Persistence of serum antiphospholipid antibodies (aPL) is associated with a high thrombotic risk, both arterial and venous, and with pregnancy complications. Due to the potential morbidity and... Show morePersistence of serum antiphospholipid antibodies (aPL) is associated with a high thrombotic risk, both arterial and venous, and with pregnancy complications. Due to the potential morbidity and mortality associated with the presence of aPL, identifying and recognizing risk factors for the development of aPL and thrombosis in aPL carriers may help to prevent and reduce the burden of disease. Multiple elements are involved in the pathomechanism of aPL development and aPL-related thrombosis such as genetics, malignancy, and infections. This review will address the role of both well-known risk factors and their evolution, and of emerging risk factors, including COVID-19, in the development of aPL and thrombosis in aPL carriers. Show less
Volkov, M.; Coppola, M.; Huizinga, R.; Eftimov, F.; Huizinga, T.W.J.; Kooi, A.J. van der; ... ; T2B Consortium 2022
The presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody... Show moreThe presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody isotype and subclass. The most prevalent isotype in serum is IgG, which is often the only isotype used in diagnostic testing. Nevertheless, autoantibody responses can have their own unique isotype/subclass profile. Because comparing autoantibody isotype profiles may yield new insights into disease pathophysiology, here we summarize the isotype/subclass profiles of the most prominent autoantibodies. Despite substantial variation between (and within) autoantibody responses, this unprecedented comparison shows that autoantibodies share distinctive isotype patterns across different diseases. Although most autoantibody responses are dominated by IgG (and mainly IgG1), several specific diseases are characterized by a predominance of IgG4. In other diseases, IgE plays a key role. Importantly, shared features of autoantibody isotype/subclass profiles are seen in clinically unrelated diseases, suggesting potentially common trajectories in response evolution, disease pathogenesis, and treatment response. Isotypes beyond IgG are scarcely investigated in many autoantibody responses, leaving substantial gaps in our understanding of the pathophysiology of autoimmune diseases. Future research should address isotype/subclass profiling in more detail and incorporate autoantibody measurements beyond total IgG in disease models and clinical studies. Show less
Liem, S.I.E.; Boonstra, M.; Cessie, S. le; Riccardi, A.; Airo, P.; Distler, O.; ... ; EUSTAR Collaborators 2022
Background We aimed to evaluate sex-specific risk of anti-topoisomerase I antibodies (ATA) on mortality, diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension... Show moreBackground We aimed to evaluate sex-specific risk of anti-topoisomerase I antibodies (ATA) on mortality, diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension in two cohorts of people with systemic sclerosis.Methods This study was a 10-year analysis of the prospective Leiden Combined Care in Systemic Sderosis (CCISS) cohort in the Netherlands and the international European Scleroderma Trials and Research (EUSTAR) cohort. We included participants with systemic sderosis according to the 2013 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) classification criteria; available autoantibody status; available skin subtyping; at least one available radiographic assessment of interstitial lung disease; and with a known date of disease onset. People with systemic sclerosis were categorised in six risk groups by sex and autoantibody status (anti-centromere antibody [ACA]-positive female, ACA-positive male, ACA and ATA-negative female, ACA and ATA-negative male, ATA-positive female, and ATA-positive male). We constructed Kaplan-Meier curves and Cox proportional hazard models, accounting for left-truncated survival to prevent bias because the date of disease onset (first non-Raynaud's symptom) preceded the date of cohort entry for all patients. The primary outcome was all-cause mortality and the secondary outcomes were diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension.Findings 445 (63%) of 708 participants between April 1,2009, and Jan 1,2022, in CCISS (101 [23%] male and 344[77%] female) and 4263 (50%) of 8590 between June 1, 2004, and March 28,2018, in EUSTAR (783[18%] male and 3480 [82%] female) were eligible for this study. In both cohorts, ATA expression occurred significantly more often in males than in females (39 [39%] of 101 males vs 67 [19%] of 344 females in CCISS; p<0.0001 and 381 [49%] of 783 males vs 1323 [38%] of 3480 females in EUSTAR; p<0. 