Systemic Sclerosis: Results from a multicenter survey of Norwegian patients

Systemic sclerosis (SSc) is a serious multiorgan disease, characterized by progressive fibrosis, vasculopathy and distinct serum auto antibodies (1, 2). Patients with SSc have an increased mortality risk and reduced quality of life (3-5). Interstitial lung disease (ILD) is a common manifestation in SSc and the leading cause of morbidity and mortality in the SSc population (3, 6). Classification of SSc was done with the 1980 American College of Rheumatology (ACR) classification criteria until 2013, when EULAR and ACR launched unified new classification criteria for SSc (7, 8). The aim of the study was to estimate the prevalence of SSc in Norway, investigate survival and causes of deaths and to study fibrosis progression and lung function by serial assessments of high resolution computed tomography (HRCT) and concurrent pulmonary function tests (PFT). Additionally, we wanted to confirm the true value of the 2013 ACR/EULAR classification criteria for SSc. We found a prevalence of SSc in Norway of 9.9/100 000, a value comparable to other Northern European countries, supporting the notion of a north-south gradient of SSc in Europe with the lowest prevalence in Northern Europe. Our data show that mortality in SSc is still increased compared to the background population and the major causes of death are pulmonary hypertension (PH) and ILD. When studying lung fibrosis and lung function in serial assessments, we demonstrate that a normal baseline HRCT was highly predictive against later fibrosis development, and that HRCT findings at baseline predicted fibrosis progression rates and the deterioration rates of pulmonary function. Male gender, SSc subtype, antibodies, baseline fibrosis and baseline lung function were main risk factors for fibrosis development and progression. The 2013 ACR/EULAR SSc criteria performed remarkably well in our cohort and the sensitivity was significantly better than the ACR1980 criteria using the combination of the ACR 1980 criteria and/or the Leroy & Medsger criteria as the “gold standard” for SSc. Our results reinforce the view that SSc is a rare but serious disease with increased morbidity and mortality and that pulmonary disease is a devastating complication. Our data support the notion that the 2013 ACR/EULAR criteria are a major step forward and that their application should improve the quality of clinical and epidemiological SSc research in the years to come

Preclinical/subclinical rheumatoid arthritis-associated interstitial lung disease: misleading terms with potentially deleterious consequences

Interstitial lung disease (ILD) is a leading cause of mortality in patients with rheumatic diseases, including rheumatoid arthritis. The 5-year mortality rate is twice as high in patients with rheumatoid arthritis-associated ILD than in patients with rheumatoid arthritis without ILD. Moreover, a report showed that mortality rates in patients with disease codes for rheumatoid arthritis-associated ILD remained unchanged from 2005–18, even though the overall rheumatoid arthritis mortality rate declined during this time period. Despite the evidence that ILD contributes to premature death in rheumatoid arthritis, screening for ILD in patients with rheumatoid arthritis is not routinely performed in clinical practice and numerous questions remain regarding the management of rheumatoid arthritis-associated ILD

Modeling Complex Disease Trajectories using Deep Generative Models with Semi-Supervised Latent Processes

In this paper, we propose a deep generative time series approach using latent temporal processes for modeling and holistically analyzing complex disease trajectories. We aim to find meaningful temporal latent representations of an underlying generative process that explain the observed disease trajectories in an interpretable and comprehensive way. To enhance the interpretability of these latent temporal processes, we develop a semi-supervised approach for disentangling the latent space using established medical concepts. By combining the generative approach with medical knowledge, we leverage the ability to discover novel aspects of the disease while integrating medical concepts into the model. We show that the learned temporal latent processes can be utilized for further data analysis and clinical hypothesis testing, including finding similar patients and clustering the disease into new sub-types. Moreover, our method enables personalized online monitoring and prediction of multivariate time series including uncertainty quantification. We demonstrate the effectiveness of our approach in modeling systemic sclerosis, showcasing the potential of our machine learning model to capture complex disease trajectories and acquire new medical knowledge.Comment: Extended Abstract presented at Machine Learning for Health (ML4H) symposium 2023, December 10th, 2023, New Orleans, United States, 23 page

Identifying unmet needs in SSc-ILD by semi-qualitative in-depth interviews

Objectives Interstitial lung disease is frequent in SSc (SSc-ILD) and associates with significantly reduced quality of life. Here we aimed to analyse patient pathways, and experiences of patients and healthcare providers (HCPs) in order to identify unmet needs in the management of SSc-ILD patients. Methods Semi-structured qualitative interviews conducted in eight European countries looked at HCP (n = 95) and patient perspectives (n = 47) using two sets of 70 research questions. Pre-diagnostic, diagnostic and post-diagnostic phases of the patient pathway were systematically explored. Results (i) In the pre-diagnostic phase several gaps were identified by HCPs and patients in all participating countries: limited disease knowledge among primary care physicians and specialists, lack of accurate patient information, and delayed and/or inappropriate referral. (ii) The diagnostic phase is in most countries coordinated by rheumatologists, who are also the main point of care. Depending on the local health system, organization of multidisciplinary collaboration varies. HCPs issued lack of national guidelines, while patients stated difficulties obtaining disease-related information. (iii) In the post-diagnostic phase, HCPs and patients indicated lack of curative treatment, specialized nurses, and paramedical and psychological support. Patients and caregivers additionally expressed the need for clear information on SSc-ILD. Conclusion Lack of disease specific knowledge, gaps in national healthcare systems and insufficient information and support for patients and caregivers were identified as unmet needs to ensure timely diagnosis, provide better patient management and to improve quality of life in SSc-ILD patients.Peer reviewe

Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts.

