Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX.

OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies. METHODS: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose. RESULTS: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors. CONCLUSIONS: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

Immunohistochemical expression of DnaJ homolog subfamily B member 9 in immunoglobulin G4-related disease: a pilot study.

OBJECTIVES: DnaJ homolog subfamily B member 9 (DNAJB9) is a co-chaperone protein that governs the functions and integrity of cells. In immunoglobulin G4-related disease (IgG4-RD), DNAJB9 was shown to be upregulated in plasma cells, but its immunohistochemical expression has never been explored. This pilot study aims to investigate the immunohistochemical distribution and intensity of DNAJB9 in IgG4-RD tissue specimens. METHODS: Patients with definite IgG4-RD and normal tissue controls were selected for anti-DNAJB9 immunohistochemistry, applying a semi-quantitative staining intensity score. RESULTS: We studied the tissue slides of 9 IgG4-RD patients and 15 controls, including salivary gland, pancreatic, pulmonary, pleural, and retroperitoneal fibrosis tissue. Median immunohistochemical intensity was 0 for IgG4-RD patients vs. 2 for controls for endothelial cells (ES=1.58, p<0.01), 2 in each group for glandular epithelial cells (ES 0.70, p=0.26), and 2 for IgG4-RD vs. 3 for controls for inflammatory cells regarding salivary glands alone (ES=0.90, p=0.11). Endothelial staining intensity was negatively correlated with serum IgG4 concentrations (r= -0.72, p=0.03) and the number of treatments required to achieve disease remission (r= -0.70, p=0.04). CONCLUSIONS: Our findings evidenced reduced immunohistochemical expression of DNAJB9 in IgG4-RD endothelial cells, and suggested loss of expression in other cell types, possibly correlating with disease severity and risk of relapse. Although DNAJB9 may not serve as a marker for IgG4-RD, it may be part of a pathophysiological pathway involved in the disease and the onset of fibrosis.

Efficacy and safety of intravenous bevacizumab on severe bleeding associated with hemorrhagic hereditary telangiectasia: A national, randomized multicenter trial.

BACKGROUND: Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted. METHODS: This study is a double-blind multicenter randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3-month period before and after treatment. RESULTS: A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm. CONCLUSION: Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure.

Cardiac sarcoidosis: systematic review of the literature on corticosteroid and immunosuppressive therapies.

BACKGROUND: Cardiac sarcoidosis (CS) is a life-threatening condition in which clear recommendations are lacking. We aimed to systematically review the literature on cardiac sarcoidosis treated by corticosteroids and/or immunosuppressive agents in order to update the management of CS. METHODS: Using PubMed, Embase and Cochrane Library databases, we found original articles on corticosteroid and standard immunosuppressive therapies for CS that provided at least a fair Scottish Intercollegiate Guidelines Network (SIGN) overall assessment of quality and we analysed the relapse rate, major cardiac adverse events (MACEs) and adverse events. We based our methods on the PRISMA statement and checklist. RESULTS: We retrieved 21 studies. Mean quality provided by SIGN assessment was 6.8 out of 14 (range 5-9). Corticosteroids appeared to have a positive impact on left ventricular function, atrioventricular block and ventricular arrhythmias. For corticosteroids alone, nine studies (45%, n=351) provided data on relapses, representing an incidence of 34% (n=119). Three studies (14%, n=73) provided data on MACEs (n=33), representing 45% of MACEs in patients treated by corticosteroid alone. Nine studies provided data on adjunctive immunosuppressive therapy, of which four studies (n=78) provided data on CS relapse, representing an incidence of 33% (n=26). Limitations consisted of no randomised control trial retrieved and unclear data on MACEs in patients treated by combined immunosuppressive agents and corticosteroids. CONCLUSION: Corticosteroids should be started early after diagnosis but the exact scheme is still unclear. Studies concerning adjunctive conventional immunosuppressive therapies are lacking and benefits of adjunctive immunosuppressive therapies are unclear. Homogenous data on CS long-term outcomes under corticosteroids, immunosuppressive therapies and other adjunctive therapies are lacking.

Givosiran in acute intermittent porphyria: A personalized medicine approach.

BACKGROUND: In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase. OBJECTIVES: To describe the efficacy and safety of givosiran based on a personalized medical approach. METHODS: We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events. RESULTS: Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism. CONCLUSION: The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient.

Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.

OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Efficacy of bortezomib in non-IgM type I cryoglobulinaemic vasculitis: a single-centre retrospective case series.

