Background Cardiovascular involvement is one of the leading causes of mortality in systemic sclerosis (SSc) and is reported to be higher in men as compared with women. However, the cause of this... Show moreBackground Cardiovascular involvement is one of the leading causes of mortality in systemic sclerosis (SSc) and is reported to be higher in men as compared with women. However, the cause of this difference is largely unknown. The objective of this study was to assess sex differences in echocardiographic characteristics, including left ventricular global longitudinal strain (LV GLS), as a potential explanation of sex differences in outcomes.Methods A total of 746 patients with SSc from four centres, including 628 (84%, 54±13 years) women and 118 (16%, 55±15 years) men, were evaluated with standard and advanced echocardiographic examinations. The independent association of the echocardiographic parameters with the combined endpoint of cardiovascular events-hospitalisation/death was evaluated.Results Men and women with SSc showed significant differences in disease characteristics and cardiac function. After adjusting for the most important clinical characteristics, while LV ejection fraction and diastolic function were not significantly different anymore, men still presented with more impaired LV GLS as compared with women (−19% (IQR −20% to −17%) vs −21% (IQR: −22% to −19%), p<0.001). After a median follow-up of 48 months (IQR: 26–80), the combined endpoint occurred in 182 patients. Men with SSc experienced higher cumulative rates of cardiovascular events-hospitalisation/mortality (χ2=8.648; Log-rank=0.003), and sex differences were maintained after adjusting for clinical confounders, but neutralised when matching the groups for LV GLS.Conclusion In patients with SSc, male sex is associated with worse cardiovascular outcomes even after adjusting for important clinical characteristics. LV GLS was more impaired in men as compared with women and potentially explains the sex difference in cardiovascular outcomes. Show less
Objectives Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with... Show moreObjectives Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these phenotypes are ill-defined. To understand how B cell autoreactivity and disease pathology connect, we determined phenotypic and functional characteristics of autoreactive B cells in ATA-positive and ACA-positive patients.Methods Levels and isotypes of autoantibodies secreted by ex vivo cultured peripheral blood mononuclear cells from patients with ATA-positive (n=22) and ACA-positive (n=20) SSc were determined. Antibody secreting cells (ASCs) were isolated by cell sorting and cultured separately. Correlations were studied between the degree of spontaneous autoantibody production and the presence and degree of interstitial lung disease (ILD).Results Circulating B cells secreting either ATA-immunoglobulin G (IgG) or ACA-IgG on stimulation was readily detectable in patients. The ATA response, but not the ACA response, showed additional secretion of autoreactive IgA. ATA-IgG and ATA-IgA were also secreted spontaneously. Additional cell sorting confirmed the presence of ATA-secreting plasmablasts. The degree of spontaneous ATA-secretion was higher in patients with ILD than in those without (p<0.001) and correlated with the degree of pulmonary fibrosis (p<0.001).Conclusion In contrast to ACA-positive patients, ATA-positive patients show signs of recent activation of the B cell response that hallmarks this disease. The degree of activation correlates with the presence and severity of ILD, the most deleterious disease manifestation. This could explain differential responsiveness to B cell depleting therapy. The abundant and spontaneous secretion of ATA-IgG and ATA-IgA may point toward a continuously activating trigger. Show less
