Papers by Pierre Charles MEBE
The Lancet Rheumatology, 2021
Background Various observations have suggested that the course of COVID-19 might be less favourab... more Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.
European Heart Journal - Cardiovascular Imaging, 2020
Annals of Internal Medicine, 2020
; for the French Vasculitis Study Group* Background: Biannual rituximab infusions over 18 months ... more ; for the French Vasculitis Study Group* 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 18month 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.
Neurology, 2020
ObjectivesThe predominance of extramuscular manifestations (e.g., skin rash, arthralgia, intersti... more ObjectivesThe predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti–melanoma differentiation-associated gene 5 antibody–positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease.MethodsTo characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5−; n = 190/201) based on selected variables, collected retrospectively, without any missing data.ResultsWithin anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologi...
Annals of the Rheumatic Diseases, 2018
BMJ Open, 2019
IntroductionImproving the appropriateness of prescriptions of oral antithrombotic (AT) drugs, esp... more IntroductionImproving the appropriateness of prescriptions of oral antithrombotic (AT) drugs, especially AT combinations, is crucial because these drugs are implicated in bleeding events. We developed a prescription support-tool synthesising guidelines on chronic management of oral AT combinations. Our main objective is to assess the impact of this tool on improving the prescription of oral ATs to comply with guidelines.Methods and analysisA randomised controlled trial will be conducted among French general practitioners and cardiologists involved in outpatient settings. Physicians will be invited to participate to an online survey by email via physician associations, social networks or word of mouth. They will be randomised to two arms: the experimental arm (access to the prescription support-tool) or the control arm (no prescription support-tool). Then, all participants will be presented three different clinical vignettes illustrating outpatient clinical situations and will be ask...
Autoimmunity Reviews, 2019
Among 308 patients with a new diagnosis of GPA in accordance with the American College of Rheumat... more Among 308 patients with a new diagnosis of GPA in accordance with the American College of Rheumatology classification criteria and/or revised Chapel Hill nomenclature definitions, we identified those with ocular involvement and a subsequent follow up in our center. Results: The prevalence of ocular involvement in our GPA series was 38.6%; 63 patients were analysed with a median follow-up of 50.5 months (IQR: 17.8-82.8). Scleritis (18 patients, 26.8%) and episcleritis (18 patients, 26.8%) were the most common ophthalmologic manifestations, followed by orbital disease (13 patients, 20.6%). Bilateral involvement and visual acuity loss was seen in 29.1% and 16.7% of patients, respectively. Ocular involvement was the first GPA manifestation in 9 patients (14.3%), concomitant with systemic manifestation in 36 (57.1%), and occurred only during follow-up in 18 (28.6%). The indication for GPA treatment was suggested by ocular involvement in 12 patients (19.4%), by systemic features in 40 (64.5%) and by both ocular and systemic involvement in 10 (16.1%). Remission of ocular involvement was achieved in 51 patients (80.9%). In the remaining 12 (19.1%), symptoms persisted or even worsened, finally leading to rituximab (RTX) therapy in 8 of them (66.7%). Altogether, when used as first line or for refractory disease, ocular remission was achieved in 11 of the 12 cases (91.7%) treated with RTX versus 34 of the 47 cases (72.3%) treated with CYC (P = .260). Eye disease relapsed in 14 patients (22.2%). RTX allowed achievement of remission in 8 of them (57.1%). In the remaining six, other immunosuppressive drugs were used. Conclusions: Scleritis and episcleritis are the most common ocular manifestations in GPA, most of the time associated with other systemic manifestations. In > 40% of cases, ocular manifestations were refractory to initial treatment or recurrent and led to RTX prescription, which appeared to be useful in these situations.