INTRODUCTION: Treatment of non-IgM type I cryoglobulinaemic vasculitis (CV) is challenging. Corticosteroids are first-line therapy, but relapses are frequent leading to therapeutic escalation. Bortezomib is a proteasome inhibitor with rapid effect on monoclonal component. However, its use in non-IgM type I CV has been barely reported. OBJECTIVE: To assess the efficacy of bortezomib in non-IgM type I CV. METHOD: Single-centre case series of four patients with non-IgM type I CV treated with bortezomib monotherapy. RESULTS: Two men and two women, 60-84 years old, received bortezomib monotherapy. Monoclonal component was IgG-λ (n = 2), IgA-λ and IgG-κ. Clinical features were necrotic rash (n = 3), synovitis (n = 3) and sensitive neuropathy (n = 2). CV was refractory to corticosteroids (n = 4), cyclophosphamide (n = 3) and rituximab (n = 2). Three patients experienced dramatic clinical improvement with undetectable cryoglobulin after three cycles (bortezomib 1.3 mg/m2 weekly). Each patient relapsed 4-18 months after treatment discontinuation. Bortezomib was unsuccessful after four cycles in one patient. Bortezomib toxicity included one pneumonia and 1 case of worsening neuropathic pain. CONCLUSION: Bortezomib in monotherapy should be considered as a valuable option in refractory non-IgM type I CV because of its swift efficacy and acceptable tolerance profile.

Intravenous immunoglobulins for the treatment of prolonged COVID-19 in immunocompromised patients: a brief report.

Primary humoral deficiency and secondary B-cell depletion may lead to prolonged Sars-Cov-2 infection due to a decreased viral clearance. Prolonged infection is mainly driven by the lack of anti-Sars-Cov-2 immunoglobulin (IVIg) especially in patients with no vaccine response. Anti-spike immunoglobulin can be provided by infusion of convalescent patients' plasma: recent studies highlighted that commercial immunoglobulin show high titers of neutralizing IgG. We conducted a single center retrospective cohort. We included 9 patients (6 males, median age 74 years old): one patient with X-linked agammaglobulinemia and 8 patients treated with rituximab (2 granulomatosis with polyangiitis, 1 neuromyelitis optica, 4 low grade B-cell lymphoma and 1 EBV post-transplant lymphoproliferative disorder). Mean serum globulin was 4 ± 1.6 g/L. 7/8 had received at least 3 doses of mRNA anti-Sars-Cov-2 vaccine (median 4) with no response (anti-Spike IgG 0 for 6 patients). In this specific population requiring oxygen therapy but no intensive care support, the administration of IVIg was well tolerated and provided a swift improvement of clinical status, a significant decrease of inflammation associated to the an improvement of radiological patterns. Our results suggest that immunoglobulin could be used as a salvage therapy as an alternative to convalescent plasma but highly stringent patient selection is required due to the worldwide shortage of IVIg.

Prevalence of FGF23 elevation in patients with hypophosphatemia.

BACKGROUND AND AIMS: To investigate the contribution of FGF23 in explaining the cases of hypophosphatemia observed in clinical practice, we aimed to determine for the first time the prevalence of FGF23 elevation in patients with hypophosphatemia and to describe the different mechanisms of FGF23-related hypophosphatemic disorders. MATERIALS AND METHODS: We performed a prospective, observational, multicenter, cohort study of 260 patients with hypophosphatemia. Blood measurements (PTH, 1,25-dihydroxyvitamin D, bone alkaline phosphatase, 25-hydroxyvitamin D, and FGF23) were performed on a Liaison XL® (DiaSorin) analyzer. RESULTS: Primary elevation of FGF23 (>95.4 pg/mL) was reported in 10.4% (95CI: 7.0-14.7) of patients (n = 27) with hypophosphatemia, suggesting that at least 1 in 10 cases of hypophosphatemia was erroneously attributed to an etiology other than FGF23 elevation. Patients with elevated blood FGF23 were grouped according to the etiology of the FGF23 elevation. Thus, 10 patients had a renal pathology, chronic kidney disease or post-renal transplantation condition. The remaining patients (n = 17) had the following etiologies: malignancies (n = 9), benign pancreatic tumor (n = 1), post-cardiac surgery (n = 4), cirrhosis (n = 2), and chronic obstructive pulmonary disease (n = 1). CONCLUSION: In order to improve patient management, it seems essential to better integrate plasma FGF23 measurement into the routine evaluation of hypophosphatemia.