Objectives Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with... Show moreObjectives Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these phenotypes are ill-defined. To understand how B cell autoreactivity and disease pathology connect, we determined phenotypic and functional characteristics of autoreactive B cells in ATA-positive and ACA-positive patients.Methods Levels and isotypes of autoantibodies secreted by ex vivo cultured peripheral blood mononuclear cells from patients with ATA-positive (n=22) and ACA-positive (n=20) SSc were determined. Antibody secreting cells (ASCs) were isolated by cell sorting and cultured separately. Correlations were studied between the degree of spontaneous autoantibody production and the presence and degree of interstitial lung disease (ILD).Results Circulating B cells secreting either ATA-immunoglobulin G (IgG) or ACA-IgG on stimulation was readily detectable in patients. The ATA response, but not the ACA response, showed additional secretion of autoreactive IgA. ATA-IgG and ATA-IgA were also secreted spontaneously. Additional cell sorting confirmed the presence of ATA-secreting plasmablasts. The degree of spontaneous ATA-secretion was higher in patients with ILD than in those without (p<0.001) and correlated with the degree of pulmonary fibrosis (p<0.001).Conclusion In contrast to ACA-positive patients, ATA-positive patients show signs of recent activation of the B cell response that hallmarks this disease. The degree of activation correlates with the presence and severity of ILD, the most deleterious disease manifestation. This could explain differential responsiveness to B cell depleting therapy. The abundant and spontaneous secretion of ATA-IgG and ATA-IgA may point toward a continuously activating trigger. Show less
Monahan, R.C.; Voorde, L.J.J. van de; Fronczek, R.; Bresser, J. de; Eikenboom, J.; Kloppenburg, M.; ... ; Steup-Beekman, G.M. 2023
Background: The short-term and long-term outcome of inflammatory neuropsychiatric SLE (NPSLE) with immunosuppressive treatment is largely unknown. We used clinical data from our tertiary referral... Show moreBackground: The short-term and long-term outcome of inflammatory neuropsychiatric SLE (NPSLE) with immunosuppressive treatment is largely unknown. We used clinical data from our tertiary referral centre for NPSLE to investigate the type of inflammatory NPSLE manifestations, type of immunosuppressive treatment prescribed for these manifestations and clinical outcomes. Methods: All patients with SLE visiting the Leiden University Medical Centre NPSLE clinic between 2007 and 2021 receiving immunosuppressive therapy for neuropsychiatric symptoms were included. Clinical, immunological and radiological information was collected in as standardised way during a 1-day multidisciplinary assessment. In a multidisciplinary consensus meeting, the presence of NPSLE and the type of NPSLE manifestations and treatment were determined. For this study, short-term (0-6 months) and long-term outcomes (7-24 months) of the NP symptoms were assessed by two independent readers and scored on a 7-point Likert scale, ranging from death to resolved. Results: In total, 95 out of 398 (24%) patients visiting the NPSLE clinic between 2007 and 2021 received any form of immunosuppressive treatment for 101 separate NPSLE events. The most common NP manifestation was cognitive dysfunction (50%) as identified by formal cognitive assessment, often present in combination with other NPSLE manifestations. Treatment modalities were induction (24%), induction and maintenance (73%) and other therapy (3%). The treatments mostly consisted of (combinations of) prednisone (97%), methylprednisolone (53%), azathioprine (generally 2 mg/kg daily) (49%) and cyclophosphamide (generally induction 750 mg/m(2) every 4 weeks for 24 weeks or 500mg biweekly for 12 weeks) (42%). Short-term outcome showed improvement on the Likert scale in 73% (improved: 22%, much improved: 29%, resolved: 22%), no change in 21% and worsening in 6% of patients. Long-term outcome was available for 78 out of 101 events and showed improvement in 70% (improved: 14%, much improved: 28%, resolved: 28%), no change in 17%, worsening in 10% and death in 3% of patients (none directly NPSLE-related). Conclusion: The outcome of inflammatory NPSLE after immunosuppressive treatment is generally good, with improvement of neuropsychiatric symptoms occuring in approximately 70% of events. Show less
Monahan, R.C.; Voorde, L.J.J. van de; Fronczek, R.; Bresser, J. de; Eikenboom, J.; Kloppenburg, M.; ... ; Steup-Beekman, G.M. 2023
