Attainment of EULAR/ERA-EDTA targets of therapy with current immunosuppressive regimens and adjustments in treatment: a multicentre, real-life observational study.

OBJECTIVE: To estimate real-life European Alliance of Associations for Rheumatology (EULAR)/European Renal Association (ERA)-European Dialysis and Transplantation Association (EDTA) response rates and predictors for no response in patients with lupus nephritis (LN) managed with conventional immunosuppressive therapies. METHODS: Ambidirectional cohort study of patients with new-onset LN (period 2014-to date). Response rates in the first year were calculated, and all treatment modifications were recorded. Univariate and multivariate regression analyses were performed to assess determinants of failure to respond at 12 months. RESULTS: 140 patients were included (81.4% women, median (IQR) age at LN diagnosis 38 (22) years). Among them, 32.1% presented with nephrotic range proteinuria, 28.6% with glomerular filtration rate <60 mL/min, 76.6% had proliferative and 19.7% class V LN. Initial treatment consisted of cyclophosphamide in 51.4% of patients (84.7% high-dose, 15.3% low-dose) and mycophenolate in 32.1%. 120 patients had available data at 12 months. EULAR/ERA-EDTA renal response rates at 3, 6 and 12 months were achieved by 72.6%, 78.5% % and 69.2% of patients, respectively. In multivariate analysis, increased Chronicity Index at baseline was associated with failure to achieve either complete or partial response at 12 months (OR 2.26, 95% CI 1.35 to 3.77). Notably, 20% of patients required treatment modifications due to suboptimal response during the first 12 months, with the addition of or switch to a different immunosuppressive drug in seven and nine patients, respectively. CONCLUSIONS: More than two-thirds of patients with LN attain EULAR/ERA-EDTA response rates by 12 months, but 20% require therapy modifications within this time period. Patients with increased chronicity in baseline biopsy, when combined with histological activity, are at higher risk for a lack of clinical response.

Relapses and serious adverse events during rituximab maintenance therapy in ANCA-associated vasculitis: a multicentre retrospective study.

OBJECTIVES: There are limited real-life data regarding the efficacy and safety of rituximab (RTX) as a remission-maintenance agent in microscopic-polyangiitis (ΜPA) and granulomatosis-with-polyangiitis (GPA). We aimed to estimate the incidence and risk factors for relapses, as well serious-adverse-events (SAEs) in MPA/GPA patients during RTX-maintenance. METHODS: Retrospective cohort of newly-diagnosed/relapsing GPA/MPA patients who received RTX-maintenance (≥1 RTX-cycle, ≥6 months follow-up) following complete-remission (Birmingham-Vasculitis-Activity-Score-version-3 = 0 plus prednisolone ≤7.5 mg/day) with induction regimens. SAEs included serious-infections, COVID-19-associated hospitalizations, deaths, cardiovascular-events, malignancies and hypogammaglobulinemia. Incidence-rates (IR) and relapse-free survival through Kaplan-Meier plots were estimated. Cox-regression was conducted to investigate factors associated with the time-to-relapse. RESULTS: 101 patients were included; 48% females, 69% GPA, 53% newly diagnosed, median age: 63 years. During follow-up (294.5 patient-years, median: 3 RTX-cycles), 30 relapses (57% major) occurred among 24 patients (24%, IR 10.2/100 patient-years). Kidney involvement (adjusted-Hazard-Ratio/aHR: 0.20; 95% CI: 0.06-0.74, p= 0.016), prior induction with RTX plus cyclophosphamide (vs RTX monotherapy: aHR = 0.02; 95% CI: 0.001-0.43, p= 0.012) and shorter time-interval until complete-remission (aHR = 1.07; 95% CI: 1.01-1.14, p= 0.023) were associated with decreased relapse-risk. We recorded 17 serious-infections (IR 5.8/100 patient-years), 11 COVID-19-associated hospitalizations (IR 3.7/100 patient-years), 4 malignancies (IR 1.4/100 patient-years), 6 cardiovascular-events (IR 2/100 patient-years) and 10 deaths (IR 3.4/100 patient-years). CONCLUSION: In this real-world study, relapses during RTX-maintenance occurred in approximately in 1 out of 4 patients. Kidney involvement, induction with RTX plus cyclophosphamide and earlier achievement of complete-remission were associated with lower relapse-risk. Serious-infections rate was consistent with previous reports, whereas an increased rate of COVID19-associated hospitalizations was observed.