ObjectiveTo compare faecal microbial composition in patients with systemic sclerosis (SSc) from 2 independent cohorts with controls and to determine whether certain genera are associated with SSc-gastrointestinal tract (GIT) symptoms.DesignAdult patients with SSc from the University of California, Los Angeles (UCLA) and Oslo University Hospital (OUH) and healthy controls participated in this study (1:1:1). All participants provided stool specimens for 16S rRNA sequencing. Linear discriminant analysis effect size demonstrated genera with differential expression in SSc. Differential expression analysis for sequence count data identified specific genera associated with GIT symptoms as assessed by the GIT 2.0 questionnaire.ResultsThe UCLA-SSc and OUH-SSc cohorts were similar in age (52.1 and 60.5 years, respectively), disease duration (median (IQR): 6.6 (2.5-16.4) and 7.0 (1.0-19.2) years, respectively), gender distribution (88% and 71%, respectively), and GIT symptoms (mean (SD) total GIT 2.0 scores of 0.7 (0.6) and 0.6 (0.5), respectively). Principal coordinate analysis illustrated significant microbial community differences between SSc and controls (UCLA: p=0.001; OUH: p=0.002). Patients with SSc had significantly lower levels of commensal genera deemed to protect against inflammation, such as Bacteroides (UCLA and OUH), Faecalibacterium (UCLA), Clostridium (OUH); and significantly higher levels of pathobiont genera, such as Fusobacterium (UCLA), compared with controls. Increased abundance of Clostridium was associated with less severe GIT symptoms in both cohorts.ConclusionsThe present analysis detected specific aberrations in the lower GIT microbiota of patients with SSc from 2 geographically and ethnically distinct cohorts. These findings suggest that GIT dysbiosis may be a pathological feature of the SSc disease state

Effects of nintedanib in patients with limited cutaneous systemic sclerosis and interstitial lung disease

OBJECTIVES: To investigate the course of interstitial lung disease (ILD) and the effects of nintedanib in patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib or placebo. Patients who completed the SENSCIS trial were eligible to enter SENSCIS-ON, in which all patients received open-label nintedanib. RESULTS: Among 277 patients with lcSSc treated in the SENSCIS trial, the rate (SE) of decline in FVC (mL/year) over 52 weeks was -74.5 (19.2) in the placebo group and -49.1 (19.8) in the nintedanib group (difference: 25.3 [95% CI -28.9, 79.6]). Among 249 patients with data at week 52, mean (SE) changes in FVC at week 52 were -86.4 (21.1) mL in the placebo group and -39.1 (22.2) mL in the nintedanib group. Among 183 patients with lcSSc who participated in SENSCIS-ON and had data at week 52, mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were -41.5 (24.0) mL in patients who took placebo in the SENSCIS trial and initiated nintedanib in SENSCIS-ON and -45.1 (19.1) mL in patients who took nintedanib in the SENSCIS trial and continued it in SENSCIS-ON. CONCLUSION: Patients with lcSSc may develop progressive fibrosing ILD. By targeting pulmonary fibrosis, nintedanib slows decline in lung function in patients with lcSSc and ILD. TRIAL REGISTRATION: ClinicalTrials.gov (https://www.clinicaltrials.gov), NCT02597933 and NCT03313180

Effect of nintedanib in patients with systemic sclerosis-associated interstitial lung disease and risk factors for rapid progression

OBJECTIVE: To investigate the rate of decline in forced vital capacity (FVC), and the effect of nintedanib on the rate of decline in FVC, in subjects with systemic sclerosis-associated interstitial lung disease (SSc-ILD) who had risk factors for rapid decline in FVC. METHODS: The SENSCIS trial enrolled subjects with SSc and fibrotic ILD of ≥10% extent on high-resolution CT. The rate of decline in FVC over 52 weeks was analysed in all subjects and in those with early SSc (<18 months since first non-Raynaud symptom), elevated inflammatory markers (C reactive protein ≥6 mg/L and/or platelets ≥330×109/L) or significant skin fibrosis (modified Rodnan skin score (mRSS) 15-40 or mRSS ≥18) at baseline. RESULTS: In the placebo group, the rate of decline in FVC was numerically greater in subjects with <18 months since first non-Raynaud symptom (-167.8 mL/year), elevated inflammatory markers (-100.7 mL/year), mRSS 15-40 (-121.7 mL/year) or mRSS ≥18 (-131.7 mL/year) than in all subjects (-93.3 mL/year). Nintedanib reduced the rate of FVC decline across subgroups, with a numerically greater effect in patients with these risk factors for rapid FVC decline. CONCLUSION: In the SENSCIS trial, subjects with SSc-ILD who had early SSc, elevated inflammatory markers or extensive skin fibrosis had a more rapid decline in FVC over 52 weeks than the overall trial population. Nintedanib had a numerically greater effect in patients with these risk factors for rapid ILD progression

Therapeutic management of fibrosis in systemic sclerosis patients - an analysis from the Swiss EUSTAR cohort

OBJECTIVES Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. METHODS Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. RESULTS A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. CONCLUSION Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported

Sex-specific difference in cardiac function in patients with systemic sclerosis: association with cardiovascular outcomes

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 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 (χ$^{2}$=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

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension

Introduction: Systemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21. Materials and methods: To investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS). Results: By IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p<0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p<0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail. Conclusion: This study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally, in vivo generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH