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Summary: Background: Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid‐related adverse events (AEs) is unproven. Objectives: To utilize data collected in a French investigator‐initiated, phase III, open‐label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV. Methods: This was an independently conducted post hoc analysis of the moderate‐to‐severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg−1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg−1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24‐month efficacy and safety results were also reported. Results: At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab‐plus‐prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS‐related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone. Conclusions: In patients with moderate‐to‐severe PV, rituximab plus short‐term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life‐threatening CS‐related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus.Corticosteroids, a standard first‐line treatment for PV, have significant side‐effects.Although their effects are unproven, adjuvant corticosteroid‐sparing agents are routinely used to minimize steroid exposure and corticosteroid‐related side‐effects.There is evidence that the anti‐CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator‐initiated trial.Rituximab plus prednisone had a steroid‐sparing effect and more patients achieved complete remission off prednisone.Fewer patients experienced grade 3 or grade 4 steroid‐related adverse events than those on prednisone alone.This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate‐to‐severe PV. Linked Comment: Scorer et al. Br J Dermatol 2020; 182:1078–1079. [ABSTRACT FROM AUTHOR]

Linked Article: Aussy et al. Br J Dermatol 2019; 180:888–893 [ABSTRACT FROM AUTHOR]

Aim: To investigate the evolution of the incretin-like peptide 26RFa in a prospective cohort of women living with obesity with or without type 2 diabetes (T2D) before and after sleeve gastrectomy (SG)., Methods: In this study, a total of 61 women were divided into three groups: women living with severe obesity without T2D (WlwOB group), women living with severe obesity and T2D (WlwOB-T2D group) and lean healthy volunteers (control group). Serum 26RFa concentrations were measured using a 26RFa enzyme-linked immunosorbent assay developed specifically for this study during meal tests before SG, and 30 and 180 days after SG., Results: At baseline, serum 26RFa levels were reduced in the WlwOB (P < .05) and WlwOB-T2D (P < .01) groups compared with controls. In the WlwOB-T2D group, fasting 26RFa levels were found to increase throughout the entire follow-up period up to 6 months after the SG (P < .001). During the meal tests, serum 26RFa levels increased, especially in the WlwOB-T2D group at baseline. At the end of the follow-up, the profile of 26RFa concentrations obtained during the meal test in patients with severe obesity and T2D was similar to that of the controls., Conclusions: This prospective clinical study provides the first evidence that circulating 26RFa is altered mainly in WlwOB-T2D, and that these defects are partially reversed after SG., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Importance: The Ritux 3 trial demonstrated the short-term efficacy and safety of first-line treatment with rituximab compared with a standard corticosteroid regimen in pemphigus. No data on the long-term follow-up of patients who received rituximab as first line are available., Objective: To assess the long-term efficacy and safety of the Ritux 3 treatment regimen., Design, Setting, and Participants: This 7-year follow-up study of the Ritux 3 trial included patients with pemphigus from 25 dermatology departments in France from January 1, 2010, to December 31, 2015., Exposure: Patients were initially randomized in the rituximab plus prednisone group or prednisone-alone group., Main Outcomes and Measures: The primary outcome was the 5- and 7-year disease-free survival (DFS) without corticosteroids, assessed by Kaplan-Meier curves. Secondary outcomes were occurrence of relapse, occurrence of severe adverse events (SAEs), and evolution of antidesmoglein (Dsg) antibody enzyme-linked immunosorbent assay values to predict long-term relapse., Results: Of the 90 patients in the Ritux 3 trial, 83 were evaluated at the end of follow-up study visit (44 in the rituximab plus prednisone group; 39 in the prednisone-alone group) with a median (IQR) follow-up of 87.3 (79.1-97.5) months. Forty-three patients (93%) from the rituximab plus prednisone and 17 patients (39%) from the prednisone-alone group had achieved complete remission without corticosteroids at any time during the follow-up. Patients from the rituximab group had much longer 5- and 7-year DFS without corticosteroids than patients from the prednisone-alone group (76.7% and 72.1% vs 35.3% and 35.3%, respectively; P < .001), and had about half the relapses (42.2% vs 83.7%; P < .001). Patients who received rituximab as second-line treatment had shorter DFS than patients treated as first line (P = .007). Fewer SAEs were reported in the rituximab plus prednisone group compared with the prednisone-alone group, 31 vs 58 respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). The combination of anti-Dsg1 values of 20 or more IU/mL and/or anti-Dsg3 values of 48 or more IU/mL yielded 0.83 positive predictive value and 0.94 negative predictive value to predict long-term relapse., Conclusions and Relevance: In this secondary analysis of the Ritux 3 trail, first-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term sustained complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.

