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PDF file - 120K, Effects of doxorubicin on the suppressive function of residual MDSC.

PDF file - 93K

PDF file - 206K, Doxorubicin eliminates tumor-induced MDSC.

PDF file - 124K, Doxorubicin administration increases the effector to suppressor ratios in 4T1 tumor bearing mice but does not alter Treg numbers.

PDF file - 46K, Characterization of in vitro generated Th1 and Th17 lymphocytes.

PDF file - 87K, Doxorubicin is more efficient at selectively eliminating MDSC than cyclophosphamide, fludarabine, melphalan, vinblastine or etoposide.

PDF file - 163K, Effects of doxorubicin on MDSC expression of immunosuppressive factors and on MDSC differentiation.

PDF file - 58K, Doxorubicin eliminates MDSC in mice bearing EMT6 breast cancer or EL4 thymoma.

PDF file - 423K, Doxorubicin increases the frequency, proliferation and cytotoxic activity of effector T lymphocytes and NK.

IntroductionThe pathogenesis of Giant Cell Arteritis (GCA) relies on vascular inflammation and vascular remodeling, the latter being poorly controlled by current treatments.MethodsThis study aimed to evaluate the effect of a novel cell therapy, Human Monocyte-derived Suppressor Cells (HuMoSC), on inflammation and vascular remodeling to improve GCA treatment. Fragments of temporal arteries (TAs) from GCA patients were cultured alone or in the presence of HuMoSCs or their supernatant. After five days, mRNA expression was measured in the TAs and proteins were measured in culture supernatant. The proliferation and migration capacity of vascular smooth muscle cells (VSMCs) were also analyzed with or without HuMoSC supernatant. ResultsTranscripts of genes implicated in vascular inflammation (CCL2, CCR2, CXCR3, HLADR), vascular remodeling (PDGF, PDGFR), angiogenesis (VEGF) and extracellular matrix composition (COL1A1, COL3A1 and FN1) were decreased in arteries treated with HuMoSCs or their supernatant. Likewise, concentrations of collagen-1 and VEGF were lower in the supernatants of TAs cultivated with HuMoSCs. In the presence of PDGF, the proliferation and migration of VSMCs were both decreased after treatment with HuMoSC supernatant. Study of the PDGF pathway suggests that HuMoSCs act through inhibition of mTOR activity. Finally, we show that HuMoSCs could be recruited in the arterial wall through the implication of CCR5 and its ligands.ConclusionAltogether, our results suggest that HuMoSCs or their supernatant could be useful to decrease vascular in flammation and remodeling in GCA, the latter being an unmet need in GCA treatment.

ImportanceResults of randomized clinical trials have demonstrated rituximab’s noninferiority to cyclophosphamide as induction therapy for antineutrophil cytoplasm antibody (ANCA)–associated vasculitides (AAV), with neither treatment having a specific advantage for granulomatosis with polyangiitis (GPA). However, post hoc analysis results have suggested that rituximab might be more effective than cyclophosphamide in inducing remission in patients with proteinase 3–positive AAV.ObjectiveTo compare the effectiveness of rituximab and cyclophosphamide in inducing GPA remission in a large population of unselected patients.Design, Setting, and ParticipantsThis comparative effectiveness study used multicenter target trial emulation observational data from 32 French hospitals in the French Vasculitis Study Group Registry. Groups were determined according to treatments received, without any intervention from the investigators. Inverse probability of treatment weighting was used to correct for baseline imbalance between groups. Participants included patients with newly diagnosed or relapsing GPA who satisfied American College of Rheumatology classification criteria and/or Chapel Hill Consensus Conference nomenclature. Data were analyzed from October 1, 2021, to May 31, 2022.ExposuresAt least 1 infusion of rituximab or cyclophosphamide for induction therapy between April 1, 2008, and April 1, 2018.Main Outcomes and MeasuresThe primary outcome was remission rate at month 6 (±2 months), with remission defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and prednisone dose of 10 mg/d or less. The BVAS is a validated tool for small-vessel vasculitis and used to assess the level of disease activity, with a numerical weight attached to each involved organ system. The BVAS has a range of 0 to 63 points; a score of 0 indicates no disease activity. Subgroup analyses included the primary outcome for patients with a new diagnosis, for most recently treated patients, and for patients with myeloperoxidase-ANCA positivity.ResultsAmong 194 patients with GPA included in the analysis (mean [SD] age, 54 [15] years; 110 men [56.7%]), 165 (85.1%) had a new diagnosis, and 147 of 182 with data available (80.8%) had proteinase 3–ANCA positivity. Sixty-one patients received rituximab and 133 received cyclophosphamide for induction therapy. In the weighted analysis, the primary outcome was reached for 73.1% of patients receiving rituximab vs 40.1% receiving cyclophosphamide (relative risk [RR], 1.82 [95% CI, 1.22-2.73]; risk difference, 33.0% [95% CI, 12.2%-53.8%]; E value for RR, 3.05). Similar results were observed in the subgroup of patients with newly diagnosed GPA and those with a more recent treatment. In the subset of 27 patients with myeloperoxidase-ANCA–positive GPA, 8 of 10 rituximab recipients and 8 of 17 cyclophosphamide recipients met the primary end point (unweighted RR, 1.73 [95% CI, 0.96-3.11]).Conclusions and RelevanceIn this comparativeness effectiveness study using clinical data, rituximab induction therapy for GPA was more frequently associated with remission than cyclophosphamide. These results inform clinical decision-making concerning the choice of remission induction therapy for this subset of patients with AAV.

Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicentre retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-Ras that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs. This article is protected by copyright. All rights reserved.

Resume L’arterite a cellules geantes (ACG) est la plus frequente des vascularites affectant l’artere temporale (AT). Neanmoins, d’autres types de pathologies vasculaires, qu’il s’agisse de vascularite ou non, peuvent toucher l’AT. Parmi les vascularites, on peut citer les vascularites necrosantes, en particulier les vascularites associees aux anticorps anti-cytoplasme des polynucleaires neutrophiles (ANCA) qui peuvent affecter les petits vaisseaux peri-adventitiels de la paroi de l’AT et mimer certains symptomes de l’ACG, ces derniers n’etant generalement pas isoles, ce qui doit faire rechercher les ANCA. Certaines vascularites infectieuses peuvent egalement toucher l’AT comme l’infection par le virus varicelle-zona (VZV) dont l’aspect histologique est tres proche de l’ACG a tel point que certains auteurs ont suggere un role du VZV dans le declenchement de l’ACG. Une vascularite de l’AT peut egalement etre secondaire a une maladie associee aux IgG4 ou d’origine medicamenteuse (inhibiteurs de checkpoint immunitaire). En dehors des vascularites, l’AT peut etre le siege d’autres vasculopathies non inflammatoires comme la maladie atheromateuse, l’arteriolopathie uremique calcifiante ou encore les atteintes post-traumatiques comme les faux-anevrysmes ou les fistules arterioveineuses de l’AT. Dans cette revue, nous decrivons ces differents types d’atteinte pouvant toucher l’AT.

Introduction Giant cell arteritis (GCA) is a frequent granulomatous vasculitis. In the diagnosis of large vessel GCA, FDG-PET/CT imaging has been recommended and its use has steadily increased. The objective of this prospective study was to evaluate the diagnostic performance of digital FDG-PET imaging with a head and neck dedicated protocol, especially to detect cranial arteries involvement, using different visual grading scores, and to assess the inter-reader agreement. Material and Methods FDG-PET/CT scans with a 10-min acquisition time on the head and neck were performed in patients suspected of having recent GCA. A score including 20 segments due to the inclusion of cranial segments and a score established only for the cranial segments were compared to the Total Vascular Score (TVS) established on 7 arterial segments. These scores were assessed by two nuclear medicine physicians on a blinded manner and, in case of disagreement, a consensus was established with a third nuclear medicine physician. Results GCA diagnosis was retained for 15 of the 52 patients included. Sensitivity and specificity of the 20-segment or the cranial scores were higher than those of TVS (sensitivity and specificity of 80% of 97% for both scores vs 73% and 89% for TVS, respectively). The inter-reader agreement was substantial in the 20-segment score (weighted kappa = 0.68) but better in the cranial segments than other segments. Conclusion This study shows the usefulness of grading scores able to highlight involvement of cranial arteries in GCA with a better inter-reader agreement in cranial segments than other segments.

Leukocyte immunoglobulin-like receptors (LILRs) are a family of inhibitory or stimulatory receptors expressed by immune cell types belonging to both myeloid and lymphoid lineage. Several members of the LILR family recognize major histocompatibility complex class I and thus play important roles in a range of clinical situations including pregnancy. Moreover, paired immunoglobulin-like receptors (PIRs), the murine orthologs of LILRs, are implicated in experimental transplant allorecognition by monocytes and contribute to the induction of donor-specific monocyte-memory. After non-self recognition, activating PIRs are transiently overexpressed at the surface of monocytes and participate in donor-specific monocyte recruitment, leading to graft rejection in vivo. In the present study, we mapped LILR expression and also their respective reported ligands at single cell level in the renal allograft and circulating cells in the context of kidney transplant rejection. Recipient-derived monocytes were shown to infiltrate the donor tissue and to differentiate into macrophages. We thus also investigate LILR expression during in vitro monocyte-to-macrophage differentiation in order to characterize the myeloid population that directly contribute to allorecognition. Altogether our results emphasize non-classical monocytes and CD68+ M1 macrophages as key players in LILRs-ligand interaction in kidney transplantation.