Kidney involvement in myelodysplastic syndromes.

Introduction: The objective of this study was to describe kidney involvement in patients with myelodysplastic syndromes (MDS), their treatments, and outcomes. Methods: We conducted a multicenter retrospective study in seven centers, identifying MDS patients with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities. Results: Fifteen patients developed a kidney disease 3 months after MDS diagnosis. Median urine protein-to-creatinine ratio was 1.9 g/g, and median serum creatinine was 3.2 mg/dL. Ten patients had AKI at presentation, and 12 had extra-renal symptoms. The renal diagnoses included anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), ANCA negative vasculitis, C3 glomerulonephritis, immune complex-mediated glomerulonephritis, polyarteritis nodosa, and IgA vasculitis. All patients but one received a specific treatment for the MDS-associated kidney injury. The effect of MDS treatment on kidney injury could be assessed in six patients treated with azacitidine, and renal function evolution was heterogenous. After a median follow-up of 14 months, four patients had CKD stage 3, five had CKD stage 4, and three had end stage kidney disease. On the other hand, three evolved to an acute myeloid leukemia and three died. Compared to 84 MDS controls, patients who had kidney involvement were younger, had a higher number of dysplasia lineages, and were more eligible to receive hypomethylating agents, but no survival difference was seen between the two groups. Compared to 265 AAV without MDS, the ten with MDS-associated pauci-immune vasculitis were older, ANCA serology was more frequently negative, and more cutaneous lesions were seen. Conclusion: The spectrum of kidney injuries associated with MDS is mostly represented by vasculitis with glomerular involvement, and especially AAV.

Polymyalgia rheumatica and giant cell arteritis following COVID-19 vaccination: Results from a nationwide survey.

We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2-30) and 7 (range 2-25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.

Antiplatelet and anticoagulant therapies in hereditary hemorrhagic telangiectasia: A large French cohort study (RETROPLACOTEL).

BACKGROUND: It is unclear whether hereditary hemorrhagic telangiectasia (HHT) patients can tolerate antithrombotic therapies (AT) including antiplatelet (AP) and/or anticoagulant (AC) agents. OBJECTIVES: Primary endpoint was tolerance to AT in HHT. Secondary endpoints were to identify factors associated with major bleeding events (MBE) and premature discontinuation of AT. METHODS: Retrospective multicenter study in French national HHT Registry patients exposed to AT. RESULTS: We included 126 patients with 180 courses of AT. Median follow-up was 24 [11-52] months. Mean age was 65.6 ± 13.1 years. The first 3 months of AT exposure had an increased risk of hospitalization for hemorrhage (p < 0.001) and transfusions (p < 0.001). MBE (n = 63) occurred more frequently in the first 3 months of AT exposure (p < 0.001). Premature discontinuation of AT occurred in 61 cases. Rate of premature discontinuation was 29 % under both AP and AT therapy but significantly higher under dual AP therapy (n = 4/7, 57 % p = 0.008). Risk factors for MBE were: age ≥ 60 years (HR 2.34 [1.12;4.87], p = 0.023), prior hospitalization in the 3 months before starting AT for hemorrhage (HR 3.59 [1.93;6.66], p < 0.001) or transfusion (HR 3.15 [1.61;6.18], p = 0.001), previous history of gastro-intestinal bleeding (HR 2.71 [1.57;4.65], p < 0.001) or MBE (HR 4.62 [2.68;7.98], p < 0.001). Frequency of MBE did not differ between groups except for a higher risk in the dual AP group (HR 3.92 [1.37;11.22], p = 0.011). CONCLUSION: Tolerance of AC or AP therapy was similar in HHT population but not dual AP therapy. We identified risk factors for MBE occurrence or premature discontinuation under AT.

Reduced peripheral blood dendritic cell and monocyte subsets in MDS patients with systemic inflammatory or dysimmune diseases.

BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) occur in 10-20% of patients with myelodysplastic syndrome (MDS). Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1 (Ubiquitin-like modifier-activating enzyme 1), encompasses a range of severe inflammatory conditions along with hematological abnormalities, including MDS. The pathophysiological mechanisms underlying the association between MDS and SIADs remain largely unknown, especially the roles of different myeloid immune cell subsets. The aim of this study was to quantitatively evaluate peripheral blood myeloid immune cells (dendritic cells (DC) and monocytes) by flow cytometry in MDS patients with associated SIAD (n = 14, most often including relapsing polychondritis or neutrophilic dermatoses) and to compare their distribution in MDS patients without SIAD (n = 23) and healthy controls (n = 7). Most MDS and MDS/SIAD patients had low-risk MDS. Eight of 14 (57%) MDS/SIAD patients carried UBA1 somatic mutations, defining VEXAS syndrome.Compared with MDS patients, most DC and monocyte subsets were significantly decreased in MDS/SIAD patients, especially in MDS patients with VEXAS syndrome. Our study provides the first overview of the peripheral blood immune myeloid cell distribution in MDS patients with associated SIADs and raises several hypotheses: possible redistribution to inflammation sites, increased apoptosis, or impaired development in the bone marrow.

