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Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials

ObjectiveTo compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively).MethodsThe Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84.Results277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25).ConclusionsAccording to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

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Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants

The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. Clinical characteristics of 130 HLHa patients (age≥ 18 years and HScore≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. Atotal of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. HLHa-associated diseases (ADs) were neoplasia (n= 49 [37.7%]), autoimmune/inflammatory disease (n= 33 [25.4%]), or idiopathic when no AD was identified (n= 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P= .0008; 2-3 vs 0: 29.4 [3.62-3810], P= .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P= .018; 2-3 vs 0: 13.2 [2.91-126.8], P= .0003). HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

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Benralizumab for eosinophilic granulomatosis with polyangiitis

BackgroundBenralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) are limited to case reports and small case series.MethodsWe conducted a multicentre, retrospective study including EGPA patients treated with off-label benralizumab. The primary endpoint was the rate of complete response defined as no disease activity (Birmingham Vasculitis Activity Score=0) and a prednisone dose ≤4 mg/day. Partial response was defined as no disease activity and a prednisone dose ≥4 mg/day.ResultsSixty-eight patients were included, including 31 (46%) who had previously received mepolizumab. The use of benralizumab was warranted by uncontrolled asthma in 54 (81%), persistent ear, nose and throat (ENT) manifestations in 27 (40%) and persistent glucocorticoids (GCs) use in 48 (74%) patients. Median (IQR) follow-up after starting benralizumab was 23 (9–34) months. Thirty-three patients (49%) achieved a complete response, 24 (36%) achieved a partial response and 10 (15%) did not respond. Among the 57 patients who initially responded, 10 (18%) eventually required further line treatments. GCs were discontinued in 23 patients (38%). Prior mepolizumab use was associated with a higher rate of primary failure (26.7% vs 5.4%, p=0.034) and less frequent GCs discontinuation (14.8% vs 55.9%, p=0.001). Vasculitis flares occurred in 7 patients (11%) and were associated with histological evidence of vasculitis and/or antineutrophil cytoplasmic antibodies positivity at benralizumab initiation (p=0.004).ConclusionsBenralizumab appears to be an effective treatment for refractory asthma or ENT manifestations in EGPA and allows GC-sparing. However, its efficacy was lower after prior failure of mepolizumab.

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Prone position versus usual care in hypoxemic COVID-19 patients in medical wards: a randomised controlled trial

BackgroundBenefit of early awake prone positioning for COVID-19 patients hospitalised in medical wards and who need oxygen therapy remains to be demonstrated. The question was considered at the time of COVID-19 pandemic to avoid overloading the intensive care units. We aimed to determine whether prone position plus usual care could reduce the rate of non-invasive ventilation (NIV) or intubation or death as compared to usual care alone.MethodsIn this multicentre randomised clinical trial, 268 patients were randomly assigned to awake prone position plus usual care (N = 135) or usual care alone (N = 132). The primary outcome was the proportion of patients who underwent NIV or intubation or died within 28 days. Main secondary outcomes included the rates of NIV, of intubation or death, within 28 days.ResultsMedian time spent each day in the prone position within 72 h of randomisation was 90 min (IQR 30–133). The proportion of NIV or intubation or death within 28 days was 14.1% (19/135) in the prone position group and 12.9% (17/132) in the usual care group [odds ratio adjusted for stratification (aOR) 0.43; 95% confidence interval (CI) 0.14–1.35]. The probability of intubation, or intubation or death (secondary outcomes) was lower in the prone position group than in the usual care group (aOR 0.11; 95% CI 0.01–0.89 and aOR 0.09; 95% CI 0.01–0.76, respectively) in the whole study population and in the prespecified subgroup of patients with SpO2 ≥ 95% on inclusion (aOR 0.11; 95% CI 0.01–0.90, and aOR 0.09; 95% CI 0.03–0.27, respectively).ConclusionsAwake prone position plus usual care in COVID-19 patients in medical wards did not decrease the composite outcome of need for NIV or intubation or death.Trial registration ClinicalTrials.gov Identifier: NCT04363463. Registered 27 April 2020.

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ANCA-associated scleritis: impact of ANCA on presentation, response to therapy and outcome.

To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests. This retrospective multicentre case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests. A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV [adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038]. Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV.

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Clinical and immunological features of patients with cancer-associated systemic sclerosis: An observational study.

