Kristofer Andréasson

Objectives: The role of anticoagulation in systemic sclerosis (SSc) with precapillary pulmonary hypertension (PH) remains controversial, with conflicting evidence regarding its impact on survival, including potential harmful effects. Aiming to address this research gap, we evaluated both mortality and PH worsening in a large SSc-precapillary PH cohort, additionally accounting for SSc-specific risk factors in our analyses, to better inform individualized treatment decisions. Methods: This retrospective cohort study included SSc patients from the European Scleroderma Trials and Research database with precapillary PH confirmed by right heart catheterization (RHC). The association of oral anticoagulants (OAC) use with survival and PH worsening was assessed using Kaplan–Meier estimates and multivariable Cox regression models. To minimize confounding, propensity score matching was additionally performed. Results: Among 614 patients included, 143 (23%) received OAC at the time of RHC. At baseline, patients on OAC had worse hemodynamic parameters. No significant association was found between OAC use and survival (HR 0.983 95%CI 0.724–1.334) or PH worsening (HR 1.070 95%CI 0.811–1.412). These findings remained consistent after propensity score matching and in the subgroup of 230 SSc patients with precapillary PH without interstitial lung disease. Conclusion: In this large SSc cohort with precapillary PH, we did not observe any clinical benefit associated with OAC, neither in terms of survival nor of PH worsening. Further prospective studies are needed to determine whether specific patient subgroups may benefit from anticoagulation therapy.

Background: Bone mineral density (BMD) is compromised in patients with systemic sclerosis (SSc) compared to the background population, yet the underlying disease related factors are less known. This study evaluates SSc disease-related features and predictability for BMD along with established risk factors for low BMD in SSc patients compared to controls. Methods: The study includes 211 SSc patients, 182 women and 29 men (mean age 61 yrs, mean disease duration 9 yrs) regularly followed at the Skåne University Hospital, Lund, Sweden and 505 age- and sex-matched controls. Data collection: BMD hip and spine, BMI, SSc-features, biomarkers and potential risk factor questionnaire. Multinomial logistic regression analysis was used to calculate BMD odds ratio (OR); multiple linear regression for associations between T-score and SSc-related variables and lifestyle factors; and machine learning to fit a model to predict total hip T-score in SSc. Results: NT-proBNP and elevated CRP were independently associated with low BMD in SSc patients (p<0.001), as were diffuse cutaneous disease subtype, finger ulcers, vital lung capacity and anti-topoisomerase I antibodies (ATA). BMI, menopausal status, low physical activity and higher medication burden were associated with lower hip T-score. Predictive modeling identified BMI and NT-proBNP as the strongest determinants of hip T-score. Conclusion: This large case–control study finds elevated NT-proBNP, indicators of low-grade inflammation and of disease severity negatively associated with BMD in SSc patients, in addition to several established risk factors. This highlights the importance of BMD assessment to identify at-risk SSc patients beyond traditional risk stratification.

Patients with pulmonary arterial hypertension (PAH) experience long diagnostic delays, high functional class at diagnosis and poor prognosis. We aimed to study the differentiative and predictive value of 90 inflammatory and immunomodulatory related proteins in idiopathic and hereditary PAH (IPAH/HPAH) and systemic sclerosis‐associated PAH (SSc‐APAH). Cohort 1 comprised patients with SSc‐APAH ( n = 36), IPAH/HPAH ( n = 54) and healthy controls ( n = 55). Cohort 2 comprised SSc patients without PAH ( n = 15) and SSc‐APAH ( n = 15), with blood samples both ~6 years before, and at PAH diagnosis. This cohort was used for internal validation and to predict future development of PAH in SSc. Cohort 3 comprised connective tissue disease (CTD) APAH ( n = 19) and IPAH ( n = 20), and was used for external validation. Plasma protein levels were measured with proximity extension assay. In cohort 1, we found that higher IL‐27 differentiated PAH patients from controls (odds ratio (OR) = 1.24; area under the curve (AUC) = 0.94), whereas higher TNFRSF4 differentiated SSc‐APAH from IPAH/HPAH (OR = 1.14; AUC = 0.82), and controls (OR = 1.30; AUC = 0.99). In cohort 2, GDF‐15 and PSP‐D were higher in female SSc patients that would develop vs those that wouldn't develop PAH, and predicted PAH‐development ~6 years before diagnosis (OR = 1.24; AUC = 0.78 and 1.22; 0.73, respectively). Using equivalence testing, levels of IL‐27, GDF‐15 and PSP‐D were equivalent ( p = 0.0072, p = 0.0048 and p = 0.00076) in cohort 3 and 1. In conclusion, GDF‐15 and PSP‐D emerged as promising potential biomarkers in early screening and prediction of future PAH development in SSc, whereas IL‐27 and TNFRSF4 appeared promising in diagnosis and subtype differentiation of PAH and SSc‐APAH.