Development and validation of a quality of life measurement scale specific to hereditary hemorrhagic telangiectasia: the QoL-HHT.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) disease is a rare genetic disorder with symptoms and complications that can significantly affect patients' daily lives. To date, no scale has been validated to assess the specific symptoms of this disease on the quality of life (QOL) of HHT patients. This makes it difficult for clinicians to accurately measure the quality of life of patients with HHT. The present study aims to develop and validate a QOL measurement tool specific to HHT disease: the QOL questionnaire in HHT (QoL-HHT). METHODS: A quantitative, non-interventional, multi-center study involving HHT patients in twenty French HHT expert centers was conducted. A calibration sample of 415 HHT patients and a validation sample of 228 HHT patients voluntarily participated in the study. Data were analyzed using exploratory factor analysis (EFA), confirmatory factor analysis (CFA), Exploratory Structural Equation Modeling (ESEM) analyses, reliability analyses, and correlational analyses. RESULTS: The EFA, CFA and ESEM results allowed us to provide evidence of the factorial structure of a questionnaire composed of 24 items measuring 6 domains of QOL: Physical limitations, social relationships, concern about bleeding, relationship with the medical profession, experience of symptoms, and concern about the evolution of the disease. Cronbach's alpha coefficients (> 0.70) demonstrated reliable internal consistency of all the QoL-HHT scores (dimensions). The results of the test-retest provided further evidence of the reliability of the QOL-HHT scores over time. Correlational analyses provided evidence for the convergent validity of the QoL-HHT scores. CONCLUSIONS: We developed a simple and quick self-assessment tool to measure quality of life specific to HHT disease. This study demonstrated reliability and validity of our QoL-HHT scores. It is a very promising tool to evaluate the impact of HHT disease on all aspects of the quality of life of HHT patients in order to offer them individualized medico-psycho-social support. TRIAL REGISTRATION: ClinicalTrials, NCT03695874. Registered 04 October 2018, https://www. CLINICALTRIALS: gov/ct2/show/NCT03695874.

Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients.

OBJECTIVE: A new adult-onset autoinflammatory syndrome has been described, named VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic). We aimed to compare the clinical characteristics, the laboratory features and the outcomes between idiopathic-relapsing polychondritis (I-RP) and VEXAS-relapsing polychondritis (VEXAS-RP). METHODS: Patients from French retrospective multicentre cohort of RP were separated into two groups: a VEXAS-RP and an I-RP. RESULTS: Compared with patients with I-RP (n=40), patients with VEXAS-RP (n=55) were men (96% vs 30%, p<0.001) and were older at diagnosis (66 vs 44 years, p<0.001). They had a greater prevalence of fever (60% vs 10%, p<0.001), of skin lesions (82% vs 20%, p<0.001), of ocular involvement (57% vs 28%, p=0.01), of pulmonary infiltrates (46% vs 0%, p<0.001), of heart involvement (11% vs 0%, p=0.0336) and with higher median C-reactive protein levels (64 mg/L vs 10 mg/L, p<0.001). Seventy-five per cent of the patients with VEXAS-RP had myelodysplastic syndrome (MDS) versus none in I-RP group. The glucocorticoids use, and the number of steroid sparing agents were similar in both groups, but patients with VEXAS-RP had more frequent refractory disease (remission obtained in 27% vs 90%, p<0001). VEXAS-RP was associated with higher risk of death: six patients (11%) died in the VEXAS-RP group after a median follow-up of 37 months and none in the I-RP group after a median follow-up of 92 months (p<0.05). CONCLUSION: We report the largest cohort of VEXAS-RP, characterised by high prevalence of male sex, fever, skin lesion, ocular involvement, pulmonary infiltration, heart involvement, older age and MDS association.

Case Report: TNFα Antagonists Are an Effective Therapy in Cardiac Sarcoidosis.