International audience; BACKGROUND: Cardiovascular risk is increased in giant cell arteritis (GCA). We aimed to characterize myocardial infarction (MI) in a GCA cohort, and to compare the GCA and non-GCA population affected by MI. METHODS: In patients with a biopsy-proven diagnosis of GCA between 1 January 2001 and 31 December 2016 in Côte D'Or (France), we identified patients with MI by crossing data from the territorial myocardial infarction registry (Observatoire des Infarctus de Côte d'Or) database. Five controls (non-GCA + MI) were paired with one case (GCA + MI) after matching for age, sex, cardiovascular risk factors and prior cardiovascular disease. MI were characterized as type 1 MI (T1MI), resulting from thrombus formation due to atherothrombotic disease, or type 2 MI (T2MI), due to a myocardial supply/demand mismatch. GCA-related MI was defined as MI occurring within 3 months of a GCA flare (before or after). RESULTS: Among 251 biopsy-proven GCA patients, 13 MI cases were identified and paired with 65 controls. MI was GCA-related in 6/13 cases, accounting for 2.4% (6/251) of our cohort. T2MI was more frequently GCA-related than GCA-unrelated (80% vs. 16.7%, p = 0.080), and GCA diagnosis was the only identified triggering factor in 75% of GCA-related T2MI. GCA-unrelated MI were more frequently T1MI and occurred in patients who had received a higher cumulative dose of prednisone (p = 0.032). GCA was not associated with poorer one-year survival. CONCLUSIONS: GCA-related MI are mainly T2MI probably caused by systemic inflammation rather than coronaritis. GCA-unrelated MI are predominantly T1MI associated with atherothrombotic coronary artery disease.

Giant cell arteritis (GCA) is the most common primary large-vessel vasculitis. Glucocorticoids (GC) therapy remains the standard of care for GCA despite frequent side effects (SEs). However, treatment modality changes, prophylactic treatment of osteoporosis, or vaccinations might have decreased the frequency of GC-related SEs. This study aims to describe GCA treatment and GC-related SEs in a recent cohort.Patients with a diagnosis of GCA between May 2009 and March 2018 were included in this multicentric retrospective study. Characteristics of patients, treatment modalities and GC-related SEs were collected and analysed. Risk factors associated with the occurrence of SE were studied.We analysed the files from 206 patients (153 women, 53 men; median age 74 years). Median follow-up was 34 months. Patients received GC for a median of 25 months, starting at 0.7 mg/kg/day, with tapering to 5 mg/day after 11 months follow-up. Flares occurred in 83/201 (41%) patients. Among the 132 patients who stopped GC, 29 (22%) experienced a relapse. SEs occurred in 129 (64%) patients: bone fractures and infections in 13% each and hypertension onset in 9%. Age75 years, treatment duration2 years, past medical history of diabetes were risk factors associated with GC-related SEs.Flares occur in 41% of patients during GC withdrawal. As much as 64% of patients had treatment related SEs. An age75 year and a past medical history of diabetes were predictive of SEs during follow-up.

During an epidemic period, we compared patients hospitalized for initial suspicion of COVID-19 but for whom an alternative diagnosis was finally retained (n = 152) with those who had COVID-19 (n = 222). Most common diagnoses were another infectious disease and heart failure. COVID-19-negative patients were more often active smokers had less often cough, fever, and digestive symptoms, as compared to the 222 COVID-19-positive patients. They had higher median neutrophil and lymphocyte counts and lower CRP level. In multivariate analysis, no current smoking, neurocognitive disorder, myalgia, and fibrinogen ≥4g/L were independently associated with a final diagnosis of COVID-19.

Erdheim–Chester disease (ECD) is a rare condition with underestimated neurological involvement. Mild psychiatric symptoms such as mood swings have been rarely described in the clinical spectrum of neuro-ECD. We here describe the first patient with psychiatric manifestations of delirium revealing ECD with neurological involvement with favorable evolution under interferon followed by BRAF inhibitor monotherapy. An 81-year-old woman was referred to the hospital because of delirium and severe cognitive impairment associated with a cerebellar syndrome. Brain magnetic resonance imaging showed “FLAIR-changes” lesions in the pons and upper cerebellum peduncles. Blood and cerebrospinal fluid (CSF) analyses showed normal results except for an elevated neopterin level in the CSF. Whole-body CT scan (18FDG-PET) showed peri-nephric fat infiltration and aorta adventitia sheathing with radiotracer uptake in the pons, vessels, peri-nephric fat, and bone lesions, which was characteristic of ECD. The diagnosis was confirmed on perirenal tissue biopsy, which also showed a BRAFV600E mutation. Treatment with interferon resulted in the resolution of delirium, and treatment with BRAF inhibitor subsequently resulted in a partial remission of all active sites. This case highlights that delirium can be the first manifestation of neurodegenerative ECD. ECD should be screened in unexplained psychiatric features as interferon and targeted therapy appear to be effective in this situation.

