows that only 43% of the treated DcSSc patients experienced clinical important improvement of skin involvement following iv CYC. Response at month 6 is the best predictor for response on month 12. This could imply that at this time point, counselling about other available treatment options, should be considered in those patients. REFERENCES: [1] Kowal-Bielecka O, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Annals of the rheumatic diseases 2009;68 (5):620-8. [2] Namas R, et al. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: Post-hoc analyses from the Scleroderma Lung Study I and II. Arthritis care & research 2017.

Research paper thumbnail of There is a need for new systemic sclerosis subset criteria. A content analytic approach

Scandinavian journal of rheumatology, Jan 9, 2017

Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpo... more Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, howeve...

Research paper thumbnail of AB0651 The effect of cyclophosphamide on pulmonary function and dependence on disease activity of interstitial lung disease associated with systemic sclerosis

Abstracts Accepted for Publication, 2017

Of 422 SSc patients in the database, 344 patients had SSc meeting ACR criteria. 89 patients were ... more Of 422 SSc patients in the database, 344 patients had SSc meeting ACR criteria. 89 patients were exclusively ATA-positive, of which n=42 with mild disease and n=47 with severe disease. Patients with severe disease appeared to be younger (mean age 50 vs 55 yr), more often non-caucasian (51 vs 12%), with a longer time since non-Raynaud (median 4 vs 2 yr) and more often diffuse skin involvement (dcSSc;62 vs 41%), calcinosis (6 vs 0%) and weight loss (23 vs 7%). Stratification by disease duration, however revealed there are no real differences between mild en severe disease. Overall 47% of ATA+ patients in our cohort presented with mild SSc. When stratifying patients according to time of non-Raynaud, 55% of ATA+ patients presented with mild disease in the first disease duration quartile (median follow-up 0.5 years, range 0-0.8 years). In the forth disease duration quartile, according non-Raynaud time (median follow-up 12.7 years, range 8.2-44.1) the percentage with mild disease was still 27% (Figure 1). Conclusions: In our cohort, 47% of ATA-positive patients presented with mild systemic sclerosis, which could not be explained by disease duration. This suggests that solely the presence of ATA is of limited clinical relevance. Readily available sociodemographic and clinical parameters including type of skin involvement seem to have only limited value in identifying ATA patients with more severe SSc. More complex serological findings as antibody titers and fine-specifity of ATA should be defined for optimal serological subsetting.

Research paper thumbnail of Continued treatment with nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from SENSCIS-ON

Annals of the Rheumatic Diseases

ObjectivesIn the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung d... more ObjectivesIn the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo, with adverse events that were manageable for most patients. An open-label extension trial, SENSCIS-ON, is assessing safety and FVC decline during longer term nintedanib treatment.MethodsPatients who completed the SENSCIS trial or a drug–drug interaction (DDI) study of nintedanib and oral contraceptive on treatment were eligible to enter SENSCIS-ON. Adverse events and changes in FVC over 52 weeks of SENSCIS-ON were assessed in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON (‘continued nintedanib’ group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for ≤28 days in the DDI study (’initiated nintedanib’ group).ResultsThere were 197 patients in the continued nintedanib group and 247 in t...

Research paper thumbnail of The -2518A>G promoter polymorphism in the CCL2 gene is not associated with systemic sclerosis susceptibility or phenotype: Results from a multicenter study of European Caucasian patients

Human Immunology, Feb 1, 2009

A single nucleotide polymorphism (SNP) of the gene encoding monocyte chemoattractant protein-1 (M... more A single nucleotide polymorphism (SNP) of the gene encoding monocyte chemoattractant protein-1 (MCP-1, CCL2) has previously been suggested to be involved in the susceptibility of systemic sclerosis (SSc). Here we have tested whether the-2518AϾG CCL2 variant is associated with SSc susceptibility and/or phenotype using a cohort of SSc patients (n ϭ 345). Clinical data from SSc patients attending rheumatology clinics in the Netherlands and Germany was collected DNA was obtained after informed consent. The control group used (n ϭ 272) was randomly recruited from comparable geographic regions. The-2518AϾG SNP in CCL2 (rs1024611) was determined using a Taqman SNP Genotyping assay. The genotype distribution was found to be similarly distributed among SSc patients and healthy controls. In addition, no association could be detected between the genotype and the presence of antinuclear antibodies, anticentromere antibodies, and antitopoisomerase antibodies or pulmonary involvement. Our results demonstrate that the functional variant-2518AϾG of CCL2 is not implicated in the susceptibility or phenotype of SSc.

Research paper thumbnail of Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

HAL (Le Centre pour la Communication Scientifique Directe), Sep 1, 2016

Research paper thumbnail of Pharmacological treatments for SSc-ILD: Systematic review and critical appraisal of the evidence

Autoimmunity Reviews, Dec 1, 2021

Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease... more Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease (SSc-ILD), including immunosuppressive therapies, antifibrotic agents, immunomodulators and monoclonal antibodies. There is a high unmet medical need to better understand the current evidence for treatment efficacy and safety. This systematic review aims to present the existing literature on different drug treatments investigated for SSc-ILD and to critically assess the level of evidence for these drugs. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A structured literature search was performed for clinical trials and observational studies on the treatment of SSc-ILD with pharmaceutical interventions from 1 January 1990 to 15 December 2020. The quality of each reference was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. A total of 77 references were reviewed and 13 different treatments were identified. We found high-quality evidence for the use of cyclophosphamide, nintedanib, mycophenolate and tocilizumab. Therefore, we would posit that the clinical community has four valid options for treatment of SSc-ILD. Further research is mandatory to provide more evidence for the optimal treatment strategy in SSc-ILD, including the optimal time to initiate treatment, selection of patients for treatment and upfront combination therapy.

Research paper thumbnail of Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria

Journal of Clinical Epidemiology, Jun 1, 2014

Objective-Classification criteria for systemic sclerosis (SSc) are being developed. The objective... more Objective-Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to: develop an instrument for collating case-data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement between experts on the probability that cases were classified as SSc. Study Design and Setting-A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank-ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and re-ranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICC). Results-Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud's phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7) and puffy fingers (5). The ICC across experts was 0.73 (95%CI 0.58,0.86) and improved to 0.80 (95%CI 0.68,0.90). Conclusions-Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (23 to 14) and weighted. Our methods reflect the rigors of measurement science, and serves as a template for developing classification criteria.

Research paper thumbnail of Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis

JAMA, Jun 25, 2014

; for the EBMT/EULAR Scleroderma Study Group IMPORTANCE High-dose immunosuppressive therapy and a... more ; for the EBMT/EULAR Scleroderma Study Group IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit.

Research paper thumbnail of The Functional Polymorphism 844 A>G in Fc<sub>α</sub>RI <i>(CD89)</i> Does Not Contribute to Systemic Sclerosis or Rheumatoid Arthritis Susceptibility

The Journal of Rheumatology, Dec 15, 2010

Objective. To investigate the role of the Fc a RI 844 A>G functional polymorphism in the genetic ... more Objective. To investigate the role of the Fc a RI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility. Methods. The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The Fc a RI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing. Results. We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results. Conclusion. Our data show that the Fc a RI 844 A>G polymorphism is not associated with SSc or RA susceptibility.

Research paper thumbnail of Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

npj Genomic Medicine, Oct 5, 2022

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including... more Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.

Research paper thumbnail of GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Nature Communications, Oct 31, 2019

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates a... more Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Research paper thumbnail of Proteomic analysis of plasma identifies the Toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype

Annals of the rheumatic diseases, 2014

Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of the skin and the i... more Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of the skin and the internal organs. Except for anticentromere, antitopoisomerase I and antipolymerase III antibodies, there are no reliable circulating markers predicting susceptibility and internal organ complications. This study has exploited a proteome-wide profiling method with the aim to identify new markers to identify SSc phenotype. 40 SSc patients were included for proteomic identification. Patients were stratified as having diffuse cutaneous SSc (dcSSc) (n=19) or limited cutaneous SSc (lcSSc) (n=21) according to the extent of skin involvement. As controls 19 healthy donors were included. Blood was drawn and plasma was stored before analysing with the SELDI-TOF-MS. For replication in serum, the cohort was extended with 60 SSc patients. Proteomic analysis revealed a list of 25 masspeaks that were differentially expressed between SSc patients and healthy controls. One of the peaks was suggestive for S...

Research paper thumbnail of Development of a five-year mortality model in systemic sclerosis patients by different analytical approaches

Clinical and experimental rheumatology

Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical feat... more Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed. We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population. The NBC outperformed the Cox-based classifier and the other data mining algorithms...

Research paper thumbnail of Efficacité du nintédanib chez des patients présentant une pneumopathie interstitielle diffuse associée à la sclérodermie systémique (PID-ScS) avec atteinte des organes internes : données de l’étude SENSCIS

Revue du Rhumatisme, 2021

Research paper thumbnail of Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis

Rheumatology

Objectives The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM ... more Objectives The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. Methods This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint. Results Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated followi...

