Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis

Introduction: Personalized medicine is the holy grail of medicine. The EULAR recommendations for the management of rheumatoid arthritis (RA) support differential treatment between patients with baseline characteristics suggestive of a non-poor prognosis (non-PP) or poor prognosis (PP) (presence of autoantibodies, a high inflammatory activity and damage on radiographs). We aimed to determine which prognostic risk groups benefit more from initial monotherapy or initial combination therapy. Methods: 508 patients were randomized t

the contribution of sex and auto antibodies to microangiopathy assessed by nailfold videocapillaroscopy in systemic sclerosis a systematic review of the literature

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Rituximab in early systemic sclerosis

Objectives (1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc). Methods A small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated. Results In total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SS

Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis

Introduction: To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years. Methods: In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years. Results: 68% of the patients had accelerated hand BMD loss (>-0.003 g/cm(2)) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage. Conclusions: In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.Pathophysiology and treatment of rheumatic disease

Detection of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease using home monitoring in the Netherlands (DecreaSSc):a prospective, observational study

Background: In patients with systemic sclerosis, interstitial lung disease (ILD) is the leading cause of mortality. Early detection of progressive ILD associated with systemic sclerosis is warranted for timely adjustment of management strategies and improved prognosis. We aimed to investigate the validity of home spirometry to detect a decline in pulmonary function in patients with systemic sclerosis-associated ILD. Methods: DecreaSSc was a prospective, observational study done in two tertiary referral centres in the Netherlands. Eligible patients were aged 18 years or older, fulfilled the American College of Rheumatology–European Alliance of Associations for Rheumatology criteria for systemic sclerosis, had a disease duration from first non-Raynaud phenomenon symptom of 5 years or less, had high-resolution CT-confirmed diagnosis of ILD, and had a maximum immunosuppressive treatment duration of 8 weeks at baseline. Patients took weekly home spirometry measurements using a handheld spirometer for 1 year. At baseline and at semi-annual study visits, patients pulmonary function testing was done in the hospital and patients completed questionnaires on patient-reported outcome measurements. The primary outcome was the κ agreement between home and hospital measurements after 1 year to detect a decline in force vital capacity (FVC) of 5% or more, estimated using separate linear regression analyses for home-based and hospital-based FVC% predicted in individual patients. The sensitivity and specificity of home spirometry to detect an absolute decline in FVC% predicted of 5% or more was assessed using the hospital pulmonary function test as the gold standard. The longitudinal correlation between hospital and home measurements was assessed with regression analysis, whereas the cross-sectional correlation was assessed with the intraclass coefficient. People with lived experience were involved at several stages of the study. Findings: Between Jan 26, 2021, and Feb 27, 2023, 43 patients were enrolled, 35 of whom completed 6 months of follow-up and 31 of whom completed 12 months of follow-up. The last follow-up visit took place on March 28, 2024. 20 (57%) of patients were women and 15 (43%) were men; 32 (91%) were White. Mean age was 57·7 years (SD 10·7). The agreement between hospital and home measurements had a κ value of 0·40 (95% CI 0·01–0·79). The sensitivity of home spirometry to detect a decline in FVC% predicted of 5% or more was 60% (95% CI 44–76) and specificity was 87% (75–98). Regression analysis showed that the course of pulmonary function was not different between hospital and home assessment as the interaction term was not significant (–0·0003 [95% CI –0·0006 to 0·000008]; p=0·057) with a longitudinal correlation of 0·55 (95% CI 0·26–0·74; p=0·0070). The intraclass coefficient between both measurements was 0·85 (95% CI 0·73–0·92; p&lt;0·0001) at baseline, 0·84 (0·71–0·92; p&lt;0·0001) at 6 months, and 0·72 (0·50–0·86; p&lt;0·0001) at 12 months. Interpretation: Home spirometry has the potential to detect a decline in pulmonary function in patients with systemic sclerosis-associated ILD earlier when used in addition to regular health care management. Future research could reveal whether home spirometry can contribute to improved outcomes of patients with systemic sclerosis-associated ILD. </p

Requirements for systemic sclerosis expert centres in the Netherlands: A Delphi consensus study

Introduction: Systemic sclerosis is a rare and complex disease. Optimal management of patients requires knowledge and experience and, importantly, intensive collaboration between hospitals and multidisciplinary teams. Definition and recognition of expert centres in systemic sclerosis is currently lacking, which complicates collaboration between centres and leaves patients poorly informed. The aim of this study was to develop a set of requirements for two types of systemic sclerosis centres in order to establish a nationwide structure for an optimal and transparent organization of care. Methods: A three-round Delphi study was conducted among a panel of rheumatologists working at university or regional hospitals across the Netherlands. Prior to the final consensus round, a session with a patient panel (N = 22) was held. The results of this meeting were described in the last round for rheumatologists. Criteria were divided into five categories: (1) medical care, (2) case load, (3) collaboration, (4) research, (5) training of staff, and (6) other. In the first round, criteria derived from literature were proposed and participants could add criteria that were missing. For every item, participants could indicate if they thought the item should be included for two types of systemic sclerosis centres: (1) systemic sclerosis expert centre or (2) systemic sclerosis treatment centres. Consensus was reached when more than 85% of the panel agreed. Results: In total, 47 rheumatologists participated in Delphi round 1, 35 in round 2 and 43 in round 3. Additional suggestions were added by the patient panel (n = 22). Consensus was reached for the requirements of systemic sclerosis expert centres (45 items) and systemic sclerosis treatment centres (29 items) including minimal caseloads of annual suspected systemic sclerosis cases and total patients in care. Conclusion: Requirements of centres for systemic sclerosis care in the Netherlands were established in this study. Feasibility of certification should be evaluated next. Our proposed list can serve as a model for other countries