Background Cardiovascular disease (CVD) in patients with multiple myeloma (MM) may derive from multiple factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior CV diseases), related to the disease and/or related to antimyeloma treatment. Based on a nationwide hospitalization database, we aimed to assess the risk of all-cause death, and CV outcomes in MM patients. Methods From 1st January 2013 to 31st December 2013, 3,381,472 adults (age ≥18 years) were hospitalized for any reason in French hospitals and then had at least 5 years of complete follow-up (or suffered death earlier). We identified 15,774 patients diagnosed with known MM at baseline. The outcome analysis (all-cause death, cardiovascular [CV] death, myocardial infarction (MI), ischemic stroke or hospitalization for major bleeding) was performed with follow-up starting at the time of last event. For each patient with MM, a propensity score-matched patient with no MM was selected (1:1) using the one-to-one nearest neighbor method. Findings The mean follow-up in the propensity-score-matched population was 3.7±2.3 years, median 5.0, IQR 1.3–5.7 years. During follow-up, matched patients with MM (15 774 patients) had a higher risk of all-death (yearly rate 20.02 vs 11.39%/year) than patients without MM. No difference was observed between MM group and no myeloma group for CV death (2.00 vs 2.02%/year). The rate of MI and stroke was markedly lower in the MM group, respectively for incidence rate, 0.86 vs 0.97%/year and 0.85 vs 1.10%/year. In contrast, MM group had a higher rate of rehospitalization for major bleeding with an incidence rate of 3.61 vs 2.24%/yr and a higher risk of intracranial bleeding (1.03 vs 0.84%/yr). Results were similar in sensitivity analysis limited to patients with recent MM (i.e. diagnosed within the 3 previous months). Interpretation From a large nationwide database, we show that although patients with MM are not at higher risk of CV death, they had a higher risk of mortality due to major bleeding and intracranial bleeding. Our findings highlight the key issue of anticoagulation treatment management in patients with MM. Funding Acknowledgement Type of funding sources: None.

This study aimed to identify markers of disease worsening in patients hospitalized for SARS-Cov2 infection.Patients hospitalized for severe recent-onset (1 week) SARS-Cov2 infection were prospectively included. The percentage of T-cell subsets and plasma IL-6 at admission (before any steroid therapy) were compared between patients who progressed to a critical infection and those who did not.Thirty-seven patients (18 men, 19 women) were included; 11 (30%) progressed to critical infection. At admission, the critical infection patients were older (P = 0.021), had higher creatinine levels (P = 0.003), and decreased percentages of circulating B cells (P = 0.04), T cells (P = 0.009), and CD4+ T cells (P = 0.004) than those with a favorable course. Among T cell subsets, there was no significant difference between the two groups except for the percentage of Th17 cells, which was two-fold higher in patients who progressed to critical infection (P = 0.028). Plasma IL-6 at admission was also higher in this group (P = 0.018). In multivariate analysis, the percentage of circulating Th17 cells at admission was the only variable associated with higher risk of progression to critical SARS-Cov2 infection (P = 0.021).This study suggests that an elevated percentage of Th17 cells in patients hospitalized for SARS-Cov2 infection is associated with an increased risk of progression to critical disease. If these data are confirmed in a larger study, this marker could be used to better target the population of patients in whom tocilizumab could decrease the risk of progression to critical COVID-19.

Objectives To investigate the performance of cranial PET/CT for the diagnosis of GCA. Methods All patients with a suspected diagnosis of GCA were prospectively enrolled in this study and had a digital PET/CT with evaluation of cranial arteries if they had not started glucocorticoids >72 h previously. The diagnosis of GCA was retained after at least 6 months of follow-up if no other diagnosis was considered by the clinician and the patient went into remission after at least 6 consecutive months of treatment. Cranial PET/CT was considered positive if at least one arterial segment showed hypermetabolism similar to or greater than liver uptake. Results For cranial PET/CT, sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were 73.3%, 97.2%, 91.7% and 89.7%, respectively. For extracranial PET/CT, diagnostic performance was lower (Se = 66.7%, Sp = 80.6%, PPV = 58.8%, NPV = 85.3%). The combination of cranial and extracranial PET/CT improved overall sensitivity (Se = 80%) and NPV (NPV = 90.3%) while decreasing overall specificity (Sp = 77.8%) and PPV (PPV = 60%). Conclusion Cranial PET/CT can be easily combined with extracranial PET/CT with a limited increase in examination time. Combined cranial and extracranial PET/CT showed very high diagnostic accuracy for the diagnosis of GCA. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT05246540.

