OBJECTIVES:Severe infection risk associated with tumour necrosis factor-α inhibitors (TNFis) remains a concern. We aimed to assess the association between TNFi and bloodstream infections (BSIs) in a population-based setting. METHODS:Nationwide, registry-based case-control study including all adults from 2010 to 2024 with a first-time microbiologically confirmed BSI (cases) compared with age and sex-matched controls from the general population. Users were defined as individuals with TNFi exposure within 6 months prior to the date of BSIs. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated using conditional logistic regression. We further assessed risk variation by type of TNFi, pathogen, and underlying disease. RESULTS:We included 174,137 cases and 1 741 294 controls. Users had significantly increased odds of BSIs compared with nonusers (aOR, 1.41; 95% CI, 1.30-1.52), driven by increased odds among users of adalimumab and infliximab (aOR, 1.51; 95% CI, 1.33-1.72, and aOR, 2.01; 95% CI, 1.76-2.29). The use of certolizumab pegol and etanercept was associated with lower odds of BSIs, and golimumab with higher odds compared with nonuse, although not statistically significant. Species-specific analyses showed increased odds of BSIs with Escherichia coli (aOR, 1.33; 95% CI, 1.16-1.53), Staphylococcus aureus (aOR, 1.69; 95% CI, 1.40-2.06), Streptococcus pneumoniae (aOR, 1.46; 95% CI, 1.05-2.04), and Enterococcus faecium (aOR, 1.62; 95% CI, 1.04-2.53). Highest odds were observed in individuals with inflammatory bowel disease (aOR, 2.27; 95% CI, 1.93-2.66), followed by individuals with rheumatoid arthritis. Compared with TNFi monotherapy, concomitant glucocorticoids increased the odds (aOR, 2.63; 95% CI, 2.06-3.36). CONCLUSIONS:TNFi use is associated with increased odds of BSIs and was observed across the most frequent species. Odds varied by TNFi type and underlying disease, with the highest odds among patients with inflammatory bowel disease, emphasizing the need for individualized infection risk assessment.

This study aimed to identify new and scalable sources of cells for forming synovial organoids that align with the pauci-immune synovial pathotype and characterise both structure and cellular organisation of such organoids. The study modified a previously published method for forming synovial organoids using Matrigel, and tested it with combinations of immortalised synovial fibroblasts derived from synovium or synovial fluid together with human umbilical vein endothelial cells or the EA.hy926 cell line. Healthy synovium and synovial fluid derived fibroblasts with human umbilical vein endothelial cells resulted in formation of synovial organoids. Organoid diameter, area and cell count showed no significant differences (p > 0.05) in organoids formed with the different fibroblasts. Median CD31 signal intensity was 213 (184-218)) in the vascular-like area, 58 (55-60) in the lining-like area, and 62 (52-72) in the stroma-like area. Median podoplanin signal intensity was 971 (880-1052) in the lining-like area, 341 (310-560) in the vascular-like area, and 342 (281-356) in the stromal-like area. Here, we present novel sources of synovial fibroblasts for successfully forming of pauci-immune-aligned basal synovial organoids. These synovial organoids showed spatial expression patterns of PDPN and CD90 consistent with in vivo synovial fibroblast phenotypes and thereby showed potential as a reproducible basal synovial organoid platform, providing a structural foundation for future mechanistic and translational extensions with additional work needed to establish a fully validated disease model.

Objectives Global rheumatology training faces immense challenges, with over 1.7 billion people affected by musculoskeletal diseases and pronounced regional disparities in specialist access. Diverse curricula, resource limitations, and variable career pathways underscore the urgency for targeted harmonisation efforts. This study aims to present a vision for harmonising rheumatology training worldwide, highlighting the contributions of continental societies and innovative young networks, based on insights from the EMerging European Alliance of Associations for Rheumatology (EULAR) NETwork (EMEUNET) Presents session at EULAR Congress 2025 ‘Rheumatology Training Around the Globe’. Methods A narrative review of current training models across Africa, Asia-Pacific, Pan-America, and Europe using data from EULAR 2025 Congress supplemented with session slides and speaker insights. Results Programmes in Africa remain limited and fragmented, with severe workforce shortages and few structured training opportunities; regional responses include Young African Rheumatologists Network and select international partnerships. Asia-Pacific features multicountry, exam-based curricula governed centrally, but faces shortfalls in infrastructure and fellowship access, addressed in part by Asia Pacific League of Associations for Rheumatology-Young Rheumatology’s educational initiatives. Pan-America is marked by significant programme heterogeneity and access barriers, with the United States standing out for its highly structured American College of Rheumatology-accredited programmes, robust educational events, and comprehensive resources. Pan-American League of Associations for Rheumatology Joven and digital education initiatives are reducing training gaps and advancing collaboration. Europe combines robust, competency-focused national programmes, with EULAR and European Union of Medical Specialties actively supporting harmonisation despite persistent local variation, and EMEUNET enhancing mentorship and career support. Conclusions Future harmonisation in rheumatology training requires flexible, competency-driven frameworks, expanded digital platforms, multilevel mentorship, and sustainable investment, integrating national programmes into global networks.