European Journal of Internal Medicine, 2018
Background: The aim of this study was to evaluate tocilizumab (TCZ) as an add-on therapy to gluco... more Background: The aim of this study was to evaluate tocilizumab (TCZ) as an add-on therapy to glucocorticoids (GC) during the first 3 months of treatment of giant cell arteritis (GCA). Methods: GCA patients, as defined by ≥3/5 ACR criteria and positive temporal artery biopsy (TAB) or angio-CTscan or PET-scan-proven aortitis, were included in this prospective open-label study. Prednisone was started at 0.7 mg/kg/day and then tapered according to a standardized protocol. All patients received four infusions of TCZ (8 mg/kg/4 weeks) after inclusion. The primary endpoint was the percentage of patients in remission with ≤0.1 mg/kg/day of prednisone at week 26 (W26). Patients were followed for 52 weeks and data prospectively recorded. Results: Twenty patients with a median (IQR) age of 72 (69-78) years were included. TAB were positive in 17/ 19 (90%) patients and 7/16 (44%) had aortitis. Remission was obtained in all cases. At W26, 15 (75%) patients met the primary endpoint. Ten patients experienced relapse during follow-up, mainly patients with aortitis (P = 0.048), or CRP > 70 mg/L (P = 0.036) or hemoglobin ≤10 g/dL (P = 0.015) at diagnosis. Among 64 adverse events (AE) reported in 18 patients, three were severe and 30, mostly non-severe infections (n = 15) and hypercholesterolemia (n = 8), were imputable to the study. Conclusion: This study shows that an alternative strategy using a short-term treatment with TCZ can be proposed to spare GC for the treatment of GCA. However, 50% of patients experienced relapse during the 9 months following TCZ discontinuation, especially patients with aortitis, or CRP > 70 mg/L or Hb ≤ 10 g/dL at diagnosis. Trial registration: ClinicalTrials.gov (NCT01910038).
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, Jan 27, 2016
Medicine, 2015
Tracheobronchial stenoses (TBSs) are potentially severe manifestations of granulomatosis with pol... more Tracheobronchial stenoses (TBSs) are potentially severe manifestations of granulomatosis with polyangiitis (Wegener's) (GPA) that usually respond poorly to corticosteroids and immunosuppressive agents. We describe 26 GPA patients with !1 tracheal (mainly subglottic, SGS) and/or bronchial stenosis(ses) (BS(s)). Sixteen patients had solitary SGS and 10 had !1 BS(s). The male/ female sex ratio was 9:17, and the median age at GPA diagnosis was 32 years (3:13 and 28 years, respectively, for SGS patients). Antineutrophil cytoplasm antibodies were proteinase 3-positive in 65.5% of the patients (50% of those with SGS). Despite conventional GPA therapy, 62% patients experienced !1 stenosis relapse(s) (81% of SGS patients, for a total of 1-8 relapses per patient). None of the several systemic or endoscopic treatments prevented future relapses. Cyclophosphamide induction therapy was effective in 4/6 patients with BS(s) and in 1 patient with SGS among the 7 treated. After many relapses, rituximab achieved remission in 3/4 SGS patients. Endoscopic treatments (dilation, laser, corticosteroid injection, etc.) had only transient efficacy. Other GPA manifestations relapsed independently of TBSs. One SGS patient died of acute respiratory distress syndrome. Our findings confirmed that TBSs are severe GPA manifestations that evolve independently of other organ involvements and do not respond to conventional systemic regimens. As previously described, our population was younger and comprised more females than usual GPA patients, especially those with SGS. The small number of patients and the wide variety of local and systemic treatments prevent us from drawing definitive conclusions about the contribution of each procedure. However, cyclophosphamide seemed to effectively treat BSs, but not SGS, and rituximab may be of interest for SGS management.
Clinical and experimental rheumatology
The 2009 pandemic A/H1N1 influenza outbreak represented a theoretical risk for patients with auto... more The 2009 pandemic A/H1N1 influenza outbreak represented a theoretical risk for patients with autoimmune diseases (AID), especially those immunosuppressed. This study was undertaken to evaluate immunogenicity and tolerance of seasonal (SFV) and A/H1N1 flu vaccines (HFV) in AID patients. This prospective, open, monocentre, vaccine phase-III study on 199 patients with AID (systemic necrotising vasculitides, progressive systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome and others), treated or not with immunosuppressants, was conducted from September 2009 to June 2010, to evaluate SFV and HFV efficacy and safety. Subjects received SFV (1 dose, Mutagrip®) and/or non-adjuvant HFV (Panenza®, 2 doses at a 3-week interval). The primary judgment criterion was the seroprotection rate. Secondary outcome measures were seroconversion rates, vaccine tolerance, and numbers of flu syndromes, and AID flares and relapses throughout the 6 month observation period. After SFV inocul...
