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George E Fragoulis,1,* Stergios Soulaidopoulos,2,* Petros P Sfikakis,1 Theodoros Dimitroulas,3 George D Kitas4,5 1Rheumatology Unit, Joint Rheumatology Program, Medical School, First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, “Laiko” General Hospital, Athens, 115 27, Greece; 2First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, 115 27, Greece; 3Fourth Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 546 41, Greece; 4Department of Rheumatology, Russells Hall Hospital, Dudley Group NHS FT, Dudley, DY1 2HQ, UK; 5Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, M13 9PT, UK*These authors contributed equally to this workCorrespondence: Stergios SoulaidopoulosFirst Department of Cardiology, National and Kapodistrian University of Athens, 114 Vasilissis Sofias av., Athens, 11527, GreeceTel +306932528561Fax +302132088676Email soulaidopoulos@hotmail.comAbstract: It is increasingly recognized that atherosclerosis and consequently cardiovascular disease (CVD) are closely linked with inflammatory processes. The latter is in the center of the pathogenic mechanism underlying autoimmune rheumatic diseases (ARD). It follows then, that optimal control of inflammation in ARDs may lead to a decrease of the accompanied CVD risk. Major trials (eg, CANTOS, CIRT), aimed at examining the possible benefits of immunomodulatory treatments in CVD, demonstrated conflicting results. On the other hand, substantial evidence is accumulating about the possible beneficial effects of biologic disease modifying antirheumatic drugs (bDMARDs) in patients with ARDs, particularly those with rheumatoid arthritis (RA). It seems that bDMARDs (some more than others) alter the lipid profile in RA patients but do not adversely affect, in most cases, the TC/HDL ratio. Favorable effects are noted for arterial stiffness and endothelial function. This is reflected in the lower risk for CVD events, seen in observational studies of RA patients treated with bDMARDs. It should be stressed that more data exist for the TNF-inhibitors than for other bDMARDs, such as tocilizumab, abatacept and rituximab. As regards the spondyloarthropathies (SpA), data are less robust. For TNF-inhibitors, effects appear to be on par with those seen in RA but no conclusions can be drawn for newer biologic drugs used in SpA (eg, IL-17 blockers). Finally, there is accumulating evidence for a beneficial effect of immunosuppressive treatment in cardiac inflammation and function in several ARDs. Introduction of newer therapeutic options in clinical practice seem to have a positive impact on CVD in the setting of ARD. This is probably due to better control of inflammation, but direct improvement in vascular pathology is also a valid hypothesis. Most data are derived from observational studies and, therefore, randomized controlled trials are needed to assess the possible favorable effect of bDMARDs on CVD outcomes.Keywords: atherosclerosis, cardiovascular disease, biologic agents, interleukins, inflammatory disorders