The first line treatment of immune thrombocytopenic purpura (ITP) is well established and based on short course of corticosteroids associated with intravenous immunoglobulins (IVIg) for the most severe forms. Predniso(lo)ne is the corticosteroid agent usually given but dexamethasone appears as an alternative. Some guidelines recommend to use dexamethasone as first line when a rapid increase of platelet count is required. Dexamethasone could be used rather than IVIg for moderate to severe but non life-threatening bleeding manifestations. Other therapeutic options such as anti FcRn monoclonal antibodies or recombinant FcγR currently in development for ITP could be an option in the future. In newly diagnosed ITP, we unfortunately lack robust predictive risk factors of severity and chronic outcome. Identifying such factors could be helpful for considering the early use of some treatments which are commonly used as second or third line.

Objective The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients. Methods We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared. Results A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th–75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0–4)], significant fatigue (55.5%, P Conclusion LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.

Since the start of the coronavirus disease 2019 (COVID-19) pandemic, patients with diabetes were rapidly recognized as a high-risk population for severe disease. Indeed, a high prevalence of diabetes among patients with COVID-19 who required hospitalization has been consistently reported, reaching 33.8% in 5,700 people hospitalized for COVID-19 in the New York City area (1). In addition, diabetes was associated with more than a doubled risk of intensive care unit (ICU) admission and more than a tripled risk of death (2). However, precise data regarding the type of diabetes are scarce. We report here the clinical characteristics and early prognosis of patients with type 1 diabetes (T1D) hospitalized for COVID-19 in the nationwide multicenter observational CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study (3). The aim of the CORONADO study was to describe the phenotypic characteristics and prognosis of patients with diabetes admitted with COVID-19 between 10 March and 10 April 2020 in 68 French hospitals. The protocol (ClinicalTrials.gov reg. no. NCT04324736) obtained all regulatory approvals as recently described (3). Inclusion criteria were 1 ) hospitalization for biologically and/or clinically/radiologically attested COVID-19 and 2 ) personal history of diabetes or newly diagnosed diabetes on admission. The composite primary end point combined tracheal intubation for mechanical ventilation and/or death on day 7 (D7). Secondary outcomes included death, tracheal intubation, and discharge on D7. Classification of diabetes was recorded in the electronic case report form as noted in the medical file by the physician in charge of the patient. In the present subanalysis, patients in whom diabetes was diagnosed on admission were excluded since the etiological diagnosis had not been formally established. All cases noted as T1D were carefully reviewed by local investigators and the steering committee …

Background Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Objective To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen. Design Randomized controlled trial. (ClinicalTrials.gov: NCT02433522). Setting 39 clinical centers in France. Patients 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy. Intervention Rituximab or placebo infusion every 6 months for 18 months (4 infusions). Measurements The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0. Results From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (P = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group. Limitation Potential selection bias based on previous rituximab response and tolerance. Conclusion Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy. Primary funding source French Ministry of Health and Hoffmann-La Roche.

ObjectiveThe randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter’s titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12.MethodsMAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV.ResultsAt M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV.ConclusionsWe were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups.

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.

Recently developed cell-based therapies have shown potential for graft-versus-host disease (GvHD) mitigation. Our team previously developed a protocol to generate human monocyte-derived suppressor Cells (HuMoSC), a subpopulation of CD33+ suppressor cells of monocytic origin. CD33+HuMoSC successfully reduced xenoGvHD severity in NOD/SCID/IL-2Rγc-/- (NSG) mice. While CD33+ HuMoSC culture supernatant inhibits T cell activation and proliferation, the recovery of CD33+ HuMoSC immunosuppressive cells and the subsequent production of their supernatant is limited. An attractive solution would be to use both the CD33+ and the large number of CD14+ cells derived from our protocol. Here, we assessed the immunoregulatory properties of the CD14+HuMoSC supernatant and demonstrated that it inhibited both CD4 and CD8 T cell proliferation and decreased CD8 cytotoxicity. In vivo, injection of CD14+HuMoSC supernatant reduced xenoGvHD in NSG mice. Furthermore, CD14+HuMoSC supernatant maintained its immunoregulatory properties in an inflammatory environment. Proteomic and multiplex analyses revealed the presence of immunosuppressive proteins such as GPNMB, galectin-3 and IL-1R(A) Finally, CD14+HuMoSC supernatant can be produced using good manufacturing practices and be used as complement to current immunosuppressive drugs. CD14+HuMoSC supernatant is thus a promising therapy for preventing GvHD.

