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Thirty-nine clinical isolates of Pseudomonas aeruginosa collected from 11 cystic fibrosis (CF) patients at two CF attention centers over 10 years were subjected to whole genome sequencing (WGS). Phenotypic tests (i.e., elastase, motility, biofilm, growth rate, and antibiotic susceptibility) were performed to correlate results. A single strain of P. aeruginosa was found to persist over time in longitudinal isolates. No transmission between patients or centers was observed. A tendency to lack genes related to pyoverdine, flagellum, pili, and O-antigen was observed, whereas those related to biofilm, phenazine, and pyochelin were conserved among isolates. In a patient with a 10-year follow-up, a single strain of P. aeruginosa persisted and showed a gradual decrease in elastase activity and growth rate, demonstrating an adaptive phenotype. IMPORTANCE This study investigates the genomic and phenotypic characteristics of Pseudomonas aeruginosa isolates from Mexican cystic fibrosis (CF) patients, an underrepresented group in CF research. To our knowledge, it is the first to use whole genome sequencing (WGS) to study longitudinally collected P. aeruginosa isolates from this population, evaluating both genomic features and clonal relationships. Remarkably, the study includes samples from one patient over 10 years, offering an extended observation time compared to existing literature. Unlike similar studies, which often lack phenotypic testing, this research incorporates various virulence-related phenotypic assays, enhancing our understanding of gene-to-phenotype correlations. Two potential mechanisms for the loss of elastolytic activity were identified. Furthermore, we conduct an in-depth mobilome analysis, an area that remains largely unexplored in CF contexts. Whole genome sequencing data are publicly available through the NCBI SRA database, facilitating further re-analysis for studies on P. aeruginosa in CF, as well as epidemiological and population structure research.

Background : Interstitial lung disease (ILD) is a common extra-muscular manifestation of idiopathic inflammatory myopathies (IIMs), often associated with a poorer prognosis and increased mortality risk. Methods : This retrospective study aimed to characterize lung involvement and treatment response in an IIM cohort at a Portuguese tertiary center, followed between June 2016 and March 2024. We analyzed data from high-resolution computed tomography (HRCT) scans and pulmonary function tests (PFTs) to assess associations with autoantibody profiles and treatment regimens. Results : A total of 198 patients were included, with 69 (34.8%) exhibiting ILD. Antisynthetase syndrome (ASyS) and dermatomyositis were the most common diagnoses among IIM-ILD patients, with ASyS being significantly more frequent in this group than in non-ILD patients ( p < 0.001). Anti-Jo1 and anti-MDA-5 antibodies were more frequent in ILD patients ( p < 0.001 and p = 0.021), while anti-Mi2 antibodies were less common ( p = 0.002). Non-specific interstitial pneumonia (NSIP) was the most common radiological pattern (69.5%). IIM-ILD patients presented with significantly lower forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) compared to non-ILD patients ( p < 0.001 for all values). Longitudinal analysis showed improved DLCO ( p = 0.022) and stable or improved FVC ( p = 0.097), especially with intravenous immunoglobulin (IVIg) and azathioprine (AZA). Combination therapies including IVIg with mycophenolate mofetil (MMF) or rituximab (RTX) also improved DLCO and FVC. Most ILD patients (89.6%) had stable HRCT patterns over time. Conclusions : Our findings highlight the potential for stabilizing or even improving lung function in IIM-ILD with appropriate immunosuppressive therapy, particularly with regimens incorporating IVIg and AZA, and combination therapies.

Objective: To optimise the organisation of care and encourage the adoption of good clinical practices, the RarERN Path © methodology was designed within ERN ReCONNET. The aim of our work was to report the application of RarERN Path © on systemic sclerosis within the ERN ReCONNET centres, providing a feasible and flexible organisational reference model for optimising the systemic sclerosis care pathway in different countries., Methods: RarERN Path © is a six-phase methodology which enables the creation of a reference organisational model co-designed on the basis of the expertise of different stakeholders. It foresees six phases, ranging from the map of existing patients' care pathways and patients' stories, to the consensus on a common organisational patient care pathways, and its key performance indicators definition., Results: The agreed reference model highlights the importance of having an organisational flow for referrals that foresees how patients may access directly the specialised unit from the different referrals. Specific specialised visits were considered as mandatory to be organised and they included cardiologist, pneumologist, gastroenterologist, psychologist, nephrologist, dermatologist, wound care specialist/nurses and other healthcare professionals (such as nurses, social workers and nutritional counselling). Moreover, specific services related to therapy were highlighted as strongly recommended to be organised, mainly represented by infusion therapy and wound care, as well as occupation therapy and physiotherapy., Conclusion: The organisational model emerged from our investigation emphasises that the organisation of specific services for systemic sclerosis treatment should be organised as a solid support for implementing the existing recommendations on systemic sclerosis management in real life., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Background: The Zic family of transcription factors (TFs) promote both proliferation and maturation of cerebellar granule neurons (CGNs), raising the question of how a single, constitutively expressed TF family can support distinct developmental processes. Here we use an integrative experimental and bioinformatic approach to discover the regulatory relationship between Zic TF binding and changing programs of gene transcription during postnatal CGN differentiation., Results: We first established a bioinformatic pipeline to integrate Zic ChIP-seq data from the developing mouse cerebellum with other genomic datasets from the same tissue. In newborn CGNs, Zic TF binding predominates at active enhancers that are co-bound by developmentally regulated TFs including Atoh1, whereas in mature CGNs, Zic TF binding consolidates toward promoters where it co-localizes with activity-regulated TFs. We then performed CUT&RUN-seq in differentiating CGNs to define both the time course of developmental shifts in Zic TF binding and their relationship to gene expression. Mapping Zic TF binding sites to genes using chromatin looping, we identified the set of Zic target genes that have altered expression in RNA-seq from Zic1 or Zic2 knockdown CGNs., Conclusions: Our data show that Zic TFs are required for both induction and repression of distinct, developmentally regulated target genes through a mechanism that is largely independent of changes in Zic TF binding. We suggest that the differential collaboration of Zic TFs with other TF families underlies the shift in their biological functions across CGN development., (© 2024. The Author(s).)