Background The short-term and long-term outcome of inflammatory neuropsychiatric SLE (NPSLE) with immunosuppressive treatment is largely unknown. We used clinical data from our tertiary referral... Show moreBackground The short-term and long-term outcome of inflammatory neuropsychiatric SLE (NPSLE) with immunosuppressive treatment is largely unknown. We used clinical data from our tertiary referral centre for NPSLE to investigate the type of inflammatory NPSLE manifestations, type of immunosuppressive treatment prescribed for these manifestations and clinical outcomes.Methods All patients with SLE visiting the Leiden University Medical Centre NPSLE clinic between 2007 and 2021 receiving immunosuppressive therapy for neuropsychiatric symptoms were included. Clinical, immunological and radiological information was collected in as standardised way during a 1-day multidisciplinary assessment. In a multidisciplinary consensus meeting, the presence of NPSLE and the type of NPSLE manifestations and treatment were determined. For this study, short-term (0–6 months) and long-term outcomes (7–24 months) of the NP symptoms were assessed by two independent readers and scored on a 7-point Likert scale, ranging from death to resolved.Results In total, 95 out of 398 (24%) patients visiting the NPSLE clinic between 2007 and 2021 received any form of immunosuppressive treatment for 101 separate NPSLE events. The most common NP manifestation was cognitive dysfunction (50%) as identified by formal cognitive assessment, often present in combination with other NPSLE manifestations. Treatment modalities were induction (24%), induction and maintenance (73%) and other therapy (3%). The treatments mostly consisted of (combinations of) prednisone (97%), methylprednisolone (53%), azathioprine (generally 2 mg/kg daily) (49%) and cyclophosphamide (generally induction 750 mg/m2 every 4 weeks for 24 weeks or 500mg biweekly for 12 weeks) (42%). Short-term outcome showed improvement on the Likert scale in 73% (improved: 22%, much improved: 29%, resolved: 22%), no change in 21% and worsening in 6% of patients. Long-term outcome was available for 78 out of 101 events and showed improvement in 70% (improved: 14%, much improved: 28%, resolved: 28%), no change in 17%, worsening in 10% and death in 3% of patients (none directly NPSLE-related).Conclusion The outcome of inflammatory NPSLE after immunosuppressive treatment is generally good, with improvement of neuropsychiatric symptoms occuring in approximately 70% of events. Show less
Monahan, R.C.; Beukel, M.D. van den; Borggreven, N.V.; Fronczek, R.; Huizinga, T.W.J.; Kloppenburg, M.; ... ; Trouw, L.A. 2022
Background Although autoantibodies are an important hallmark of systemic lupus erythematosus (SLE), most are not specific for SLE or any of its clinical manifestations. Autoantibodies against post... Show moreBackground Although autoantibodies are an important hallmark of systemic lupus erythematosus (SLE), most are not specific for SLE or any of its clinical manifestations. Autoantibodies against post-translationally modified (PTM) proteins have been studied extensively in rheumatoid arthritis and associate with disease progression. While PTMs have also been detected in patients with SLE, studies on anti-PTM antibodies remain scarce. We studied the presence of anti-PTM antibodies in SLE and neuropsychiatric SLE (NPSLE), a manifestation that lacks serological markers. Methods IgG antibody responses against six PTMs (malondialdehyde-acetaldehyde adducts (MAA), advanced glycation end-products (AGE), carbamylation (CarP), citrullination, acetylation and nitration) were tested using ELISA in sera of 349 patients with SLE (mean age 44 +/- 13 years; 87% female) and compared with 108 healthy controls. Levels and positivity were correlated with clinical features and SLE manifestations. Results Anti-MAA, anti-AGE and anti-CarP antibodies were more prevalent in SLE compared with controls (MAA: 29% vs 3%, AGE: 18% vs 4%, CarP: 14% vs 5%, all p <= 0.0001). Anti-MAA and anti-AGE antibodies correlated with clinical manifestations and serological inflammatory markers. Patients with major NPSLE showed higher positivity of anti-MAA (39% vs 24%, p=0.01) and anti-CarP antibodies (20% vs 11%, p=0.04) than patients without major NPSLE. In addition, anti-PTM antibody levels correlated with brain volumes, an objective measure of nervous system involvement. Conclusions In our NPSLE cohort, a subset of patients with SLE have anti-PTM antibodies against MAA, AGE and CarP modified proteins. Interestingly, anti-MAA and anti-CarP were more prevalent in NPSLE, a manifestation for which no biomarkers exist. Show less
Monahan, R.C.; Inglese, F.; Middelkoop, H.; Buchem, M. van; Huizinga, T.W.J.; Kloppenburg, M.; ... ; Bresser, J. de 2021