The family of heterodimeric CD11/CD18 integrins facilitate leukocyte adhesion and migration in a wide range of normal physiologic responses, as well as in the pathology of inflammatory diseases. Soluble CD18 (sCD18) is found mainly in complexes with hydrodynamic radii of 5 and 7.2 nm, suggesting a compositional difference. Earlier work reported that the complexes include at least part of the CD11a or CD11b chains containing the intercellular adhesion molecule (ICAM)-1 binding domain, and that sCD18 is capable of quantitatively competing with the cell membrane-bound form for ICAM-1 binding. However, it is not clear if the size differences between the sCD18 complexes reflect any functional variance regarding shedding from the cell membrane or binding to ICAM-1. Here, we show evidence that sCD18 found in serum regulates release of the proinflammatory cytokine monocyte chemoattractant protein-1 (MCP-1/CCL2) from fibroblast-like synovial cells. Further, only large sCD18 complexes are capable of binding to ICAM-1. Migrating neutrophils shed large, but not small, sCD18 complexes. Together, these observations explain results measured from patients with rheumatoid arthritis (RA), where large sCD18 complexes dominated in local inflammatory processes involving neutrophil influx into zones of inflammation. Our data points to a previously unappreciated aspect of sCD18 integrin biology as regulators of inflammation in the context of migrating leukocyte. Surprisingly, this regulation is tied to sCD18 complex size, opening new opportunities for therapeutic intervention in serious inflammatory diseases such as arthritis.

Rheumatoid arthritis (RA) involves a breakdown of immune tolerance to citrullinated proteins, leading to chronic inflammation and joint damage. Despite advances in treatment, achieving long-term remission remains a major challenge. Restoring immune tolerance to citrullinated proteins represents a promising strategy to halt disease progression and establish lasting remission. This review examines the potential of using citrullinated proteins or peptides to reestablish immune tolerance in RA. It explores the potential role of anti-citrullinated protein antibodies (ACPAs) in disease pathology and how utilizing or targeting specific citrullinated antigens could modulate immune responses. The review also highlights the therapeutic relevance of altering T and B cell function to regulate immune state. We explore mechanisms through which tolerance can be induced, including the use of citrullinated peptides to promote regulatory T (Treg) cell expansion and alter pathogenic B cell subsets. Emerging strategies aimed at re-educating the immune system are discussed, focusing on their potential to provide effective and durable treatment outcomes. These tolerance-based approaches are evaluated for their capacity to shift the immune response away from autoimmunity and towards sustained remission.

Janus kinase inhibitors (JAKi) have been associated with an increased risk of venous thromboembolism (VTE) limiting the use of JAKi-based therapy. To improve risk stratification and drug development, it is crucial to understand the implication of dysregulated JAK-Signal Transducers and Activators of Transcription (STAT) signaling in the pathogenesis of VTE. The objective of this study is to clarify the putative genomic vulnerability to dysregulated JAK-STAT signaling in VTE through systematic mining of large-scale datasets generated from studies comparing VTE patients with healthy controls. Particularly, we assess the representation of entities of the JAK-STAT signaling pathway including STAT target genes among sets of miRNA, mRNA, and proteins differentially abundant in VTE patients, and we explore the putative cumulative genetic association of JAK-STAT signaling gene sets to VTE. Genes related to the JAK-STAT pathway were found significantly altered in VTE patients compared to healthy controls, indicating that genes under transcriptional control of STAT may be dysregulated in VTE. In support of this notion, we find a significant overrepresentation of predicted STAT target genes among genes downregulated in VTE patients, and promoter sequences of differentially regulated genes were significantly enriched with STAT transcription factor binding site motifs. Further linking STAT signaling to the molecular signature of VTE, genes targeted by miRNAs differentially regulated in patients are significantly enriched with STAT target genes and genes acting in the JAK-STAT signaling pathway. Together, our findings indicate that disruptions in the JAK-STAT pathway contribute to the molecular profile of VTE. This offers hope for identifying ways to interact with the JAK-STAT pathway that do not carry the risk of VTE.