Juvenile Idiopathic Arthritis (JIA) represents a diverse group of chronic inflammatory conditions that begin in childhood or adolescence and continue into adulthood, with varying severity and outcomes. This review discusses the complexities of transitioning JIA patients emphasizing that inadequate transition from pediatric to adult care leads to loss of follow-up, treatment discontinuation, and increased disease activity. Furthermore, challenges in disease classification hinder continuity of care across lifespan. It is also pointed out that predicting long-term outcomes in JIA remains complex due to heterogeneity and evolving phenotypes. Factors such as disease category, joint involvement, and treatment influence disease activity, functional disability, and quality of life. Despite advancements in treatment strategies, a substantial proportion of patients experience long-term disability and joint damage. Finally, it is underscored that optimising long-term outcomes in adults with JIA requires a multifaceted approach encompassing structured transition processes, personalised treatment strategies, and comprehensive management of comorbidities. Further research is needed to refine predictive models, enhance disease monitoring tools, and understand the complex interplay between disease activity, treatment response, and long-term outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The objective is to characterize transcriptomic profiles and immune cell composition and distribution in juvenile idiopathic arthritis (JIA) synovial biopsies, assess for associations of these features with clinical parameters, and compare JIA and rheumatoid arthritis (RA) synovial features., Methods: RNA sequencing (RNASeq) was performed on 24 samples, with pathway analysis and inference of relative abundance of immune cell subsets based on gene expression data. Two multiplex fluorescence immunohistochemistry (IHC) panels were performed on 28 samples (including 13 on which RNASeq was performed), staining for CD206 - classical and CD206 + nonclassical macrophages, and CD8 + and CD4 + T and B lymphocytes. Data were compared to a published series of early RA synovial biopsies., Results: Pathway analysis of the most variably expressed genes (n = 339) identified a B and plasma cell signature as the main driver of heterogeneity in JIA synovia, with strong overlap between JIA and RA synovitis. Multiplex IHC confirmed heterogeneity of immune cell infiltration. M1-like macrophage-rich synovial lining was associated with greater lining hypertrophy and higher (CD45 + ) pan-immune cell and CD8 + T cell infiltration., Conclusion: Our study indicates significant similarities between JIA and RA synovitis. Similar to RA, JIA synovia may be broadly categorized into two groups: (1) those with an inflammatory/adaptive immune transcriptomic signature, M1-like macrophage and CD8 + T cell infiltration, and thicker, M1-like macrophage-rich synovial lining, and (2) those with an M2-like macrophage transcriptomic signature, greater M2/M1-like macrophage ratios, and thinner, M2-like macrophage-rich synovial lining. Synovial features were not significantly associated with clinical parameters, likely because of group size and heterogeneity., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: With this work, we evaluated the impact of the Lisbon Early ARthritis cliNic (LEARN) on untreated inflammatory arthritis clinical and patient-reported outcomes., Methods: A retrospective cohort study enrolled patients in LEARN since its inception. Patients were followed for 12 months and treated to achieve disease remission. Clinical, structural, and quality of life outcomes were assessed. The early arthritis module of the Portuguese Rheumatic Diseases Registry (Reuma.pt) is described., Results: We assessed 292 patients between 2015 and 2022. Mean symptom duration and DAS-28-4 V-ESR at baseline were 6.2 ± 3.5 months and 5.6 ± 1.3, respectively. Rheumatoid arthritis (56.4%; 40.1% seropositive) and psoriatic arthritis (12.4%) were the most common diagnoses. Most patients were treated with methotrexate (75.3%) combined with low-dose oral prednisolone (88.1%). At 12 months, a mean ΔDAS28-4 V-ESR improvement of 2.3 ± 0.4 was registered, with 29.5% and 48.9% of patients achieving remission (DAS28-4 V-ESR < 2.6) or low disease activity (DAS28-4 V-ESR < 3.2), respectively. Among RA patients only, these figures were 20.6% and 46.6%, respectively. A clinically meaningful functional improvement was observed in 72.1% of the patients. Structural progression was limited, affecting only 16.1% of the patients. Fatigue, anxiety, depression, and quality of life also improved substantially, translated by improvements in FACIT, HADS, EQ5D, and SF-36 scores., Conclusions: A structured, dedicated approach to patients with early arthritis resulted in good clinical, structural, and functional outcomes. Furthermore, our findings suggest the window of opportunity for early intervention may have implications for mental health and global well-being. Key Points • Patient assessment is facilitated by reliable electronic clinical records, such as the early arthritis module of the Rheumatic Diseases Portuguese Register (Reuma.pt) which we describe here for the first time. • Inflammatory arthritis was confirmed in the majority of patients observed, but the time to first appointment was above the recommended. • Prompt start of conventional therapy allowed significant disease activity improvement and remission to be achieved in about one-third of the patients. • Key patient-reported outcomes elucidate disease impact and confirm the benefit of early treatment initiation, suggesting a window of opportunity also for mental health and global well-being., Competing Interests: Declarations. Ethics approval and consent to participate: As previously declared, all studies have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Ethical approval was granted by the local authorities, Centro Académico de Medicina de Lisboa Ethical Commission, by the approval dispatch 138/19. All patients gave their informed consent prior to their inclusion in the study. Details that would disclose the identity of the subjects under study were omitted. Disclosures: None., (© 2024. The Author(s).)

Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV., Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed., Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00-4.06): 102 (2.13% 95% CI 1.73-2.56) with stroke and 81 (1.68% 95% CI 1.33-2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet's disease (9.5%, 95% CI 5.79-14.37), polyarteritis nodosa (6.2%, 95% CI 3.25-10.61), and Takayasu's arteritis (6.0%, 95% CI 4.30-8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09-3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20-3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05-9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01-2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period., Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet's. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence., (© 2024. The Author(s).)

VEXAS syndrome is a recently described autoinflammatory syndrome caused by the somatic acquisition of UBA1 mutations in myeloid precursors and is frequently associated with hematologic malignancies, chiefly myelodysplastic syndromes. Disease presentation can mimic several rheumatologic disorders, delaying the diagnosis. We describe a case of atypical presentation resembling late-onset axial spondylarthritis, later progressing to a systemic inflammatory syndrome with chondritis, cutaneous vasculitis, and transfusion-dependent anemia, requiring high doses of steroids. Ruxolitinib was used as the first steroid-sparing strategy without response. However, azacitidine showed activity in controlling both inflammation and the mutant clone. This case raises the question of whether azacitidine's anti-inflammatory effects are dependent on or independent of clonal control. We discuss the potential relevance of molecular remission in VEXAS syndrome and highlight the importance of a multidisciplinary team for the care of such complex patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pereira da Costa, Sapinho, Bandeira, Infante, Marques, Mimoso Santos, Forjaz de Lacerda, Fonseca and Romeu.)

In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12 high ) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2 high SAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis., Competing Interests: J.L., M.D.P.P.C., T.P., S.L., and M.F.B. are employees of BioMed X GmbH, Heidelberg, Germany. The other authors declare no competing interests., (© 2024 The Authors.)