Introduction: Cardiac sarcoidosis (CS) is a life-threatening disease in which clear recommendations are lacking. We report a case series of CS successfully treated by tumor necrosis factor (TNF)α antagonists. Methods: We conducted a single-center retrospective study of our patients with CS treated by TNFα antagonists. Results: Four cases (4/84, 4.7%) were found in our database. Mean age was 40 years (range 34-53 years), and all were Caucasian men. Mean follow-up was 54.75 months (range 25-115 months). All patients received corticosteroid therapy (CT) and immunosuppressive therapy (IT). TNFα antagonists (infliximab or adalimumab) were started after the first or second CS relapse under CT and IT. One patient experienced relapse under TNFα antagonists (isolated decreased left ventricular ejection) and responded to a shorter interval of TNFα antagonist infusion. CT was discontinued in three patients treated with TNFα antagonists without relapse or major cardiac events during follow-up. No serious adverse event occurred in our case series, possibly due to dose sparing and frequent arrest of CT. Conclusion: TNFα antagonists were effective in refractory and/or relapsing CS treated by corticosteroids and/or immunosuppressive agents, without serious adverse events, and should be considered earlier in CS treatment scheme.

Anti-Ro52 antibodies are a risk factor for interstitial lung disease in primary Sjögren syndrome.

OBJECTIVE: To determine whether anti-Ro52 antibodies are associated with ILD in pSS. METHODS: Retrospective study based on the presence or absence of anti-Ro52 antibodies in patients with pSS. Patients underwent chest HRCT at the time of diagnosis or during follow-up. RESULTS: Sixty-eight patients were included. Two groups were defined by the presence (n = 31) or absence (n = 37) of anti-Ro52 antibodies. ILD was significantly higher in the presence of anti-Ro52 (41.9%, n = 13) versus in the anti-Ro52-negative group (16.2%, n = 6; p = 0.019). Multivariate analysis adjusted for anti-SSA/Ro60, anti-SSB antibodies and rheumatoid factor status confirmed that anti-Ro52 antibodies positivity is a predictive factor for ILD (p = 0.01). Nonspecific interstitial pneumonia was the most common pattern of ILD (31.6%). The majority of patients were diagnosed with pSS simultaneously to ILD (52.6%). In the anti-Ro52-negative group, no patients develop ILD after 5 years of follow-up. CONCLUSION: In pSS, the risk of developing ILD is higher in the presence of anti-Ro52 antibodies. In patients with pSS and anti-Ro52 antibodies, a clinical screening and pulmonary functional tests with DLCO is necessary during the follow-up and should comprise chest HRCT if there is a decline in the DLCO or clinical symptoms or inspiratory crackles.

Rituximab for rheumatoid arthritis-associated large granular lymphocytic leukemia, a retrospective case series.

OBJECTIVES: To assess the efficacy and tolerance profile of rituximab in rheumatoid arthritis (RA)-associated large granular lymphocyte leukemia (LGLL). METHODS: Multicenter retrospective case series. Inclusion criteria were RA defined by the ACR/EULAR 2010 criteria and LGLL defined by absolute LGL count ≥ 0.3 × 109/L with evidence of an expanded clonal LGL population (flow cytometry, TCR-γ polymerase chain reaction, or Stat3 mutation). RESULTS: Fourteen patients (10 women, mean age 55.2 ± 14.2 years) included; 13 were seropositive for anti-cyclic citrullinated peptides (n = 11) or rheumatoid factor (n = 10). LGLL diagnosis was made 9.5 [IQR: 3.25;15.5] years after RA diagnosis. Thirteen patients had T-LGLL. Rituximab was the first-line therapy for LGLL for 4 patients. Previous treatment lines included methotrexate (n = 7), cyclophosphamide (n = 2), cyclosporin A (n = 1), or granulocyte colony-stimulating factor (n = 4). Rituximab was used in monotherapy (n = 8) or associated to methotrexate (n = 3), granulocyte colony-stimulating factor (n = 2), or alkylating agents (n = 1). The number of rituximab cycles ranged from 1 to 11 (median 6), with high heterogeneity in dosing regimens. Median duration response after rituximab initiation was 35 [IQR: 23.5;41] months. The overall response rate was 100%: 8 patients experienced complete response (normalization of blood count and LGL ≤ 0.3 × 109/L) and 6 experienced partial responses (improvement in blood counts without complete normalization). The tolerance profile was good, with no infectious complications. CONCLUSION: rituximab appears as a valuable therapeutic option for RA-associated LGLL.

Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial.

Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.