Background Bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated 2-year efficacy in non-radiographic axial spondyloarthritis (nr-axSpA) and radiographic axSpA (r-axSpA) phase III studies.Objective Assess the impact of BKZ on peripheral manifestations to week 104 of those studies.Methods BE MOBILE 1 (nr-axSpA) and 2 (r-axSpA) each comprised a 16-week double-blind, placebo-controlled period, then all received BKZ 160 mg every 4 weeks for 36 weeks. Patients not meeting withdrawal criteria could enter a combined open-label extension. We report change in enthesitis (Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)) in patients with baseline MASES>0, peripheral arthritis (swollen joint count (SJC)/Disease Activity Index for Psoriatic Arthritis (DAPSA)) in patients with baseline SJC>0 and proportions achieving DAPSA disease states to week 104. Resolution of enthesitis (MASES=0)/arthritis (SJC=0) is reported to week 104 for those with baseline enthesitis/arthritis. We also report associations between peripheral manifestation resolution (MASES=0/SJC=0) and week 104 clinical outcomes in those with baseline enthesitis/arthritis.Results At baseline, 186/254 (73.2%) and 88/254 (34.6%) patients with nr-axSpA had enthesitis (MASES>0) and arthritis (SJC>0), respectively, compared with 199/332 (59.9%) and 66/332 (19.9%) patients with r-axSpA. Pooled BKZ/placebo-randomised patients with enthesitis (nr-axSpA/r-axSpA) showed average MASES improvement from 4.8/4.3 (baseline) to 1.6/1.3 (week 52) and 1.6/1.0 (week 104). Pooled BKZ/placebo-randomised patients with arthritis showed average SJC improvement from 4.0/4.5 (baseline) to 1.2/0.7 (week 52) and 0.9/0.6 (week 104). Over 60% of patients achieved DAPSA low disease activity/remission by week 52. Over 40%/60% patients achieved resolution of enthesitis (MASES=0)/arthritis (SJC=0) at week 104; enthesitis resolution was associated with larger improvements in week 104 clinical outcomes for patients with r-axSpA.Conclusion BKZ resulted in sustained improvements in peripheral manifestations to 2 years across the full disease spectrum of axSpA.

Understanding how inflammatory cytokines influence profibrogenic wound healing responses in fibroblasts is important for understanding the pathogenesis of fibrosis. TNF-α and IL-13 are key cytokines in Th1 and Th2 immune responses, respectively, while TGF-β1 is the principal pro-fibrotic mediator. We show that 12-day fibroblast culture with TNF-α or IL-13 induces fibrogenesis, marked by progressively increasing type III and VI collagen formation, and that TGF-β1 co-stimulation amplifies these effects. Tofacitinib substantially reduced the formation of ECM proteins in response to IL-13, while fibrogenesis in response to TNF-α or TGF-β1 was marginally inhibited. The in vitro findings were supported by clinical observations in patients with active rheumatoid arthritis, which had elevated serum type III collagen formation, indicating ongoing fibrogenesis during inflammation. After 48-60 weeks of tofacitinib treatment, type III collagen degradation, aswell as formation, were significantly decreased compared to baseline, highlighting dual anti-inflammatory and anti-fibrogenic effects of tofacitinib. In contrast, other anti-inflammatory treatments including methotrexate, adalimumab and tocilizumab demonstrated anti-inflammatory effects only. Our results highlight fibro-inflammatory profiles associated with TNF-α or IL-13 stimulation, both alone and in combination with TGF-β1, and support the use of tofacitinib as an anti-fibrogenic treatment in chronic inflammatory conditions.

BACKGROUND:Potential associations between targeted therapies and a new cancer in patients with inflammatory arthritis (IA) and a previous malignancy are a frequent concern in daily rheumatology practice. OBJECTIVES:To develop points to consider (PTC) to assist rheumatologists when initiating a targeted therapy in the context of a previous malignancy. METHODS:Following EULAR standardised operating procedures, a task force met to define the research questions for a systematic literature review and to formulate the overarching principles (OPs) and the PTC. RESULTS:The group formulated five OPs; seven PTC were formulated concerning the initiation of targeted therapies in patients with active IA and a previous malignancy in remission and one PTC concerning patients with active IA who were not in cancer remission. Major themes included (a) the need to assess the individualised risk of cancer recurrence based on the characteristics of the patient, cancer and the underlying disease; (b) the importance of engaging with specialists caring for cancer and defining treatment based on a shared decision between the patient and the rheumatologist; (c) the value of initiating without delay an appropriate targeted therapy for the treatment of the IA in patients in remission of their cancer; (d) the proposal to use Janus kinase inhibitors and abatacept with caution and in the absence of therapeutic alternatives, based on the absence of any data concerning their use in the context of previous malignancy. CONCLUSION:The 2024 EULAR points to consider provide guidance on the management of targeted therapies in patients with IA and a previous malignancy.

