Jacob M. van Laar

BACKGROUND Difficult-to-treat (D2T) rheumatoid arthritis (RA) remains a major clinical challenge, with limited tools to personalize management strategies in routine care. OBJECTIVE The STRATA-FIT project aims to develop and validate computational models to identify and stratify D2T RA into clinically meaningful phenotypes, predict which patients are at high risk of developing D2T RA, and evaluate a patient-tailored treatment strategy supported by an artificial intelligence (AI)-based decision aid. METHODS STRATA-FIT (Stratification of Rheumatoid Arthritis: compuTational models to personalize mAnagement strategies for difFIcult-to-Treat disease) is a European multicenter real-world (RW) cohort study using a federated learning (FL) approach complemented with a prospective cross-over clinical pilot study evaluating the developed personalized treatment strategies for D2T RA patients compared to usual care. Six expert rheumatology centers across Europe (Netherlands, Portugal, Germany, Sweden, Austria, Hungary) will contribute to the cohort, using data from electronic health records (EHRs) and two established RA registries. Approximately 14,000 RA patients with up to 15 years of follow-up are included in the RW cohort, while 263 patients with D2T RA will be enrolled in the prospective clinical pilot study. RESULTS For the RW cohort, the primary outcome is identification and phenotypic stratification of D2T RA according to the EULAR definition. For the clinical pilot study, the primary outcome is change in health-related quality of life (EQ-5D-5L) over 12 months; secondary outcomes include feasibility and usability of the AI-based decision aid, disease activity, physical function, radiographic progression, adherence, and work productivity. Stage I establishes a federated RW RA cohort using the privacy-preserving Personal Health Train infrastructure and three computational models. Stage II translates the identification and stratification models into a proof-of-concept decision aid evaluated in ACCESS-STRATA, comprising a 12-month observational and 12-month intervention phase. Biomarker analyses on biobanked samples will further explore mechanisms underlying D2T RA. The federated learning infrastructure has been implemented in five of the six participating centers. As of September 2026, 12 participants have been enrolled. This protocol describes the STRATA-FIT study design, computational modeling strategy, and planned analyses. CONCLUSIONS STRATA-FIT will provide evidence on the use of computational models to identify D2T RA, stratify patients into clinically relevant phenotypes, and predict which patients are at increased risk of developing D2T RA. The prospective ACCESS-STRATA study will provide pilot evidence on the feasibility and potential clinical utility of translating these models into an AI-supported decision aid for personalized management. Findings will inform further model refinement and validation and the design of larger studies evaluating implementation and clinical impact in routine rheumatology care. CLINICALTRIAL NL-OMON58205 (ACCESS-STRATA-I)

Objectives: In rheumatoid arthritis (RA) patients with an insufficient response to conventional synthetic DMARDs (csDMARDs), both biologic DMARDs and low-to-moderate dose glucocorticoids are effective treatment options. However, direct comparative evidence on their relative effectiveness and safety is lacking. Methods: This investigator-initiated, open-label, randomized trial compared 10 mg daily prednisone to weekly subcutaneous tocilizumab (TCZ, 162 mg), both added to stable csDMARD therapy, in a 12-month treat-to-target strategy. If treatment response was inadequate at 3 months, patients switched to the alternative arm. The primary end point was Clinical Disease Activity Index (CDAI) averaged over months 6–12. Secondary outcomes included the Glucocorticoid Toxicity Index (GTI), TCZ-related adverse events and radiographic progression. Results: Sixty-five patients with established RA were included in the intention-to-treat population. TCZ was superior in reducing CDAI over months 6–12 (mean difference on square root scale: −0.64; 95% CI: −1.18 to −0.09). Treatment was switched in 28% (TCZ) and 52% (prednisone). No significant differences were observed in toxicity (GTI: P = 0.922; TCZ-related adverse events: P = 1.00) or in radiographic progression (P = 0.376). On-treatment analyses yielded similar results. Conclusion: TCZ led to greater improvement in disease activity than prednisone. There was no significant difference in joint damage progression over 12 months and there were no major differences in adverse events. Clinical trial registration: EudraCT Number: 2017–003037-28

Objectives: The HandScan is a novel method to quickly and objectively quantify RA disease activity using optical spectral transmission in hands and wrists. The aim of this study was to investigate whether treat-to-target (T2T) in early RA patients aimed at ‘HandScan’ remission is non-inferior to that aimed at ACR/EULAR 2011 ‘Boolean’ remission. Methods: We performed a multicentre randomized double-blind, non-inferiority trial. Newly diagnosed RA patients naive to DMARDs were randomized 1:1 to targeting HandScan remission or Boolean remission. At monthly visits, treatment was intensified/continued/deescalated according to the respective target following a predefined treatment schedule. Primary outcome was the HAQ score at 18 months, and non-inferiority was tested using a non-inferiority margin of 0.2 with a one-sided alpha of 0.05. Results: Of the 56 patients included per arm, a remarkably high number was not able to follow the T2T protocol (HandScan: 95%, Boolean: 80%, P = 0.01). The main reason was that patients and/or rheumatologists felt there was overtreatment (43%, 32%). HAQ at 18 months was 0.21 (95% CI: 0.01–0.40) units lower (i.e. better) in the Boolean arm. Thus, non-inferiority was absent for the HandScan target. Sensitivity analyses confirmed this conclusion. The HandScan target required more intensive treatment than the Boolean target, indicating overtreatment. Conclusion: Current HandScan remission criteria are not suitable for a T2T strategy in early RA since they may lead to overtreatment and inferior clinical outcomes. Additionally, both treatment targets lead to extraordinarily high non-adherence rates predominantly based on the feeling of overtreatment. Trial registration: International Clinical Trials Registry Platform, www.trialsearch.who.int, NTR6388