Background: We aimed to investigate the impact of the first COVID-19 lockdown on medication adherence, physician access, lifestyle behaviours, and mental health in patients with chronic conditions. Methods: A cross-sectional phone survey was conducted in 1274 housebound adults recruited from 8 regional chronic disease cohorts (CLEO CD study: NCT04390126). Results: Medication adherence was 97%; 305 (41%) patients declared that at least one scheduled visit with a physician was missed during the first lockdown. The main changes in lifestyle behaviours were deterioration in sleep time (duration and/or quality; 71%), increase in screen time (46%), and decrease in physical activity (46%). Nineteen percent experienced psychological distress (Kessler-6 score ≥ 5). An urban living place (OR, 1.76 vs. rural; 95% CI, 1.32–2.33; p = 10−4), worse self-reported mental health (OR, 1.62 vs. about the same or better; 95% CI, 1.17–2.25; p = 0.003), and a K6 score ≥ 5 (OR, 1.52 vs.

Polymyalgia rheumatica (PMR) is an inflammatory rheumatism of the shoulder and pelvic girdles. In 16 to 21% of cases, PMR is associated with giant cell arteritis (GCA) that can lead to severe vascular complications. Ruling out GCA in patients with PMR is currently a critical challenge for clinicians. Two GCA phenotypes can be distinguished: cranial GCA (C-GCA) and large vessel GCA (LV-GCA). C-GCA is usually suspected when cranial manifestations (temporal headaches, jaw claudication, scalp tenderness, or visual disturbances) occur. Isolated LV-GCA is more difficult to diagnose, due to the lack of specificity of clinical features which can be limited to constitutional symptoms and/or unexplained fever. Furthermore, many studies have demonstrated the existence—in varying proportions—of subclinical GCA in patients with apparently isolated PMR features. In PMR patients, the occurrence of clinical features of C-GCA (new onset temporal headaches, jaw claudication, or abnormality of temporal arteries) are highly predictive of C-GCA. Additionally, glucocorticoids’ resistance occurring during follow-up of PMR patients, the occurrence of constitutional symptoms, or acute phase reactants elevation are suggestive of associated GCA. Research into the predictive biomarkers of GCA in PMR patients is critical for selecting PMR patients for whom imaging and/or temporal artery biopsy is necessary. To date, Angiopoietin-2 and MMP-3 are powerful for predicting GCA in PMR patients, but these results need to be confirmed in further cohorts. In this review, we discuss the diagnostic challenges of subclinical GCA in PMR patients and will review the predictive factors of GCA in PMR patients.

Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flar...

Background and ObjectivesSpinal cord sarcoidosis is a rare manifestation of sarcoidosis with a consequent risk of neurologic sequelae for the patient. We investigated prognostic factors and efficacy of immunosuppressive treatments in a longitudinal cohort.MethodsWe retrospectively studied patients with spinal cord sarcoidosis followed between 1995 and 2021 in 7 centers in France. Patients with definite, probable, or possible spinal cord sarcoidosis according to the Neurosarcoidosis Consortium Consensus Group criteria and with spinal cord involvement confirmed by MRI were included. We analyzed relapse or progression rate with a Poisson model, initial Rankin score with a linear model, and change in the Rankin score during follow-up with a logistic model.ResultsA total of 97 patients were followed for a median of 7.8 years. Overall mean relapse or progression rate was 0.17 per person-year and decreased over time. At last visit, 46 (47.4%) patients had a loss of autonomy (Rankin score ≥2). The main prognostic factors significantly associated with relapse or progression rate were gadolinium enhancement (relative rate [95% CI] 0.61 [0.4, 0.95]) or meningeal involvement (relative rate [95% CI] 2.05 [1.31, 3.19]) on spinal cord MRI and cell count (relative rate [95% CI] per 1 log increase 1.16 [1.01, 1.33]) on CSF analysis. Relapse or progression rate was not significantly associated with initial Rankin score or Expanded Disability Status Scale. Tumor necrosis factor–α (TNF-α) antagonists significantly decreased relapse or progression rate compared with corticosteroids alone (relative rate [95% CI] 0.33 [0.11, 0.98]). Azathioprine was significantly less effective than methotrexate on relapse or progression rate (relative rate [95% CI] 2.83 [1.04, 7.75]) and change in Rankin score (mean difference [95% CI] 0.65 [0.23, 1.08]).DiscussionRegarding the relapse or progression rate, meningeal localization of sarcoidosis was associated with a worse prognosis, TNF-α antagonists resulted in a significant decrease compared to corticosteroids alone, and methotrexate was more effective than azathioprine.Classification of EvidenceThis study provides Class IV evidence that in individuals with spinal cord neurosarcoidosis, TNF-α antagonists were associated with decreased relapse or progression rate compared to corticosteroids alone, but other therapies showed no significant benefit.

Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

Objective To describe the efficacy and safety of off-label use of biologics for refractory and/or relapsing granulomatosis with polyangiitis (GPA). Methods We conducted a French retrospective study including GPA patients who received off-label biologics for refractory and/or relapsing disease after failure of conventional immunosuppressive regimens. Results Among 26 patients included, 18 received infliximab (IFX), 2 adalimumab (ADA) and 6 abatacept (ABA). Biologics were initiated in median as 4th-line therapy (IQR 3–6) for relapsing and/or refractory disease in 23 (88%) and/or significant glucocorticoid-dependency in 8 cases (31%). At biologics initiation, median (IQR) BVAS and prednisone dose in anti- TNF-α and ABA recipients were 7 (3–8) and 2 (1–6), and 20 (13–30) mg/day and 20 (15–25) mg/day, respectively. Clinical manifestations requiring biologics were mainly pulmonary and ENT manifestations in 58% each. Anti-TNF-α and ABA were continued for a median duration of 8 months (IQR 6–13) and 11 months (IQR 6–18) respectively. Anti-TNF-α recipients showed remission, partial response and treatment failure in 10%, 30% and 60% at 6 months, and 25%, 20% and 55% at 12 months, respectively. ABA recipients showed remission, partial response and treatment failure in 17%, 33% and 50% at 6 months and 17%, 33% and 50% at 12 months. One patient treated with IFX experienced life-threatening reaction while one patient treated with ABA experienced a severe infection. Conclusion This real-life study suggests that off-label use of anti-TNF-α and abatacept shows efficacy in less than 50% of refractory and/or relapsing GPA.

Introduction La TEP-TDM est de plus en plus utile pour faire le diagnostic d’arterite a cellules geantes (ACG), en particulier en cas de forme extra-cephalique. Sa performance diagnostique est excellente avec une sensibilite de 82 % et une specificite proche de 100 % [1] . Au cours du suivi, la place et les modalites d’interpretation de la TEP-TDM sont moins bien definis. L’objectif de notre travail etait de determiner si le degre d’hypermetabolisme vasculaire a la TEP-TDM, au diagnostic d’ACG et apres 3 a 12 mois de suivi, etait predictif de la survenue de rechute d’ACG. Patients et methodes Nous avons mene une etude retrospective multicentrique portant sur 53 patients atteints d’ACG avec atteinte des gros vaisseaux au diagnostic. Chaque patient avait eu une TEP-TDM au diagnostic (TEP no 1), et un controle dans les 3 a 12 mois suivant le diagnostic (TEP no 2). Pour chacun des 14 segments arteriels, le niveau d’hypermetabolisme vasculaire etait cote de facon semi-quantitative selon les recommandations internationales [2] : grade 0 en l’absence d’hypermetabolisme, grade 1 (SUV max arteriel SUV max hepatique). Le grade de fixation de chaque segment arteriel etait additionne pour obtenir un score nomme Total Vascular Score (TVS) qui variait de 0 a 42 points. Nous avons etudie le risque de survenue de rechute en fonction des TVS de la TEP no 1 et de la TEP no 2. La rechute etait definie comme la reapparition, apres une periode de remission d’au moins 3 mois, d’au moins un signe clinique d’ACG ou de PPR, ou d’un syndrome inflammatoire (CRP > 10 mg/L) pendant plus de 2 semaines consecutives sans autre cause que l’ACG et ayant conduit a majorer le traitement de l’ACG. Les resultats sont exprimes en mediane (espace interquartile) ou nombre (%) et compares par des tests de Mann–Whitney, Wilcoxon, Chi2 ou Fisher. Le risque de rechute a ete evalue par des courbes de Kaplan–Meier et les facteurs associes au risque de rechute ont ete analyses a l’aide de tests de log-rank. Resultats Cinquante-trois patients ont ete inclus dans cette etude, âges de 70 (63–75) ans, dans 79 % des cas de sexe feminin. La BAT etait positive dans 51 % des cas. Le TVS variait de 24 (18–32) points lors la TEP no 1 a 6,5 (0–14) points lors de la TEP no 2 (p 14 (p = 0,067). Pour la TEP no 2, nous avons analyse les 44 patients pour lesquels la TEP avait ete realisee en dehors d’un episode de rechute. Lors du suivi, un TVS superieur a 14 points ou 23 points etait associe a un risque de rechute de 50 % ou 67 % a 12 mois, et 67 % ou 100 % a 24 mois respectivement (p = 0,019 vs TVS ≤ 14 et p = 0,001 vs TVS ≤ 23 points respectivement). Discussion Nos donnees suggerent que la TEP realisee au cours du suivi de l’ACG est plus discriminante que celle realisee au diagnostic pour predire le risque de rechute. De plus, l’utilisation d’un score semi-quantitatif (TVS) permet d’en standardiser l’analyse et de determiner des seuils (≤ 14, 14 a 20, et > 20 points) pour predire le risque de rechute. Ces resultats sont concordants avec ceux de l’etude de Grayson et al. [3] qui rapportaient qu’un score vasculaire (PETVAS) superieur a 20 points etait predictif de la survenue de rechute au cours du suivi. Conclusion Un TVS > 14 points et a fortiori > 20 points lors d’une TEP de suivi realisee apres 3 a 12 mois de traitement est predictif de rechute au cours de l’ACG avec atteinte des gros troncs.