Background: In 2023, the EULAR-UEMS standards for the training of European rheumatologists have been published encompassing 28 competences within 7 domains that should be achieved by the end of postgraduate rheumatology training (Table 1) [1]. Objectives: To evaluate the expectations and viewpoints of rheumatology trainees and newly certified rheumatologists regarding the alignment of their training with the competencies outlined in the EULAR-UEMS standards for training Methods: In December 2023, a survey was developed in English language and distributed through the network of the EULAR EMEUNET Committee. For each of the 28 competences, respondents were asked to report on a 0-5 Likert scale (0=unable to do; 5=fully able to do) the expectation of achievement by the end of training (first year trainee) or a self-assessment of achievement (last year trainees/recently certified rheumatologists). Descriptive results (the mean for each competence±SD) are shown. Results: 27 trainees (12 first year and 15 last year trainees) and 26 certified rheumatologists from 17 Countries completed the survey. Respondents were mainly women (68%) aged between 26-35 years (78%). Trainees in the first year have high expectations of completing competences in the following domains (scored ≥4): “basic activity in rheumatology” (particularly, in the core theme “history taking and physical examination”) and in almost all “physician-patients relationship” related competences. Last year trainees and certified rheumatologists were more confident in all the domains, showing higher scores than the group of trainees (Table 1). Respondents were less confident (average score <3.5) in specific tasks such as performing interventional and investigational procedures and managing conditions such as osteoarthritis, metabolic bone conditions and chronic pain syndromes. In total, 20% of respondents reported that their training programs do not include these competences or those in the field of pregnancy. Seemingly current training programs also lacked training in the following competences: “understand and respond to the health needs of the community”, “demonstrate capacity and responsibility as future leader of a rheumatology team” and those in the core theme of “research, teaching and learning” (competence 26 and 28). On the other hand, the training programs seemed satisfactory in training residents for the domain of “new onset RMDs” since respondents declared that their programs allowed them to achieve the related competences in 100% of cases. Conclusion: The evaluation of training in the 28 competences among rheumatology trainees resulted in mostly satisfactory responses, especially in clinical domains. The self-assessment of certified rheumatologists and of last year trainees was overall higher than the expectations of first year trainees. However, some knowledge/skill gaps were reported in training programs and the EULAR educational offer could help with filling these gaps. REFERENCES: [1] Alunno A et al, Ann Rheum Dis 2023.Table 1. Mean value (± standard deviation) calculated for each competence. In bold, mean scores ≥4. The specific question of the questionnaire reported: “By the end of your training, how would you judge your ability to perform the following competences on a 0-5 scale (where 0 means “Unable to do” and 5 means “Fully able to do independently”)”? Acknowledgements: NIL. Disclosure of Interests: None declared.

ObjectivesEarly identification of interstitial lung disease (ILD) among patients with rheumatoid arthritis (RA) is a challenge for clinicians. The aim of this study was to evaluate screening algorithms for ILD by comparing the proportion of patients assigned a high-risk profile by three recently proposed models.MethodWe used the four-factor risk score, categorizing patients into high and low risk; the ILD screening criteria, categorizing patients into high, intermediate, and low risk; and the risk score for detection of subclinical RA-ILD, with four different risk categories, on patients with RA followed for 5 years after the RA diagnosis with pulmonary function tests, dyspnoea score, and pulmonary imaging.ResultsThe four-factor risk score identified 22% of the cohort (25/115) as eligible for further ILD investigations, while the ILD screening criteria identified 37% as high risk (43/115) and 34% as intermediate risk (39/115). The risk score for detection of subclinical RA-ILD identified 44% of the cohort as being at increased risk, with 7% in the highest risk group. The agreement between high-risk groups in the two clinical ILD screening models was moderate (kappa 0.43). Three patients in the cohort had clinical or subclinical ILD, and they were identified as high risk in the two clinical models.ConclusionThe three algorithms identified approximately one-third of the cohort as being at increased risk of ILD. Further development and validation of these algorithms are needed to reduce false positives and balance the potential benefit of earlier ILD diagnosis and healthcare resources used for respiratory assessment.