Research paper thumbnail of AB0441 NAILFOLDCAPILLAROSCOPY and Candidate Biomarker Levels in Systemic Sclerosis- Associated Pulmonary Hypertension; Profiling of Non-Invasive Markers, a Cohort Study

Annals of the Rheumatic Diseases, 2021

Systemic sclerosis (SSc) is characterized by inflammation, vasculopathy and progressive fibrosis.... more Systemic sclerosis (SSc) is characterized by inflammation, vasculopathy and progressive fibrosis. Pulmonary Hypertension (PH) is one of the leading causes of death in SSc (1). Currently, most patients with SSc are screened for the presence of PH, and focus lies on early detection and early treatment. Recent literature describes potential for both nailfoldcapillaroscopy (NCM) and several biomarkers to serve as non-invasive tools to identify SSc patients at risk for developing PH (2). Ideally this could attribute to further improvement of risk stratification in SSc and PH screenings algorithms.To explore NCM characteristics and plasma levels of selected candidate biomarkers in a cross-sectional cohort of SSc patients with and without different forms of PH.From 02-2018 until 02-2019 we included 40 consecutive SSc patients with associated PH (30 (75%) were female, 32 (80%) LcSSc, median age 72 years (IQR 69-77), median SSc duration 10.7 years (IQR 4.3-17.8), median PH duration 3.9 years...

Research paper thumbnail of SAT0313 CORRELATION Between Progression of Skin Fibrosis and Progression of Interstitial Lung Disease (Ild) in Patients with SSC-Ild: Data from the Senscis Trial

Annals of the Rheumatic Diseases, 2020

In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC over... more In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks vs placebo, with no difference between groups in change in mRSS.Analyse correlation between progression of skin fibrosis and progression of SSc-ILD in the SENSCIS trial.Patients with SSc-ILD were randomised to receive nintedanib or placebo until the last patient reached week 52 but for ≤100 weeks. We calculated Spearman correlation coefficients between FVC (mL) at baseline and change from baseline in mRSS, mRSS at baseline and change from baseline in FVC (mL), and changes from baseline in mRSS and FVC at weeks 52 and 100 in all patients. We analysed the rate of decline in FVC (mL/year) in patients who did and did not have progression of skin fibrosis (relative change from baseline in mRSS >25% and absolute change from baseline >5 points) at week 52.In the nintedanib (n=288) and placebo (n=288) groups, respectively, mean (SD) baseline FVC (mL) was 2459 (736) and 2541 (816)...

Research paper thumbnail of Treatment decision-making in diffuse cutaneous systemic sclerosis: a patient’s perspective

Rheumatology, 2019

Objectives To examine the treatment decision-making process of patients with dcSSc in the context... more Objectives To examine the treatment decision-making process of patients with dcSSc in the context of haematopoietic stem cell transplantation (HSCT). Methods A qualitative semi-structured interview study was done in patients before or after HSCT, or patients who chose another treatment than HSCT. Thematic analysis was used. Shared decision-making (SDM) was assessed with the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Results Twenty-five patients [16 male/nine female, median age 47 (range 27–68) years] were interviewed: five pre-HSCT, 16 post-HSCT and four following other treatment. Whereas the SDM-Q-9 showed the decision-making process was perceived as shared [median score 81/100 (range 49–100)], we learned from the interviews that the decision was predominantly made by the rheumatologist, and patients were often steered towards a treatment option. Strong guidance of the rheumatologist was appreciated because of a lack of accessible, reliable and SSc-specific information,...

Research paper thumbnail of Treatment with cyclophosphamide i.v. pulse therapy is an option for effective treatment of skin fibrosis in patients with early systemic sclerosis

Rheumatology, 2019

Objectives SSc is a autoimmune disease characterized by fibrosis of the skin and internal organs.... more Objectives SSc is a autoimmune disease characterized by fibrosis of the skin and internal organs. There is a lack of evidence for the efficacy of i.v. CYC pulse therapy on skin thickening. We aimed to examine the response of i.v. CYC pulse therapy on skin thickening in our cohort of SSc patients and analysed factors that predict this response. Methods We retrospectively evaluated the data for 143 patients with SSc from baseline to 12, 24 and 36 months. All patients were treated with at least 6 i.v. CYC pulses (750 mg/m2/month). We applied the modified Rodnan Skin Score (mRSS) to assess skin thickening. A clinically relevant response was defined as a decrease in mRSS of 5 points and 25% from baseline. Different baseline variables for predicting response on month 12 were tested in logistic regression analyses. Results Baseline characteristics of the patients with dcSSc and lcSSc were collected. Forty-three percent (n = 42) of dcSSc patients had a clinically relevant response on month ...