Although several studies have explored the geoepidemiology of autoimmune rheumatic diseases (ARD), trends of their frequency overtime are under-investigated. Herein, in a nation-wide study, we examine trends in the prevalence of various ARD over-time, taking also into account the Covid-19 pandemic. In this retrospective study in the entire Greek adult population (approximately 10.000.000 people), we searched the electronic prescription database of the e-Government Centre for Social Security Services using prespecified ICD-10 codes to capture all adult patients with Psoriatic Arthritis (PsA), Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS), Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc) and Polymyalgia Rheumatica or Giant Cell Arteritis (PMR/GCA). Two sequential 4-year periods, namely 2016-2019 and 2020-2023 were compared. Prevalence of RA, PsA, AxSpA, SLE and SSc increased significantly during 2020-2023 compared to 2016-2019. This applies to both genders and to all age groups for RA, PsA and AxSpA, to female patients in SLE and SSc and to patients 18-39 years in SLE and ≥ 60 years in SSc. Overall, there was 47% increase in prevalence for AxSpA (0.100% in 2016-19 vs 0.147% in 2020-23), 36.5% for PsA (0.148% vs 0.202%), 20.6% for RA (0.467% vs 0.563%), 19% for SLE (0.137% vs 0.163%) and 13% for SSc (0.023% vs 0.026%). A 16.3% decrease was evident in GCA/PMR, limited to those ≥ 40 years old. In a nation-wide study we confirm that ARD prevalence increases over-time, whereas a contribution of Covid-19 pandemic to our results during 2020-2023, cannot be excluded. Additional human, medical and financial resources will be needed to cover the increased needs of ARD patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Psoriatic arthritis (PsA) is an immune-mediated inflammatory disease with heterogeneity regarding its clinical features, mainly affecting the skin and the musculoskeletal system; additionally, extra-musculoskeletal manifestations and comorbidities are common, adding complexity to its treatment. In the last decades, a plethora of therapeutic options have been available, including conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), and many recommendations have been published regarding the proper use of them in patients with PsA. In rheumatoid arthritis, the combination of conventional with bDMARDs or tsDMARDs is a common and recommended practice, whereas in PsA there is scarce data about the benefit of this combination. This review summarizes all the available data from randomized clinical trials, observational studies, and registries about the value of this therapeutic strategy., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Objective: To present the characteristics of patients with potential difficult-to-treat (D2T) PsA., Methods: We used data from the Greek multicentre registry of PsA patients. D2T PsA was defined as follows: patients with at least 6 months' disease duration, who have failed to at least one conventional synthetic DMARD and at least two biologic DMARDs/targeted synthetic DMARDs with a different mechanism of action and have either at least moderate disease activity (MODA) defined as DAPSA (Disease Activity index in PSoriatic Arthritis) >14, and/or are not at minimal disease activity (MDA). Demographic and clinical characteristics were compared between D2T and non-D2T PsA patients. In two sensitivity analyses, patients classified as D2T solely according to the MODA or MDA criterion were examined separately., Results: Among 467 patients included, 77 (16.5%) were considered D2T and 390 non-D2T PsA. Compared with non-D2T, patients with D2T PsA presented more commonly with extensive psoriasis (P < 0.0001) and were more likely to have higher BMI (P = 0.023) and a history of IBD (P = 0.026). In the MODA and MDA sensitivity analyses, 7.5% and 12.5% of patients were considered D2T, respectively. In both sensitivity analyses, extensive psoriasis was again identified as an independent variable for D2T PsA (P = 0.001 and P = 0.008, respectively). Moreover, female gender (P = 0.034) in the MODA analysis and axial disease (P = 0.040) in the MDA analysis were independent variables for D2T PsA., Conclusion: Despite the availability of therapies, D2T PsA is common in real-life cohorts of patients with PsA and extensive psoriasis. High BMI, female gender, axial disease and history of IBD were also associated with D2T PsA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Data on COVID-19 re-infections in patients with systemic rheumatic diseases (SRDs) are lacking. We aimed to describe the course and outcomes of COVID-19 re-infections in these patients versus controls. In this single-center retrospective study, we included 167 consecutive SRD patients with at least one COVID-19 re-infection (mean age 47.3 years, females 70.7%). SRD patients were compared in terms of patient-perceived COVID-19 re-infection severity and hospitalizations/deaths with 167 age/sex-matched non-SRD controls. Logistic regression analysis was performed to assess potential milder re-infection versus primary infection severity, adjusting for study group, demographics (age, sex), vaccination status, body mass index, smoking, and comorbidities. 23 and 7 out of 167 re-infected SRD patients experienced two and three re-infections, respectively, which were comparable to the re-infection rates in controls (two: 32; and three: 2) who also had comparable COVID-19 vaccination history (89% and 95% vaccinated, respectively). In the initial infection, patients with SRDs were hospitalized (7.2% versus 1.8%, p = 0.017), and had received antiviral treatment (16.1% versus 4.7%, p < 0.001) more frequently than controls. However, hospitalizations (1.8% vs 0.6%) and antiviral treatment (7.8% vs 3.5%) did not differ (p > 0.05) between patients and controls at the first re-infection, as well as during the second and third re-infection; no deaths were recorded. Perceived severity of re-infections was also comparable between patients and controls (p = 0.847) and among those on biologic DMARDs or not (p = 0.482). In multivariable analysis, neither SRDs presence nor demographics or comorbidities were associated with COVID-19 re-infection severity. COVID-19 re-infection severity (patient-perceived/hospitalizations/deaths) did not differ between SRDs and controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Hepatitis B reactivation (HBVr) constitutes a side effect of the treatment of autoimmune rheumatic diseases. Even though HBVr risk of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) and anti-tumor necrosis factor (anti-TNF) agents has long been established, the risk of targeted synthetic (ts)DMARDs and anti-interleukin (anti-IL) agents remains largely unknown., Methods: We conducted a SLR (PubMed, Scopus and EMBASE) and metanalysis to examine the HBVr risk for the following: anti-IL17, anti-IL12/23, anti-IL23 and JAK-inhibitors in patients with chronic HBV infection (HBsAg presence or detectable HBV-DNA) and in patients with prior HBV infection (HBcAb-positive and HBsAg-negative). Meta-analysis was performed using both the fixed and random effects method and was conducted using the R computing language., Results: Overall, our study revealed a low HBVr risk of < 6% in all agents; the risk was significantly higher for people having chronic compared with those with resolved HBV (14,4% vs 5.1%, respectively p< 0.01). There was no difference among different drugs in the HBVr rates [anti-IL-17: 4% (95% CI: 1-9%), anti-IL-12/IL-23: 2% (95% CI: 0-5%), JAK-inhibitors: 4% (95% CI: 1-8%), anti-IL23: 0%]. Of note, HBVr rate reached 28% in patients with chronic HBV who did not receive anti-viral treatment. For patients with resolved hepatitis the respective percentage was 4.7%., Conclusion: Overall, our meta-analysis shows that patients with chronic HBV receiving anti-IL-17, anti-IL-12/23, anti-IL-23 and JAK-inhibitors have significant risk for HBVr, especially if they are not under anti-viral treatment. In contrast, resolved HBV seems to offer minor risk for HBVr even without anti-viral treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To understand (1) what guidance exists to assess the methodological quality of qualitative research; (2) what methods exist to grade levels of evidence from qualitative research to inform recommendations within European Alliance of Associations for Rheumatology (EULAR)., Methods: A systematic literature review was performed in multiple databases including PubMed/Medline, EMBASE, Web of Science, COCHRANE and PsycINFO, from inception to 23 October 2020. Eligible studies included primary articles and guideline documents available in English, describing the: (1) development; (2) application of validated tools (eg, checklists); (3) guidance on assessing methodological quality of qualitative research and (4) guidance on grading levels of qualitative evidence. A narrative synthesis was conducted to identify key similarities between included studies., Results: Of 9073 records retrieved, 51 went through to full-manuscript review, with 15 selected for inclusion. Six articles described methodological tools to assess the quality of qualitative research. The tools evaluated research design, recruitment, ethical rigour, data collection and analysis. Seven articles described one approach, focusing on four key components to determine how much confidence to place in findings from systematic reviews of qualitative research. Two articles focused on grading levels of clinical recommendations based on qualitative evidence; one described a qualitative evidence hierarchy, and another a research pyramid., Conclusion: There is a lack of consensus on the use of tools, checklists and approaches suitable for appraising the methodological quality of qualitative research and the grading of qualitative evidence to inform clinical practice. This work is expected to facilitate the inclusion of qualitative evidence in the process of developing recommendations at EULAR level., Competing Interests: Competing interests: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Fresenius-Kabi, Lilly and holds research grants from Pfizer and Lilly., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Programmed cell death protein-1 (PD-1) maintains peripheral immune tolerance by preventing T cell continuous activation. Aiming to understand the extent of PD-1 expression in inflammatory arthritis beyond its involvement with T cells, we assess its presence on various circulating single cells., Methods: Mass cytometry analysis of patients with active seropositive/seronegative rheumatoid (RA; n=9/8) and psoriatic (PsA; n=9) arthritis versus healthy controls (HC; n=13), re-evaluating patients after 3 months of anti-rheumatic treatment., Results: PD-1 was expressed in all leukocyte subpopulations, with the highest PD-1 + cell frequencies in eosinophils (59-73%) and T cells (50-60%), and the lowest in natural-killer cells (1-3%). PD-1 + cell frequencies and PD-1 median expression were comparable between patient subgroups and HC, in the majority of cell subsets. Exceptions included increases in certain T cell/B cell subsets of seropositive RA and specific monocyte subsets and dendritic cells of PsA; an expanded PD-1 + CD4 + CD45RA + CD27 + CD28 + T subset, denoting exhausted T cells, was common across patient subgroups. Strikingly, significant inverse correlations between individual biomarkers of systemic inflammation (ESR and/or serum CRP) and PD-1 + cell frequencies and/or median expression were evident in several innate and adaptive immunity cell subsets of RA and PsA patients. Furthermore, all inverse correlations noted in individuals with active arthritis were no longer discernible in those who attained remission/low disease activity post-treatment., Conclusion: PD-1 expression may be insufficient, relative to the magnitude of the concomitant systemic inflammatory response on distinct leukocyte subsets, varying between RA and PsA. Our results point to the potential therapeutic benefits of pharmacological PD-1 activation, to rebalance the autoimmune response and reduce inflammation., 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 Vetsika, Fragoulis, Kyriakidi, Verrou, Tektonidou, Alissafi and Sfikakis.)