The NYMERIA Study: A Real-World, Multicentre Contemporary Assessment of Disease- and Patient-Related Burden and Treatment Strategies in Patients with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) has a spectrum of phenotypes. Its management should target remission or low disease activity, prevention of relapses and organ damage, minimisation of drug-related harms, and optimisation of health-related quality of life. Advances in our understanding of the disease pathophysiology have expanded the treatment armamentarium with targeted biologics that demonstrate superiority over conventional drugs in controlling activity, reducing flares and glucocorticoid exposure, and improving patient-related outcomes. In view of this, there is a critical need for real-world evidence providing insight into the spectrum of activity, the treatment landscape, and unmet needs among SLE patients. Such information can support regulatory and reimbursement decision-making. The primary objective of the NYMERIA multicentre study is to generate real-world evidence on the activity state of SLE patients treated in routine care settings in Greece. The overarching aim is to capture the disease burden based on both clinical aspects and the patient perspective.

Anifrolumab for systemic lupus erythematosus with multi-refractory skin disease: A case series of 18 patients.

OBJECTIVE: Skin involvement is common in systemic lupus erythematosus (SLE), but may be resistant to conventional treatment. We sought to evaluate the efficacy of anifrolumab (ANI) in refractory cutaneous manifestations of SLE. METHODS: Case series of patients with refractory cutaneous SLE from three Rheumatology Departments in Greece. Outcome measures were improvement in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), physician global assessment (PGA) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Clinically relevant improvement in skin was defined as decrease ≥50% (CLASI50) from baseline values. RESULTS: Eighteen patients received ANI; all had active skin involvement at baseline. Mean (SD) SLEDAI and PGA at ANI initiation were 7.4 (2.7) and 1.4 (0.5), respectively, with a mean prednisone dose 4.9 (4.5) mg/day. Mean CLASI (Activity/Damage) at baseline was 13.9 (9.7)/2.9 (4.6). Patients were refractory to a mean 6.3 (1.5) immunomodulatory agents (including hydroxychloroquine and glucocorticoids) before the initiation of ANI. After a mean 8.5 (4.6) months, 89% (n = 16/18) of patients demonstrated significant improvement in general lupus and cutaneous disease activity, and glucocorticoid tapering. Mean SLEDAI and mean CLASI at last visit were 3.4 (1.9) and 2.1 (2.4)/1.4 (2.2), respectively, and mean daily prednisone dose decreased to 2.4 (2.2). Of note, in this group of highly refractory patients CLASI50 was achieved in 16/18 (89%) patients. One patient discontinued ANI after 4 infusions due to a varicella-zoster virus infection and one patient, who initially responded to treatment with ANI, experienced a skin flare due to temporary discontinuation due to Covid 19 infection. DORIS remission and LLDAS were attained in two (11.1%) and eleven (61.1%) patients, respectively. CONCLUSION: Anifrolumab is highly effective in various skin manifestations of SLE, even after prior failure to multiple treatments.

Mesenchymal Stem Cell and Hematopoietic Stem and Progenitor Cell Co-Culture in a Bone-Marrow-on-a-Chip Device toward the Generation and Maintenance of the Hematopoietic Niche.