Objective To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter... Show moreObjective To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter hyperintensity (WMH) volumes. Methods Patients attending the Leiden University Medical Centre NPSLE clinic between 2007 and 2015 without large brain infarcts were included (n=151; 42 +/- 13 years, 91% women). In a multidisciplinary consensus meeting, neuropsychiatric symptoms were attributed to systemic lupus erythematosus (SLE) (NPSLE, inflammatory (n=24) or ischaemic (n=12)) or to minor/non-NPSLE (n=115). Multiple regression analyses were performed to compare cognitive function between NPSLE phenotypes and to assess associations between brain and WMH volumes and cognitive function cross-sectionally. Results Global cognitive function was impaired in 5%, learning and memory (LM) in 46%, executive function and complex attention (EFCA) in 39% and psychomotor speed (PS) in 46% of all patients. Patients with inflammatory NPSLE showed the most cognitive impairment in all domains (p <= 0.05). Higher WMH volume associated with lower PS in the total group (B: -0.14 (95% CI -0.32 to -0.02)); especially in inflammatory NPSLE (B: -0.36 (95% CI -0.60 to -0.12). In the total group, lower total brain volume and grey matter volume associated with lower cognitive functioning in all domains (all: 0.00/0.01 (0.00;0.01)) and lower white matter volume associated with lower LM, EFCA and PS (all: 0.00/0.01 (0.00;0.01)). Conclusion We demonstrated that an association between brain and WMH volumes and cognitive function is present in patients with SLE, but differs between (NP)SLE phenotypes. WMHs associated with PS especially in inflammatory NPSLE, which suggests a different, potentially more severe underlying pathophysiological mechanism of cognitive impairment in this phenotype. Show less
Leeuwen, N.M. van; Maurits, M.; Liem, S.; Ciaffi, J.; Marsan, N.A.; Ninaber, M.; ... ; Vries-Bouwstra, J. de 2021
Objectives To develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity. Methods A machine learning approach was used to... Show moreObjectives To develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity. Methods A machine learning approach was used to develop a model that can identify patients without disease progression. SSc patients included in the prospective Leiden SSc cohort and fulfilling the ACR/EULAR 2013 criteria were included. Disease progression was defined as progression in >= 1 organ system, and/or start of immunosuppression or death. Using elastic-net-regularisation, and including 90 independent clinical variables (100% complete), we trained the model on 75% and validated it on 25% of the patients, optimising on negative predictive value (NPV) to minimise the likelihood of missing progression. Probability cutoffs were identified for low and high risk for disease progression by expert assessment. Results Of the 492 SSc patients (follow-up range: 2-10 years), disease progression during follow-up was observed in 52% (median time 4.9 years). Performance of the model in the test set showed an AUC-ROC of 0.66. Probability score cutoffs were defined: low risk for disease progression (<0.197, NPV:1.0; 29% of patients), intermediate risk (0.197-0.223, NPV:0.82; 27%) and high risk (>0.223, NPV:0.78; 44%). The relevant variables for the model were: previous use of cyclophosphamide or corticosteroids, start with immunosuppressive drugs, previous gastrointestinal progression, previous cardiovascular event, pulmonary arterial hypertension, modified Rodnan Skin Score, creatine kinase and diffusing capacity for carbon monoxide. Conclusion Our machine-learning-assisted model for progression enabled us to classify 29% of SSc patients as 'low risk'. In this group, annual assessment programmes could be less extensive than indicated by international guidelines. Show less
Kerschbaumer, A.; Smolen, J.S.; Nash, P.; Doerner, T.; Dougados, M.; Fleischmann, R.; ... ; Heijde, D. van der 2020
Objectives Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs). Methods A systematic literature research (SLR) of all publications on JAK... Show moreObjectives Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs). Methods A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library. Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation. Results 3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13). Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated. Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included. Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn's disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA). Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events. No increased malignancy rates or major adverse cardiac events were observed. Conclusion JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence. Show less