Objectives: Patients with RA were at increased risk for COVID-19-associated hospitalization and death during the first year of the pandemic in Greece. We aimed to examine their outcomes after the SARS-Cov-2 Omicron, a more contagious but with milder clinical impacts variant, prevailed., Methods: A retrospective, nationwide study was conducted between 1 January 2022 and 30 June 2022 in all RA patients under treatment and matched (1:5) on age, sex and region of domicile random general population comparators. Confirmed SARS-CoV-2 infections, hospitalizations and deaths, anti-rheumatic medications, prior COVID-19, vaccinations and anti-viral medications were recorded., Results: Among 34 182 RA patients, infections (n = 5569, 16.29%), hospitalizations (n = 489, 1.43%) and deaths (n = 106, 0.31%) were more frequent than among comparators. Incidence rates per 1000 person/years of infection [IRR (95% CI):1.19 (1.16, 1.23)], hospitalization [IRR (95% CI):2.0 (1.82, 2.24)], and death [IRR (95% CI):1.81 (1.44, 2.27)] were increased in RA despite better vaccination coverage (89% vs 84%) and more frequent use of anti-viral medications (2.37% vs 1.08). Logistic regression analysis after correcting for age, sex, vaccinations, prior COVID-19, and anti-viral medications in SARS-CoV-2 infected RA patients and comparators revealed increased risk of hospitalization (OR: 2.02, 95% CI: 1.79, 2.27) and death [OR: 1.73, (95% CI: 1.36, 2.20)] in RA. Among infected RA patients, rituximab treatment conferred increased risks for hospitalization [OR: 6.12, (95% CI: 2.89, 12.92)] and death [OR: 12.06 (95% CI: 3.90, 37.31)], while JAK inhibitors increased only hospitalization risk [OR: 2.18 (95% CI: 1.56, 3.06)]., Conclusion: RA remains a risk factor for hospitalization and death in an era of a relatively low COVID-19 fatality rate, pointing to the need of perseverance in vaccination programs and wider use of anti-viral medications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Chronic systemic inflammation contributes to increased CVD burden in Ankylosing Spondylitis (AS). Since long-term follow-up data on subclinical atherosclerosis acceleration are lacking, we examined its progression in contemporary AS patients during 10 years. Fifty-three (89% male, aged 50.4 (36.3-55.9) years,) non-diabetic, CVD-free AS patients and 53 age-sex-matched non-diabetic, control individuals were re-evaluated after 9.2-10.2 years by ultrasonography for carotid/femoral atheromatosis, pulse wave velocity (PWV) and intima-media thickness (IMT), performed by the same operator/protocol. New atheromatic plaque formation, PWV deterioration, and IMT increase were associated only with classical CVD risk factors, as reflected by the heartSCORE (age, gender, smoking status, blood pressure and cholesterol levels) by multivariate analysis, rather than disease presence. However, among AS patients, despite remission/low disease activity at follow-up end in 79%, atheromatosis progression was associated by multivariate analysis with higher BASDAI scores (p = 0.028), independently of biologic therapies administered in 2/3 of them. Moreover, in AS patients, but not in controls, PWV values at baseline were associated with plaque progression during the 10-year follow-up after taking into account baseline heartSCORE and plaque burden status (p = 0.033). Despite comparable prevalence of both hypertension and hypercholesterolemia at baseline between patients and controls, a lower percentage of AS patients had achieved "adequate" CVD risk factor control at follow-up end (11% vs 25% respectively, p = 0.076). Classical CVD risk factors and residual disease activity account for the progression of subclinical atherosclerosis in AS, pointing to the unmet needs in the contemporary management of these patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As our research interest and knowledge increases in the field of Spondyloarthritis, new aspects also emerge as regards to their therapeutic approach. JAK inhibitors (JAKi) are a relatively new treatment option, aiming molecules in the JAK-STAT pathway, which has a leading role in the pathophysiology of both Psoriatic Arthritis and Axial Spondyloarthritis. JAKi exhibit different selectivity towards the four different members of the JAK family (namely JAK1, JAK2, JAK3, and TYK2), possibly reflecting different efficacy and safety profile. Although knowledge is more consolidated for rheumatoid arthritis in which JAKi are being used for more than 10 years, data are still accumulating for PsA/SpA. In this review we aim to present and assess current knowledge about the efficacy of JAKi (with a focus on selective JAKi) in the treatment of patients with SpA and evaluate their safety profile as some concerns may arise around this therapeutic option., Competing Interests: The authors declare no conflict of interest., (© 2024 The Mediterranean Journal of Rheumatology (MJR).)

Objectives: A reduced adrenal reserve-associated cortisol production relative to the enhanced needs of chronic inflammation ( disproportion principle ) has been observed in rheumatoid arthritis (RA). We examined the possible clinical value of diurnal cortisol measurements in active RA on treatment response prediction., Methods: Diurnal cortisol production (measured at: 08-12:00/18:00-22:00) was assessed by electrochemiluminescence immunoassay in 28 consecutive patients with moderately/highly active RA, as well as 3 and 6 months after treatment initiation or/escalation. Twenty-eight COVID-19 patients and 28 age-matched healthy individuals (HC) served as controls., Results: Saliva diurnal cortisol production in patients with RA was similar to that of HC, despite 12-fold higher serum C reactive protein (CRP) levels, and lower than COVID-19 patients (area under the curve: RA: 87.0±37.6 vs COVID-19: 146.7±14.3, p<0.001), having similarly high CRP. Moreover, a disturbed circadian cortisol rhythm at baseline was evident in 15 of 28 of patients with RA vs 4 of 28 and 20 of 28 of HC and COVID-19 patients, respectively. Treatment-induced minimal disease activity (MDA) at 6 months was achieved by 16 of 28 patients. Despite comparable demographics and clinical characteristics at baseline, non-MDA patients had lower baseline morning cortisol and higher adrenocorticotropic hormone (ACTH) levels compared with patients on MDA (cortisol: 10.9±4.0 vs 18.4±8.2 nmol/L, respectively, p=0.005 and ACTH: 4.8±3.3 vs 2.4±0.4 pmol/L, respectively, p=0.047). Baseline morning cortisol <13.9 nmol/L predicted non-MDA at 6 months (75% sensitivity, 92% specificity, p=0.006). Prospective measurements revealed that individualised diurnal cortisol production remained largely unchanged from baseline to 3 and 6 months., Conclusions: An impaired adrenal reserve is present in patients with RA. Further studies to confirm that assessment of diurnal cortisol production may be useful in guiding treatment decisions and/or predicting treatment response in RA are warranted., Trial Registration Number: NCT05671627., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Psoriatic arthritis (PsA) is a heterogenous chronic inflammatory disease affecting skin, joints, entheses, and spine with various extra-musculoskeletal manifestations and comorbidities. The reported patient, disease and treatment characteristics in the modern therapeutic era are limited., Methods: In this cross-sectional, multi-centre, nationwide study, we recorded the demographic, clinical, and therapeutic characteristics as well as the comorbidities of patients with PsA seen for 1 year (1/1/2022-31/12/2022)., Results: 923 patients (55% females) with a median (IQR) age of 57 (48-65) years and a mean disease duration of 9.5 years were enrolled. Family history of psoriasis and PsA was noted in 28.3% and 6.3%, respectively. Most patients had limited psoriasis (BSA<3: 83%) while enthesitis, dactylitis, nail and axial involvement reported in 48.3%, 33.2%, 43% and 25.9% of patients, respectively. Regarding comorbidities, approximately half of patients had dyslipidaemia (42%) or hypertension (45.4%), 36.8% were obese and 17% had diabetes while 22.7% had a depressive disorder. Overall, 60.1% received biologics and among them more patients treated with anti-IL-17 or -12/23 agents were on monotherapy (64.2%) compared to those on TNFi monotherapy (49.4%, p=0.0001). The median PsA activity as assessed by the DAPSA score was 6 (IQR: 2.3 - 13.1) with 46% of patients reaching minimal disease activity status (MDA)., Conclusion: In this large, real life, modern cohort of patients with PsA with frequent comorbidities who were treated mainly with biologics, almost half achieved minimal disease activity. These results show the value of existing therapeutic approaches while at the same time highlight the existing unmet needs., Competing Interests: The authors declare no conflict of interest., (© 2023 The Mediterranean Journal of Rheumatology (MJR).)

Objectives: The abnormal DNA damage response is associated with upregulation of the type-1 interferon (IFN-I) pathway in certain rheumatic diseases. We investigated whether such aberrant mechanisms operate in psoriatic arthritis (PsA)., Methods: DNA damage levels were measured by alkaline comet assay in peripheral blood mononuclear cells from 52 PsA patients and age-sex-matched healthy individuals. RNA expression of IFIT1 , MX1 and IFI44 , which are selectively induced by IFN-I, was quantitated by real-time polymerase chain reaction and their composite normalized expression resulted in IFN-I score calculation. RNA expression of IL1β , IL6 , TNF , IL17A and IL23A was also assessed in PsA and control subgroups., Results: In PsA, DNA damage accumulation was increased by almost two-fold compared to healthy individuals (olive tail moment arbitrary units, mean ± SD; 9.42 ± 2.71 vs 4.88 ± 1.98, p<0.0001). DNA damage levels significantly correlated with serum C-Reactive-protein and IL6 RNA expression in PBMCs. Despite increased DNA damage, the IFN-I score was strikingly lower in PsA patients compared to controls (-0.49 ± 6.99 vs 4.24 ± 4.26; p<0.0001). No correlation was found between IFN-I pathway downregulation and DNA damage. However, the IFN-I score in a PsA subgroup was lower in those patients with higher IL1β expression, as well as in those with higher TNF / IL23A PBMCs expression., Conclusion: DNA damage in PsA correlates with measures of inflammation but is not associated with the IFN-I pathway induction. The unexpected IFN-I downregulation, albeit reminiscent to findings in experimental models of spondyloarthritis, may be implicated in PsA pathogenesis and explained by operation of other cytokines., Competing Interests: GF: honoraria/speaker fees: Pfizer, Novartis, Abbvie, AEnorasis. UCB, Janssen, Lilly. IM: honoraria/speaker fees/grants: Astra Zeneca, Abbvie, GSK, Lilly, Evelo, Causeway, Cabaletta, Compugen, Janssen, Novartis, Pfizer, UCB. MT: consultant fees and unrestricted grants from AbbVie, GSK, Genesis, MSD, Novartis, Pfizer and UCB deposited to the Special Account for Research Funding ELKE of the National and Kapodistrian University of Athens Medical School. PS: consultant fees and unrestricted grants from AbbVie, Pfizer, MSD, Roche, UCB, GSK, Novartis deposited to the Special Account for Research Funding ELKE of the National and Kapodistrian University of Athens Medical School. The remaining 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 © 2023 Fragoulis, Ntouros, Nezos, Vlachogiannis, McInnes, Tektonidou, Skarlis, Souliotis, Mavragani and Sfikakis.)