Bone marrow has raised a great deal of scientific interest, since it is responsible for the vital process of hematopoiesis and is affiliated with many normal and pathological conditions of the human body. In recent years, organs-on-chips (OoCs) have emerged as the epitome of biomimetic systems, combining the advantages of microfluidic technology with cellular biology to surpass conventional 2D/3D cell culture techniques and animal testing. Bone-marrow-on-a-chip (BMoC) devices are usually focused only on the maintenance of the hematopoietic niche; otherwise, they incorporate at least three types of cells for on-chip generation. We, thereby, introduce a BMoC device that aspires to the purely in vitro generation and maintenance of the hematopoietic niche, using solely mesenchymal stem cells (MSCs) and hematopoietic stem and progenitor cells (HSPCs), and relying on the spontaneous formation of the niche without the inclusion of gels or scaffolds. The fabrication process of this poly(dimethylsiloxane) (PDMS)-based device, based on replica molding, is presented, and two membranes, a perforated, in-house-fabricated PDMS membrane and a commercial poly(ethylene terephthalate) (PET) one, were tested and their performances were compared. The device was submerged in a culture dish filled with medium for passive perfusion via diffusion in order to prevent on-chip bubble accumulation. The passively perfused BMoC device, having incorporated a commercial poly(ethylene terephthalate) (PET) membrane, allows for a sustainable MSC and HSPC co-culture and proliferation for three days, a promising indication for the future creation of a hematopoietic bone marrow organoid.

Six-month supplementation with high dose coenzyme Q10 improves liver steatosis, endothelial, vascular and myocardial function in patients with metabolic-dysfunction associated steatotic liver disease: a randomized double-blind, placebo-controlled trial.

BACKROUND: Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) has been associated with increased cardiovascular risk. The aim of this Randomized Double-blind clinical Trial was to evaluate the effects of coenzyme-Q10 supplementation in patients with MASLD in terms of endothelial, vascular and myocardial function. METHODS: Sixty patients with MASLD were randomized to receive daily 240 mg of coenzyme-Q10 or placebo. At baseline and at 6-months, the a)Perfused boundary region of sublingual vessels using the Sideview Darkfield imaging technique, b)pulse-wave-velocity, c)flow-mediated dilation of the brachial artery, d)left ventricular global longitudinal strain, e)coronary flow reserve of the left anterior descending coronary artery and f)controlled attenuation parameter for the quantification of liver steatosis were evaluated. RESULTS: Six months post-treatment, patients under coenzyme-Q10 showed reduced Perfused boundary region (2.18 ± 0.23vs.2.29 ± 0.18 µm), pulse-wave-velocity (9.5 ± 2vs.10.2 ± 2.3 m/s), controlled attenuation parameter (280.9 ± 33.4vs.304.8 ± 37.4dB/m), and increased flow-mediated dilation (6.1 ± 3.8vs.4.3 ± 2.8%), global longitudinal strain (-19.6 ± 1.6vs.-18.8 ± 1.9%) and coronary flow reserve (3.1 ± 0.4vs.2.8 ± 0.4) compared to baseline (p < 0.05). The placebo group exhibited no improvement during the 6-month follow-up period (p > 0.05). In patients under coenzyme-Q10, the reduction in controlled attenuation parameter score was positively related to the reduction in Perfused boundary region and pulse wave velocity and reversely related to the increase in coronary flow reserve and flow-mediated dilation (p < 0.05 for all relations). CONCLUSIONS: Six-month treatment with high-dose coenzyme-Q10 reduces liver steatosis and improves endothelial, vascular and left ventricle myocardial function in patients with MASLD, demonstrating significant improvements in micro- and macro-vasculature function. TRIAL REGISTRATION: NCT05941910.

Mediterranean diet and exercise are associated with better disease control in psoriatic arthritis.