Uveitis is a heterogeneous collection of infrequent diseases, which poses significant challenges to cost-effective research in the field. Medical registries are being increasingly recognized as crucial tools to provide high-quality data, thus enabling prospective clinical research. This paper describes the design and technical structure development of an innovative countrywide electronic medical record for uveitis, Uveite.pt, and gives an overview of the cohort registered since its foundation, March 2020.Uveite.pt is an electronic medical record platform developed by the Portuguese Ocular Inflammation Group (POIG), a scientific committee of the Portuguese Ophthalmology Society. This is a nationwide customized web-based platform for uveitis patients useful for both clinical practice and real-world-based research, working as a central repository and reporting tool for uveitis. This paper describes the technical principles, the design and the development of a web-based interoperable registry for uveitis in Portugal and provides an overview of more than 400 patients registered in the first 18 months since inception.In infrequent diseases, the existence of registries enables to gather evidence and increase research possibilities to clinicians. The adoption of this platform enables standardization and improvement of clinical practice in uveitis. It is useful to apprehend the repercussion of medical and surgical treatments in uveitis and scleritis, supporting clinicians in the strict monitoring of drug adverse reactions and surgical outcomes.

Objectives: Systemic extraglandular involvement in SS has been reported in one-third of patients but may be more frequent. We aimed to evaluate systemic disease prevalence at baseline and throughout follow-up and find its predictors., Methods: We conducted a retrospective cohort study including SS patients followed in a tertiary centre. The cumulative EULAR SS disease activity index (ESSDAI) was calculated by adding each domain's maximum score throughout follow-up. We identified independent predictors of systemic involvement (ESSDAI ≥1 at baseline and/or follow-up) through logistic regression modelling. A survival analysis was conducted to identify predictors of new/worsening ESSDAI domains., Results: A total of 216 patients were included, most of whom had systemic involvement (86%), frequently at diagnosis (76%). Biological (53%) and articular ESSDAI domains (44%) were most commonly involved, but all were affected at least once. Around half of the patients with baseline systemic disease developed an additional/worsening domain throughout follow-up. Although most patients had low disease activity at baseline, 60% eventually reached moderately active disease. Younger age at diagnosis [odds ratio (OR) 0.95 (95% CI 0.91, 0.99)], a positive minor salivary gland biopsy [OR 4.08 (95% CI 1.40, 11.86)] and RF [OR 4.67 (95% CI 1.52, 14.33)] were independent predictors of systemic involvement. Patients with baseline constitutional involvement [hazard ratio (HR) 2.23 (95% CI 1.13, 4.40)] and RF [HR 1.89 (95% CI 1.20, 3.00)] were more likely to develop new/worsening systemic disease activity., Conclusion: Systemic involvement is seen in most SS patients. Younger and RF and salivary gland biopsy-positive patients are at higher risk of systemic disease. Around half of patients with systemic involvement experienced aggravated disease over time, especially those with constitutional involvement or RF., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: During the COVID-19 pandemic, there was a significant impact on the management of non-COVID-19 related diseases, potentially increasing the incidence of paraneoplastic syndromes such as cancer-associated myositis (CAM).The aim of this study is to determine the incidence of CAM in our cohort before and after the COVID-19 pandemic onset., Methods: We included patients with idiopathic inflammatory myopathy (IIM), diagnosed between June 2016 and June 2023. The patients were divided into two groups according to the date of IIM diagnosis., Results: We included 132 patients; 65.1% (n=86) were diagnosed prior to and 34.9% (n=46) after the COVID-19 pandemic. The most common IIM was dermatomyositis (DM) before and after the COVID-19 pandemic onset (p=0.750). The most frequent myositis-specific antibody (MSA) before the COVID-19 pandemic was anti-Mi2 (15.1%). After the COVID-19 pandemic onset, anti-TIF1γ was the most common MSA (21.7%), with a significantly higher relative prevalence (p=0.006). The incidence of CAM was significantly higher after the COVID-19 pandemic onset (11 vs. 3 new cases, p<0.002). Patients with CAM more frequently had anti-TIF1γ-positivity (p<0.001) and a diagnosis after the pandemic (p=0.001) than non-CAM-IIM patients. No significant differences were found regarding vaccination status or previous COVID-19 infection in CAM and non-CAM-IIM patients. Diagnosis after the COVID-19 pandemic was an independent predictor of CAM among IIM patients (OR 0.012, 95% CI 0.000-0.400, p=0.013), regardless of age, sex or previous COVID-19 infection., Conclusions: There was a significant increase in the incidence of CAM after the COVID-19 pandemic. IIM diagnosis after the COVID-19 pandemic was an independent predictor of CAM.

Objectives: To compare the prevalence of anxiety and depression in patients with GCA with that in the general population, using the Hospital Anxiety and Depression Scale (HADS), and to identify independent predictors of these psychiatric manifestations in patients with GCA., Methods: We conducted a cross-sectional study including all patients diagnosed with GCA followed during 1 year in a vasculitis outpatient clinic. The HADS and 36-item Short Form (SF-36) questionnaires were prospectively collected. Patients' HADS results were compared with an age- and gender-matched control group. HADS anxiety (HADS-A) and HADS depression (HADS-D) scores between 8 and 10 defined possible anxiety and depression and ≥11 defined probable anxiety and depression, respectively., Results: We included 72 patients and 288 controls. Compared with controls, patients with GCA had a statistically significant higher prevalence of HADS-A ≥8 (48.6% vs 26.4%), HADS-A ≥11 (30.6% vs 12.2%) and HADS-D ≥11 (33.3% vs 18.1%). GCA was an independent predictor of HADS-A ≥8 [odds ratio (OR) 3.3 (95% CI 1.9, 5.9)], HADS-A ≥11 [OR 3.8 (95% CI 2.0, 7.4)] and HADS-D ≥11 [OR 2.6 (95% CI 1.4, 4.7)]. Among patients with GCA, a negative correlation was observed between HADS-A/D and SF-36 mental health scores ( r  = -0.780 and r  = -0.742, respectively). Glucocorticoid therapy was a predictor of HADS-A ≥8 [OR 10.4 (95% CI 1.2, 94.2)] and older age of HADS-D ≥8 [OR 1.2 (95% CI 1.1, 1.3)] and HADS-D ≥11 [OR 1.1 (95% CI 1.0, 1.2)]., Conclusions: Compared with the general population, patients with GCA have a higher prevalence of anxiety and depression and GCA is an independent predictor of these symptoms. Glucocorticoid treatment and older age are predictors of anxiety and depression, respectively, in patients with GCA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To estimate digit circumference and the impact of sex and body mass index (BMI) for the calculation of the Leeds Dactylitis Index (LDI) in psoriatic arthritis (PsA) patients with bilateral dactylitis., Methods: Digit circumference of the hands and the foot were measured with a dactylometer and were studied according to sex and BMI (divided in 4 weight categories) in healthy Portuguese subjects, using Student's t-test and One-way ANOVA, respectively. The effect size of sex and BMI were calculated using Cohen's d test and Eta squared, respectively. Multiple linear regression was used to calculate the effect of sex and BMI, as well as their interaction, to create a formula to predict digit circumference., Results: Fifty-nine participants (33 women, 26 men) with a mean BMI of 24.8 were included. Men's mean digit circumferences were statistically higher than those of women (p<0.001), with a large sex effect size in most of the digits. Differences in the mean circumference between the four BMI categories were statistically significant (p<0.05) for all digits, with a large BMI effect size. Sex and BMI were independent variables to predict mean digit circumference (p<0.001). A new tool (based on regression analysis) allowing to estimate the circumference of digits for males and females of different BMIs is presented., Conclusions: Our data allows the calculation of digit circumference for males and females of different BMIs in the Portuguese population; and shows that BMI influences digital circumference supporting BMI inclusion in LDI references tables.

