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A systematic review and meta-analysis were conducted, according to the PRISMA methodology, to summarize current evidence on the prevalence and predictors of long-term glucocorticoid (GC) treatment and disease relapses in the real-life management of polymyalgia rheumatica (PMR). Out of 5442 retrieved studies, 21 were eligible for meta-analysis and 24 for qualitative analysis. The pooled proportions of patients still taking GCs at 1, 2, and 5 years were respectively 77% (95%CI 71–83%), 51% (95%CI 41–61%), and 25% (95CI% 15–36%). No significant difference was recorded by distinguishing study cohorts recruited before and after the issue of the international recommendations in 2010. The pooled proportion of patients experiencing at least one relapse at 1 year from treatment initiation was 43% (95%CI 29–56%). Female gender, acute-phase reactants levels, peripheral arthritis, starting GCs dosage, and tapering speed were the most frequently investigated potential predictors of prolonged GC treatment and relapse, but with inconsistent results. Only a few studies and with conflicting results evaluated the potential role of early treatment with methotrexate in reducing the GC exposure and the risk of relapse in PMR. This study showed that a high rate of prolonged GC treatment is still recorded in the management of PMR. The relapse rate, even remarkable, can only partially explain the long-term GC treatment, suggesting that other and not yet identified factors may be involved. Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies. Key Points: • High rate of long-term glucocorticoid (GC) treatment is recorded in polymyalgia rheumatica (PMR), being 77%, 51%, and 25% of patients still on GCs after respectively 1, 2, and 5 years. • A pooled relapse rate of 43% at 1 year, even remarkable, can only partially explain the long-term GC treatment in PMR. • Several studies have attempted to identify potential predictors of prolonged treatment with GCs and relapse, but with inconsistent results. • Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies.

Background The aim was to assess the attainability and outcome of the lupus low disease activity state (LLDAS) in the early stages of systemic lupus erythematosus (SLE). Methods LLDAS prevalence was evaluated at 6 (T1) and 18 (T2) months after diagnosis and treatment initiation (T0) in a monocentric cohort of 107 (median disease duration 9.7 months) prospectively followed Caucasian patients with SLE. Reasons for failure to achieve LLDAS were also investigated. Multivariate models were built to identify factors associated with lack of LLDAS achievement and to investigate the relationship between LLDAS and Systemic Lupus International Collaboration Clinics (SLICC)/Damage Index (SDI) accrual. Results There were 47 (43.9%) patients in LLDAS at T1 and 48 (44.9%) at T2. The most frequent unmet LLDAS criterion was prednisolone dose >7.5 mg/day (83% of patients with no LLDAS at T1). Disease manifestations with the lowest remission rate during follow up were increased anti-double-stranded DNA (persistently present in 85.7% and 67.5% of cases at T1 and T2, respectively), low serum complement fractions (73.2% and 66.3%) and renal abnormalities (46.4% and 28.6%). Renal involvement at T0 was significantly associated with failure to achieve LLDAS both at T1 (OR 7.8, 95% CI 1.4–43.4; p  = 0.019) and T2 (OR 3.9, 95% CI 1.4–10.6; p  = 0.008). Presence of any organ damage (SDI ≥1) at T2 was significantly associated with lack of LLDAS at T1 (OR 5.0, 95% CI 1.5–16.6; p  = 0.009) and older age at diagnosis (OR 1.05 per year, 95% CI 1.01–1.09; p  = 0.020). Conclusion LLDAS is a promising treatment target in the early stages of SLE, being attainable and negatively associated with damage accrual, but it fit poorly to patients with renal involvement.

Objectives To explore the role of newly emerging autoantibodies (AAbs) - peptidyl-arginine deiminase 4 (aPAD4), carbamylated proteins (aCarP), and anti-RA33 (aRA33) - alongside the traditionally assessed rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), in predicting the response to abatacept (ABT) and its retention rate in rheumatoid arthritis (RA) patients. Methods Data from 121 consecutive ABT-treated RA patients were recorded. The RF and ACPA status were retrospectively assessed by reviewing the patients’ clinical records. Positivity for aPAD4, aCarP and aRA33 were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The achievement of a moderate or good EULAR response at 6 months and the 3-years retention were analyzed as treatment outcomes. Multiple logistic regression models and Cox regression hazard analysis models were built to identify the association between such outcomes and the different AAbs, after adjustment for different confounders. The AAbs were assessed both individually and in different combinations to identify the most robust predictive model. Results In the studied cohort, RF, ACPA, aPAD4, aCarP and aRA33-Ab tested positive in 74.4%, 69.4%, 43.8%, 23.9%, 14.9% patients, respectively. A moderate or good EULAR response at 6 months was achieved by 64.5% of subjects and the cumulative 3-years retention rate was 56.6%. A higher EULAR response rate was recorded in patient with positivity for RF (67% in subjects tested positive vs. 58% in negative), ACPA (68% vs. 57%), aPAD4 (68% vs. 62%), and aCarP (72% vs. 62%), although statistical significance was not reached likely due to sample size limitations. Similarly, ACPA, aPAD4, aCarP were associated with higher 3-year retention rates, though not statistically significant individually. The combined analysis revealed that positivity for ACPA and/or aPAD4 predicted a significantly higher EULAR response rate at 6 months compared with double negativity (adjusted OR 2.7, p 0.026). Furthermore, positivity for at least one of ACPA, aPAD4, or aCarP predicted a significantly higher 3-year ABT retention rate compared to triple negativity (62.1% single or double positive vs. 33.5% triple negative, adjusted HR 0.48, p 0.022). Conclusion This study highlights the potential benefits of using a combined assessment of ACPA aPAD4 and aCarP in predicting effectiveness of ABT in RA.

The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined. To identify brain-reactive autoantibodies possibly related to NPSLE, immunofluorescence (IF) and transmission electron microscopy (TEM) on rat and human brains were performed. ELISA was used to reveal the presence of known circulating autoantibodies, while western blot (WB) was applied to characterize potential unknown autoantigen(s). We enrolled 209 subjects, including patients affected by SLE (n=69), NPSLE (n=36), Multiple Sclerosis (MS, n=22), and 82 age- and gender-matched healthy donors (HD). Autoantibody reactivity by IF was observed in almost the entire rat brain (cortex, hippocampus, and cerebellum) using sera from NPSLE and SLE patients and was virtually negative in MS and HD. NPSLE showed higher prevalence (OR 2.4; p = 0.047), intensity, and titer of brain-reactive autoantibodies than SLE patients. Most of the patient sera with brain-reactive autoantibodies (75%) also stained human brains. Double staining experiments on rat brains mixing patients' sera with antibodies directed against neuronal (NeuN) or glial markers showed autoantibody reactivity restricted to NeuN-containing neurons. Using TEM, the targets of brain-reactive autoantibodies were located in the nuclei and, to a lesser extent, in the cytoplasm and mitochondria. Given the high degree of colocalization between NeuN and brain-reactive autoantibodies, we assumed NeuN was a possible autoantigen. However, WB analysis with HEK293T cell lysates expressing or not expressing the gene encoding for NeuN protein (RIBFOX3) showed that patients' sera carrying brain-reactive autoantibodies did not recognize the NeuN corresponding band size. Among the panel of NPSLE-associated autoantibodies (e.g., anti-NR2, anti-P-ribosomal protein, antiphospholipid) investigated by ELISA assay, only the anti-β2-glycoprotein-I (aβ2GPI) IgG was exclusively found in those sera containing brain-reactive autoantibodies. In conclusion, SLE and NPSLE patients possess brain-reactive autoantibodies but with higher frequency and titers found in NPSLE patients. Although many target antigens of brain-reactive autoantibodies are still undetermined, they likely include β2GPI.