Research paper thumbnail of SAT0485 What is the effect of cyclophosphamide iv pulse therapy in patients with diffuse cutaneous systemic sclerosis on skin involvement: an observational study

Saturday, 16 JUNE 2018, 2018

SAT0485-Figure 1. mRSS course of all patients during iv CYC Conclusions: This study shows that on... more SAT0485-Figure 1. mRSS course of all patients during iv CYC Conclusions: This study shows that only 43% of the treated DcSSc patients experienced clinical important improvement of skin involvement following iv CYC. Response at month 6 is the best predictor for response on month 12. This could imply that at this time point, counselling about other available treatment options, should be considered in those patients. REFERENCES: [1] Kowal-Bielecka O, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Annals of the rheumatic diseases 2009;68 (5):620-8. [2] Namas R, et al. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: Post-hoc analyses from the Scleroderma Lung Study I and II. Arthritis care & research 2017.

Research paper thumbnail of There is a need for new systemic sclerosis subset criteria. A content analytic approach

Scandinavian journal of rheumatology, Jan 9, 2017

Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpo... more Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, howeve...

Research paper thumbnail of AB0651 The effect of cyclophosphamide on pulmonary function and dependence on disease activity of interstitial lung disease associated with systemic sclerosis

Abstracts Accepted for Publication, 2017

Of 422 SSc patients in the database, 344 patients had SSc meeting ACR criteria. 89 patients were ... more Of 422 SSc patients in the database, 344 patients had SSc meeting ACR criteria. 89 patients were exclusively ATA-positive, of which n=42 with mild disease and n=47 with severe disease. Patients with severe disease appeared to be younger (mean age 50 vs 55 yr), more often non-caucasian (51 vs 12%), with a longer time since non-Raynaud (median 4 vs 2 yr) and more often diffuse skin involvement (dcSSc;62 vs 41%), calcinosis (6 vs 0%) and weight loss (23 vs 7%). Stratification by disease duration, however revealed there are no real differences between mild en severe disease. Overall 47% of ATA+ patients in our cohort presented with mild SSc. When stratifying patients according to time of non-Raynaud, 55% of ATA+ patients presented with mild disease in the first disease duration quartile (median follow-up 0.5 years, range 0-0.8 years). In the forth disease duration quartile, according non-Raynaud time (median follow-up 12.7 years, range 8.2-44.1) the percentage with mild disease was still 27% (Figure 1). Conclusions: In our cohort, 47% of ATA-positive patients presented with mild systemic sclerosis, which could not be explained by disease duration. This suggests that solely the presence of ATA is of limited clinical relevance. Readily available sociodemographic and clinical parameters including type of skin involvement seem to have only limited value in identifying ATA patients with more severe SSc. More complex serological findings as antibody titers and fine-specifity of ATA should be defined for optimal serological subsetting.

Research paper thumbnail of Continued treatment with nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from SENSCIS-ON

Annals of the Rheumatic Diseases

ObjectivesIn the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung d... more ObjectivesIn the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo, with adverse events that were manageable for most patients. An open-label extension trial, SENSCIS-ON, is assessing safety and FVC decline during longer term nintedanib treatment.MethodsPatients who completed the SENSCIS trial or a drug–drug interaction (DDI) study of nintedanib and oral contraceptive on treatment were eligible to enter SENSCIS-ON. Adverse events and changes in FVC over 52 weeks of SENSCIS-ON were assessed in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON (‘continued nintedanib’ group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for ≤28 days in the DDI study (’initiated nintedanib’ group).ResultsThere were 197 patients in the continued nintedanib group and 247 in t...

Research paper thumbnail of The -2518A>G promoter polymorphism in the CCL2 gene is not associated with systemic sclerosis susceptibility or phenotype: Results from a multicenter study of European Caucasian patients

Human Immunology, Feb 1, 2009

A single nucleotide polymorphism (SNP) of the gene encoding monocyte chemoattractant protein-1 (M... more A single nucleotide polymorphism (SNP) of the gene encoding monocyte chemoattractant protein-1 (MCP-1, CCL2) has previously been suggested to be involved in the susceptibility of systemic sclerosis (SSc). Here we have tested whether the-2518AϾG CCL2 variant is associated with SSc susceptibility and/or phenotype using a cohort of SSc patients (n ϭ 345). Clinical data from SSc patients attending rheumatology clinics in the Netherlands and Germany was collected DNA was obtained after informed consent. The control group used (n ϭ 272) was randomly recruited from comparable geographic regions. The-2518AϾG SNP in CCL2 (rs1024611) was determined using a Taqman SNP Genotyping assay. The genotype distribution was found to be similarly distributed among SSc patients and healthy controls. In addition, no association could be detected between the genotype and the presence of antinuclear antibodies, anticentromere antibodies, and antitopoisomerase antibodies or pulmonary involvement. Our results demonstrate that the functional variant-2518AϾG of CCL2 is not implicated in the susceptibility or phenotype of SSc.