Psoriatic arthritis (PsA) is associated with obesity and other related comorbidities, which impose an additional burden on disease activity and response to treatment. We investigated the impact of Mediterranean diet, and exercise on the presentation and severity of PsA. Three hundred fifty-five patients with PsA (n = 279) and psoriasis (PsO) (n = 76) were included in a cross-sectional study. Demographic and clinical characteristics and dietary and exercise patterns were recorded. Patients were grouped into (i) high, moderate, and low Mediterranean diet adherence and (ii) high, medium, and low activity level. Levels of diet and exercise were correlated with disease activity indices. PsA patients had more comorbidities than their PsO counterparts (42.7% vs. 26.3%, p = .038). The majority showed a low exercise pattern (total = 71.3%, PsA = 72.4%, PsO = 67.1%). Approximately half (total = 44.2%, PsA = 43.4%, PsO = 47.4%) did not follow a Mediterranean diet. Disease Activity in Psoriatic Arthritis Score (DAPSA) (p = .004), tender (p = .003) and swollen (p = .015) joint counts, erythrocyte sedimentation rate (ESR) (p = .001), and Psoriasis Area and Severity Index (PASI) (p = .015) had an inverse correlation with exercise. Higher Mediterranean diet adherence was associated with reduced ESR (p = .056), PASI (p = .011), and body surface area (BSA) (p = .009) indices. After adjusting for body mass index (BMI), exercise retained its positive correlation with PsA disease activity, but diet showed significant correlation only with enthesitis (p = 0.015). Uptake of a Mediterranean diet and exercise have positive effects on PsA activity, independently of BMI. These findings support lifestyle recommendations to supplement conventional treatment for improvement in disease outcomes. Key points • Diet and lifestyle are important influencers of health-related outcomes in PsA. • In this cross-sectional study of 355 patients with psoriatic disease, we found that Med Diet and exercise improve outcomes in PsA independently of weight loss. • Our results suggest that diet and lifestyle modifications should supplement conventional medical treatments.

Single-cell transcriptomic analysis of hematopoietic progenitor cells from patients with systemic lupus erythematosus reveals interferon-inducible reprogramming in early progenitors.

Introduction: Immune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult hematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). For this reason, we reasoned that fundamental abnormalities in SLE can be traced to a BM-derived HSPC inflammatory signature. Methods: BM samples from four SLE patients, six healthy controls, and two umbilical cord blood (CB) samples were used. CD34+ cells were isolated from BM and CB samples, and single-cell RNA-sequencing was performed. Results: A total of 426 cells and 24,473 genes were used in the analysis. Clustering analysis resulted in seven distinct clusters of cell types. Mutually exclusive markers, which were characteristic of each cell type, were identified. We identified three HSPC subpopulations, one of which consisted of proliferating cells (MKI67 expressing cells), one T-like, one B-like, and two myeloid-like progenitor subpopulations. Differential expression analysis revealed i) cell cycle-associated signatures, in healthy BM of HSPC clusters 3 and 4 when compared with CB, and ii) interferon (IFN) signatures in SLE BM of HSPC clusters 3 and 4 and myeloid-like progenitor cluster 5 when compared with healthy controls. The IFN signature in SLE appeared to be deregulated following TF regulatory network analysis and differential alternative splicing analysis between SLE and healthy controls in HSPC subpopulations. Discussion: This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors-and qualitative differences-characterized by an IFN signature in SLE, which is known to drive loss of function and depletion of HSPCs. Chronic IFN exposure affects early hematopoietic progenitors in SLE, which may account for the immune aberrancies and the cytopenias in SLE.

Identification and characteristics of patients with potential difficult-to-treat psoriatic arthritis: exploratory analyses of the Greek PsA registry.

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.

Can we predict kidney involvement in patients with systemic lupus erythematosus? A retrospective cohort study with independent validation.