In psoriatic arthritis (PsA), the primary goal of treatment is clinical remission. This study aimed to characterize the molecular profile underlying the induced clinical remission in patients with PsA, comparing the remission state and the healthy condition. Whole blood transcriptomic analysis was performed on groups of 14 PsA patients in TNFi-induced clinical remission (DAPSA ≤ 4), 14 PsA patients with active disease (DAPSA > 14), and 14 healthy controls (HCs). Then, all differentially expressed genes (DEGs) derived from remission vs. HC comparison were analyzed for functional and biological characteristics by bioinformatics software. The gene expression of 12 genes was then validated by RT-qPCR in an extended cohort of 39 patients in clinical remission, 40 with active disease, and 40 HCs. The transcriptomic analysis of PsA remission vs. HCs highlighted the presence of 125 DEGs, and out of these genes, 24 were coding genes and showed a great involvement in immune system processes and a functional network with significant interactions. The RT-qPCR validation confirming the down- and upregulation of (FC -2.0; 0.005) and (FC +1.5; 0.005) genes, respectively, in line with their role in orchestrating inflammation and bone metabolism processes, may be related to PsA pathophysiology. The transcriptomic profile of clinical remission in PsA is similar to a healthy condition, but not identical, differing for the expression of and genes, which appears to play a key role in its achievement.

ObjectivesTo explore the variations in glucocorticoid prescribing practices according to the physician’s years of experience in managing SLE.MethodsThe LUPHPOS (LUpus PHysician’ Perspective On glucocorticoidS) study is an online cross-sectional self-reported survey on the physician’s perspective of glucocorticoids in the management of SLE, disseminated between April-August 2023. We have compared responses between practitioners with ≤10 years (shorter experience, SE) and those with >10 years of experience (longer experience, LE).ResultsA weight-based regimen for prescribing glucocorticoids was preferred by both groups, table 1. No differences in glucocorticoid prescribing practices were found in mild and moderate flares. The most common dose was 0.10 mg/kg/day or 5–10 mg/day in mild flares, and 0.25–0.3 mg/kg/day or 15–20 mg/day in moderate flares. In severe flares, pulse therapy was used more often by SE physicians (79% vs 65%, p=0.01). The commonest dose was 500 mg/day for both groups over 3 days. SE physicians more frequently prescribed pulse doses >500 mg/day (41% vs 29%, p=0.02), and pulses for >3 days (24% vs 5%, p<0.001).The most frequently reported target dose for tapering steroids was ≤5mg/day in both groups, however LE physicians targeted 0 mg/day more frequently (22% vs 13%, p=0.04). Steroid withdrawal >12 months after achieving remission/LLDAS was preferred by both groups.Both groups agreed that current disease activity, and type of organ involvement, were the main deciding factors for selecting steroid dose. LE physicians rated comorbidities as their third key driver (39%), whereas SE physicians ranked the course of the disease (44%). There was agreement that infection, cushingoid features, and osteoporosis were the most influencing factors for withdrawing steroids.ConclusionsThe years of experience influence the use of glucocorticoid therapy in severe flare management, tapering protocols, and steroid withdrawal. These differences underscore the need for wide-reaching dissemination and implementation strategies to ensure the adoption of evidence-based care practices across all levels of clinical experience.Abstract O3 Table 1Glucocorticoid prescribing practices in SE and LE physicians Physicians with shorter experience (SE) (≤ 10 years) (n=176) Physicians with longer experience (LE ) (> 10 years ) (n= 144) Determining factors for glucocorticoid dose Disease activityOrgan involvementComorbiditiesCourse 159 (90%)150 (85%)51 (29%)78 (44%) 122 (85%)119 (83%)57 (39%)36 (25%) Side effects InfectionCushingoid featuresOsteoporosis 61 (35%)27 (15%)24 (14%) 50 (35%)24 (17%)23 (16%) Weight dose Fixed dose 98 (56%)78 (44%) 82 (57%)62 (43%) Mild flare Weight regimen 0.10 mg/kg/day0.25 mg/kg/dayIntramuscular glucocorticoidsNo glucocorticoidsOther 32 (33%)31 (32%)6 (6%)24 (25%)5 (5%) 32 (39%)25 (30%)8 (10%)17 (21%)0 (0%) Fixed regimen 5–10 mg/day10–15 mg/dayIntramuscular glucocorticoidsNo glucocorticoids 29 (37%)22 (28%)15 (19%)12 (15%) 23 (37%)15 (24%)11 (18%)13 (21%) Moderate flare Weigh regimen 0.1–0.25 mg/kg/day0.25–0.3 mg/kg/day0.5 mg/kg/dayIntramuscular glucocorticoidsPulse therapyNo glucocorticoids 17 (17%)47 (48%)27 (28%)3 (3%)4 (4%)0 (0%) 11 (13%)33 (40%)31 (37%)5 (6%)2 (2%)0 (0%) Fixed regimen 7.5–15 mg/day15–20 mg/day20–40 mg/dayIntramuscular glucocorticoidsPulse therapyNo glucocorticoids 16 (21%)31 (40%)13 (17%)8 (10%)10 (13%)0 (0%) 14 (23%)22 (35%)12 (19%)3 (5%)11 (18%)0 (0%) Severe flare Weight regimen Pulse therapy1 mg/kg/day0.3–0.5 mg/kg/day 78 (80%)18 (18%)2 (2%) 54 (65%)22 (27%)6 (7%) Fixed regimen Pulse therapy40–80 mg/day20–40 mg/day 61 (78%)12 (15%)5 (6%) 39 (63%)14 (23%)9 (15%) Pulse therapy 125 mg250 mg500 mg750 mg1000 mgNo pulsesOther 6 (3%)16 (9%)65 (37%)23 (13%)49 (28%)16 (9%)1 (0.5%) 10 (7%)17 (12%)38 (27%)12 (8%)30 (21%)33 (23%)4 (3%) N° days for pulses 1 day3 days5 days7 days 3 (2%)119 (74%)25 (16%)13 (8%) 21 (19%)85 (77%)5 (5%)0 (0%) Taper dose for glucocorticoids >12.5 mg/day12.5 mg/day10 mg/day7.5 mg/day6 mg/day5 mg/day0 mg/day 0 (0%)1 (0.6%)18 (10%)28 (16%)18 (10%)88 (50%)23 (13%) 0 (0%)0 (0%)10 (7%)18 (12.5%)17 (12%)68 (47%)31 (22%) Determining factors for withdrawing glucocorticoids Organ involvementDisease activityTime since latest flare 78 (44%)114 (65%)63 (36%) 73 (51%)96 (67%)36 (25%)

A subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP). Patients starting prednisone (PDN) ≥5 mg/day and concomitant hydroxychloroquine or immunosuppressant within 12 months of SLE classification were enrolled. Core set variables were recorded at baseline and every 6 months, including changes in PDN dose, European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics damage index. Regression models analysed predictors of tapering PDN<5 mg/day at any time and outcomes associated with different patterns of GCs tapering. The GULP study included 127 patients with SLE; 73 (57.5%) tapered and maintained PDN <5 mg/day, and 17 (13.4%) discontinued PDN within a 2-year follow-up. Renal involvement (HR: 0.41; p=0.009) and lower C3 serum levels (HR: 1.04; p=0.025) predicted a lack of PDN tapering below 5 mg/day. High ECLAM scores were associated with a greater probability of increasing PDN dose (OR: 1.6; p=0.004), independently of daily intake. Disease relapse rate did not statistically differ (p=0.706) between patients tapering PDN <5 mg/day (42/99, 42.4%) and those tapering PDN without dropping below 5 mg/day (13/28, 46.4%). Every month on PDN <5 mg/day associated with lower damage accrual (IRR: 0.96; p=0.007), whereas never tapering PDN <5 mg/day associated with a higher risk of developing GC-related damage (OR 5.9; p=0.014). Tapering PDN <5 mg/day was achieved and maintained in half of newly diagnosed patients with SLE and may represent a good balance between the need to prevent damage accrual and the risk of disease relapse.