Introduction Les monocytes jouent un role important dans la pathogenese des histiocytoses [1] , [2] . Peu de donnes sont disponibles concernant l’etude de leur phenotype dans les histiocytoses ; et les differences avec d’autres syndromes myeloproliferatifs ou maladies inflammatoires. Materiels et methodes Le phenotype des sous-populations des monocytes de patients atteints d’histiocytose a ete compare a celui de patients atteints de leucemie myelomonocytaire chronique (LMMC), de thrombocytemie essentielle (TE), d’arterite a cellules geantes (ACG) et de donneurs sains (HD). Les monocytes ont ete definis comme classiques (CD14 + +CD16-), intermediaires (CD14 + CD16 + ) et non classiques (CD14 + CD16 + +) par cytometrie en flux. Resultats Soixante-douze patients ont ete inclus (16 histiocytoses, 7 LMMC, 7 TE, 21 ACG et 21 sujets sains). Parmi les histiocytoses, 8 patients avaient une maladie d’Erdheim-Chester dont 5 etaient BRAFV600E mutes. Quatre patients avaient une histiocytose Langerhansienne et un seul avait une mutation BRAFV600. Quatre patients avaient une maladie de Rosai-Dorfman dont 2 avaient une mutation MAP2K1. Trois patients avaient une histiocytose et un syndrome myeloproliferatif associe (2 LMMC, 1 TE) et 6 patients une hematopoiese clonale associee. La proportion de monocytes « classiques » etait plus elevee dans les histiocytoses compare aux TE (mediane avec ecart interquartile : 92 % [83,5–96,0] vs 76 % [71,0–84,0] ; p : 0,0149). La proportion de monocytes intermediaires etait plus faible dans les histiocytoses comparees aux TE (4,5 % [3,00–7,75] vs 13 % [9,00–18,00] ; p : 0,0230) et aux ACG (4,5 % [3,00–7,75] vs 7,91 % [6,01–20,75] ; p : 0,0175). Les proportions de monocytes classiques (87,50 % [78,50–92,50] vs 97 % [96,0–98,0] ; p :0,0015), intermediaires (5 % [4,0–12,25] vs 2,5 % [1,250–2,750] ; ip :0,043) et non classiques (4 % [3,250–11,0] vs 0,5 % [0,500–1,500] ; p :0,0086) differaient entre les patients atteints de LMMC et les patients presentant une histiocytose et une hematopoiese clonale. La repartition etait identique chez les patients avec histiocytose et une mutation sur la voie des MAP-kinases et les patients avec une LMMC. La repartition des monocytes ne differait pas selon le type d’histiocytose, le statut moleculaire, l’association avec une neoplasie myeloide ou hematopoiese clonale ou le traitement par therapie ciblee. La proportion de monocytes non classiques etait plus faible dans les histiocytoses avec atteintes vasculaires (1,00 % [0,775–2,500] vs 4,00 % [1,750–9,500] ; p : 0,0425). La proportion de monocytes intermediaires etait plus faible chez les patients avec une maladie controlee (3,5 % [2,00–5,00] vs 7,5 % [4,00–16,00] ; p : 0,0311). Conclusion La distribution des sous-populations monocytaire est homogene dans les histiocytoses. Cette derniere est proche de la LMMC, un syndrome myeloproliferatif avec une implication possible de la voie des MAP-kinases ; mais elle est differente de la TE et de l’ACG. L’analyse des sous-populations monocytaire peut etre une aide diagnostique et un marqueur d’activite de la maladie.