0001). According to estimated survival rates, 30% of ATA-positive males versus 12% of ATA-positive females died in the CCISS cohort and 33% versus 15% died in the EUSTAR cohort within 10 years. After adjustment for age, race, and autoantibody status, male sex remained the most important risk factor for all-cause mortality (HR 2.9 [95% CI 1.5-5.5] in CCISS, 0.0018; and HR 2.6 [2.0-3.4] in EUSTAR, p<0.0001).Interpretation We show that the association between male sex and increased mortality in systemic sclerosis cannot be explained by higher ATA prevalence. However, additional research on the effect of sex-specific characteristics on people with systemic sclerosis is required. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Wesemael, T.J. van; Huizinga, T.W.J.; Toes, R.E.M.; Woude, D. van der 2022
Objective. To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.Methods. Daily practice... Show moreObjective. To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.Methods. Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis <45 years, 45-65 years, >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders.Results. The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of -0.02 and -0.05 DAS points and, -0.01 and 0.02 HAQ points per month in the <45 and 45-65 years age-groups as compared with the >65 year age group, a difference that did not seem clinically relevant.Conclusion. In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ. Show less
Objectives To evaluate the success rate of glucocorticoid discontinuation and to study which factors are associated with successful discontinuation.Methods Data from two treat-to-target studies,... Show moreObjectives To evaluate the success rate of glucocorticoid discontinuation and to study which factors are associated with successful discontinuation.Methods Data from two treat-to-target studies, BeSt (target Disease Activity Score (DAS) <= 2.4) and IMPROVED (target DAS <1.6), were evaluated for all patients initially treated with a tapered high dose of prednisone with conventional synthetic disease-modifying antirheumatic drugs. Prednisone was discontinued when DAS <= 2.4 was maintained for 28 weeks in BeSt and as soon as DAS was <1.6 in IMPROVED. Discontinuation was considered successful if the target was maintained at the next visit. Logistic regression analyses were performed to identify predictors of successful discontinuation. A mixed effects logistic regression model was used to assess whether primary versus secondary discontinuation was as successful.Results In the BeSt study, 40% (47 of 93) of patients flared after primary prednisone discontinuation, and of the other 60% (56 of 93), 38% had to restart later. Of those who restarted (secondary discontinuation), 47% (17 of 35) again flared. In IMPROVED, after primary discontinuation 39% (158 of 400) flared, and of the other 61% (242 of 400), 40% had to restart later. After secondary discontinuation 49% (68 of 139) flared. Only in IMPROVED a secondary attempt was less successful (BeSt OR 0.71, p=0.45; IMPROVED OR 0.60, p=0.01). A lower DAS both at baseline and stop visit and male gender (in IMPROVED) were associated with successful primary discontinuation.Conclusion Primary glucocorticoid discontinuation resulted in direct loss of disease control in approximately 40% and secondary in 50% of patients. 'Standard' baseline characteristics seem insufficient to personalise the duration of temporary glucocorticoid bridging, but the DAS at the time of discontinuation might provide guidance. Show less
Kissel, T.; Wesemael, T.J. van; Lundquist, A.; Kokkonen, H.; Kawakami, A.; Tamai, M.; ... ; Toes, R.E.M. 2021
Objectives In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if... Show moreObjectives In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if and how HRQoL changes over time, and (ii) assess how different SSc domains and functional impairments contribute to changes in HRQoL over time. Methods All SSc patients from the Leiden SSc cohort were included; patients with disease duration <24 months were classified as incident cases. HRQoL was assessed prospectively on an annual basis using the EQ-5D and the SF36. To assess baseline associations between clinical characteristics and HRQoL, linear regressions were performed. To identify possible associations between SSc characteristics and HRQoL change over time, linear mixed models were performed in both incident and