Introduction: This study aimed to determine whether the introduction of anti-SARS-CoV-2 vaccines and the dominance of the omicron variant had a significant impact on the outcome of COVID-19 in patients with systemic autoimmune rheumatic diseases (SAIRDs)., Methods: Using data entered to the Greek Rheumatology Society COVID-19 registry, we investigated the incidence of hospitalization and death due to COVID-19, during the successive periods of the pandemic according to the prevalent strain (wild-type, Alpha, Delta, Omicron) in vaccinated and unvaccinated patients. Variables independently associated with hospitalization and death were explored using multivariate regression analyses, while Kaplan-Meier curves were used to depict survival data., Results: From August 2020 until June 30, 2022, 456 cases (70.2% females) of COVID-19 with a mean age (± SD) of 51.4 ± 14.0 years were reported. In unvaccinated patients, the proportions of hospitalization and death were 24.5% and 4%, compared to 12.5% and 0.8% in the vaccinated group (p < 0.001 for both comparisons). The rates of hospitalization for the wild-type, Alpha, Delta, and Omicron periods were 24.7%, 31.3%, 25.9%, and 8.1% respectively (p < 0.0001), while the case fatality rates were 2.7%, 4%, 7%, and 0%, respectively (p = 0.001). Using multivariable regression analysis, factors independently associated with hospitalization were infection by a non-Omicron variant, being non-vaccinated, exposure to rituximab, older age, and respiratory and cardiovascular disease. Independent predictors for death were contracting COVID-19 during the Alpha or Delta period, pulmonary disease, and older age, while being vaccinated was protective., Conclusions: In this 2-year analysis, the rates of hospitalization and death among patients with SAIRDs have declined significantly. Vaccination and the dominance of the Omicron variant appear to be the major determinants for this shift. Key points • During the late phase of the pandemic, the proportion of severe COVID-19 cases, defined as requiring hospitalization or resulting in death, in patients with systemic autoimmune rheumatic diseases has declined. • Anti-SARS-CoV-2 vaccination and the dominance of the Omicron strain are the key factors that have independently contributed to this shift., (© 2023. The Author(s).)

Background/objective: Data on risk factors predicting uveitis development in spondyloarthritis (SpA) is scarce. Our aim was to examine associations between demographic, clinical and/or laboratory characteristics of SpA with the occurrence and the course of uveitis, including ocular damage and recurrence rate., Methods: Characteristics (at disease diagnosis and ever-present) from axSpA and Psoriatic arthritis (PsA) patients followed in 3 tertiary rheumatology-clinics were retrospectively recorded. Comparisons were made between patients with and without uveitis, as well as between those with uveitis-rate [episodes/year] above the median uveitis-rate in the whole cohort ("recurrent"-uveitis) and the remaining uveitis patients ("non-recurrent uveitis"). In multivariable models, age, gender and variables significantly different in univariate analyses were included., Results: 264 axSpA and 369 PsA patients were enrolled. In axSpA, uveitis occurred in 11.7% and was associated with HLA-B27 (OR = 4.15, 95%CI 1.16-14.80, p = 0.028) and ever-present peripheral arthritis (OR = 3.05 (1.10-8.41, p = 0.031). In contrast, uveitis in PsA occurred only in 2.7% of patients and was associated with SpA family-history (OR = 6.35 (1.29-31.27), p = 0.023) axial disease at diagnosis (OR = 5.61 [1.01-28.69], p = 0.038) and disease duration (OR = 1.12 [1.04-1.21], p = 0.004). Median uveitis recurrence rate was comparable between axSpA and PsA (0.205 and 0.285 episodes/year, respectively). No associations were found between recurrent uveitis and demographic/clinical/laboratory characteristics. Ocular damage (e.g. synechiae) was seen in 16.1% of axSpA and 30% of PsA patients, all of them with recurrent uveitis., Conclusion: Uveitis occurred more commonly in axSpA than in PsA patients, while uveitis recurrence rate was similar. Permanent ocular damage may occur more often in PsA than axSpA., (© 2023. The Author(s).)

Objective: The objective of this study was to assess the possibility of HBV reactivation (HBVr) in patients with RA under anti-IL-6 treatment., Methods: Using PubMed, Scopus and EMBASE, we performed a systematic literature search for articles related to HBVr in RA patients under anti-IL-6 treatment. The search was performed with no date limits and was last updated 28 January 2023. The results from all the databases were combined and duplicates were excluded, as were non-English articles, case reports, position articles, comments, and paediatric studies., Results: Our initial search led to 427 articles; 28 were duplicates, 46 non-English, 169 reviews, 31 books/letters, 25 case reports, and 88 irrelevant to the meta-analysis aim; 21 were excluded due to inadequate information, leaving 19 articles, with a sum of 372 RA patients with chronic HBV (CHB) or resolved HBV infection, for further analysis. The overall risk for HBVr in RA patients with CHB was 6.7%, increasing to 37% when only RA patients with CHB and no antiviral prophylaxis were included. On the contrary, HBVr was close to 0% in RA patients with resolved HBV infection, irrespective of antiviral prophylaxis. All RA patients experiencing HBVr in these studies were successfully managed with antiviral treatment and/or drug withdrawal., Conclusion: Overall, anti-IL-6 treatment comes with a significant risk of HBVr in RA patients with CHB; risk is diminished when antiviral prophylaxis is used. In contrast, in RA patients with resolved HBV infection, the risk of HBVr seems to be extremely low. Large, well-designed studies (either controlled trials or multicentre/international observational studies) are warranted to further validate these results., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Inflammatory rheumatic diseases (IRDs), such as rheumatoid arthritis (RA) and spondyloarthropathy (SpA), comprise a heterogeneous group of immune-mediated disorders, characterised by the presence of localised and/or systemic inflammation. The limited knowledge of the pathogenesis and the complex mechanisms involved in the induction and maintenance of inflammation in IRDs have impeded the development of reliable biomarkers and the discovery of new therapeutic targets. Although the involvement of heterogeneous cell populations in the pathogenesis of IRDs has been recognised, the characterisation of these cellular subsets in the peripheral blood of patients has not been studied yet. Mass cytometry, allowing the simultaneous detection of more than 120 different parameters in single-cell resolution, will enable the identification of circulating cell subpopulations that might play a pivotal role in IRDs pathophysiology and their potential use as therapeutic targets., Competing Interests: The authors declare no conflict of interest., (© 2024 The Mediterranean Journal of Rheumatology (MJR).)