ObjectivesTo explore the effects of anti-ribosomal P protein (anti-P) and anti-N-methyl-D-aspartic acid receptor subunit 2 (anti-NR2) autoantibodies on depression and cognitive dysfunction and their relationships with functional brain connectivity in SLE.MethodsThis cross-sectional study included adult patients who fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology 2019 SLE criteria. Anti-P and anti-NR2 were quantified using ELISA. A 1-hour battery of neuropsychological testing interpreted by a neuropsychologist explored depressive symptoms (Center for Epidemiologic Studies Depression Scale, CES-D), cognitive domains and quality of life (SF-12). Resting-state functional connectivity (rs-fc) MRI analysis was performed within 1 month, and region-of-interest to region-of-interest (ROI-to-ROI) analyses with the graph theory were performed.ResultsThirty-three patients with SLE (9% male) were enrolled, mean age (SD) of 43.5 (14) years and median disease duration of 10.4 years (2.9–25.4). Anti-P was positive in 6 (18.2%) and anti-NR2 in 14 (42.4%) patients. Depressive symptoms were found in 14 (42.4%) patients using the CES-D (range 0–51). After correction for age, disease duration, disease activity and white matter lesion load, the CES-D score was independently associated with anti-P serum level (β=0.32; p=0.049) and prednisone daily dose (β=0.38; p=0.023). Nineteen patients (57.6%) showed at least a cognitive test alteration, but no significant association with autoantibodies was found. The rs-fc MRI analysis revealed an independent association between the anti-P serum levels and many altered brain ROI properties but no anti-NR2 and prednisone effects on the cerebral network.ConclusionsAnti-P was associated with brain network perturbation, which may be responsible for depressive symptoms in patients with SLE.

ObjectiveTo develop and validate the evidence-based and consensus-based Behçet’s Syndrome Overall Damage Index (BODI).MethodsStarting from 120 literature-retrieved preliminary items, the BODI underwent multiple Delphi rounds with an international multidisciplinary panel consisting of rheumatologists, internists, ophthalmologists, neurologists, and patient delegates until consensus was reached on the final content. The BODI was validated in a cross-sectional multicentre cohort of 228 patients with Behçet’s syndrome (BS) through the study of (a) correlation between BODI and Vasculitis Damage Index (VDI) and (b) correlation between BODI and disease activity measures (ie, Behçet’s Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA)), c) content and face validity and (d) feasibility.ResultsThe final BODI consists of 4 overarching principles and 46 unweighted-items grouped into 9 organ domains. It showed good to excellent reliability, with a mean Cohen’s k of 0.84 (95% CI 0.78 to 0.90) and a mean intra-class correlation coefficient of 0.88 (95% CI 0.80 to 0.95). Overall, 128 (56.1%) patients had a BODI score ≥1, with a median score of 1.0 (range 0–14). The BODI significantly correlated with the VDI (r=0.693, p<0.001), demonstrating to effectively measure damage (construct validity), but had greater sensitivity in identifying major organ damage and did not correlate with disease activity measures (ie, BDCAF: p=0.807, PGA: p=0.820, PtGA: p=0.794) discriminating damage from the major confounding factor. The instrument was deemed credible (face validity), complete (content validity) and feasible by an independent group of clinicians.ConclusionsPending further validation, the BODI may be used to assess organ damage in patients with BS in the context of observational and controlled trials.

ObjectivesTo analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA).MethodsPatients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0–3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA.ResultsA total of 350 patients (89% female; median age: 42 years, IQR: 34–52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2–6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models.ConclusionFatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.