Stress fractures are common in young and active individuals, associated with aggressive or repetitive physical activity and their early detection is fundamental to optimise patient care, decrease complications and avoid unnecessary exams. Currently, magnetic resonance imaging is the standard of care for detecting these lesions. Recently, ultrasound has been getting an increasing interest for the detection of stress fractures. In this article, we describe a clinical case that involved a second metatarsal stress fracture diagnosed by ultrasound and review the literature regarding the use of ultrasound in the diagnosis of stress fractures, particularly of the metatarsals.

Background: Hepatitis B virus (HBV) vaccination is recommended for non-immunised patients with rheumatic diseases starting biological disease-modifying antirheumatic drugs (bDMARDs). There is some evidence that HBV vaccination is effective in patients under conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), but it is currently unclear whether this also applies to bDMARDs., Objectives: To assess the efficacy and safety of HBV vaccination in patients with inflammatory arthritides treated with bDMARDs., Methods: A prospective cohort with inflammatory arthritides treated with bDMARDs, negative for anti-HBs and anti-HBc and never vaccinated for HBV was recruited. Engerix B was administered at 0, 1 and 6 months and anti-HBs was reassessed ≥1 month after last dose. Response was defined as anti-HBs≥10 IU/L and compared against vaccinated healthy controls. Disease flare, serious adverse events and immune-related disorders not previously present were recorded., Results: 62 patients, most treated with TNF inhibitors (TNFi), and 38 controls were recruited. Most patients were taking csDMARDs (67.7%) and were in remission/low disease activity (59.4%). Only 20/62 patients (32.3%) had a positive response to vaccination, in comparison to 36/38 age-matched controls (94.7%, p<0.001). Response was seen in 19/51 patients treated with TNFi (37.3%) and in 1/11 (9.1%) patients treated with non-TNFi (p=0.07), including 1/6 treated with tocilizumab (16.7%). Among TNFi, response rates ranged from 4/22 (18.2%) for infliximab to 8/14 (57.1%) for etanercept. No relevant safety issues were identified., Conclusions: HBV vaccination response in patients with rheumatic diseases treated with bDMARDs was poorer than expected. Our data reinforce the recommendation for vaccination prior to starting bDMARDs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We aimed to compare two matched populations of patients with MTCD with and without associated ILD and to identify predictive factors for ILD progression and severity., Methods: This international multicenter retrospective study (14 tertiary hospitals), included MCTD patients who fulfilled at least one historical MCTD classification criteria. ILD was defined by the presence of typical chest high-resolution computed tomography (HRCT) abnormalities. Factors associated with ILD were assessed at baseline. Long-term progressive ILD was assessed in MCTD-ILD patients with multiple forced vital capacity (FVC) measurements., Results: 300 patients with MCTD were included. Mean age at diagnosis was 39.7 ± 15.4 years and 191 (63.7%) were women. Mean follow-up was 7.8 ± 5.5 years. At baseline, we identified several factors associated with ILD presence: older age (p = 0.01), skin thickening (p = 0.03), upper gastro-intestinal (GI) symptoms (p<0.001), FVC <80% (p<0.0001), diffusing capacity for carbon monoxide <80% (p<0.0001), anti-topoisomerase antibodies (p = 0.01), SSA/Ro antibodies (p = 0.02), cryoglobulinemia (p = 0.04) and elevated C-reactive protein (p<0.001). Patients with MTCD-ILD were more likely to be treated with synthetic immunosuppressant agents (p<0.001) in particular mycophenolate mofetil (p = 0.03). Digital ulcers (DU) were identified as a risk factor for FVC decline >10%. During follow-up mortality was higher in the MTCD-ILD group (p<0.001)., Conclusion: In this large international cohort of patients with MTCD, we identified different factors associated with ILD. Our findings also provide evidence that MCTD-ILD patients have increased mortality and that DU are associated with progressive lung disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Vaccination is one of the most important measures to contain the COVID-19 pandemic, especially for frail patients. VACCINATE is a multicentre prospective observational study promoted by the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET) aimed at assessing the long-term outcomes of COVID-19 vaccination in patients with rare and complex connective tissue diseases (rcCTDs) in terms of efficacy and safety., Methods: Adult rcCTDs patients were eligible for recruitment. Demographic, clinical and vaccination data were collected at enrolment. Follow-up visits were scheduled 4, 12, 24, 36 and 48 weeks after completion of the first vaccination cycle; data on adverse events, disease exacerbations and the occurrence of new SARS-CoV-2 infections were collected at these time-points., Findings: 365 rcCTDs patients (87 % female, mean age 51.8 ± 14.6 years) were recruited. Overall, 200 patients (54.8 %) experienced at least one adverse event, generally mild and in most cases occurring early after the vaccination. During follow-up, 55 disease exacerbations were recorded in 39 patients (10.7 %), distributed over the entire observation period, although most frequently within 4 weeks after completion of the vaccination cycle. The incidence of new SARS-CoV-2 infections was 8.9 per 1000 person-months, with no cases within 12 weeks from vaccine administration and an increasing trend of infections moving away from the primary vaccination cycle. Only one case of severe COVID-19 was reported during the study period., Interpretation: COVID-19 vaccination seems effective and safe in rcCTDs patients. The rate of new infections was rather low and serious infections were uncommon in our cohort. No increased risk of disease flares was observed compared to previous disease history; however, such exacerbations may be potentially severe, emphasising the need for close monitoring of our patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V.)