Mass cytometry was employed to investigate 47 circulating leukocyte subsets in patients with active psoriatic arthritis (PsA, n = 16) compared to healthy controls (n = 13), seropositive (RF and/or anti-CCP, n = 12) and seronegative (n = 9) RA patients. Comparing PsA to controls, different cell frequencies were found in both innate and adaptive immunity cell subsets, as well as in cells bridging innate and adaptive immunity. In some T cell subsets increased costimulatory molecules' expression in PsA, was also noted.No changes were observed in patients who remained disease-active after 3 months of treatment, in contrast to those who achieved remission/low-disease activity. Comparing PsA to seropositive RA, elevated frequencies of naïve and activated CD8 + T cells, B cells, MAIT/iNKT and ILCs were found, while the opposite was the case for terminal effector, senescent, and Th2-like cells. Strikingly, the composition of the leukocyte pool in PsA was comparable to seronegative RA, providing evidence for the pathogenetic similarities between these two entities., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Physical activity (PA) is a key strategy for improving symptoms in people with rheumatic and musculoskeletal diseases (RMDs). The aim of this study was to investigate and rank the importance of known barriers and facilitators for engaging in PA, from the perspective of people living with RMD. Five hundred thirty-three people with RMD responded to a survey (nine questions) disseminated by the People with Arthritis and Rheumatism (PARE) network of the European Alliance of Associations for Rheumatology (EULAR). The survey required participants to rank - based on their perceived importance - known PA barriers and facilitators from the literature, and specifically RMD symptoms as well as healthcare and community factors that may affect PA participation. Of the participants, 58% reported rheumatoid arthritis as their primary diagnosis, 89% were female, and 59% were between 51 and 70 years of age. Overall, participants reported fatigue (61.4%), pain (53.6%) and painful/swollen joints (50.6%) as the highest ranked barriers for engaging in PA. Conversely, less fatigue (66.8%) and pain (63.6%), and being able to do daily activities more easy (56.3%) were identified as the most important facilitators to PA. Three literature identified PA barriers, i.e., general health (78.8%), fitness (75.3%) and mental health (68.1%), were also ranked as being the most important for PA engagement. Symptoms of RMDs, such as pain and fatigue, seem to be considered the predominant barriers to PA by people with RMD; the same barriers are also the ones that they want to improve through increasing PA, suggesting a bi-directional relationship between these factors. Key Points • Symptoms of rheumatic and musculoskeletal disease (RMD) are the predominant barriers for lack of physical activity engagement. • RMD symptoms are the factors that people with RMDs want to improve when engaging in PA. • The barriers that stop people living with RMDs to do more PA are the ones that can be significantly improved through PA engagement., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Qualitative data on how the COVID-19 pandemic has affected the lives of people with rheumatic and musculoskeletal diseases (RMDs) in different European countries are lacking., Objectives: To describe the impact of the first two waves of the COVID-19 pandemic on people with inflammatory RMDs concerning (self)management of their disease, interaction with the health care team, emotional well-being and overall health., Methods: A mixed-methods study of adults (>18 years) with RMDs on immunosuppression from Cyprus, England, Greece, and Portugal took part on online focus groups (FG) after the first wave (July-August, 2020). The data was transcribed verbatim and thematically analyzed. Informed by the qualitative findings, a follow-up survey was developed for the same participants after the second wave, allowing to compare the perceived impact., Results: Twenty-four patients (6 from each country; 21 women; 33-74 years range) participated. Three key themes were identified (with 3-7 subthemes each), focusing on the impact of COVID-19 on the: (i) individual, (ii) health settings, and (iii) work and community. Overall, qualitative results were similar across countries. The follow-up survey during the second wave highlighted a worsening of psychosocial aspects, e.g. sleep problems, stress, and isolation., Conclusions: People with RMDs felt vulnerable and anxious, specifically about how to cope with isolation and difficulties in communicating with healthcare providers. The second wave had a more significant impact on patients. Healthcare providers and policymakers need to consider measures to ameliorate the longer-term impact that many may still face.

Background: Overweight and/or obese patients with inflammatory arthritis (IA) have higher disease activity and lower chances of achieving and/or maintaining the treatment targets. Weight/obesity also appears to negatively affect the response to tumor necrosis factor (TNF) inhibitors in IA patients, including rheumatoid arthritis -RA, psoriatic arthritis -PsA, axial spondyloarthritis -AxSpA. We conducted a systematic literature review (SLR) for the effect of weight/body-mass-index (BMI) in the efficacy of all approved biologic (b) and targeted-synthetic (ts) DMARDs for the treatment of IA., Methods: For this PROSPERO-registered SLR, we searched PubMed, Scopus and Cohrane-Library from inception up to June 21st 2022. Clinical-trials (randomized and non-randomized) and observational studies of RA, PsA or AxSpA patients that reported the effect of weight/BMI on response (all possible outcomes) to b/ts-DMARDs were included. Risk-of-bias was assessed via RoB2-Cochrane-tool and Newcastle-Ottawa-scale for randomized and non-randomized studies, respectively., Findings: Out of 996 references, 75 eventually fulfilled the inclusion criteria (of which 10 studies were retrieved through manual-search). Among the included studies (TNF-inhibitors: 34, IL-12/23 inhibitors: 4, IL-23 inhibitor: 1, IL-17 inhibitors: 7, tocilizumab: 18, abatacept: 8, rituximab: 3, JAK-inhibitors: 5), most had medium RoB. Efficacy of TNF-inhibitors was affected by BMI in all forms of IA. Data are not robust to compare the effect among various TNF-inhibitors. In contrast, favorable results of IL-23 and IL-17 inhibitors did not appear to be influenced by increased BMI in PsA or AxSpA patients. Similar evidence exists for tocilizumab (in RA) and for abatacept (in RA and PsA), while no conclusion can be drawn for rituximab. More data are needed for JAK-inhibitors, although the effect of weight/BMI does not seem to be significant so far., Interpretation: Weight/BMI should be considered in the treatment-plan of IA patients, with its effect being more pronounced for TNF-inhibitors compared to other b/ts-DMARDs., Competing Interests: Declaration of Competing Interest CGG: none. MP: none. GE: None. EN: honoraria/speaker fees from Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Fresenius; research grants from Pfizer and Lilly. GEF: GEF has received honoraria/speaker fees from AbbVie, Genesis, Pfizer, Novartis, Lilly, UCB, Janssen, Amgen and Aenorasis., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To develop EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in patients with autoimmune inflammatory rheumatic diseases (AIIRD)., Methods: An international Task Force (TF) (22 members/15 countries) formulated recommendations, supported by systematic literature review findings. Level of evidence and grade of recommendation were assigned for each recommendation. Level of agreement was provided anonymously by each TF member., Results: Four overarching principles (OAP) and eight recommendations were developed. The OAPs highlight the need for infections to be discussed with patients and with other medical specialties, in accordance with national regulations. In addition to biologic/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for which screening for latent tuberculosis (TB) should be performed, screening could be considered also before conventional synthetic DMARDs, glucocorticoids and immunosuppressants. Interferon gamma release assay should be preferred over tuberculin skin test, where available. Hepatitis B (HBV) antiviral treatment should be guided by HBV status defined prior to starting antirheumatic drugs. All patients positive for hepatitis-C-RNA should be referred for antiviral treatment. Also, patients who are non-immune to varicella zoster virus should be informed about the availability of postexposure prophylaxis should they have contact with this pathogen. Prophylaxis against Pneumocystis jirovecii seems to be beneficial in patients treated with daily doses >15-30 mg of prednisolone or equivalent for >2-4 weeks., Conclusions: These recommendations provide guidance on the screening and prevention of chronic and opportunistic infections. Their adoption in clinical practice is recommended to standardise and optimise care to reduce the burden of opportunistic infections in people living with AIIRD., Competing Interests: Competing interests: GEF: Consulting fees/honoraria: Pfizer, Abbvie, Novartis, UCB, AENorasis, Janssen, Pharmaserv-Lilly. EN: speaker fees/honoraria: Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Fresenius. Research funding: Pfizer, Lilly. MD: none SZ: consulting fees: UCBDC: None. LA: has received consulting fees and/or research funding from Astra-Zeneca, GSK, Pfizer. FA: none. GMNB: has received consulting fees/honoraria as speaker from Gilead, ViiV Healthcare, Janssen, MSD, Roche, Moderna unrelated to this work. JWJB: none PB: none CAC: none SG-D: none MCK: none KL: has received consulting/speaker fees from Pfizer, Viatris, Celltrion outside of the submitted work. ML: none. JM: none GN: consulting fees/honoraria as speaker from AbbVie, Amgen, Boehringer Ingelheim, Janssen, Miltenyi Biotech, Lilly, Pfizer, Roche unrelated to this work. EP: consulting fees/honoraria as speaker from Bayer, Menarini, Grifols, Zambon, Pfizer, Chiesi, Teva, Shire, Shionogi, Insmed, Boehringer-Ingelheim, unrelated to this work. JvR: none MS: consulting fees: BMS, Boehringer-Ingheleim, Eli Lilly, Celltrion, Amgen, Pfizer, Janssen Cilag. AS: has received consulting fees/honoraria as speaker from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Pfizer, Roche unrelated to this workAdT: none JG: speaker fees/honoraria: Abbvie, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB. Research funding: Abbvie, Astrazeneca, Galapagos, Gilead, Gritstone, Janssen, Moderna, Novovax, PfizerKH: honoraria from Abbvie; grant income from Pfizer and BMS., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ongoing education of health professionals in rheumatology (HPR) is critical for high-quality care. An essential factor is education readiness and a high quality of educational offerings. We explored which factors contributed to education readiness and investigated currently offered postgraduate education, including the European Alliance of Associations for Rheumatology (EULAR) offerings., Methods and Participants: We developed an online questionnaire, translated it into 24 languages and distributed it in 30 European countries. We used natural language processing and the Latent Dirichlet Allocation to analyse the qualitative experiences of the participants as well as descriptive statistics and multiple logistic regression to determine factors influencing postgraduate educational readiness. Reporting followed the Checklist for Reporting Results of Internet E-Surveys guideline., Results: The questionnaire was accessed 3589 times, and 667 complete responses from 34 European countries were recorded. The highest educational needs were 'professional development', 'prevention and lifestyle intervention'. Older age, more working experience in rheumatology and higher education levels were positively associated with higher postgraduate educational readiness. While more than half of the HPR were familiar with EULAR as an association and the respondents reported an increased interest in the content of the educational offerings, the courses and the annual congress were poorly attended due to a lack of awareness, comparatively high costs and language barriers., Conclusions: To promote the uptake of EULAR educational offerings, attention is needed to increase awareness among national organisations, offer accessible participation costs, and address language barriers., Competing Interests: Competing interests: VR, LS, MRRA, MB, CB, JC, TD, JdlT, AdT, AD, FE-L, RJOF, GEF, JG, KK, MLK, CM-B, AM, JM, RHM, ElM, ErM, CN-S: no competing interest to declare. RD: Speaker fees from Abbvie, Elly Lilly, EwoPharma, Sandoz, and Novartis, all outside the submitted work., (© 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.)