Clinical and immunological features of patients with cancer-associated systemic sclerosis: an observational study. Several studies have reported an increased incidence of cancer in patients with systemic sclerosis (SSc). The presence of RNA polymerase III antibodies (anti-RNA Pol 3) associates with an increased risk of cancer, but other risk factors need yet to be identified. We aimed to assess clinical and immunological predictive factors of cancer-associated SSc to guide clinicians when setting up selective cancer screening. We conducted a monocentric, retrospective, observational study of SSc patients with and without associated malignancy. Clinical, laboratory and imaging data were collected, as well as SSc treatment. Subgroup analyses were performed according to the type of cancer and the time of diagnosis. Of 464 SSc patients, 74 (16%) had cancer, with breast (n=26) and lung cancer (n=13) being the most frequent. Diagnosis of cancer was made less than 3 years before or after SSc diagnosis for 23 patients (31%). In a multivariate analysis, anti-RNA Pol 3 and anti-SSA antibodies were significantly associated with an increased overall risk of cancer with an odds ratio (OR) of 4.12 (95% CI [1.6-10.7]; P<0.01) and 2.43 (95% CI [1.1-5.4]; P<0.05), respectively. Age at diagnosis of SSc and delay from the SSc diagnosis were also independent risk factors of cancer. Interstitial lung disease and anti-topoisomerase antibodies were associated with an increased risk of lung cancer and cancer occuring more than three years after SSc diagnosis. In addition to anti-RNA Pol 3 antibodies, anti-SSA antibodies associated with an increased risk of cancer in SSc patients. Interstitial lung disease was a risk factor specifically for lung cancer and cancers diagnosed more than 3 years after SSc diagnosis. For these patients, a systematic and regular cancer screening should be considered.

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WITHDRAWN: Prone-position versus usual care in hypoxemic COVID-19 patients in medical wards: a randomized controlled trial

Abstract Background: Benefit of early awake prone positioning (PP) for COVID-19 patients hospitalised in medical wards and who need oxygen therapy remains to be demonstrated. The question was considered at the time of COVID-19 pandemic to avoid overloading the intensive care units. We aimed to determine whether PP plus usual care could reduce the rate of non-invasive ventilation (NIV) or intubation or death as compared with usual care alone. Methods: In this multicentre randomised clinical trial, 268 patients were randomly assigned to awake PP plus usual care (N=135) or usual care alone (N=132). The primary outcome was the proportion of patients who underwent NIV or intubation or died within 28 days. Mains secondary outcomes included the rates of NIV, of intubation or death, within 28 days. Results: The proportion of NIV or intubation or death within 28 days was 14.1% (19/135) in the PP group and 12.9% (17/132) in the usual care group (odds ratio adjusted for stratification [aOR] 0.43; 95% confidence interval [CI] 0.14 to 1.35). The probability of intubation, or intubation or death (secondary outcomes) was reduced in the PP versus usual care group (aOR 0.11; 95%CI 0.01 to 0.89 and aOR 0.09; 95%CI 0.01 to 0.76, respectively) in the whole study population and in the prespecified subgroup of patients with SpO2 ≥95% on inclusion (aOR 0.11; 95%CI 0.01 to 0.90, and aOR 0.09; 95%CI 0.03 to 0.27, respectively). Conclusions: Awake PP plus usual care in COVID-19 patients in medical wards did not decrease the need for NIV or intubation or death. Trial registration: ClinicalTrials.gov Identifier: NCT04363463. Registered 27 April 2020.

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Ultrasonography performed by an infectiologist in hip and knee prosthetic joint and native joint infections

IntroductionClinical ultrasonography (US) by infectiologists has only recently been developing, and as now there is little literature on the subject. Our study focuses on the conditions and diagnostic performance of clinical ultrasound imaging by infectiologists in cases of hip and knee prosthetic and native joint infection. MethodsA retrospective study carried out between June 1st 2019 and March 31st 2021 in the University Hospital of Bordeaux, South-Western France. We measured US sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV), combined or not with the analysis of articular fluid, compared to the MusculoSketetal Infection Society (MSIS) score in prosthetic joints, or to expert diagnosis in native joints. ResultsFifty-four patients underwent US by an infectiologist in an infectious disease ward, including 11 (20.4%) for native joint and 43 (79.6%) for prosthetic joint. Joint effusion and/or periarticular collection were highlighted in 47 (87%) patients, and US led to 44 punctures. In all patients (n = 54), Se, Sp, PPV and NPV of US alone were 91%, 19%, 64% and 57%, respectively. When US was combined with fluid analysis, Se, Sp, PPV, NPV were 68%, 100%, 100%, 64% in all patients (n = 54), 86%, 100%, 100%, 60% in acute arthritis (n = 17) and 50%, 100%, 100% and 65% respectively in non-acute arthritis (n = 37). ConclusionThese results suggest that US by infectiologists effectively diagnoses osteoarticular infections (OAIs). This approach has many applications in infectiology routines. Consequently, it would be interesting to define the contents of a first level of infectiologist competence in US clinical practice.

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