BACKGROUND:Targeted therapies have been associated with potential risk of malignancy, which is a common concern in daily rheumatology practice in patients with inflammatory arthritis (IA) and a history of cancer. OBJECTIVES:To perform a systematic literature review to inform a Task Force formulating EULAR points to consider on the initiation of targeted therapies in patients with IA and a history of cancer. METHODS:Specific research questions were defined within the Task Force before formulating the exact research queries with a librarian. We included studies reporting a relative risk measure of patients with a history of cancer initiating a targeted therapy or a conventional synthetic disease-modifying antirheumatic drug (csDMARD), regardless of the time since diagnosis of cancer. All relevant studies included in PubMed or Embase up to 15 July 2022 were included. Two reviewers independently performed standardised article selection, data extraction, synthesis and risk of bias assessment. RESULTS:14 published articles and one ACR abstract fulfilled the inclusion criteria. All studies were high-quality observational studies, representing a median follow-up from treatment initiation of 4.52 years among 4428 patients and 15 062 patient-years of follow-up for new or recurrent cancer. All patients had a history of cancer, most frequently solid cancer, most frequently receiving treatment for rheumatoid arthritis and most frequently treated with tumour necrosis factor-alpha inhibitors. Across these studies, the overall HR of new incident cancer or cancer recurrence was 0.90 (95% CI 0.74 to 1.10) for patients receiving a targeted therapy versus a csDMARD. CONCLUSION:Overall, the targeted therapies and clinical contexts covered by the included studies were not associated with an increased risk of new incident cancer or cancer recurrence as compared with csDMARDs.

Background: Prospective monitoring of patients in nationwide registries is the backbone of rheumatic patient care in several countries. To keep such clinical infrastructures viable and up to date, continuous improvements are needed. Automatic data-capture directly from source may improve the quality of data by minimizing incorrect and double entries and missing data. Objectives: In patients with rheumatoid arthritis, RA, to describe the current dataflow in DANBIO from year 2021 including the mode of data-entry and the data coverage for selected clinical variables. Methods: DANBIO is a nationwide clinical registry for routine care monitoring of patients with RA in hospitals and in rheumatology specialized primary care. Patient reported outcomes (PRO) are captured through touch screens in waiting areas or remotely through DANBIO-from-home (smartphone, tablet, computer) and clinical data, are registered by the physician at least yearly. Data in DANBIO may be enriched automatically with data from other health care systems e.g. laboratory measures, prescription of disease modifying agents (DMARDs), and vital status.We identified RA patients monitored in DANBIO (until Jan 2024). For year 2021-2023, we identified the number of patients monitored including the number of newly diagnosed patients per calendar year. For a range of variables in DANBIO, we identified number of data-entries. Variables included: PROs, laboratory measures (CRP, ACPA/IgM-RF), physician evaluation (swollen joint count), and DMARD treatment. For laboratory measures, we identified proportion of patients with available data. We characterized if data-entry was performed 1) by the treating physician, 2) by patients themselves, or 3) through automatic capture from other health care systems. Results: Overall, 43022 patients with RA had ever been monitored in DANBIO (71% female, median age 67 years (IQR 57-75), 67% seropositive).In year 2023, 23768 patients were monitored whereof 1689 patients were newly diagnosed. (Table 1) In year 2023, total number of data-entries in DANBIO included: 38700 PROs, 45075 measurements of CRP, 39623 swollen joint counts, and 37979 DMARD treatments (drug name, dose, start date).Since Jan 2022, all laboratory measurements (CRP, IgM-RF status and ACPA) were captured from the nationwide laboratory database. The proportion of patients with available measurement of IgM-RF increased from 60% in year 2021 to >90% in year 2023, and similar for ACPA. The proportion of patients with at least one contact with available CRP in DANBIO increased from 79% in year 2021 to 89% in year 2023. (Table 1) By Jan 2024, all DMARD prescriptions will be captured from the national prescription drug registry (Figure 1). Conclusion: Increasing use of automatic data-capture from other health systems and self-entry of PROs by patients minimizes manual work tasks for rheumatologists in routine care and improves monitoring and data-coverage. Further studies are needed to explore if these efforts improve patient outcomes. REFERENCES: [1] Glintborg et al. doi: 10.1136/rmdopen-2022-002549 Acknowledgements: Patients and colleagues contributing to DANBIO. Innovationsfonden, The Swedish Research Council, the Federal Ministry of Education and Research in Germany and The Research Council of Norway, under the frame of ERA PerMed (Project ScandRA). Disclosure of Interests: Bente Glintborg AbbVie, BMS, Sandoz (paid to institution). Chairs the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies., Dorte Vendelbo Jensen: None declared, Niels Steen Krogh: None declared, Lene Dreyer BMS, AbbVie (paid to institution). Member of the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies.Ada Colic UCB Advisory Board, Novartis Advisory Board, Janssens Clinical study, GSK Clinical study, Oliver Hendricks UCB, Pfizer, Novartis, GSK, Abbvie, Iris Marie Jakobsen: None declared, Connie Ziegler: None declared, Henrik Leffers: None declared, Signe Møller-Bisgaard: None declared, Klaus Westenbæk: None declared, Salome Kristensen: None declared, Tue Wenzel Kragstrup Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie, Bristol-Myers Squibb, UCB, Gilead, and Eli-Lilly, Gilead.ue, Mads Ammitzbøll Danielsen: None declared, Merete Lund Hetland Medac, Novartis, Pfizer, Sandoz, AbbVie, BMS, Eli Lilly, MSD, Pfizer, Sandoz, Novartis Table 1Patients with RA in DANBIO, n, and proportion with available laboratory measures, by calendar year.Year202120222023Patients monitored in DANBIO, n257192587523768Newly diagnosed, n187218381689Available laboratory measures, yesIgM RF*60%93%90%ACPA*64%97%94%IgM-RF and ACPA*59%92%87%CRP**79%87%89%Newly diagnosed is a subgroup of all monitored patients*Proportion shown for newly diagnosed patients** Proportion of all monitored patients in calendar year with at least one measurementAbbreviations: ACPA: anti-citrullinated peptides, CRP: C-reactive protein, DMARD: disease modifying antirheumatic drug, IgM-RF: immunoglobulin M rheumatoid factor