There are limited data regarding cycling between interleukin-17 (IL-17) inhibitors in psoriatic arthritis (PsA). We aimed to report the efficacy of an IL-17 inhibitor (ixekizumab-IXE) after inadequate response (IR) of another one (secukinumab-SEC) in patients with PsA. Case series of PsA patients who received IXE after SEC-IR in four rheumatology centers between 1/9/2021 and 1/9/2022 were included. Peripheral arthritis was assessed with disease activity in psoriatic arthritis score (DAPSA) and skin involvement with body surface area (BSA). Axial disease was defined as having both imaging and clinical features and its activity was measured with the ankylosing spondylitis disease activity score (ASDAS). Twenty-four patients (54.2% female, mean [SD] age: 51.6 [14.1]) who were SEC-IR and received IXE either immediately (n = 11) or after ≥ 1 interposed biologic disease modifying anti-rheumatic drug (bDMARD) (n = 13) were included. Patients were followed on IXE for a mean [SD] period of 9.6 [4.9] months. Among patients with peripheral arthritis (n = 24), the mean [SD] DAPSA decreased from 22.8 [8.6] to 13.6 [7.8] during follow-up (p =  0.0001) with 62.5% of patients showing improvement in the DAPSA disease activity categories. For patients with axial involvement (n = 16), a clinically meaningful improvement (Δ ≥ 1.1 in ASDAS) was noted in 50% (8/16), while dactylitis and enthesitis resolution was observed in 60% (3/5) and 83% (5/6) of patients, respectively. Regarding psoriasis, the mean [SD] BSA of involved skin decreased from 8.7 [8.7] to 2.4 [3.3] (p =  0.001). In this case series, treatment with IXE after inadequate response to another IL-17 inhibitor (SEC) was efficacious in a real-world setting in patients with PsA, including axial disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aging is characterized by the progressive deregulation of homeostatic mechanisms causing the accumulation of macromolecular damage, including DNA damage, progressive decline in organ function and chronic diseases. Since several features of the aging phenotype are closely related to defects in the DNA damage response (DDR) network, we have herein investigated the relationship between chronological age and DDR signals in peripheral blood mononuclear cells (PBMCs) from healthy individuals. DDR-associated parameters, including endogenous DNA damage (single-strand breaks and double-strand breaks (DSBs) measured by the alkaline comet assay (Olive Tail Moment (OTM); DSBs-only by γH2AX immunofluorescence staining), DSBs repair capacity, oxidative stress, and apurinic/apyrimidinic sites were evaluated in PBMCs of 243 individuals aged 18-75 years, free of any major comorbidity. While OTM values showed marginal correlation with age until 50 years (r s = 0.41, p = 0.11), a linear relationship was observed after 50 years (r = 0.95, p < 0.001). Moreover, individuals older than 50 years showed increased endogenous DSBs levels (γH2Ax), higher oxidative stress, augmented apurinic/apyrimidinic sites and decreased DSBs repair capacity than those with age lower than 50 years (all p < 0.001). Results were reproduced when we examined men and women separately. Prospective studies confirming the value of DNA damage accumulation as a biomarker of aging, as well as the presence of a relevant agethreshold, are warranted.

Primary diagnosis of celiac disease (CD) in rheumatology department is not common in daily clinical practice, due to the fact that diarrhoea is usually the dominant symptom. Extra-intestinal manifestations, such as arthralgia, myalgia, osteomalacia, and osteoporosis are not rare in these patients. We present a case of a 66-year-old man, who came to the outpatient rheumatology clinic, complaining of back and knee pain. Osteopenia was observed in plain radiographs, whereas extensive laboratory testing revealed celiac disease, vitamin D deficiency, and extremely low bone mineral density (BMD) due to osteomalacia. Gluten-free diet (GFD) initiation and administration of vitamin D and calcium supplements resulted in significant symptom and BMD improvement over 6 months. A significant proportion of CD patients might present with arthralgia, arthritis, back pain, myalgia, or bone pain. Importantly, up to 75% of patients might have reduced BMD, due to osteoporosis or osteomalacia, while they also carry a significant risk for fracture. However, the introduction of GFD and calcium/vitamin D supplementation significantly ameliorates symptoms and BMD in most cases. Increased awareness of CD's musculoskeletal manifestations by rheumatologists is important for early recognition and management of this condition and its complications., Competing Interests: Authors declare no conflicts of interest for this case report., (© 2023 The Mediterranean Journal of Rheumatology (MJR).)