Background and Objective: The conventional technique of general anesthesia induction during a Cesarean section involves the use of opioids only after cord clamping. We hypothesized that the use of remifentanil before cord clamping might reduce the use of maternal supplemental anesthetic agents and improve the maternal hemodynamics status and neonatal adaptation of the preterm neonate., Methods: A phase III, double-blind, randomized, placebo-controlled, hospital-based trial enrolled parturients undergoing a Cesarean section under general anesthesia before 37 weeks of gestation. Block randomization allocated pregnant women to remifentanil or placebo. The primary outcome was the rate of newborns with Apgar scores < 7 at 5 min. Secondary outcomes were maternal hemodynamic parameters, complications of anesthetic induction, use of adjuvant anesthetic agents, neonatal respiratory distress, umbilical cord pH, and lactate levels., Results: A total of 52/55 participants were analyzed, comprising 27 women in the remifentanil group and 25 in the placebo group. Nine of 27 (33.3%) neonates had an Apgar score < 7 at 5 min in the remifentanil group versus 11/25 (44.0%) in the placebo group (p = 0.45, odds ratio = 0.66, 95 confidence interval 0.20-2.18). The blood cord gases, cognitive, behavior, sensory, sleeping, and feeding scores at 1 and 2 years of corrected age were not different. For the mothers, hemodynamic parameters, anesthesia duration, and the cumulative treatment dose until cord clamping did not differ between the groups., Conclusions: The use of a low dose of remifentanil before cord clamping for a Cesarean section appears to be safe both for the mother and the preterm newborn, but it does not improve maternal or neonatal outcomes., Clinical Trial Registration: ClinicalTrials.gov: NCT02029898., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To determine a potential window of opportunity for retreatment with rituximab in patients with rheumatoid arthritis (RA) from a multicentre longitudinal real-life study based on tight monitoring with ultrasonography (US)., Methods: Thirty RA patients treated with rituximab were included. US parameters were collected at each time (8 visits) of the 18-month follow-up, notably the global score of power Doppler (PD) activity. Clinical relapse was defined as a DAS28 ESR of >3.2 after 6 months in responders while US relapse was defined as an increase of ≥20% of the global score of PD activity. The decision of retreatment was based exclusively on clinical findings., Results: A total of 29 patients were analysed (mean (SD) age: 57.2 (12.2) years; female gender: 66%). The mean (SD) PD score decreased from 8.8 (5.2) at baseline to 4.9 (4.3) at 6 months (p <0.0001). A clinical response was observed at Month 4 or Month 6 for 93% of patients. A total of 19 patients had a first clinical relapse (with or without US relapse) after Month 6 (18 of them were retreated with rituximab). Among 10 patients without clinical relapse, 3 had US relapse (only one was retreated) and 7 had no US relapse (but 4 were retreated)., Conclusions: This study highlights a great heterogeneity in terms of sequence of clinical relapse, US relapse and retreatment in RA patients receiving rituximab. Therefore, US monitoring does not seem to be relevant to determine the best time for retreatment with rituximab.

Importance: Poor therapeutic results have been reported in patients with alopecia areata totalis (AT) or universalis (AU), the most severe and disabling types of alopecia areata (AA). Methotrexate, an inexpensive treatment, might be effective in AU and AT., Objective: To evaluate the efficacy and tolerance of methotrexate alone or combined with low-dose prednisone in patients with chronic and recalcitrant AT and AU., Design, Setting, and Participants: This academic, multicenter, double-blind, randomized clinical trial was conducted at 8 dermatology departments at university hospitals between March 2014 and December 2016 and included adult patients with AT or AU evolving for more than 6 months despite previous topical and systemic treatments. Data analysis was performed from October 2018 to June 2019., Interventions: Patients were randomized to receive methotrexate (25 mg/wk) or placebo for 6 months. Patients with greater than 25% hair regrowth (HR) at month 6 continued their treatment until month 12. Patients with less than 25% HR were rerandomized: methotrexate plus prednisone (20 mg/d for 3 months and 15 mg/d for 3 months) or methotrexate plus placebo of prednisone., Main Outcome and Measures: The primary end point assessed on photos by 4 international experts was complete or almost complete HR (Severity of Alopecia Tool [SALT] score <10) at month 12, while receiving methotrexate alone from the start of the study. Main secondary end points were the rate of major (greater than 50%) HR, quality of life, and treatment tolerance., Results: A total of 89 patients (50 female, 39 male; mean [SD] age, 38.6 [14.3] years) with AT (n = 1) or AU (n = 88) were randomized: methotrexate (n = 45) or placebo (n = 44). At month 12, complete or almost complete HR (SALT score <10) was observed in 1 patient and no patient who received methotrexate alone or placebo, respectively, in 7 of 35 (20.0%; 95% CI, 8.4%-37.0%) patients who received methotrexate (for 6 or 12 months) plus prednisone, including 5 of 16 (31.2%; 95% CI, 11.0%-58.7%) who received methotrexate for 12 months and prednisone for 6 months. A greater improvement in quality of life was observed in patients who achieved a complete response compared with nonresponder patients. Two patients in the methotrexate group discontinued the study because of fatigue and nausea, which were observed in 7 (6.9%) and 14 (13.7%) patients receiving methotrexate, respectively. No severe treatment adverse effect was observed., Conclusions and Relevance: In this randomized clinical trial, while methotrexate alone mainly allowed partial HR in patients with chronic AT or AU, its combination with low-dose prednisone allowed complete HR in up to 31% of patients. These results seem to be of the same order of magnitude as those recently reported with JAK inhibitors, with a much lower cost., Trial Registration: ClinicalTrials.gov Identifier: NCT02037191.