Research paper thumbnail of Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

HAL (Le Centre pour la Communication Scientifique Directe), Sep 1, 2016

Research paper thumbnail of Pharmacological treatments for SSc-ILD: Systematic review and critical appraisal of the evidence

Autoimmunity Reviews, Dec 1, 2021

Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease... more Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease (SSc-ILD), including immunosuppressive therapies, antifibrotic agents, immunomodulators and monoclonal antibodies. There is a high unmet medical need to better understand the current evidence for treatment efficacy and safety. This systematic review aims to present the existing literature on different drug treatments investigated for SSc-ILD and to critically assess the level of evidence for these drugs. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A structured literature search was performed for clinical trials and observational studies on the treatment of SSc-ILD with pharmaceutical interventions from 1 January 1990 to 15 December 2020. The quality of each reference was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. A total of 77 references were reviewed and 13 different treatments were identified. We found high-quality evidence for the use of cyclophosphamide, nintedanib, mycophenolate and tocilizumab. Therefore, we would posit that the clinical community has four valid options for treatment of SSc-ILD. Further research is mandatory to provide more evidence for the optimal treatment strategy in SSc-ILD, including the optimal time to initiate treatment, selection of patients for treatment and upfront combination therapy.

Research paper thumbnail of Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria

Journal of Clinical Epidemiology, Jun 1, 2014

Objective-Classification criteria for systemic sclerosis (SSc) are being developed. The objective... more Objective-Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to: develop an instrument for collating case-data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement between experts on the probability that cases were classified as SSc. Study Design and Setting-A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank-ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and re-ranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICC). Results-Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud's phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7) and puffy fingers (5). The ICC across experts was 0.73 (95%CI 0.58,0.86) and improved to 0.80 (95%CI 0.68,0.90). Conclusions-Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (23 to 14) and weighted. Our methods reflect the rigors of measurement science, and serves as a template for developing classification criteria.

Research paper thumbnail of Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis

JAMA, Jun 25, 2014

; for the EBMT/EULAR Scleroderma Study Group IMPORTANCE High-dose immunosuppressive therapy and a... more ; for the EBMT/EULAR Scleroderma Study Group IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit.

Research paper thumbnail of The Functional Polymorphism 844 A>G in Fc<sub>α</sub>RI <i>(CD89)</i> Does Not Contribute to Systemic Sclerosis or Rheumatoid Arthritis Susceptibility

The Journal of Rheumatology, Dec 15, 2010

Objective. To investigate the role of the Fc a RI 844 A>G functional polymorphism in the genetic ... more Objective. To investigate the role of the Fc a RI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility. Methods. The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The Fc a RI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing. Results. We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results. Conclusion. Our data show that the Fc a RI 844 A>G polymorphism is not associated with SSc or RA susceptibility.

Research paper thumbnail of Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

npj Genomic Medicine, Oct 5, 2022

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including... more Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.

Research paper thumbnail of GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Nature Communications, Oct 31, 2019

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates a... more Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Research paper thumbnail of Proteomic analysis of plasma identifies the Toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype

Annals of the rheumatic diseases, 2014

Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of the skin and the i... more Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of the skin and the internal organs. Except for anticentromere, antitopoisomerase I and antipolymerase III antibodies, there are no reliable circulating markers predicting susceptibility and internal organ complications. This study has exploited a proteome-wide profiling method with the aim to identify new markers to identify SSc phenotype. 40 SSc patients were included for proteomic identification. Patients were stratified as having diffuse cutaneous SSc (dcSSc) (n=19) or limited cutaneous SSc (lcSSc) (n=21) according to the extent of skin involvement. As controls 19 healthy donors were included. Blood was drawn and plasma was stored before analysing with the SELDI-TOF-MS. For replication in serum, the cohort was extended with 60 SSc patients. Proteomic analysis revealed a list of 25 masspeaks that were differentially expressed between SSc patients and healthy controls. One of the peaks was suggestive for S...

Research paper thumbnail of Development of a five-year mortality model in systemic sclerosis patients by different analytical approaches

Clinical and experimental rheumatology

Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical feat... more Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed. We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population. The NBC outperformed the Cox-based classifier and the other data mining algorithms...