As life expectancy increases, psoriatic arthritis (PsA) in older individuals becomes more prevalent. We explored whether late-onset versus earlier-onset PsA patients display different clinical features at diagnosis and/or during the disease course, as well as different treatment approaches and comorbidity profiles. We retrospectively collected data from consecutive PsA patients attending two rheumatology centers (December 2017-December 2022). Late-onset PsA patients (diagnosis-age: ≥60 years) were compared to those diagnosed before 60 years old. Univariate analyses and logistic regression were performed to examine for factors associated with late-onset PsA. For sensitivity analyses, the cohort's mean diagnosis age was used as the cut-off value. Overall, 281 PsA patients were included (mean ± SD diagnosis-age: 46.0 ± 13.3 years). Of them, 14.2% (N = 40) had late-onset PsA. At diagnosis, after controlling for confounders, no demographic and clinical differences were identified. During the disease course, the late-onset group exhibited 65% fewer odds of manifesting enthesitis (adjusted Odds-ratio-adOR 0.35; 95% confidence interval 0.13-0.97), but higher frequency of dyslipidemia (adOR 3.01; 1.30-6.95) and of major adverse cardiovascular events (adOR 4.30; 1.42-12.98) compared to earlier-onset PsA group. No differences were found in the treatment approaches. In sensitivity analyses, PsA patients diagnosed after 46 (vs. ≤46) years old had an increased frequency of hypertension (adOR 3.18; 1.70-5.94) and dyslipidemia (adOR 2.17; 1.25-3.74). The present study underpins that late-onset PsA is not uncommon, while the age at PsA onset may affect the longitudinal clinical expression of the disease. Patients with late-onset PsA were less likely to manifest enthesitis but displayed increased cardiovascular risk.

Objectives: To investigate coronavirus disease 2019 (COVID-19)-associated risk of hospitalization and death in RA, AS, PsA, SLE and SSc in comparison with the general population during the first year of the pandemic, and compare their overall mortality with 2019., Methods: Interlinking nationwide electronic registries, we recorded confirmed COVID-19-associated infections, hospitalizations and deaths, and all-cause deaths between 1 March 2020 and 28 February 2021 in all adults with RA, AS, PsA, SLE and SSc under treatment (n = 74 970, median age 67.5, 51.2, 58.1, 56.2 and 62.2 years, respectively) and in random comparators from the general population matched (1:5) on age, sex and region of domicile. Deaths from all causes during 2019 were also recorded., Results: Compared with the general population, incidence rates (IR) for COVID-19-associated hospitalization were higher in RA [IR ratio (IRR) 1.71(1.50-1.95)], SLE [2.0 (1.4-2.7)] and SSc [2.28 (1.29-3.90)], while COVID-19-associated death rates were higher in RA [1.91 (1.46-2.49)]. When focusing only on severe acute respiratory syndrome coronavirus 2-infected subjects, after adjusting for age and gender, the odds ratio for COVID-19 associated death was higher in RA [1.47 (1.11-1.94)] and SSc [2.92 (1.07-7.99)] compared with the general population. The all-cause mortality rate compared with the general population increased in RA during the first year of the pandemic (IRR 0.71) with reference to 2019 (0.59), and decreased in SSc (IRR 1.94 vs 4.36)., Conclusion: COVID-19 may have a more severe impact in patients with systemic rheumatic disease than in the general population. COVID-19-related mortality is increased in subgroups of patients with specific rheumatic diseases, underscoring the need for priority vaccination and access to targeted treatments., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

JAK inhibitors (JAKinibs) have been approved for several immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (axSpA), and non-radiographic axSpA. Although they have been proved to be very effective, some safety concerns have emerged. These mainly pertain to their profile regarding major adverse cardiovascular events (MACEs) as well as to thromboembolic events (VTEs). In fact, there are accumulating data showing that the concerns might be greater for the latter. Herein, we provide a critical analysis of the so far published major studies, discussing also some thoughts (e.g., different VTE risk across IMIDs) that could be taken into account in the interpretation of these results. In addition, we highlight the need for assessment of patients' profile for cardiovascular as well as for thromboembolic risk factors. Incorporation of the respective tools (that need further validation) should be considered in clinical practice., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Purpose: Psoriatic arthritis (PsA) is a common type of inflammatory arthritis. Patients with PsA present with certain extra-articular manifestations and comorbidities (often collectively called psoriatic disease). The purpose of the present review was to highlight the main comorbidities in the setting of PsA., Methods: A narrative review was performed using data from articles found in a search of PubMed and Scopus using the terms psoriatic arthritis and comorbidities., Findings: Cardiovascular disease (CVD), as well as metabolic and mental health disorders, are the most common comorbidities in patients with PsA. In most cases, underlying inflammation seems to be involved in the increased risk for CVD in PsA, while a bidirectional relationship seems to operate between mental health disorders and psoriatic disease. The treatment of patients with PsA, especially with biologic disease-modifying antirheumatic drugs, has been shown to lead to favorable outcomes regarding the CVD risk. However, it is debatable whether specific drug classes are more effective than others or should be avoided in patients with CVD risk factors. Comorbidity of mental health disorders is even more complex, given the difficulties in measuring and reporting these comorbidities in clinical trials and in clinical practice., Implications: Future studies are needed for a better understanding of the pathogenic mechanisms of, and the development of better protocols for the identification and treatment of patients with, comorbidities in patients with PsA. The education of clinicians, health care professionals in rheumatology, and patients could be useful in achieving this goal., Competing Interests: Declaration of Interest G.E.F. has received speaker's fees and/or honoraria from AbbVie, Aenorasis, Janssen, Eli Lilly and Co, Novartis, Pfizer, and UCB. The authors have indicated that they have no conflicts of interest with regard to the content of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Longitudinal studies using validated tools to evaluate depression and anxiety in psoriatic arthritis (PsA) are lacking. We aimed to estimate their course in PsA and to examine possible associations with disease-related parameters and patient-reported outcomes (PROs)., Methods: PsA patients attending two outpatient rheumatology clinics were consecutively enrolled (January 2019-June 2021, n=128). The hospital anxiety and depression scale (HADS) was used at two sequential visits (mean±SD: 10±6 months) to prospectively assess depression (HADS-Depression) and anxiety (HADS-Anxiety) (cut-off scores ≥11). Associations with demographic, clinical, laboratory features and PROs for quality of life (QoL) (EQ-5D), functional status (HAQ-DI) and nocebo-behaviour (Q-No) were examined. 'Change' was the difference between values at the first and second visit., Results: Prevalence of depression and anxiety at the first visit was 19.5% and 21.1%, respectively. Depression was associated with EQ-5D [OR (95% CI): 1.70 (1.02-2.59), p=0.019] and anxiety with EQ-5D [1.81 (1.20 to 2.72), p=0.005], nocebo-behaviour [1.19 (1.01-1.40), p=0.04] and current corticosteroid use [6.95 (1.75-27.59), p=0.006]. At the second visit, HADS-Depression and HADS-Anxiety scores were improved in 40.9% and 41.9% of patients, respectively. While no associations were found for HADS-Anxiety score change, changes in HADS-Depression score correlated with changes in subjective (tender joint count, r= 0.204, p=0.049; PtG, r= 0.236, p=0.023; patient pain assessment, r= 0.266, p=0.01) but not objective (swollen joint count, ESR, CRP) parameters of disease activity., Conclusions: In PsA, depression and anxiety are associated with worse PROs, including QoL. Subjective parameters of disease activity parallel course of depression.

