On the road to better care for patients with systemic sclerosis

My thesis primarily focused on projects concerning the role of autoantibodies in patients with systemic sclerosis (SSc), disease outcomes, and the assessment of non-pharmacological interventions for this group. SSc is a rare and complex disease that presents challenges in both diagnosis and management. Further understanding of the role of autoantibodies in SSc would aid in risk stratification and potentially offer new treatment avenues. In the first part of my thesis, we identified possible indications for a pathogenic role of SSc-specific autoantibodies, particularly anti-topoisomerase I antibodies (ATA). Regarding disease outcomes, we gained deeper insight into the trajectory of the Health Assessment Questionnaire, disease duration and severity in SSc patients from the Leiden CCISS cohort. In the last part, we evaluated two non-pharmacologic interventions: silver fiber gloves and physical therapy. We conducted a randomized controlled cross-over trial to assess the effect of silver fiber gloves on the burden of Raynaud’s Phenomenon in SSc patients. Lastly, we evaluated the levels of physical activity in SSc patients, assessed the contents, use, and preferences of physical therapy care from the perspective of patients and their physical therapists, and proposed recommendations for improved communication between physical therapists, patients, and other healthcare providers, as well as postgraduate education on SSc for physical therapists.Nationale Vereniging voor Lupus; APS; Sclerodermie en MCTD (NVLE); Chipsoft; Boehringer IngelheimLUMC / Geneeskund

The effect and safety of exercise therapy in patients with systemic sclerosis: a systematic review

Given the shortcomings of previous literature reviews evaluating the effect and safety of exercise therapy in SSc, we aimed to carry out a systematic review of the literature specifically on this topic. A structured search strategy was performed in Medline (via PubMed) and other electronic databases from 1990 to 3 September 2019. Randomized controlled trials, observational designs, conference abstracts and trial registrations were included if they concerned SSc patients >= 18 years of age, exercise therapy and reported outcomes related to physical functioning. Nine articles were included. Four randomized controlled trials compared (a) hand exercises, (b) orofacial exercises, (c) aerobic exercises or (d) aerobic exercises plus resistance training with no exercise, demonstrating effects on hand function (a), maximum mouth opening (b), peak oxygen uptake (c+d) and quality of life. All five observational studies concerning hand, orofacial, aerobic and/or strengthening exercises reported improvements of hand function, mouth opening, aerobic capacity and/or muscle strength. In conclusion, the evidence on the effect and safety of exercise therapy in SSc is scanty

Health-related quality of life in patients with systemic sclerosis: evolution over time and main determinants

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 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.Pathophysiology and treatment of rheumatic disease

Anti-C1q autoantibodies may not serve as an adequate biomarker for lung manifestations in systemic sclerosis: a single-centre, cross-sectional study

Pathophysiology and treatment of rheumatic disease

Lung function is associated with minimal EQ-5D changes over time in patients with systemic sclerosis

In systemic sclerosis (SSc) therapeutic efforts are often directed to prevent progressive respiratory impairment, but it is unclear to what extent changes in pulmonary function tests (PFTs) are associated with health-related quality of life (HRQoL). The aim of our study is to evaluate how modifications in PFTs contribute to longitudinal variations in HRQoL, assessed through the multidimensional questionnaire EQ-5D, in patients with SSc. We included SSc patients with forced vital capacity (FVC%), diffusing capacity of the lungs for carbon monoxide (DLCO%) and EQ-5D assessed in at least two visits. The EQ-5D consists of two parts, a utility score ranging from - 0.59 to 1, and a 0-100 Visual Analogue Scale (VAS). Higher values represent better health. The association between changes in FVC% and DLCO%, and evolution of EQ-5D over time, was investigated using generalized estimating equations. Three hundred seventy-eight patients were included, accounting for a total of 1619 measurements. The models showed that improvement in FVC% is significantly associated with increase in both utility score (beta = 0.001; 95% CI 0.000 to 0.002; p = 0.003) and VAS over time (beta = 0.188; 95% CI 0.111 to 0.264; p < 0.001). Moreover, improvement in DLCO% is longitudinally associated with increase in utility score (beta = 0.001; 95% CI 0.000 to 0.002; p = 0.038), while the results for VAS were non-significant (beta = 0.020; 95% CI -0.079 to 0.120; p = 0.690). We show that change in PFTs has a significant, although minor, impact on HRQoL as measured by EQ-5D in SSc.Pathogenesis and treatment of chronic pulmonary disease