Purpose: To assess the relationship between adherence to the Mediterranean Diet (MD) /individual Dietary Inflammatory Index (DII) and disease activity, disease impact, and functional status in Rheumatoid Arthritis (RA) patients., Methods: RA patients followed at a hospital in Lisbon, Portugal, were recruited. DII was calculated using dietary intake data collected with a food frequency questionnaire (FFQ). Adherence to the MD was obtained using the 14-item Mediterranean Diet assessment tool. Disease Activity Score of 28 Joints (DAS28) and the DAS28 calculated with C-Reactive Protein (DAS28-CRP) were used to assess disease activity. Impact of disease and functional status were evaluated using the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire and the Health Assessment Questionnaire (HAQ), respectively., Results: 120 patients (73.3% female, 61.8 ± 10.1 years of age) were included. Patients with higher adherence to the MD had significantly lower DAS28-CRP (median 3.27(2.37) vs 2.77(1.49), p = 0.030), RAID (median 5.65(2.38) vs 3.51(4.51), p = 0.032) and HAQ (median 1.00(0.56) vs 0.56(1.03), p = 0.013) scores. Higher adherence to the MD reduced the odds of having a higher DAS28 by 70% (OR = 0.303, 95%CI = (0.261, 0.347), p = 0.003). Lower adherence to MD was associated with higher DAS28-CRP (β = - 0.164, p = 0.001), higher RAID (β = - 0.311, p < 0.0001), and higher HAQ scores (β = - 0.089, p = 0.001), irrespective of age, gender, BMI and pharmacological therapy. Mean DII of our cohort was not significantly different from the Portuguese population (0.00 ± 0.17 vs - 0.10 ± 1.46, p = 0.578). No associations between macronutrient intake or DII and RA outcomes were found., Conclusions: Higher adherence to the MD was associated with lower disease activity, lower impact of disease, and lower functional disability in RA patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Juvenile idiopathic arthritis (JIA) treatment is aimed at inducing remission to prevent joint destruction and disability. However, it is unclear what is the long-term impact on health-related outcomes of the timing of biological disease-modifying antirheumatic drug (bDMARD) initiation in JIA. Our aim was to evaluate the long-term impact of the time between JIA onset and the initiation of a bDMARD in achieving clinical remission, on physical disability and health-related quality of life (HRQoL)., Methods: Adult JIA patients registered in the Rheumatic Diseases Portuguese Register (Reuma.pt) and ever treated with bDMARD were included. Data regarding socio-demographic, JIA-related characteristics, disease activity, physical disability (HAQ-DI), HRQoL (SF-36), and treatments were collected at the last visit. Patients were divided into 3 groups (≤ 2 years, 2-5 years, or > 5 years), according to the time from disease onset to bDMARD initiation. Regression models were obtained considering remission on/off medication, HAQ-DI, SF-36, and joint surgeries as outcomes and time from disease onset to bDMARD start as an independent variable., Results: Three hundred sixty-one adult JIA patients were evaluated, with a median disease duration of 20.3 years (IQR 12.1; 30.2). 40.4% had active disease, 35.1% were in remission on medication, and 24.4% were in drug-free remission; 71% reported some degree of physical disability. Starting a bDMARD > 5 years after disease onset decreased the chance of achieving remission off medication (OR 0.24; 95% CI 0.06, 0.92; p = 0.038). Patients who started a bDMARD after 5 years of disease onset had a higher HAQ and worse scores in the physical component, vitality, and social function domains of SF-36, and more joint surgeries when compared to an earlier start., Conclusion: Later initiation of bDMARDs in JIA is associated with a greater physical disability, worse HRQoL, and lower chance of drug-free remission in adulthood., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Competing Interests: The idea for this collaborative global response was born at the inaugural meeting of the EULAR study group for Reproductive Health and Family Planning in Milan in June, 2023. We would like to thank Kirsten Frøhlich (Danish Centre for Expertise in Rheumatology (CeViG), Danish Hospital for Rheumatic Diseases, Sonderborg, Denmark) for her immense logistic support throughout the process of this work. CN-P reports consultancy fees from Sanofi Aventis and UCB; speakers fees from UCB, Sanofi and Otsuka; is a medical advisor (medical advisory board) for the pregnancy sickness support charity; and a patron of the Lauren Page Trust. RJEMD reports grants from Galapagos and UCB; speakers fees from Galapagos, Eli Lilly, Novartis, and UCB; support for attending meetings from UCB; and participation on advisory boards for Galapagos and UCB. MM reports consulting fees from GSK, Eli Lilly, and AstraZeneca; speaker fees from UCB, Eli Lilly, AstraZeneca, GSK, Janssen, and AbbVie; participation on an advisory board for Idorsia; and has received Anifrolumab from AstraZeneca for compassionate use. RF-B reports consulting fees from AbbVie, Otsuka, and UCB; and speakers fees from Biogen, Bristol Myers Squibb, GSK, MSD, Novartis, Sanofi, and UCB. AM reports consulting fees from AbbVie, Biogen, Bristol Myers Squibb, MSD, Novartis, Janssen, Eli Lilly, Pfizer, Amgen, UCB, Gilead, Galapagos; speakers fees from AbbVie, Biogen, Bristol Myers Squibb, MSD, Novartis, Janssen, Eli Lilly, Pfizer, Amgen, UCB, Gilead, Galapagos; and support for attending meetings from AbbVie, Novartis, Galapagos, UCB, Janssen. AT reports speakers fees from GSK and UCB, and participation on advisory boards for Galapagos and UCB. BLB reports royalties from Up To Date and is a member of the data safety monitoring committee for the Stop Bloq study. MEBC reports grants from GSK and UCB and consulting fees from UCB. CC reports research support form Amgen, AstraZeneca, GSK, Janssen, Pfizer, Regeneron, Hoffman La-Roche-Genentech, Genzyme Sanofi-Aventis, Takeda Pharmaceutical Company, Sanofi, UCB, Leo Pharma, Sun Pharma Global FZE, Gilead, Novartis, and the Gerber Foundation; and Speaker honorarium from the American Academy of Allergy, Asthma & Immunology aunual meeting. JB reports consultancy fees from Related Sciences, GSK, and Bristol Myers Squibb. DA reports speakers fees from Bristol Myers Squibb. LA reports consulting fees from Sanofi. GB reports grants from AstraZeneca and Pfizer; consulting fees from AstraZeneca and Eli Lilly; and speakers fees from Aenorasis, AstraZeneca, GSK, Eli Lilly, Novartis, and SOBI. WB reports grants from UCB; is an advisory board member for UCB; payment for expert testimony; and is a member of data safety monitoring boards for the Lutein and Zeaxanthin in Pregnancy study and the Stop Bloq study. AB reports research grants from SOBI and participation on an advisory board for SOBI. IB reports consulting fees from AstraZeneca; speakers fees from Amgen, AstraZeneca, GSK, Eli Lilly, MSD, Roche, Sanofi Genzyme, and UCB; support for attending meetings from UCB; and is an advisory group member for AstraZeneca. RC reports speakers fees from GSK, AstraZeneca, Celgene, Janssen, Eli Lilly, Pfizer, UCB, Rubió, and Werfen. SAE reports support for attending meetings from Pfizer. GE reports consulting fees from GSK and Otsuka; and speakers fees from GSK, Otsuka, and Boehringer Ingelheim. JF reports speakers fees and support for attending meetings from UCB. RF-S reports consultancy fees, speakers fees, and support for attending meetings from AstraZeneca. BG reports grants from Bristol Myers Squibb, Pfizer, and Sandoz. IG reports speakers’ fees from Otsuka and participation on an advisory board for Novartis. MH reports research grants from AbbVie, Biogen, Bristol Myers Squibb, Celltrion, Eli Lilly, Janssen Biologics BV, Lundbeck Foundation, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, and Nordforsk; speakers fees from Pfizer, Medac, and Sandoz; and participation on an advisory board for AbbVie. MH has chaired the steering committee of the Danish Rheumatology Quality Registry, which receives public funding from the hospital owners and funding from pharmaceutical companies. MH cochairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondylorthritis on the basis of secondary data and is partly funded by Novartis. MK is an employee of GSK. RL is an employee of GSK. LFP-G reports consulting fees from Galapagos. MR is a member of the data safety monitoring committee for the Comparison of Step-up and step-down therapeutic strategies in childhood ArthritiS, which is partly supported by Pfizer. AS reports speakers fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, MSD, Eli Lilly, Pfizer, Roche, and UCB; and is principle investigator of the German Biologics Register RABBIT, which is supported by grants from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Galapagos, Hexal, Eli Lilly, MSD, Pfizer, Samsung Bioepis, Sanofi Aventis, Viatris Sante, UCB, and previously Roche. JV reports speakers’ fees from Eli Lilly, Novartis, Sandoz, and AbbVie. All other authors declare no competing interests.