Background: In patients with obesity and metabolic syndrome (MetS), lifestyle interventions combining diet, in particular, and physical exercise are recommended as the first line treatment. Previous studies have suggested that leucine or arginine supplementation may have beneficial effects on the body composition or insulin sensitivity and endothelial function, respectively. We thus conducted a randomized controlled study to evaluate the effects of a supervised adapted physical activity program associated or not with oral supplementation with leucine and arginine in MetS-complicated patients with obesity. Methods: Seventy-nine patients with obesity and MetS were randomized in four groups: patients receiving arginine and leucine supplementation (ALs group, n = 20), patients on a supervised adapted physical activity program (APA group, n = 20), patients combining ALs and APA (ALs+APA group, n = 20), and a control group (n = 19). After the baseline evaluation (m0), patients received ALs and/or followed the APA program for 6 months (m6). Body composition, MetS parameters, lipid and glucose metabolism markers, inflammatory markers, and a cardiopulmonary exercise test (CPET) were assessed at m0, m6, and after a 3-month wash-out period (m9). Results: After 6 months of intervention, we did not observe variable changes in body weight, body composition, lipid and glucose metabolism markers, inflammatory parameters, or quality of life scores between the four groups. However, during the CPET, the maximal power (Pmax and Ppeak), power, and O2 consumption at the ventilatory threshold (P(VT) and O2(VT)) were improved in the APA and ALs+APA groups (p < 0.05), as well as the forced vital capacity (FVC). Between m6 and m9, a gain in fat mass was only observed in patients in the APA and ALs+APA groups. Conclusion: In our randomized controlled trial, arginine and leucine supplementation failed to improve MetS in patients with obesity, as did the supervised adapted physical activity program and the combination of both. Only the cardiorespiratory parameters were improved by exercise training.

Background: Traditionally, patients with peritonitis Hinchey III and IV due to perforated diverticulitis were treated with Hartmann's procedure. In the past decade, resection and primary anastomosis have gained popularity over Hartmann's procedure and recent guidelines recommend Hartmann's procedure in two situations only: critically ill patients and in selected patients with multiple comorbidity (at high risk of complications). The protective stoma (PS) is recommended after resection with primary anastomosis, however its interest has never been studied. The aim of this trial is to define the role of systematic PS after resection and primary anastomosis for peritonitis Hinchey III and IV due to perforated diverticulitis., Methods/design: This DIVERTI 2 trial is a multicenter, randomized, controlled, superiority trial comparing resection and primary anastomosis with (control group) or without (experimental group) PS in patients with peritonitis Hinchey III and IV due to perforated diverticulitis. Primary endpoint is the overall 1 year morbidity according to the Clavien-Dindo classification of surgical complications. All complications occurring during hospitalization will be collected. Late complications occurring after hospitalization will be collected during follow-up. In order to obtain 80% power for a difference given by respective main probabilities of 67% and 47% in the protective stoma and no protective stoma groups respectively, with a two-sided type I error of 5%, 96 patients will have to be included in each group, hence 192 patients overall. Expecting a 5% rate of patients not assessable for the primary end point (lost to follow-up), 204 patients will be enrolled. Secondary endpoints are postoperative mortality, unplanned reinterventions, incisional surgical site infection (SSI), organ/space SSI, wound disruption, anastomotic leak, operating time, length of hospital stay, stoma at 1 year after initial surgery, quality of life, costs and quality-adjusted life years (QALYs)., Discussion: The DIVERTI 2 trial is a prospective, multicenter, randomized, study to define the best strategy between PS and no PS in resection and primary anastomosis for patients presenting with peritonitis due to perforated diverticulitis., Trial Registration: ClinicalTrial.gov: NCT04604730 date of registration October 27, 2020. https://clinicaltrials.gov/ct2/show/NCT04604730?recrs=a&cond=Diverticulitis&draw=2&rank=12 ., (© 2022. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Many pregnant women, in the world, drink caffeine-containing beverages. Maternal caffeine consumption during pregnancy may have adverse effects on foetus but results are conflicting. Our goals were to estimate the prevalence of caffeine use in a cohort of French pregnant women using maternal self-reports and to evaluate the association between caffeine consumption during pregnancy and delivery and newborn characteristics. All pregnant women who gave birth in a large French urban area during a limited period of time were included (in total 724 mothers were included). Coffee, tea or cola consumption as well as pregnancy and neonate characteristics were analysed. The mean consumption of caffeine per day slightly decreased from the first to the third trimester of pregnancy: 587 caffeine users, with a consumption of caffeine of 59.2 ± 61.5 mg/day during the first trimester as compared to 577 consumers (54.3 ± 55.4 mg/day) during the third trimester, respectively. A significant decrease of neonates' birth length was observed when mothers were using at least 100 mg/day (or two cups) of caffeine during the second and third trimesters but this difference was no longer significant after adjustment on potential confounding factors such as tobacco use. The potential existence of other confounders (e.g. poorer dietary habits or other lifestyle variables) that might also be associated with reduced birth length, may not be excluded. Caffeine use during pregnancy was associated with reduced birth length but this effect was no longer significant after adjustment on potential confounding variables.