prevalent cases. Results In total, 492 SSc patients were included (n = 202 incident cases), with a median follow-up duration of 3.4 years. At baseline, presence of organ involvement was independently associated with a worse SF36 physical component score and lower EQ-5D score. Over time, gastrointestinal symptoms, Raynaud and digital ulcers were independently associated with deterioration of HRQoL in both incident and prevalent cases. In prevalent cases, pulmonary arterial hypertension (PAH) was associated with a decrease in HRQoL over time. Worse functioning as measured by six-min walking distance, mouth-opening, finger-to-palm distance and grip-strength contributed significantly to deterioration of HRQoL over time. Conclusion In SSc, key clinical burdens that contribute to worsening of HRQoL over time include digital ulcers, Raynaud and gastrointestinal involvement. In addition, PAH is a significant burden in prevalent disease. Show less
Objective. Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases.... Show moreObjective. Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentrornere antibody (ACA)- and antitopoisomerase antibody (ATA)-specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc).Methods. ACA and MA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG-positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed.Results. In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43-6.60), interstitial lung disease (OR 3.41, 95% CI 1.11-10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05-17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05-4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity.Conclusion. We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc. Show less
ObjectiveWe aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018... Show moreObjectiveWe aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018.MethodsPatients visiting the tertiary referral NPSLE clinic of the Leiden University Medical Center were included. NP symptoms were attributed to SLE requiring treatment (major NPSLE) or to other and mild causes (minor/non-NPSLE). Municipal registries were checked for current status (alive/deceased). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using data from the Dutch population. Rate ratio (RR) and 95% CI were calculated using direct standardization to compare mortality between major NPSLE and minor/non-NPSLE.Results351 patients were included and 149 patients were classified as major NPSLE (42.5%). Compared with the general population, mortality was increased in major NPSLE (SMR 5.0 (95% CI: 2.6-8.5)) and minor/non-NPSLE patients (SMR 3.7 (95% CI: 2.2-6.0)). Compared with minor/non-NPSLE, mortality was similar in major NPSLE patients (RR: 1.0 (95% CI: 0.5-2.0)). Cause-specific mortality rates demonstrated an increased risk of death due to infections in both groups, whereas death due to cardiovascular disease was only increased in minor/non-NPSLE patients.ConclusionMortality was increased in both major NPSLE and minor/non-NPSLE patients in comparison with the general population. There was no difference in mortality between major NPSLE and minor/non-NPSLE patients. Show less
Bijnen, S. van; Vries-Bouwstra, J. de; Ende, C.H. van den; Boonstra, M.; Kroft, L.; Geurts, B.; ... ; Vonk, M.C. 2020
Background Autologous haematopoietic stem cell transplantation (HSCT) improves survival in systemic sclerosis (SSc) with poor prognosis, but is hampered by treatment-related mortality (TRM).... Show moreBackground Autologous haematopoietic stem cell transplantation (HSCT) improves survival in systemic sclerosis (SSc) with poor prognosis, but is hampered by treatment-related mortality (TRM). Objective To evaluate event-free survival (EFS), TRM, response to treatment, disease progression and patient characteristics associated with events.Methods All patients treated with HSCT for SSc in The Netherlands until 2017 (n=92) were included. Data on skin involvement (modified Rodnan skin score (mRSS), pulmonary function (forced vital capacity (FVC) and diffusion capacity of the lungs for carbon monoxide (DLCO)), extent of interstitial lung disease on high-resolution CT using Goh scores and left ventricular ejection fraction (LVEF) were collected at baseline, 1, 2 and 5 years. Occurrence of events, defined as death or major organ failure, were collected until 2019. As control, a comparison between patients treated with cyclophosphamide (CYC) and patients with HSCT who participated in the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial was performed.Results Median follow-up was 4.6 years. EFS estimates at 5, 10 and 15 years were 78%, 76% and 66%, respectively. Twenty deaths occurred. Mean FVC, DLCO, mRSS and Goh scores all improved significantly. Disease progression occurred in 22 patients. Frequency of TRM decreased over time and occurred more often in males. Events were independently associated with male sex, LVEF <50% and older age. In ASTIS, patients treated with HSCT (n=23) 7 events occurred versus 13 in the CYC group (n=22).Conclusion Our data confirm long-term efficacy of HSCT in improving survival, skin and lung involvement in SSc. Male sex, lower LVEF and older age at baseline were identified as risk factors for events. Show less