Objectives: Epidemiological evidence supports a link between atherosclerosis and osteoporosis. These conditions might share common pathophysiological mechanisms, with inflammation being one of the hypotheses.Apolipoprotein E deficient mice (ApoE-/-) develop atherosclerotic lesions spontaneously, further aggravated by a high-fat diet. Their bone remodelling is also disturbed. We hypothesised that a proinflammatory state could be a common contributive factor for vessel and bone disturbances observed in this animal model., Methods: We evaluated vessels and bones of ApoE-/- and control C57BL/6 (B6) female mice fed a high-fat diet in five time-points (8, 16, 20, 24 and 28 weeks of age) and quantified the development of atherosclerotic lesions, analysed gene expression of inflammatory and bone remodelling proteins (IL-1β, IL-6, IL-17A, TNF, RANKL, and OPG), measured serum bone turnover markers (P1NP and CTX-I), performed bone (L3-L4 vertebras) histomorphometric analysis and evaluated biomechanical properties of bones., Results: We compared the outcomes of B6 and ApoE-/- groups at each time-point and, within each group, over time. Atherosclerotic lesions developed as previously described for ApoE-/- mice, but no significant differences were found in bone histomorphometry or biomechanical properties between ApoE-/- and B6 mice. Also, gene expression (either in bones or aortas) and serum biomarkers were similar in both groups. When considering over time evaluations we found that bone histomorphometry changes were similar between ApoE-/- and B6 mice, but CTX-I/P1NP ratio was significantly increased (meaning higher resorption than bone formation) in ApoE-/- as compared to B6 mice., Conclusions: Our study suggests that inflammation is not the principal driver for atherosclerosis progression and bone disturbances in this animal model.

Objectives: The main goal of this study was to characterise the frequency and phenotype of B, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in peripheral blood and the cytokine environment present in circulation in children with extended oligoarticular juvenile idiopathic arthritis (extended oligo JIA) and polyarticular JIA (poly JIA) when compared with healthy controls, children with persistent oligoarticular JIA (persistent oligo JIA) and adult JIA patients., Methods: Blood samples were collected from 105 JIA patients (children and adults) and 50 age-matched healthy individuals. The frequency and phenotype of B, Tfh and Tfr cells were evaluated by flow cytometry. Serum levels of APRIL, BAFF, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IFN-γ, PD-1, PD-L1, sCD40L, CXCL13 and TNF were measured by multiplex bead-based immunoassay and/or ELISA in all groups included., Results: The frequency of B, Tfh and Tfr cells was similar between JIA patients and controls. Children with extended oligo JIA and poly JIA, but not persistent oligo JIA, had significantly lower frequencies of plasmablasts, regulatory T cells and higher levels of Th17-like Tfh cells in circulation when compared with controls. Furthermore, APRIL, BAFF, IL-6 and IL-17A serum levels were significantly higher in paediatric extended oligo JIA and poly JIA patients when compared with controls. These immunological alterations were not found in adult JIA patients in comparison to controls., Conclusions: Our results suggest a potential role and/or activation profile of B and Th17-like Tfh cells in the pathogenesis of extended oligo JIA and poly JIA, but not persistent oligo JIA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: The primary endpoint of the pivotal phase III study of infliximab (IFX) s.c. demonstrated non-inferiority of s.c. to i.v. IFX, based on 28-joint DAS-CRP (DAS28-CRP) improvement at week (W) 22 (NCT03147248). This post-hoc analysis investigated whether numerical differences in efficacy outcomes at W30/54 were statistically significant, using conservative imputation methods., Methods: Patients with active RA and inadequate response to MTX received IFX i.v. 3 mg/kg at W0 and W2 (induction) and were randomized (1:1) to IFX s.c. 120 mg every 2 weeks or i.v. 3 mg/kg every 8 weeks thereafter (maintenance). Patients randomized to IFX i.v. switched to IFX s.c. from W30-54. This post-hoc analysis compared efficacy outcomes for s.c. and i.v. groups pre-switch (W30) and post-switch (W54) using last observation carried forward (LOCF) and non-responder imputation (NRI) methods., Results: Of 343 randomized patients, 165 (IFX s.c.) and 174 (IFX i.v.) were analysed. At W30, significantly improved outcomes were identified with s.c. vs i.v. IFX for DAS28-CRP/DAS28-ESR/Clinical Disease Activity Index (CDAI)/Simplified Disease Activity Index (SDAI) scores (LOCF); ACR/good EULAR responses, DAS28-CRP/Boolean remission, and DAS28-CRP/DAS28-ESR/CDAI/SDAI low disease activity and remission (LOCF and/or NRI); and minimal clinically important difference in HAQ score (LOCF and NRI). After switching to IFX s.c. from IFX i.v., fewer significant between-group differences were identified at W54., Conclusion: IFX s.c. showed improved efficacy at W30 compared with IFX i.v., and the reduced between-group difference in efficacy outcomes at W54 after switching supports the results suggesting benefits of IFX s.c. compared with IFX i.v. at W30., Trial Registration: ClincialTrials.gov, http://clinicaltrials.gov, NCT03147248, https://clinicaltrials.gov/ct2/show/NCT03147248., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Aims: To characterise the idiopathic inflammatory myopathies (IIM) module of the Rheumatic Diseases Portuguese Register (Reuma.pt/myositis) and the patients in its cohort., Methods: Reuma.pt is a web-based system with standardised patient files gathered in a registry. This was a multicentre open cohort study, including patients registered in Reuma.pt/myositis up to January 2022., Results: Reuma.pt/myositis was designed to record all relevant data in clinical practice and includes disease-specific diagnosis and classification criteria, clinical manifestations, immunological data, and disease activity scores. Two hundred eighty patients were included, 71.4% female, 89.4% Caucasian, with a median age at diagnosis and disease duration of 48.9 (33.6-59.3) and 5.3 (3.0-9.8) years. Patients were classified as having definite (N=57/118, 48.3%), likely (N=23/118, 19.5%), or possible (N=2/118, 1.7%) IIM by 2017 EULAR/ACR criteria. The most common disease subtypes were dermatomyositis (DM, N=122/280, 43.6%), polymyositis (N=59/280, 21.1%), and myositis in overlap syndromes (N=41/280, 14.6%). The most common symptoms were proximal muscle weakness (N=180/215, 83.7%) and arthralgia (N=127/249, 52.9%), and the most common clinical signs were Gottron's sign (N=75/184, 40.8%) and heliotrope rash (N=101/252, 40.1%). Organ involvement included lung (N=78/230, 33.9%) and heart (N=11/229, 4.8%) involvements. Most patients expressed myositis-specific (MSA, N=158/242, 65.3%) or myositis-associated (MAA, 112/242, 46.3%) antibodies. The most frequent were anti-SSA/SSB (N=70/231, 30.3%), anti-Jo1 (N=56/236, 23.7%), and anti-Mi2 (N=31/212, 14.6%). Most patients had a myopathic pattern on electromyogram (N=101/138, 73.2%), muscle oedema in magnetic resonance (N=33/62, 53.2%), and high CK (N=154/200, 55.0%) and aldolase levels (N=74/135, 54.8%). Cancer was found in 11/127 patients (8.7%), most commonly breast cancer (N=3/11, 27.3%). Most patients with cancer-associated myositis had DM (N=8/11, 72.7%) and expressed MSA (N=6/11) and/or MAA (N=3/11). The most used drugs were glucocorticoids (N=201/280, 71.8%), methotrexate (N=117/280, 41.8%), hydroxychloroquine (N=87/280, 31.1%), azathioprine (N=85/280, 30.4%), and mycophenolate mofetil (N=56/280, 20.0%). At the last follow-up, there was a median MMT8 of 150 (142-150), modified DAS skin of 0 (0-1), global VAS of 10 (0-50) mm, and HAQ of 0.125 (0.000-1.125)., Conclusions: Reuma.pt/myositis adequately captures the main features of inflammatory myopathies' patients, depicting, in this first report, a heterogeneous population with frequent muscle, joint, skin, and lung involvements.