Presse médicale (Paris, France : 1983), 2013
Presse médicale (Paris, France : 1983), 2013
of five patients with Behçet's syndrome had clinical improvement after rituximab with a full remi... more of five patients with Behçet's syndrome had clinical improvement after rituximab with a full remission in one. Two have remained controlled on repeat rituximab but two have required other therapies. Experience in large vessel vasculitis, cryoglobulinaemia, polyarteritis nodosa, Henoch-Schönlein purpura and urticarial vasculitis has been too limited to draw meaningful conclusions. Conclusions The addition of rituximab to the management of AAV has been of major benefit to our patients permitting improved disease control and reduced immunosuppressive and glucocorticoid exposure. The published experience has been sufficient to enable treatment recommendations that emphasise the place of rituximab for relapsing or refractory disease and those in whom cyclophosphamide is contra-indicated [11]. Although we have found associations between B cell return and ANCA rises with relapse, there is considerable variability and some relapses are seen without changes in these indices. Falling immunoglobulin levels are a concern as patient exposure to rituximab increases, that will limit further use of this agent in such patients.
La Presse Médicale, 2013
Pour citer cet article : Charles P et al., Rituximab: Recommendations of the French Vasculitis St... more Pour citer cet article : Charles P et al., Rituximab: Recommendations of the French Vasculitis Study Group (FVSG) for induction and maintenance treatments of adult, antineutrophil.. .
PLoS Medicine, 2012
Background: Previous studies indicate that in published reports, trial results can be distorted b... more Background: Previous studies indicate that in published reports, trial results can be distorted by the use of ''spin'' (specific reporting strategies, intentional or unintentional, emphasizing the beneficial effect of the experimental treatment). We aimed to (1) evaluate the presence of ''spin'' in press releases and associated media coverage; and (2) evaluate whether findings of randomized controlled trials (RCTs) based on press releases and media coverage are misinterpreted. Methods and Findings: We systematically searched for all press releases indexed in the EurekAlert! database between December 2009 and March 2010. Of the 498 press releases retrieved and screened, we included press releases for all twoarm, parallel-group RCTs (n = 70). We obtained a copy of the scientific article to which the press release related and we systematically searched for related news items using Lexis Nexis. ''Spin,'' defined as specific reporting strategies (intentional or unintentional) emphasizing the beneficial effect of the experimental treatment, was identified in 28 (40%) scientific article abstract conclusions and in 33 (47%) press releases. From bivariate and multivariable analysis assessing the journal type, funding source, sample size, type of treatment (drug or other), results of the primary outcomes (all nonstatistically significant versus other), author of the press release, and the presence of ''spin'' in the abstract conclusion, the only factor associated, with ''spin'' in the press release was ''spin'' in the article abstract conclusions (relative risk [RR] 5.6, [95% CI 2.8-11.1], p,0.001). Findings of RCTs based on press releases were overestimated for 19 (27%) reports. News items were identified for 41 RCTs; 21 (51%) were reported with ''spin,'' mainly the same type of ''spin'' as those identified in the press release and article abstract conclusion. Findings of RCTs based on the news item was overestimated for ten (24%) reports. Conclusion: ''Spin'' was identified in about half of press releases and media coverage. In multivariable analysis, the main factor associated with ''spin'' in press releases was the presence of ''spin'' in the article abstract conclusion.