OBJECTIVES: To discern predictive factors for incident kidney involvement in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE from the 'Attikon' Lupus cohort were monitored for lupus nephritis (LN), defined by kidney histology and/or classification criteria. Demographic and clinical characteristics at baseline were compared against patients who did not develop LN. LN-free survival curves were generated by Kaplan-Meier. A multivariate Cox proportional hazards model was used to identify independent predictors of LN. Independent validation was performed in the University of Crete Lupus registry. RESULTS: Among the 570 patients in the derivation cohort, 59 exhibited LN as their initial presentation, while an additional 66 developed LN during the follow-up period (collectively, 21.9% incidence). In the latter group, baseline factors predictive of subsequent kidney involvement were male sex (multivariable-adjusted [a]HR 4.31, 95% CI: 1.82-10.2), age of SLE diagnosis below 26 years (aHR 3.71, 95% CI: 1.84-7.48), high anti-dsDNA titre (aHR 2.48, 95% CI: 1.03-5.97) and low C3 and/or C4 (although not statistically significant, aHR 2.24, 95% CI: 0.83-6.05, p= 0.11). A combination of these factors at time of diagnosis conferred an almost 90-fold risk compared with serologically inactive, older, female patients (aHR 88.77, 95% CI : 18.75-420.41), signifying a very high-risk group. Independent validation in the Crete Lupus registry showed concordant results with the original cohort. CONCLUSION: Male sex, younger age and serologic activity at SLE diagnosis are strongly associated with subsequent kidney involvement. Vigilant surveillance and consideration of early use of disease-modifying drugs is warranted in these subsets of patients.

Management of systemic lupus erythematosus: a systematic literature review informing the 2023 update of the EULAR recommendations.

OBJECTIVES: To analyse the new evidence (2018-2022) for the management of systemic lupus erythematosus (SLE) to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations. METHODS: Systematic literature reviews were performed in the Medline and the Cochrane Library databases capturing publications from 1 January 2018 through 31 December 2022, according to the EULAR standardised operating procedures. The research questions focused on five different domains, namely the benefit/harm of SLE treatments, the benefits from the attainment of remission/low disease activity, the risk/benefit from treatment tapering/withdrawal, the management of SLE with antiphospholipid syndrome and the safety of immunisations against varicella zoster virus and SARS-CoV2 infection. A Population, Intervention, Comparison and Outcome framework was used to develop search strings for each research topic. RESULTS: We identified 439 relevant articles, the majority being observational studies of low or moderate quality. High-quality randomised controlled trials (RCTs) documented the efficacy of the type 1 interferon receptor inhibitor, anifrolumab, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN), when compared with standard of care. For the treatment of specific organ manifestations outside LN, a lack of high-quality data was documented. Multiple observational studies confirmed the beneficial effects of attaining clinical remission or low disease activity, reducing the risk for multiple adverse outcomes. Two randomised trials with some concerns regarding risk of bias found higher rates of relapse in patients who discontinued glucocorticoids (GC) or immunosuppressants in SLE and LN, respectively, yet observational cohort studies suggest that treatment withdrawal might be feasible in a subset of patients. CONCLUSION: Anifrolumab and belimumab achieve better disease control than standard of care in extrarenal SLE, while combination therapies with belimumab and voclosporin attained higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favourable long-term outcomes. In patients achieving these targets, GC and immunosuppressive therapy may gradually be tapered. Cite Now.

Disentangling the riddle of systemic lupus erythematosus with antiphospholipid syndrome: blood transcriptome analysis reveals a less-pronounced IFN-signature and distinct molecular profiles in venous versus arterial events.