Rheumatoid arthritis (RA) management is driven by evidence, and new 2019 EULAR recommendations help in refining the relevant place of different disease-modifying anti-rheumatic drugs (DMARDs) in... Show moreRheumatoid arthritis (RA) management is driven by evidence, and new 2019 EULAR recommendations help in refining the relevant place of different disease-modifying anti-rheumatic drugs (DMARDs) in treatment schedules. At present, new drugs are in phase of development, mainly Janus Kinase inhibitors (JAKis), however, specific treatment strategies seem to count more than individual DMARDs in terms of treatment responses, given the substantial lack of head-to-head comparisons between specific biological (b) and targeted synthetic (ts)DMARDs, and with the general perception of a similar efficacy profile across drugs. In this setting, when reliable biomarkers able to predict treatment responses are lacking, treatment decisions are mainly driven by specific clinical or individual factors, given the recognised role of comorbidities, treatment-specific side effects, patients' preferences, and costs on drug choice. In this narrative review, the authors give their specific point of view on the management of RA, based on a critical revision of the literature published in 2019, focusing on relevant novelties and future research directions. Show less
Objective. To investigate whether systemic sclerosis (SSc) patients exposed to active tobacco smoke exhibit a different autoantibody profile or are at higher risk for severe microangiopathy... Show moreObjective. To investigate whether systemic sclerosis (SSc) patients exposed to active tobacco smoke exhibit a different autoantibody profile or are at higher risk for severe microangiopathy compared to never-smokers, and to assess differences between men and women.Methods. We performed an exploratory observational study in a cohort of SSc patients fulfilling the 2013 ACR/EULAR classification criteria. According to the smoking habit, patients were categorised as ever-smokers or never-smokers. Microvascular damage was assessed at baseline using nailfold videocapillaroscopy. The presence of SSc-specific autoantibodies was investigated.Results. The studied population was composed of 361 patients (279 women, 82 men). Of these, 208 (58%) were ever-smokers and 153 (42%) were never-smokers. Anti-centromere, anti-topoisomerase I (ATA) and anti-RNA polymerase III antibodies were found, respectively, in 90 (43%), 41 (20%), and 11 (5%) ever-smokers, and in 66 (43%), 40 (26%) and 5 (3%) never-smokers (all p>0.05). Scleroderma patterns early, active and late were present respectively in 12%, 44% and 21% of ever-smokers, and in 9%, 48%, and 29% of never-smokers (all p>0.05). In multivariable logistic regression, being a never-smoker was significantly associated with ATA positivity (OR 1.77, 95% CI 1.04-2.99, p=0.034). In the gender-based sub-cohorts, 36 (27%) female patients who never smoked were ATA positive, compared to 16 (11%) ever-smoking women (p<0.001).Conclusion. We observed a significant association between smoking history and positivity of ATA and we outlined the idea of a different effect of smoking on autoantibody expression between men and women. Show less
Kissel, T.; Schie, K.A. van; Hafkenscheid, L.; Lundquist, A.; Kokkonen, H.; Wuhrer, M.; ... ; Rantapaa-Dahlqvist, S. 2019
Objective Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable... Show moreObjective Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable domains (V-domains). Recently, we showed that N-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients.Methods ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative).Results V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG.Conclusion Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA. Show less
Leeuwen, N.M. van; Boonstra, M.; Marsan, N.A.; Ninaber, M.K.; Huizinga, T.W.J.; Vries-Bouwstra, J.K. de 2019