Disease progression in systemic sclerosis

Cardiolog

The long-term course of the Health Assessment Questionnaire in patients with systemic sclerosis

Objective: The Health Assessment Questionnaire-Disability Index is an important outcome measure reflecting functional disability, but knowledge on its course over time in patients with systemic sclerosis is scarce. Therefore, we investigated the long-term course of the Health Assessment Questionnaire-Disability Index and its association with baseline characteristics in systemic sclerosis patients. Methods: Systemic sclerosis patients, fulfilling the European League Against Rheumatism and the American College of Rheumatology 2013 criteria, were included from the Leiden Combined Care in Systemic Sclerosis cohort with annual assessments including the Scleroderma Health Assessment Questionnaire-Disability Index (range = 0-3). The course of the Health Assessment Questionnaire-Disability Index was evaluated over the total follow-up (baseline to last available Health Assessment Questionnaire-Disability Index) and between yearly visits. Based on a minimal clinical important difference of 0.22, courses were categorized into worsening, stable or improvement. The course of the Health Assessment Questionnaire-Disability Index over time was evaluated with linear mixed models. Baseline characteristics were compared between patients with a worsening or improvement of the Health Assessment Questionnaire-Disability Index over the total follow-up period with logistic regression analyses. Results: A total of 517 systemic sclerosis patients were included, with a median follow-up of 7 years (interquartile range = 4-9; 2649 visits) and a baseline Health Assessment Questionnaire-Disability Index of 0.625 (interquartile range = 0.125-1.25). On group level, the Health Assessment Questionnaire-Disability Index is stable with an annual increase of 0.019 (95% confidence interval = 0.011 to 0.027). Looking at subgroups, patients >65 years or who died/were physically unable to come during follow-up had a worse mean Health Assessment Questionnaire-Disability Index. In individual courses from baseline to the last follow-up, the proportions of patients with a clinically meaningful worsening, stable or improved Health Assessment Questionnaire-Disability Index were 35%, 42% and 23%, respectively. Patients with immunosuppressants (odds ratio = 0.5, 95% confidence interval = 0.3 to 0.9) or gastrointestinal involvement (odds ratio = 0.6, 95% confidence interval = 0.4 to 0.9) at baseline showed a reduced chance of worsening of the Health Assessment Questionnaire-Disability Index over the total follow-up period. Conclusion: Over time, the average course of the Health Assessment Questionnaire-Disability Index was stable in systemic sclerosis patients. However, individual courses vary, with worsening occurring in one-third. Worsening occurred less often in individuals using immunosuppressants or with gastrointestinal involvement at baseline.Pathophysiology and treatment of rheumatic disease

Step forward in early recognition of systemic sclerosis: data from the Leiden CCISS cohort

Background: Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival has changed over time. Methods: 643 SSc patients fulfilling American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria were included and categorised into three groups based on cohort-entry year: (1) 2010-2013 (n=229 (36%)), (2) 2014-2017 (n=207 (32%)) and (3) 2018-2021 (n=207 (32%)). Variables including disease duration, interstitial lung disease (ILD), digital ulcers (DU), diffuse cutaneous SSc (dcSSc), antitopoisomerase (ATA) and anticentromere (ACA) antibodies, and survival from disease onset were compared between cohort-entry groups, including analyses stratified for sex and autoantibodies. Results: Over time, duration between onset of disease symptoms and cohort entry decreased in males and females, but was always longer in females than in males.The proportion of patients presenting with DU decreased, especially in ACA+SSc patients. Almost no ACA+ patients presented with ILD, while in ATA+ patients this proportion was 25% in 2010-2013 and decreased to 19% in 2018-2021. A reduction in patients presenting with clinically meaningful ILD and dcSSc was observed.Overall 8-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Eight-year survival showed a trend for improvement over time, and was always worse in males. Conclusion: We observed a decrease in disease duration in Leiden CCISS cohort at cohort entry, possibly indicating more timely diagnosis of SSc. This could provide opportunities for early interventions. While symptom duration at presentation is longer in females, mortality is consistently higher in males, underlining the urge for sex-specific treatment and follow-up.Pathophysiology and treatment of rheumatic disease

Criteria for the pathogenicity of anticentromere (anti-CENP-B) autoantibodies in systemic sclerosis: comment on the article by van Leeuwen et al Reply

Pathophysiology and treatment of rheumatic disease

Criteria for the pathogenicity of anticentromere (anti-CENP-B) autoantibodies in systemic sclerosis: comment on the article by van Leeuwen et al Reply

Pathophysiology and treatment of rheumatic disease