INTRODUCTION: Systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS) represents a challenging SLE endotype whose molecular basis remains unknown. METHODS: We analysed whole-blood RNA-sequencing data from 299 patients with SLE (108 SLE-antiphospholipid antibodies (aPL)-positive, including 67 SLE-APS; 191 SLE-aPL-negative) and 72 matched healthy controls (HC). Pathway enrichment analysis, unsupervised weighted gene coexpression network analysis and machine learning were applied to distinguish disease endotypes. RESULTS: Patients with SLE-APS demonstrated upregulated type I and II interferon (IFN) pathways compared with HC. Using a 100-gene random forests model, we achieved a cross-validated accuracy of 75.6% in distinguishing these two states. Additionally, the comparison between SLE-APS and SLE-aPL-negative revealed 227 differentially expressed genes, indicating downregulation of IFN-α and IFN-γ signatures, coupled with dysregulation of the complement cascade, B-cell activation and neutrophil degranulation. Unsupervised analysis of SLE transcriptome identified 21 gene modules, with SLE-APS strongly linked to upregulation of the 'neutrophilic/myeloid' module. Within SLE-APS, venous thromboses positively correlated with 'neutrophilic/myeloid' and 'B cell' modules, while arterial thromboses were associated with dysregulation of 'DNA damage response (DDR)' and 'metabolism' modules. Anticardiolipin and anti-ß2GPI positivity-irrespective of APS status-were associated with the 'neutrophilic/myeloid' and 'protein-binding' module, respectively. CONCLUSIONS: There is a hierarchical upregulation and-likely-dependence on IFN in SLE with the highest IFN signature observed in SLE-aPL-negative patients. Venous thrombotic events are associated with neutrophils and B cells while arterial events with DDR and impaired metabolism. This may account for their differential requirements for anticoagulation and provide rationale for the potential use of mTOR inhibitors such as sirolimus and the direct fIIa inhibitor dabigatran in SLE-APS.

The safety and potential efficacy of exosomes overexpressing CD24 (EXO-CD24) in mild-moderate COVID-19 related ARDS.

INTRODUCTION: EXO-CD24 are exosomes genetically manipulated to over-express Cluster of Differentiation (CD) 24. It consists of two breakthrough technologies: CD24, the drug, as a novel immunomodulator that is smarter than steroids without any side effects, and exosomes as the ideal natural drug carrier. METHODS: A randomized, single blind, dose-finding phase IIb trial in hospitalized patients with mild to moderate Coronavirus disease 2019 (COVID-19) related Acute Respiratory Distress Syndrome (ARDS) was carried out in two medical centers in Athens. Patients received either 109 or 1010 exosome particles of EXO-CD24, daily, for five consecutive days and monitored for 28 days. Efficacy was assessed at day 7 among 91 patients who underwent randomization. The outcome was also compared in a post-hoc analysis with an income control group (n = 202) that fit the inclusion and exclusion criteria. RESULTS: The mean age was 49.4 (± 13.2) years and 74.4% were male. By day 7, 83.7% showed improved respiratory signs and 64% had better oxygen saturation (SpO2) (p < 0.05). There were significant reductions in all inflammatory markers, most notably in C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, fibrinogen and an array of cytokines. Conversely, levels of the anti-inflammatory cytokine Interleukin-10 (IL-10) were increased (p < 0.05). Of all the documented adverse events, none were considered treatment related. No drug-drug interactions were noted. Two patients succumbed to COVID-19. Post-hoc analysis revealed that EXO-CD24 patients exhibited greater improvements in clinical and laboratory outcomes compared to an observational income control group. CONCLUSIONS: EXO-CD24 presents a promising therapeutic approach for hyper-inflammatory state and in particular ARDS. Its unique combination of exosomes, as a drug carrier, and CD24, as an immunomodulator, coupled with inhalation administration, warrants further investigation in a larger, international, randomized, quadri-blind trial against a placebo.