Aim: The STARR (Stapled Trans-Anal Rectal Resection) procedure consists of a surgical correction of symptomatic rectocele refractory to medical treatment, involving anal dilatation. The aim of the study was to determine the impact of the STARR procedure on anal distensibility using EndoFLIP ® device. Methods: All female patients with a minimal rectocele of 3 cm and with symptoms of obstructed defecation syndrome (ODS) refractory to medical treatment were included prospectively. Patients with previous anal incontinence were not included. Wexner, ODS and Kess scores were recorded. Endoanal ultrasounds and EndoFLIP ® measurements were performed pre-surgery and 3 months following the STARR procedure. The distensibility index (DI) at 40 mL of inflation at rest was the primary study endpoint. Results: Seven patients (median age: 52.5, range: 44-62) were included between 2014 and 2017. The DI after surgery was the same as the pre-surgery DI. No patient developed symptoms of faecal incontinence or urge to defecate in the three months following the STARR procedure. All patients reported an improvement in their ODS and Kess scores three months after the STARR procedure. No anal sphincter defects were detected by endoanal ultrasound. Conclusion: Anal dilatation did not appear to alter anal distensibility in patients with a normal anal function before the STARR procedure.

Importance: Rituximab and short-term corticosteroid therapy are the criterion standard treatments for patients with newly diagnosed moderate to severe pemphigus., Objective: To examine factors associated with short-term relapse in patients with pemphigus treated with rituximab., Design, Setting, and Participants: This post hoc analysis of a randomized clinical trial (Comparison Between Rituximab Treatment and Oral Corticosteroid Treatment in Patients With Pemphigus [RITUX 3]) conducted from January 1, 2010, to December 31, 2015, included patients from 20 dermatology departments of tertiary care centers in France from the RITUX 3 trial and 3 newly diagnosed patients treated according to the trial protocol. Data analysis was performed from February 1 to June 30, 2019., Exposure: Patients randomly assigned to the rituximab group in the RITUX 3 trial and the 3 additional patients were treated with 1000 mg of intravenous rituximab on days 0 and 14 and 500 mg at months 12 and 18 combined with a short-term prednisone regimen., Main Outcomes and Measures: Baseline (pretreatment) clinical and biological characteristics (Pemphigus Disease Area Index [PDAI] score, ranging from 0-250 points, with higher values indicating more severe disease) and changes in anti-desmoglein (DSG) 1 and anti-DSG3 values as measured by enzyme-linked immunosorbent assay during the 3 months after rituximab treatment were compared between patients with disease relapse and those who maintained clinical remission during the first 12 months after treatment. The positive and negative predictive values of these factors were calculated., Results: Among 47 patients (mean [SD] age, 54.3 [17.0] years; 17 [36%] male and 30 [64%] female) included in the study, the mean (SD) baseline PDAI score for patients with relapsing disease was higher than that of the patients with nonrelapsing disease (54 [33] vs 28 [24]; P = .03). At month 3, 7 of 11 patients with relapsing disease (64%) vs 7 of 36 patients with nonrelapsing disease (19%) had persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher (P = .01). A PDAI score of 45 or higher defining severe pemphigus and/or persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher at month 3 provided a positive predictive value of 50% (95% CI, 27%-73%) and a negative predictive value of 94% (95% CI, 73%-100%) for the occurrence of relapse after rituximab., Conclusions and Relevance: The findings suggest that initial PDAI score and changes in anti-DSG antibody values after the initial cycle of rituximab might help differentiate a subgroup of patients with high risk of relapse who might benefit from maintenance rituximab infusion at month 6 from a subgroup of patients with low risk of relapse who do not need early maintenance therapy., Trial Registration: NCT00784589.