Background Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis in the lungs. Activated fibroblasts play a central role in fibrogenesis and express fibroblast activation protein α. A truncated, soluble form (sFAP) can be measured in blood and is a potential novel biomarker of disease activity. Objectives The aim was to study the association between sFAP and clinical, radiological, and histopathologic measures of disease severity, progression and survival in a prospective, multicenter, real-world cohort of patients with IPF. Methods Patients with IPF were recruited from the tertiary interstitial lung disease centers in Denmark and followed for up to three years. Baseline serum levels of sFAP were measured by ELISA in patients with IPF and compared to healthy controls. Pulmonary function tests, 6-minute walk test and quality of life measures were performed at baseline and during follow-up. Results The study comprised 149 patients with IPF. Median sFAP in IPF was 49.6 ng/mL (IQR: 43.1–61.6 ng/mL) and in healthy controls 73.8 ng/mL (IQR: 62.1–92.0 ng/mL). Continuous sFAP was not associated with disease severity, progression or survival (p > 0.05). After dichotomization of sFAP below or above mean sFAP + 2 SD for healthy controls, higher levels of sFAP were associated with lower FVC % predicted during follow-up (p < 0.01). Conclusions Higher than normal serum levels of sFAP were associated with longitudinal changes in FVC % predicted, but sFAP did not show clear associations with other baseline or longitudinal parameters. sFAP may be used to identify patients with IPF having a progressive disease course.

Background: Current treatment strategies for rheumatoid arthritis (RA) involve disease-modifying antirheumatic drugs (DMARDs) that treat symptoms rather than the underlying drivers of disease. This study investigates a novel drug candidate composed of a citrullinated cyclic peptide aptamer in a hyaluronic acid/chitosan nanoparticle (APT001). The citrullinated peptide was chosen as a potential T and B cell epitope based on theoretic and experimental evidence and showed association with disease activity in RA (1) and the nanoparticle was designed for uptake by neutrophils and monocytes for drug delivery to the site of inflammation (2). Previously, we showed that APT001 can reduce signs of arthritis in rodent models of RA.(3) Objectives: This study aims to investigate the therapeutic efficacy, safety profile, and mode-of-action of APT001 in a rat model of collagen-induced arthritis (CIA). Methods: Rats were dosed with APT001 subcutaneously (s.c.) at 5 mg/kg or 2.5 mg/kg for 3 weeks and followed for additional 4 weeks observation period. The effect of APT001 was evaluated by degree of paw swelling, histopathological examination, and RNA sequencing. Toxicology was assessed by hematoxylin and eosin (H&E) staining of liver, kidney, brain, spleen, and lung. Biodistribution was explored using NIR microscopy and APT001 labelled with Cy5.5 in the peptide component. Results: APT001 at 5 mg/kg completely mitigated joint swelling (score 0) already after the 3 weeks treatment period. Disease activity score at week 7 was 0 in both APT001 treatment groups, 6.4 in untreated rats, 2.2 in rats treated with nanoparticle without peptide, and 1.8 in rats treated with peptide without nanoparticle. Cartilage damage score by H&E staining was 3 in untreated group versus 0 in group treated with APT001 5 mg/kg. The number of pathologic TRAP positive cells was 12 in untreated group versus 4 in group treated with APT001 5 mg/kg. RNA sequencing revealed upregulation in 1459 and downregulation in 1424 DEGs in the joints. In ontology and pathway analyses cell metabolism and cell division were most affected with significant decrease in the IL-17 pathway. In the spleen, treatment with APT001 5 mg/kg compared with untreated rats resulted in only 32 upregulated and 33 downregulated DEGs. In the biodistribution study APT001 was primarily found in synovium and kidneys after 6 hours and in the spleen after 48 hours. At termination point after 7 weeks, no peptide was detected in any organ indicating complete clearance. Citrullinated peptide without nanoparticle distributed differently, targeting mostly liver and kidney at both 6-hour and 48-hour time points. No histology changes were seen in organs from rats treated with APT001 5 mg/kg compared with untreated rats. Conclusion: We here confirm previous observations that APT001 attenuates CIA in rats. This study highlights a sustained efficacy over the extended observation period. This study further adds mechanistic insights revealing changes in gene expression in the joints but not in the spleen. This is in line with the proposed mechanism of action being uptake by neutrophils and monocytes and transport and release of APT001 in the joints and modulation of the immune imbalance caused by break of tolerance to citrullinated peptides. REFERENCES: [1] S. Khatri, J. Hansen, K. Astakhova, Antibodies to synthetic citrullinated peptide epitope correlate with disease activity and flares in rheumatoid arthritis, PLoS One. 15 (2020). https://doi.org/10.1371/JOURNAL.PONE.0232010. [2] S. Khatri, J. Hansen, A.C. Mendes, I.S. Chronakis, S.C. Hung, E.D. Mellins, K. Astakhova, Citrullinated Peptide Epitope Targets Therapeutic Nanoparticles to Human Neutrophils, Bioconjug. Chem. 30 (2019) 2584–2593. https://doi.org/10.1021/acs.bioconjchem.9b00518. [3] S. Khatri, J. Hansen, N.B. Pedersen, I.P. Brandt-Clausen, S. Gram-Nielsen, A.C. Mendes, I.S. Chronakis, U.B. Keiding, A.I. Catrina, B. Rethi, M.H. Clausen, T. Kragstrup, K. Astakhova, Cyclic Citrullinated Peptide Aptamer Treatment Attenuates Collagen-Induced Arthritis, Biomacromolecules. 23 (2022). https://doi.org/10.1021/ACS.BIOMAC.2C00144/ASSET/IMAGES/LARGE/BM2C00144_0005.JPEG. Acknowledgements: We express our gratitude to Susanne Primdahl for their outstanding contributions with histology part of the study. Disclosure of Interests: Kira Astakhova Stock ownership and affiliation with the biotech company developing the studied compound (Aptol Pharma)., Tue Wenzel Kragstrup Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie., Stock ownership and affiliation with the biotech company developing the studied compound (Aptol Pharma)., Bristol-Myers Squibb, UCB, Gilead, and Eli-Lilly., Gilead., Adrian Hernández Bustos: None declared, Nadia Bom Pedersen: None declared, Christopher Mahony: None declared, Adam P. Croft: None declared, Mads Hartvig Clausen Stock ownership and affiliation with the biotech company developing the studied compound (Aptol Pharma).