During the last decades the efficacy of biologic agents, mainly of anti-TNFs, in controlling the activity of serious manifestations of Behcet's Disease (BD) has been established. On the other hand, the clinical heterogeneity of BD has precluded the validation of a widely-accepted composite index for disease assessment and for target disease-state definitions, such as low disease activity and remission, and the testing of their implementation in clinical practice. Therefore, in contrast to other systemic rheumatic diseases, a treat-to-target strategy has not yet been developed in BD. There are several challenges towards this approach, including standardization of outcome measures for assessing the disease activity in each-affected organ and construction of a composite disease activity index. The challenges for the development of a treat-to-target strategy and possible solutions are discussed in this position paper, which stemmed from a round table discussion that took place in the 19th International Conference on BD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To conduct a systematic literature review (SLR) on the screening and prophylaxis of opportunistic and chronic infections in autoimmune inflammatory rheumatic diseases (AIIRD)., Methods: SLR (inception-12/2021) based on the following search domains: (1) infectious agents, (2) AIIRD, (3) immunosuppressives/immunomodulators used in rheumatology, (4) screening terms and (5) prophylaxis terms. Articles were retrieved having the terms from (1) AND (2) AND (3) plus terms from (4) OR(5). Databases searched: PubMed, Embase and Cochrane Library., Exclusion Criteria: studies on postoperative infections, paediatric AIIRD, COVID-19, vaccinations and non-Εnglish literature. Study quality was assessed with Newcastle-Ottawa scale for non-randomised controlled trials (RCTs), RoB-Cochrane for RCTs, AMSTAR2 for SLRs., Results: From 5641 studies were retrieved, 568 full-text articles were assessed for eligibility, with 194 articles finally included. For tuberculosis, tuberculin skin test (TST) is affected by treatment with glucocorticoids and conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) and its performance is inferior to interferon gamma release assay (IGRA). Agreement between TST and IGRA is moderate to low. For hepatitis B virus (HBV): risk of reactivation is increased in patients positive for hepatitis B surface antigen. Anti-HBcore positive patients are at low risk for reactivation but should be monitored periodically with liver function tests and/or HBV-viral load. Risk for Hepatitis C reactivation is existing but low in patients treated with biological DMARDs. For Pneumocystis jirovecii , prophylaxis treatment should be considered in patients treated with prednisolone ≥15-30 mg/day for >2-4 weeks., Conclusions: Different screening and prophylaxis approaches are described in the literature, partly determined by individual patient and disease characteristics., Competing Interests: Competing interests: GEF: speaker fees/honoraria: Pfizer, UCB, Novartis, Abbvie, Aenorasis, Genesis. MD: None. SSZ: consulting fees: UCB. JS: none. DSC: none. JG: speaker fees/honoraria: Abbvie, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB. Research funding: Abbvie, Astrazeneca, Galapagos, Gilead, Gritstone, Janssen, Moderna, Novovax, Pfizer. KH: honoraria from Abbvie; grant income from Pfizer and BMS. EN: speaker fees/honoraria: Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Fresenius. Research funding: Pfizer, Lilly., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterised by musculoskeletal and extra-articular manifestations, most notably psoriasis. While the underlying pathogenetic mechanisms are not yet fully understood, a central role has been identified for the IL-23/IL-17 pathway., Objectives: We briefly describe the role of IL-23 in the pathogenesis of PsA and go on to describe the available anti-IL-23 agents and their place in the management of PsA., Methods: This is a narrative review of the current literature, focussing on the results of the phase 3 studies in PsA for the IL-12/23 p40 inhibitor ustekinumab and the more recent IL-23 p19 inhibitors guselkumab, risankizumab and tildrakizumab., Results: IL-23 triggers expression of IL-17 and other effector cytokines in a variety of cells, leading to tissue inflammation and injury. Targeting IL-23, particularly with p19 inhibitors, appears to be an effective and safe strategy for multiple clinical domains in PsA, most notably the skin, with some differences in efficacy emerging between these agents., Conclusion: The development of IL-23 inhibitors represents a significant advance in the management of psoriatic disease. In the absence of head-to-head studies, future data emerging from real-world experiences of individual IL-23 p19 inhibitors will help inform the use of these agents in relation to other biologics in PsA., (© 2022 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Objective: Serious infection remains a concern when prescribing immune-modulatory drugs for immune-mediated inflammatory diseases. The 'summary of product characteristics' (SmPCs) provide information on adverse events for example, infections, from clinical trials and postmarketing pharmacovigilance.This review aimed to compare infection frequency, site and type across immune-modulatory drugs, reported in SmPCs., Methods: The Electronic Medicines Compendium was searched for commonly prescribed immune-modulatory drugs used for: rheumatoid arthritis, spondyloarthritis, connective tissue disease, autoimmune vasculitis, autoinflammatory syndromes, inflammatory bowel disease, psoriasis, multiple sclerosis and/or other rarer conditions.Information was extracted on infection frequency, site and organisms. Frequency was recorded as per the SmPCs: very common (≥1/10); common (≥1/100 to<1/10); uncommon (≥1/1,000 to<1/100); rare (≥1/10,000 to<1/1,000); very rare (<1/10 000)., Results: 39 drugs were included, across 20 indications: 9 conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), 6 targeted synthetic DMARDs, 24 biologic (b)DMARDs.Twelve infection sites were recorded. Minimal/no site information was available for most csDMARDs, certolizumab pegol and rituximab. Upper respiratory tract was the most common site, especially with bDMARDs. Lower respiratory, ear/nose/throat and urinary tract infections were moderately common, with clustering within drug groups.Data for 27 pathogens were recorded, majority viruses, with herpes simplex and zoster and influenza most frequent. Variable/absent reporting was noted for opportunistic and certain high-prevalence infections for example, Epstein-Barr., Conclusion: Our findings show differences between drugs and can aid treatment decisions alongside real-world safety data. However, data are likely skewed by trial selection criteria and varying number of trials per drug and highlight the need for robust postmarketing pharmacovigilance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Psoriatic arthritis (PsA) affects approximately 0.8% of the general population. PsA, together with psoriasis (PsO), constitute psoriatic disease (PsD). Comorbidities play an important role in the clinical expression and treatment of PsD. Aging adds another level of complexity, partly because age directly accrues increasing risk of comorbidities, but also because of its complex interactions with several factors such as depression and social determinants. Aging seems to have a "paradoxical association" with cardiovascular comorbidities, for which the relative risk is more pronounced in younger patients with PsD. It also affects treatment decisions and treatment response in patients with PsD. Finally, there is convincing evidence that there are clinical, genetic, and histopathological differences between early- and late-onset PsA and PsO. Herein, we review the effect of age in patients with PsD, with a focus on PsA, highlighting the need to consider this factor in routine clinical practice as well as in research., (Copyright © 2022 by the Journal of Rheumatology.)

Purpose of the present paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients with Behçet's disease (BD). The Registry is a clinical physician-driven non-population- and electronic-based instrument implemented for the retrospective and prospective collection of real-life data about demographics, clinical, therapeutic, laboratory, instrumental and socioeconomic information from BD patients; the Registry is based on the Research Electronic Data Capture (REDCap) tool, which is thought to collect standardised information for clinical real-life research, and has been realised to change over time according to future scientific acquisitions and potentially communicate with other existing and future Registries dedicated to BD. Starting from January 31st, 2021, to February 7th, 2022, 110 centres from 23 countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 5993 fields organised into 16 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. The development of the AIDA International Registry for BD patients will facilitate the collection of standardised data leading to real-world evidence, enabling international multicentre collaborative research through data sharing, international consultation, dissemination of knowledge, inclusion of patients and families, and ultimately optimisation of scientific efforts and implementation of standardised care.Trial registration NCT05200715 in 21/01/2022., (© 2022. The Author(s).)