Purpose: To find ultrasound prognostic factors for shoulder pain., Methods: This was an observational, prospective study, comparing the evolution of ultrasound findings with clinical outcomes, in patients with shoulder pain. Data were collected in two appointments, from February 2018 to March 2021. Two-tailed non-parametric statistics were used, and p values <0.05 were considered significant., Results: A total of 79 participants were included in this study (median age 59 years, range 24-70, 61 women). A positive Doppler signal on tendons (p = 0.002) and absent tendon heterogeneity (p = 0.01) were associated with the patient's self-reported improvement. Tendon calcifications with poorly defined contours (p = 0.03) and sparse distribution (p = 0.001) were associated with VAS improvement. A reduction in the number of calcifications (p = 0.004), in the supraspinatus tendon thickness (p = 0.01), in subacromial effusions (p = 0.03), and in color Doppler grade (p = 0.02), between initial and follow-up exams, was found in patients with an improved DASH outcome., Conclusion: A positive Doppler signal on shoulder tendons can be a marker for a better prognosis in shoulder pain. Poorly defined and sparsely distributed calcifications can also indicate a better course of the disease., (© 2023 The Authors. Journal of Clinical Ultrasound published by Wiley Periodicals LLC.)

Objectives: To compare the effectiveness of the infliximab biosimilar CT-P13 with originator infliximab over 24 months of follow-up in biological-naïve patients with rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA)., Methods: Biological-naïve patients from the Rheumatic Diseases Portuguese Register (Reuma.pt), with a clinical diagnosis of RA or axSpA, who were starting either the infliximab biosimilar CT-P13 or the originator infliximab after 2014 (date of market entry of CT-P13 in Portugal), were included. Patients on biosimilar and originator were compared regarding different response outcomes at 3 and 6 months, adjusting for age, sex and baseline C-reactive protein (CRP). The main outcome was the change in DAS28-erytrocyte sedimentation rate (ESR) for RA and the ASDAS-CRP for axSpA. Additionally, the effect of infliximab biosimilar vs originator on different response outcomes over 24 months of follow-up was tested with longitudinal generalized estimating equations (GEE) models., Results: In total, 140 patients were included, 66 (47%) of which with RA. The distribution of patients starting the infliximab biosimilar and the originator was the same between the two diseases (approximately 60% and 40%, respectively). From the 66 patients with RA, 82% were females, mean age was 56 years (SD 11) and mean DAS28-ESR 4.9 (1.3) at baseline. As for the patients with axSpA, 53% were males, mean age was 46 years (13) and mean ASDAS-CRP 3.7 (0.9) at baseline. There were no differences in efficacy between RA patients treated with the infliximab biosimilar and the originator, either at 3 months (∆DAS28-ESR: -0.6 (95% CI -1.3; 0.1) vs -1.2 (-2.0; -0.4)), or at 6 months (∆DAS28-ESR: -0.7 (-1.5; 0.0) vs -1.5 (-2.4; -0.7)). This was also true for patients with axSpA (∆ASDAS-CRP at 3 months: -1.6 (-2.0; -1.1) vs -1.4 (-1.8; -0.9) and at 6 months: -1.5 (-2.0; -1.1) vs -1.1 (-1.5; -0.7)). Results were similar with the longitudinal models over 24 months., Conclusion: There are no differences in effectiveness between the infliximab biosimilar CT-P13 and the infliximab originator in the treatment of biological-naïve patients with active RA and axSpA in clinical practice.