Objective: Mounting evidence supports an association between the intestinal microbiota and diverse pulmonary pathologies (ie, gut‐lung axis). Although intestinal dysbiosis is a feature of systemic sclerosis (SSc), no prior studies have investigated the relationship between intestinal microbiota and SSc‐associated interstitial lung disease (ILD) in a multinational cohort. This study aimed to characterize the intestinal microbiota of SSc‐ILD and determine whether specific bacterial species and functional pathways are associated with ILD severity. Methods: Patients with SSc with and without ILD from seven SSc Centers across five continents provided a stool sample. Shotgun metagenomic sequencing was performed using the Illumina NovaSeq 6000 to characterize microbial composition at the species level. Quantitative image analysis of high‐resolution computed tomography scans of the chest was used to measure radiologic extent of ILD (QILD). Multivariate sparse partial least squares analyses were employed to identify a species signature of ILD and to determine whether specific species and functional pathways are associated with QILD. Results: Among 285 participants (mean disease duration of 9.8 years), 62.5% had ILD. In a multivariate analysis of all participants, patients with ILD had a unique microbial signature compared to those without ILD characterized by increased abundance of candidate pathobiont species. In a subgroup of participants with SSc‐ILD (n = 103), specific bacterial species and functional pathways were associated with QILD. Conclusion: This multicenter study demonstrates that distinct intestinal bacterial species are linked to the presence and radiologic extent of ILD in SSc. These species and/or their metabolic products may influence ILD pathogenesis and represent novel treatment targets.

Objective: To evaluate the fecal metabolome in patients with early systemic sclerosis (SSc) compared with unaffected controls and to determine if altered metabolites are associated with specific bacterial genera in patients with early SSc. Methods: Stool samples and clinical data were collected from 106 patients with early SSc and 79 unaffected control patients. Targeted metabolomics was performed on fecal samples using liquid chromatography mass spectrometry, and 16S ribosomal RNA gene sequencing was used to determine the microbial composition of fecal samples. Results: Compared with unaffected controls, patients with early SSc had higher levels of nicotinamide, 5’‐methylthioadenosine, and several short‐chain fatty acids (SCFAs) including valeric acid, propionic acid, and caproic acid. Conversely, patients with early SSc had lower levels of xylonic acid, orotate, methionine sulfoxide, and sarcosine. SCFAs were associated with unique bacterial genera, several of which were more abundant in patients with SSc compared with unaffected controls. Conclusion: The fecal metabolome is altered in patients with early SSc, with a shift toward increased SCFAs.

Background: In axial spondyloarthritis (axSpA), 5–10% of patients have comorbid inflammatory bowel disease (IBD). Beyond that, 50–60% display histologic inflammation in ileum/colon biopsies, and fecal calprotectin (F-calprotectin) is elevated in relation to healthy controls. Prior studies have shown such, often subclinical, gut inflammation in axSpA to be associated with more active disease, as measured by clinical indices as well as magnetic resonance imaging – both known risk factors for structural spinal damage development. In light of this, in the current study we aimed to examine whether gut inflammation, assessed by F-calprotectin, is associated with more structural spinal damage in axSpA. Methods: Patients with well-characterized non-radiographic or radiographic axSpA (nr-axSpA/r-axSpA; n = 76/152), according to ASAS or modified New York criteria, enrolled in a population-based cohort study in southern Sweden, were assessed for structural spinal damage (modified Stoke ankylosing spondylitis spinal score [mSASSS]) and gut inflammation (F-calprotectin). mSASSS values were compared between patients with normal (< 50 mg/kg), moderately elevated (50–149 mg/kg) or distinctly elevated (≥ 150 mg/kg) F-calprotectin, reflecting no/some/evident gut inflammation, respectively (one-way ANOVA). Moreover, logistic regression was applied to explore if elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, adjusted for sex, symptom duration, HLA-B27 status, smoking, CRP, NSAID and anti-TNF therapy. Analyses limited to r-axSpA were also performed. Results: In both axSpA patients overall and separately in r-axSpA, mSASSS distributions differed significantly between subjects with normal/moderately/distinctly elevated F-calprotectin, with more damage observed in those with higher F-calprotectin levels. Furthermore, elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, in both the entire axSpA group (adjusted odds ratio [OR] 2.2 [95%CI 1.1–4.2]); and in r-axSpA alone (adjusted OR 2.9 [1.2–7.1]). Conclusion: In the current study, the presence of gut inflammation, assessed by F-calprotectin, was cross-sectionally associated with more structural damage in the spine in patients with axSpA, even after adjustments for known risk factors for spinal damage. Prospective studies are, however, needed to investigate whether gut inflammation may be a predictor of spinal radiographic progression in axSpA.

Objectives: (1) To assess the risk of haematological malignancies in individuals with systemic sclerosis (SSc) compared with individuals without SSc; (2) to explore how the risk varies across groups stratified by sex and age; and (3) to determine when these malignancies present in relation to SSc diagnosis in a population-based setting. Methods: We performed a nationwide cohort study using high-quality administrative healthcare registers covering virtually all Swedish residents. All individuals with SSc diagnosed during 2004–2019 and matched general population comparators were included. We identified all haematological malignancies in the study population using the Swedish Cancer Register and estimated the incidence rates using Poisson regression and the HRs using flexible parametric models. We stratified by sex and age and explored the incidence over time since SSc diagnosis. Results: We observed 1720 individuals with incident SSc and 16 983 comparators for 11 480 and 131 021 person-years, respectively. Individuals with SSc had a higher risk of haematological malignancies compared with individuals without SSc (HR 2.2, 95% CI 1.4 to 3.1), especially B-cell malignancies (HR 3.0, 95% CI 1.7 to 4.8). The incidence rate and the HR were highest in men. The SSc over-representation of haematological malignancies was most evident in individuals aged 18–49 years at SSc diagnosis. Myeloid malignancies presented around SSc diagnosis (median 0.1 (IQR 8.2) years after SSc diagnosis) while lymphoid malignancies presented a few years later (median 3.1 (IQR 9.5)). Conclusion: Individuals with SSc are afflicted by an increased risk of haematological malignancies, especially B-cell malignancies. The risk is highest in men. Myeloid malignancies tend to present closer to SSc diagnosis than lymphoid malignancies.