Background: Many axial spondyloarthritis (axSpA) patients present normal CRP levels despite having substantial inflammation. Erosions and new bone formation in the axial skeleton are hallmarks of axSpA. Further, the disease is characterized by aberrant neutrophil activation. We hypothesize that mechanistic biomarkers reflecting these processes may be superior to CRP for assessing disease activity in the axial skeleton. Objectives: We investigated the associations between the soluble biomarkers Cpa9-HNE, C3M and PRO-C3 and MRI inflammation in the spine and sacroiliac joints of axSpA patients. Additionally, we tested whether these biomarkers were more sensitive to detect inflammation compared with CRP. Methods: Biomarkers for neutrophil activity (Cpa9-HNE), type III collagen degradation (C3M) and type III collagen formation (PRO-C3) were measured in plasma samples from axSpA patients (n=21) in the INTASAH cohort [1]. EDTA plasma samples collected at baseline (week 0) and after 12 and 52 weeks of adalimumab treatment were measured. Changes in biomarker levels were analyzed using linear mixed models. MRI scoring of active inflammatory and chronic changes in spine and sacroiliac joints (SIJ) at weeks 0, 20 and 52 were published previously [1]. Spearman correlations were used to compare MRI scores and biomarkers at week 0 and 52. ROC analysis was used to investigate the sensitivity of biomarkers to indicate columna inflammation at week 52. Results: Adalimumab treatment decreased Cpa9-HNE (week 12 estimate: -65.3 [-102.9 to -27.5], p<0.01; week 52 estimate: -57.3 [-95.0 to 19.6], p<0.01) (Figure 1A), C3M (week 12 estimate: -101.8 [-146.1 to -57.4], p<0.001; week 52 estimate: -70.7 [-115.1 to -26.45], p<0.01) (Figure 1B) and CRP (week 12 estimate: -10.3 [-16.7 to -3.9], p<0.01; week 52 estimate: -11.381 [-17.7 to -4.9], p<0.01) (Figure 1D). In contrast, PRO-C3 increased in response to adalimumab treatment (week 12 estimate: 14.0 [8.3 to 19.6], p<0.001; week 52 estimate: 9.4 [3.7 to 15.0], p<0.01) (Figure 1C). The biomarkers had the strongest association with spine inflammation. The correlation at baseline for CRP was ρ = 0.62 [0.25 to 0.83], p<0.01; Cpa9-HNE ρ = 0.6 [0.22 to 0.81], p<0.01; C3M ρ = 0.5 [0.08 to 0.76], p<0.05; PRO-C3 ρ = -0.08 [-0.49 to 0.36], p=0.73 (Figure 2A). After 52 weeks of treatment, 13/21 patients had residual inflammatory activity in the spine. CRP was detectable in only 6 of these 13 patients. In contrast, Cpa9-HNE and C3M was measured above the detection limit in all 13 patients. The correlation with columna activity after 52 weeks for CRP was ρ=0.29 [-0.17 to 0.65], p=0.21; CPa9-HNE ρ=0.42 [-0.03 to 0.72], p=0.07; C3M ρ=0.31 [-0.15 to 0.66], p=0.18; PRO-C3 ρ=0.05 [-0.4 to 0.48], p=0.83 (Figure 2B). When dividing patients into cases and controls based on any presence of columna inflammation at week 52, at their respective optimal cutoffs, Cpa9-HNE (AUC = 0.83 [0.62-1-0], p<0.02, sensitivity = 93%, specificity = 67%) and C3M (AUC = 0.70 [0.45-0.95], p = 0.16, sensitivity = 78.57%, specificity = 66.67%), had a superior sensitivity for detecting spine inflammation compared to CRP (AUC = 0.73 [0.50-0.95], p=0.11, sensitivity = 46.15%, specificity = 100%), while PRO-C3 had inferior sensitivity (AUC = 0.53 [0.22-0.84], p = 0.80, sensitivity = 57%, specificity = 66.67%) (Figure 2C–F). Conclusion: Overall, CPa9-HNE, C3M and CRP had a similar correlation with spine MRI inflammation at baseline. CPa9-HNE and C3M had a superior sensitivity to indicate spine MRI inflammation compared to CRP at week 52. This holds promise for using these biomarkers to detect changes in disease activity in axSpA patients with normal CRP levels. PRO-C3 increased with adalimumab treatment, which may indicate tissue regeneration in response to adalimumab. REFERENCES: [1] Østgård, R. D. et al. Faecal calprotectin detects subclinical bowel inflammation and may predict treatment response in spondyloarthritis. Scandinavian Journal of Rheumatology 47, 48–55 (2018) Acknowledgements: NIL. Disclosure of Interests: Frederik Gillesberg: None declared, Renè Østgård Pfizer, Merck Sharp & Dohme, AbbVie, Bristol-Meyer-Squibb, Janssen, Novartis, Galapagos and Lilly, Pfizer, Merck Sharp & Dohme, AbbVie, Bristol-Meyer-Squibb, Janssen, Novartis, Galapagos and Lilly, Novartis, Joachim Høgh Mortensen Nordic Bioscience A/S, Martin Pehrsson Nordic Bioscience A/S, Signe Holm Nielsen Nordic Bioscience A/S, Bent Deleuran Astra-Zeneca, Anne-Christine Bay-Jensen Nordic Bioscience, Nordic Bioscience, Tue Wenzel Kragstrup Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie., Bristol-Myers Squibb, UCB, Gilead, and Eli-Lilly., Gilead.Figure 1Changes in soluble biomarkers over time. Figure 2Association of MRI scores and biomarkers.