Background: Systemic sclerosis (SSc) primary heart involvement (SSc‐pHI) is one of the leading causes of mortality in SSc. We aimed to evaluate risk factors for SSc‐pHI and its progression and the outcomes in the EUSTAR (European Scleroderma Trials and Research) cohort. Methods: SSc‐pHI was defined according to the World Scleroderma Foundation/Heart Failure Association definition. Data from 5741 patients with SSc in the EUSTAR cohort were analyzed. Additional cardiovascular data were collected from a subcohort of 838 patients with SSc. Lasso regression was used for risk factor analyses. Kaplan–Meier estimator was used for survival analyses. Progression of SSc‐pHI was evaluated by a study definition developed by rheumatology and cardiology experts. Results: Risk factors for the presence of SSc‐pHI comprised skeletal muscle atrophy (odds ratio [OR], 2.00 [95% CI, 1.00–2.68]), age (OR, 1.91 [95% CI, 1.73–2.03]), male sex (OR, 1.77 [95% CI, 1.42–2.05]), swollen joints (OR, 1.70 [95% CI, 1.47–1.98]), skeletal muscle weakness (OR, 1.38 [95% CI, 1.00–1.85]), and tendon friction rubs (OR, 1.46 [95% CI, 1.00–1.77]) (n=3276). Telangiectasia (OR, 2.10 [95% CI, 1.38–2.72]), intestinal symptoms (OR, 1.70 [95% CI, 1.04–2.42]), age (OR, 1.47 [95% CI, 1.21–1.62]), and antitopoisomerase I antibodies (OR, 1.37 [95% CI, 1.00–1.77]) were associated with an increased risk for new onset of SSc‐pHI (n=1000). Survival rate was significantly lower in patients with SSc‐pHI than in those without ( P value <0.0001, n=3768). Patients with SSc‐pHI had a lower survival rate than patients with interstitial lung disease (n=3365). Swollen joints were associated with an increased risk of progressive SSc‐pHI (OR, 2.49 [95% CI, 1.79–3.52]) (n=595). Tendon friction rubs (OR, 1.21 [95% CI, 0.94–1.90]) increased the risk of heart failure with preserved ejection fraction in patients with SSc‐pHI. Conclusions: We defined progressive SSc‐pHI and identified risk factors for new onset and progression of SSc‐pHI and for SSc‐pHI‐associated heart failure with preserved ejection fraction in the largest cohort with SSc. These findings may guide patient stratification for diagnostic workup and therapy.

Objectives: Cellular senescence and endothelial-to-mesenchymal transition (EndMT) are profibrotic cellular processes involved in systemic sclerosis (SSc), but how they respond to treatment is largely unknown. Methods: Skin biopsies from diffuse cutaneous SSc (dcSSc) patients who underwent either autologous haematopoietic stem cell transplantation (aHSCT) or cyclophosphamide pulse (iv CYC) treatment were collected before and 6 months after randomization in the Autologous Stem Cell Transplantation International Scleroderma trial. The extent of fibrosis, inflammation, senescence, EndMT and tissue remodelling were examined in histopathology. Results: Fourteen pairs of skin biopsies were analysed. Decrease in modified Rodnan skin score was more pronounced in aHSCT-treated patients compared with iv CYC at 6 months (median change −14 [IQR −16 to −9] vs -6 [IQR −9 to −4], respectively, P = 0.028). Histologically, expression of urokinase-type plasminogen activator receptor (uPAR) on fibroblasts, P21 on vessels and EndMT decreased after treatment in both groups, yet the reduction was more pronounced in the aHSCT group. Poor skin response was associated with high baseline connective tissue growth factor (CTGF) on fibroblasts and low baseline P21 on vessels, with an odds ratio (OR) of 1.43 and 0.41, respectively. Furthermore, poor response was also seen in patients with a rise in CTGF on fibroblasts (OR 1.29) and P21 on vessels (OR 3.02) after treatment, P < 0.001. Conclusion: Both aHSCT and iv CYC in dcSSc reduced skin thickening clinically and attenuated EndMT, but affected cellular senescence not significantly different. EndMT and uPAR were associated with fibro-remodelling activity, whereas senescence, CTGF, uPAR and vascularity were associated with treatment response.

Difficult-to-treat RA (D2T RA) is an area of high unmet need. The prevalence reported in the first D2T RA cohort studies ranged from 5.5% to 27.5%. Key to the definition is a conviction by the patient and/or rheumatologist that disease management has become problematic and failure of at least two biological or targeted synthetic DMARDs. D2T RA is a multifactorial disease state which was reflected in data from D2T RA cohort studies: these pointed towards high prevalence of comorbidities and/or lower socioeconomic status in D2T RA subgroups, while others had persistent symptoms without these factors being present. A holistic approach is necessary to identify the root problems underlying D2T RA in individual patients. In this review, biological and non-biological drivers that should be considered to be optimized will be discussed in view of what we have learned from patient data emerging from the first D2T RA cohort studies.

Introduction: In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need. Methods and analysis: We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×10 ⁶ , 10×10 ⁶ and 15×10 ⁶ tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes. Ethics and dissemination: Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations. Trial registration numbers: NCT05251870 ; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).