A Phase II study of avenciguat, a novel soluble guanylate cyclase activator, in patients with systemic sclerosis: Study design and rationale of the VITALISScE™ study

INTRODUCTION Systemic sclerosis is a rare autoimmune connective tissue disease characterised by (1) microvasculopathy; (2) immune dysregulation; and (3) progressive fibrosis of the skin and internal organs. Soluble guanylate cyclase plays an important role in maintaining vascular and immunological homeostasis and preventing organ fibrosis. Pharmacological modulation of soluble guanylate cyclase with soluble guanylate cyclase stimulators has shown anti-inflammatory and antifibrotic effects in animal models of systemic sclerosis, with a trend towards clinical efficacy in a Phase II study (RISE-SSc). However, the efficacy of soluble guanylate cyclase stimulators may be reduced under conditions of hypoxia and oxidative stress. Soluble guanylate cyclase activators have the potential to overcome this limitation. This paper describes the study design of VITALISScE™, a Phase II clinical trial assessing the efficacy, safety and tolerability of avenciguat, a novel soluble guanylate cyclase activator in patients with active systemic sclerosis at risk of progression. METHODS The VITALISScE™ study (NCT05559580) is evaluating the action of avenciguat on all three aspects of systemic sclerosis pathophysiology. The primary endpoint is the rate of decline in forced vital capacity (mL) over 48 weeks. Secondary endpoints include absolute change from baseline at Week 48 in modified Rodnan skin score, Health Assessment Questionnaire Disability Index score and the proportion of responders based on the revised Composite Response Index in Systemic Sclerosis. Additional endpoints include a composite assessment of Raynaud's phenomenon, digital ulcer burden, functional outcomes and quality of life, safety, pharmacokinetics, and biomarkers associated with systemic sclerosis and the mechanism of action of avenciguat. RESULTS VITALISScE™ is an ongoing, multicentre (180 sites; 38 countries), placebo-controlled, double-blind, parallel-group, Phase II clinical study. Recruitment is currently ongoing. CONCLUSIONS The VITALISScE™ study is assessing the efficacy, safety and tolerability of avenciguat in patients with active systemic sclerosis at risk of progression. Results will inform further development of avenciguat. TRIAL REGISTRATION VITALISScE™; EU CT No. 2022-500332-11-00; Clinicaltrials.gov: NCT05559580 (https://www.clinicaltrials.gov/study/NCT05559580)

Lung function and skin fibrosis changes as predictors of survival in SSc-associated interstitial lung disease: a EUSTAR study

OBJECTIVES This study assessed how changes in lung function, skin fibrosis and digital ulceration (DU) burden predict mortality in patients with SSc-associated interstitial lung disease (SSc-ILD), the leading cause of death in SSc. METHODS Adult SSc-ILD patients from the European Scleroderma Trials and Research (EUSTAR) database enrolled since January 2009 with a date of diagnosis, a follow-up visit for change evaluation within 12 months plus a further visit, or mortality information were eligible. Twelve-month changes in lung function (per cent predicted forced vital capacity [FVC%pred] and diffusing capacity of the lungs for carbon monoxide [DLCO%pred]), modified Rodnan skin score (mRSS) and change in DU burden were assessed for associations with survival, using multivariable Cox regression analyses adjusted for age, sex, smoking status and immunosuppressive therapy. RESULTS Of 893 SSc-ILD patients included, 94 (10.5%) died over a mean follow-up of 39.0 ± 23.9 months. Absolute deterioration in FVC >10%pred within 12 months (n = 78/638 evaluable) was predictive for decreased survival (hazard ratio [HR] 3.81; 95% CI 1.67-8.66), as were composite measures combining (i) >10% FVC decline or mRSS worsening (HR 2.82; 95% CI 1.43-5.56) and (ii) FVC decline ≥10% or 5-9% with DLCO decline ≥15% (HR 3.42; 95% CI 1.68-7.00), but not changes in DLCO, mRSS or DU burden alone. CONCLUSIONS Changes in lung function and skin fibrosis within 12 months should be considered when evaluating risk of mortality. The effect of pharmacological treatments aiming at stabilization of these variables should be evaluated prospectively in clinical trials

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

Systemic sclerosis : state of the art on clinical practice guidelines

Systemic sclerosis (SSc) is an orphan disease characterised by autoimmunity, fibrosis of the skin and internal organs, and vasculopathy. SSc may be associated with high morbidity and mortality. In this narrative review we summarise the results of a systematic literature research, which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines or recommendations. Only in the domains 'Vascular & Ulcers' (ie, non-pharmacological approach to digital ulcer), 'PAH' (ie, screening and treatment), 'Treatment' and 'Juveniles' (ie, evaluation of juveniles with Raynaud's phenomenon) evidence-based and consensus-based guidelines could be included. Hence there is a preponderance of unmet needs in SSc referring to the diagnosis and (non-) pharmacological treatment of several SSc-specific complications. Patients with SSc experience significant uncertainty concerning SSc-related taxonomy, management (both pharmacological and non-pharmacological) and education. Day-to-day impact of the disease (loss of self-esteem, fatigue, sexual dysfunction, and occupational, nutritional and relational problems) is underestimated and needs evaluation