Medicine, 2011
Mycobacterium genavense, a nontuberculous mycobacterium, led to devastating infections in patient... more Mycobacterium genavense, a nontuberculous mycobacterium, led to devastating infections in patients with acquired immunodeficiency syndrome (AIDS) before highly active antiretroviral therapy (HAART) was available, as well as in other immunocompromised patients. We conducted the current study to describe the features of this infection in patients infected with human immunodeficiency virus (HIV) in the HAART era and in non HIV-infected patients.We conducted a retrospective cohort survey in France. All patients with M. genavense infection diagnosed from 1996 to 2007 at the National Reference Center, Institut Pasteur, Paris, were identified and their clinical, laboratory, and microbiologic data were centralized in a single database. Twenty-five cases of M. genavense infection originating from 19 centers were identified. Twenty patients had AIDS, 3 had solid organ transplantation, and 2 had sarcoidosis. Sixty-four percent (n = 16) were male, mean age was 42 years, and median CD4 count was 13/mm (range, 0-148/mm) in patients with AIDS. Twenty-four patients had disseminated infection with fever (75%, n = 18), weight loss (79%, n = 19), abdominal pain (71%, n = 17), diarrhea (62.5%, n = 15), splenomegaly (71%, n = 17), hepatomegaly (62.5%, n = 15), or abdominal adenopathy (62.5%, n = 15). M. genavense was isolated from the lymph node (n = 13), intestinal biopsy (n = 9), blood (n = 6), sputum (n = 3), stool (n = 3), and bone marrow (n = 5). Eleven patients (44%) died, 8 (32%) were considered cured with no residual symptoms, and 6 (24%) had chronic symptoms. The 1-year survival rate was 72%.The prognosis of M. genavense infection in HIV-infected patients has dramatically improved with HAART. Clinical presentations in HIV and non-HIV immunocompromised patients were similar.
Journal of Autoimmunity, 2014
The aim of this study was to evaluate the efficacy and safety of rituximab (RTX) associated with ... more The aim of this study was to evaluate the efficacy and safety of rituximab (RTX) associated with glucocorticoid treatment based on disease severity, as a remission induction treatment for granulomatosis with polyangiitis (GPA) (Wegener's) and to analyze the results of long-term maintenance therapy with low doses of RTX in a routine time-based protocol. This single-center retrospective study used standardized data collection from all GPA patients receiving RTX between 2002 and 2013. The remission induction regimen consisted of RTX and glucocorticoids, adapted according to disease severity. Once remission was achieved, patients received RTX maintenance treatment (500 mg every 6 months) for 18 months. Sixty-six GPA patients received RTX for remission induction. After six months, a response had been achieved in 78.8% of these patients, with a moderate oral prednisone regimen (mean dose at baseline, 32.8 AE 23.4 mg/day). Subglottic stenosis increased the risk of treatment failure (OR ¼ 31.2, P ¼ 0.0104). RTX maintenance treatment was continued for 18 months in 92% of the GPA patients, who were followed for 34.2 AE 26.2 months (mean total cumulative RTX dose of 4.6 AE 1.7 g). The relapse rate was 11.2/100 patient-years. The relapses occur a mean of 13.5 AE 14.7 months after the last RTX infusion. Twenty-one severe adverse events were recorded; 13.6% patients had severe infections. We conclude that in this single-center cohort, RTX associated with glucocorticoid treatment adapted for disease severity appeared to induce remission effectively in GPA patients. Maintenance treatment with low doses of RTX in a routine time-based protocol was safe and associated with low rates of relapse on treatment.
BMJ, 2009
Objectives To assess quality of reporting of sample size calculation, ascertain accuracy of calcu... more Objectives To assess quality of reporting of sample size calculation, ascertain accuracy of calculations, and determine the relevance of assumptions made when calculating sample size in randomised controlled trials. Design Review. Data sources We searched MEDLINE for all primary reports of two arm parallel group randomised controlled trials of superiority with a single primary outcome published in six high impact factor general medical journals between 1 January 2005 and 31 December 2006. All extra material related to design of trials (other articles, online material, online trial registration) was systematically assessed. Data extracted by use of a standardised form included parameters required for sample size calculation and corresponding data reported in results sections of articles. We checked completeness of reporting of the sample size calculation, systematically replicated the sample size calculation to assess its accuracy, then quantified discrepancies between a priori hypothesised parameters necessary for calculation and a posteriori estimates. Results Of the 215 selected articles, 10 (5%) did not report any sample size calculation and 92 (43%) did not report all the required parameters. The difference between the sample size reported in the article and the replicated sample size calculation was greater than 10% in 47 (30%) of the 157 reports that gave enough data to recalculate the sample size. The difference between the assumptions for the control group and the observed data was greater than 30% in 31% (n=45) of articles and greater than 50% in 17% (n=24). Only 73 trials (34%) reported all data required to calculate the sample size, had an accurate calculation, and used accurate assumptions for the control group. Conclusions Sample size calculation is still inadequately reported, often erroneous, and based on assumptions that are frequently inaccurate. Such a situation raises questions about how sample size is calculated in randomised controlled trials.
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Papers by Pierre Charles MEBE