Persistence on subcutaneous tocilizumab as monotherapy or in combination with synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients in Greece (EMBRACE study): a multicenter, post-marketing, non-interventional, observational trial.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic, inflammatory disease affecting multiple organs and causing physical disability over time. OBJECTIVE: The primary objective was to evaluate treatment persistence to subcutaneous tocilizumab (TCZ-SC). Additionally, treatment effects on persistence and their associations with clinical and patient-reported outcomes were assessed. METHOD: We performed a multicenter, non-interventional, 52-week observational study on 222 patients with moderate or severe RA. Clinical outcomes were evaluated by using disease activity score for 28 joints (DAS28) and European League Against Rheumatism (EULAR) response, and patients' perceptions were evaluated by using Health Assessment Questionnaire (HAQ), Visual Analog Scale (VAS) for pain, and patient global assessment (PtGA) of disease activity. Safety was assessed throughout the study. RESULTS: The mean age of the overall cohort was 62.2 ± 12.3 years, and 83.8% were females. Persistence to TCZ-SC was 89.6% at week 24 and 85.1% at week 52 in the overall cohort with slightly increased persistence in the combination group. At week 52, changes from the baseline were - 2.68 in DAS28, - 0.76 in HAQ, - 43.21 in VAS pain, and - 41.66 in PtGA (p < 0.0001 for all). Moderate and good EULAR response was achieved in 83.2% of patients. Non-serious and serious adverse events occurred in 18.5% and 3.2% of the participants, respectively. CONCLUSIONS: The current study confirms the favorable safety and effectiveness of TCZ-SC as well as its acceptability by RA patients in Greece, with sustained high persistence rates up to 52 weeks. TCZ-SC offers a sustainable treatment response in RA. Key Points • Based upon clinical and patient-reported outcomes, TCZ-SC is a highly effective and safe treatment modality in patients with moderate-to-severe RA. • Persistence to TCZ-SC was high throughout the study, both as monotherapy and in combination with csDMARDs. • TCZ-SC is effective both as monotherapy and when used in combination with other csDMARDs regardless of the line of treatment.

Enhanced medullary and extramedullary granulopoiesis sustain the inflammatory response in lupus nephritis.

OBJECTIVES: In SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH) as a key player for tissue injury in systemic autoimmune disorders. METHODS: Transcriptomic analysis of bone marrow (BM)-derived HSPCs from patients with SLE and NZBW/F1 lupus-prone mice was performed in combination with DNA methylation profile. Trained immunity (TI) was induced through ß-glucan administration to the NZBW/F1 lupus-prone model. Disease activity was assessed through lupus nephritis (LN) histological grading. Colony-forming unit assay and adoptive cell transfer were used to assess HSPCs functionalities. RESULTS: Transcriptomic analysis shows that splenic HSPCs carry a higher inflammatory potential compared with their BM counterparts. Further induction of TI, through ß-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsens LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which is in part driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice. CONCLUSIONS: These data support a key role of granulocytes derived from primed HSPCs both at medullary and extramedullary sites in the pathogenesis of LN. EMH and TI contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare.

Glucocorticoid discontinuation rate and risk factors for relapses in a contemporary cohort of patients with giant cell arteritis.

The rates of relapses and therapy discontinuation in patients with giant cell arteritis (GCA) in the modern therapeutic era have not been defined. We aimed to evaluate the glucocorticoid (GC) discontinuation rate and the factors associated with relapses in a contemporary GCA cohort. Patient and treatment data were collected cross-sectionally at first evaluation and 2 years later (second evaluation), in a multicenter, prospective GCA cohort. Predictors of relapses were identified by logistic regression analyses. 243 patients with GCA were initially included (67% women, mean age at diagnosis: 72.1 years, median disease duration: 2 years) while 2 years later complete data for 160 patients were available and analyzed. All patients had received GCs at diagnosis (mean daily prednisolone dose: 40 mg) while during follow-up, 37% received non-biologic and 16% biologic agents, respectively. At second evaluation, 72% of patients were still on therapy (GCs: 58% and/or GC-sparing agents: 29%). Relapses occurred in 27% of patients during follow-up; by multivariable logistic regression analysis, large vessel involvement at diagnosis [odds ratio (OR) = 4.22], a cardiovascular event during follow-up (OR = 4.60) and a higher initial GC daily dose (OR = 1.04), were associated with these relapses. In this large, real-life, contemporary GCA cohort, the rates of GC discontinuation and relapses were 40% and 27%, respectively. Large vessel involvement, a higher GC dose at diagnosis and new cardiovascular events during follow-up were associated with relapses.