Objective European Alliance of Associations for Rheumatology (EULAR) task forces (TF) requires participation of ≥2 junior members, a health professional in rheumatology (HPR) and two patient research partners for the development of recommendations or points to consider. In this study, participation of these junior and representative members was compared with the one of traditional TF members (convenor, methodologist, fellow and expert TF members).Methods An online survey was developed and emailed to previous EULAR TF members. The survey comprised multiple-choice, open-ended and 0–100 rating scale (fully disagree to fully agree) questions.Results In total, 77 responded, 48 (62%) women. In total, 46 (60%) had participated as a junior or representative TF member. Most junior/representative members reported they felt unprepared for their first TF (10/14, 71%). Compared with traditional members, junior/representative members expressed a significantly higher level of uncertainty about their roles within the TF (median score 23 (IQR 7.0–52.0) vs 7 (IQR 0.0–21.0)), and junior/representative members felt less engaged by the convenor (54% vs 71%). Primary factors that facilitated interaction within a TF were experience, expertise and preparation (54%), a supportive atmosphere (42%) and a clear role (12%).Conclusion Juniors, patients and HPR experience various challenges when participating in a EULAR TF. These challenges differ from and are generally less pronounced than those experienced by traditional TF members. The convenor should introduce the participants to the tasks, emphasise the value of their contributions and how to prepare accordingly for the TF meeting.