Objectives: Idiopathic inflammatory myopathies (IIM) are a group of rare disorders that can affect the heart. This work aimed to find predictors of cardiac involvement in IIM., Methods: Multicenter, open cohort study, including patients registered in the IIM module of the Rheumatic Diseases Portuguese Register (Reuma.pt/Myositis) until January 2022. Patients without cardiac involvement information were excluded. Myo(peri)carditis, dilated cardiomyopathy, conduction abnormalities, and/or premature coronary artery disease were considered., Results: 230 patients were included, 163 (70.9%) of whom were females. Thirteen patients (5.7%) had cardiac involvement. Compared with IIM patients without cardiac involvement, these patients had a lower bilateral manual muscle testing score (MMT) at the peak of muscle weakness [108.0 ± 55.0 vs 147.5 ± 22.0, p=0.008] and more frequently had oesophageal [6/12 (50.0%) vs 33/207 (15.9%), p=0.009] and lung [10/13 (76.9%) vs 68/216 (31.5%), p=0.001] involvements. Anti-SRP antibodies were more commonly identified in patients with cardiac involvement [3/11 (27.3%) vs 9/174 (5.2%), p=0.026]. In the multivariate analysis, positivity for anti-SRP antibodies (OR 104.3, 95% CI: 2.5-4277.8, p=0.014) was a predictor of cardiac involvement, regardless of sex, ethnicity, age at diagnosis, and lung involvement. Sensitivity analysis confirmed these results., Conclusion: Anti-SRP antibodies were predictors of cardiac involvement in our cohort of IIM patients, irrespective of demographical characteristics and lung involvement. We suggest considering frequent screening for heart involvement in anti-SRP-positive IIM patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bandeira, Dourado, Melo, Martins, Fraga, Ferraro, Saraiva, Sousa, Parente, Soares, Correia, Almeida, Dinis, Pinto, Oliveira Pinheiro, Rato, Beirão, Samões, Santos, Mazeda, Chícharo, Faria, Neto, Lourenço, Brites, Rodrigues, Silva-Dinis, Dias, Araújo, Martins, Couto, Valido, Santos, Barreira, Fonseca and Campanilho-Marques.)

Intra-articular glucocorticoid injection (IAGCI) is frequently used to treat joint pain and inflammation. While its efficacy has been extensively studied, there are not as many detailed descriptions regarding safety. This review aimed to describe the immediate-, short- and long-term complications of IAGCI and their predictors. Most studies mainly report mild and self-limited adverse events with an incidence similar to placebo. However, the reported incidences vary significantly and are mostly inferred from retrospective data. Septic arthritis is the most feared adverse event due to its association with high mortality. Other short-term local complications include injection site pain, post-injection flare, skin hypopigmentation and atrophy, and tendon rupture. Systemic side effects are common, including vasovagal reactions, flushing, increased appetite and mood changes, hyperglycemia in diabetic patients, and bleeding in high-risk patients. Few predictors of complications have been systematically evaluated. However, male gender, advanced age, and pre-existing joint disease have been suggested in retrospective studies to correlate with infection risk. Overall, in most studies, only severe adverse event rates are reported, with no systematic prospective evaluations of safety and no report of predictors of complications. Therefore, since IAGCI is a routinely used treatment, more detailed knowledge of adverse events and complications is warranted.

Objectives: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field., Methods: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item., Results: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations., Conclusions: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Synovial tissue research has become widely developed in several rheumatology centres, however, large discrepancies exist in the way synovial tissue is handled and, more specifically, how data pertaining to biopsy procedure, quality check and experimental results are reported in the literature. This heterogeneity hampers the progress of research in this rapidly expanding field. In that context, under the umbrella of European Alliance of Associations for Rheumatology, we aimed at proposing points to consider (PtC) for minimal reporting requirements in synovial tissue research., Methods: Twenty-five members from 10 countries across Europe and USA met virtually to define the key areas needing evaluation and formulating the research questions to inform a systematic literature review (SLR). The results were presented during a second virtual meeting where PtC were formulated and agreed., Results: Study design, biopsy procedures, tissue handling, tissue quality control and tissue outcomes (imaging, DNA/RNA analysis and disaggregation) were identified as important aspects for the quality of synovial tissue research. The SLR interrogated four databases, retrieved 7654 abstracts and included 26 manuscripts. Three OPs and nine PtC were formulated covering the following areas: description of biopsy procedure, overarching clinical design, patient characteristics, tissue handling and processing, quality control, histopathology, transcriptomic analyses and single-cell technologies., Conclusions: These PtC provide guidance on how research involving synovial tissue should be reported to ensure a better evaluation of results by readers, reviewers and the broader scientific community. We anticipate that these PtC will enable the field to progress in a robust and transparent manner over the coming years., Competing Interests: Competing interests: AN has received consulting and/or speaker’s fees from UCB, CHUGAI, BMS all unrelated to this manuscript. FC has received consulting and/or speaker’s fees from Lilly, Novartis and UCB, all unrelated to this manuscript. M-AD'A has received consulting and/or speaker’s fees from Lilly, Novartis, AbbVie, BMS, Pfizer, Galapagos, and UCB, all unrelated to this manuscript. AF has received consulting and/or speaker’s fees from Janssen, GSK, Abbvie, Galapagos and receives research funding from Janssen, GSK, Mestag, Roche and Celsius, all unrelated to this manuscript. EN has received consulting and/or speaker’s fees from Roche, BMS, UCB, Lilly Celgene GmbH, all unrelated to this manuscript. SA has received research funding by Abbvie, Pfizer, BMS and GSK and has received consulting and/or speaker’s fees from Abbvie, Pfizer, BMS, Galapagos, Novartis, Janssen and Lilly all unrelated to this manuscript. JEF has received research funding and/or speaker’s fees from Abbvie, Ache, Biogen, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, all unrelated to this manuscript. SWT received research funding and/or speaker’s fees from AbbVie, Arthrogen/MeiraGTx, AstraZeneca, BMS, Celgene, Galapagos, GSK, MSD, Pfizer, Roche, Sanofi-Genzyme, all unrelated to this manuscript. VCR has received research funding and non-financial support from Merck Sharp and Dohme; personal fees and non-financial support from Pfizer and Janssen; non-financial support from Lilly and Roche, outside the submitted work. MM Supported by the National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The author(s) views unrelated to the NIHR or the department of Health and Social Care., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Searches for the genetic underpinnings of uniquely human traits have focused on human-specific divergence in conserved genomic regions, which reflects adaptive modifications of existing functional elements. However, the study of conserved regions excludes functional elements that descended from previously neutral regions. Here, we demonstrate that the fastest-evolved regions of the human genome, which we term "human ancestor quickly evolved regions" (HAQERs), rapidly diverged in an episodic burst of directional positive selection prior to the human-Neanderthal split, before transitioning to constraint within hominins. HAQERs are enriched for bivalent chromatin states, particularly in gastrointestinal and neurodevelopmental tissues, and genetic variants linked to neurodevelopmental disease. We developed a multiplex, single-cell in vivo enhancer assay to discover that rapid sequence divergence in HAQERs generated hominin-unique enhancers in the developing cerebral cortex. We propose that a lack of pleiotropic constraints and elevated mutation rates poised HAQERs for rapid adaptation and subsequent susceptibility to disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)