Estelle Houivet

First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial

BACKGROUND High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. METHODS We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 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, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harmans criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589. FINDINGS Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]). INTERPRETATION Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. FUNDING French Ministry of Health, French Society of Dermatology, Roche.

Enzyme-Linked Immunosorbent Assay for the Combination of Bullous Pemphigoid Antigens 1 and 2 in the Diagnosis of Bullous Pemphigoid

OBJECTIVE To assess the usefulness of enzyme-linked immunosorbent assay (ELISA) assessment of the combination of bullous pemphigoid antigen 1 (BPAG1) and BPAG2 in the diagnosis of bullous pemphigoid (BP). DESIGN Retrospective study of serum samples from patients with BP. SETTING Tertiary care center. PATIENTS A total of 190 patients with newly diagnosed BP and 78 controls with other autoimmune bullous diseases. INTERVENTION Serum samples were tested using commercialized BPAG1 and BPAG2 ELISA and indirect immunofluorescence (IIF). MAIN OUTCOME MEASURES The sensitivity and specificity of ELISA for the combination of BPAG1 and BPAG2 in the diagnosis of BP were contrasted with ELISA for each of the antigens alone and with IIF. RESULTS The sensitivity and specificity of ELISA for the combination of BPAG1 and BPAG2 were 87% and 88%, respectively, compared with 79% and 90% for BPAG2 ELISA, 61% and 96% for BPAG1 ELISA, and 81% and 63% for IIF. The combination of BPAG1 ELISA and BPAG2 ELISA permitted 8% and 16% gains in sensitivity compared with each of BPAG2 ELISA and BPAG1 ELISA alone, respectively. Anti-BPAG1 antibodies were detected in 15 of 40 BP serum samples with no anti-BPAG2 antibodies (38%) and in 8 of 13 serum samples from patients with BP and mucosal involvement (62%) compared with 2 of 22 samples of cicatricial pemphigoid (P = .002) and 0 of 16 epidermolysis bullosa acquisita serum samples (P < .001). The BPAG2 ELISA values were more closely correlated with initial extent of BP lesions (r = 0.44, P < .001) than BPAG1 ELISA values (r = 0.16, P = .03). CONCLUSION Since the combination of BPAG1 and BPAG2 ELISA only slightly increases the sensitivity of BP diagnosis over BPAG2 ELISA alone, BPAG1 ELISA could be adequately proposed in a minority of BP cases with mucosal involvement and in those with no circulating anti-BPAG2 antibodies.

School-Age Outcomes following a Randomized Controlled Trial of Magnesium Sulfate for Neuroprotection of Preterm Infants

In a French randomized trial, children at school-age demonstrated no evidence of harm from fetal exposure to MgSO4 before very preterm birth. Motor dysfunction/death, qualitative behavioral disorders, cognitive difficulties, school grade repetition, and education services were decreased in the children exposed to MgSO4, although the differences were not significant.

Impact of MenBvac, an outer membrane vesicle (OMV) vaccine, on the meningococcal carriage.

The aim of the study was to analyze the impact of MenBvac, an outer membrane vesicle (OMV) vaccine against P1.7,16 strains, on meningococcal carriage. During a B:14:P1.7,16/ST-32 outbreak in Normandy (France), children aged 1-7 years were randomly selected to participate in the study. Among the 1082 volunteers, there were 17 Neisseria meningitidis carriers (carriage rate of 1.57%). MenBvac vaccination appeared associated with lower carriage rate, i.e., 0.31% among the vaccinated children versus 2.10% among the non-vaccinated (p=0.03). The beneficial effect on carriage was observed regardless of the strain serogroup. OMV-vaccinated mice also showed reduction of bacterial acquisition of OMV-homolog and hererolog strains in respiratory pathways after intranasal challenge. These results suggest that meningococcal OMV-based vaccines reduce meningococcal carriage and may hence confer herd immunity.

Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers

Several studies have reported that, in Lynch syndrome resulting from mutations of the mismatch repair (MMR) genes, a CA repeat ≤17 within the IGF1 promoter, SNPs within the xenobiotic metabolizing enzyme gene CYP1A1 and SNPs on 8q23.3 and 11q23.1 modify colorectal cancer (CRC) risk in MMR mutation carriers. We analysed the impact of these polymorphisms on CRC risk in 748 French MMR mutation carriers derived from 359 families. We also analysed the effect of the Novel 1 SNP (18q21), which has recently been shown to increase CRC risk in the general population. We observed a significant difference in the CRC-free survival time between males and females, between MSH2 and MSH6 mutation carriers and between MLH1 and MSH6, indicating that this series is representative of Lynch syndrome. In contrast, the univariate log-rank test, as well as multivariate Cox model analysis controlling for familial aggregation and mutated MMR gene, year of birth and gender showed that the polymorphic alleles tested were not associated with a significant CRC risk increase, neither on the entire sample nor among males and females. This discrepancy with previous reports might be explained both by the genetic heterogeneity between the different populations analysed and the allelic heterogeneity of the MMR mutations. We conclude that genotyping of these polymorphisms is not useful to evaluate CRC risk in MMR mutation carriers and to optimize their clinical follow-up.

Evolution of immune response against Neisseria meningitidis B:14:P1.7,16 before and after the outer membrane vesicle vaccine MenBvac

A meningococcal B:14:P1.7,16 outbreak in Normandy (France) was recently controlled using MenBvac, an outer membrane vesicle vaccine previously designed against the B:15:P1.7,16 strain. The further emergence of a new B:14:P1.7,16 outbreak in another district in Normandy led us to explore immunity against B:14:P1.7,16 before and after the MenBvac campaign using a 2+1 (day 0, week 6, month 8) schedule. Children (1-5 years) were sampled before, during and up to one year after vaccination. Serum bactericidal activity against B:14:P1.7,16 was titrated using human complement (hSBA) and immune response was defined by hSBA titer ≥4 as a surrogate for protection. The percentage of hSBA titer ≥4 was 10.8% before vaccination, raised to 84.1% 6 weeks after the completion of the schedule, but declined to 39.7% one year later. This level is lower than the targeted 60% level and suggests only short-term persistence of response against B:14:P1.7,16 using this schedule.

Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk.

To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case–control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearsons χ2 test, Cochran–Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30–2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11–1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13–1.98; P=0.007 and OR: 1.49, CI: 1.14–1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10–2.37), 2.09 (CI: 1.43–3.07), 2.87 (CI: 1.76–4.70) and 3.88 (CI: 1.72–8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18–2.46), 2.29 (CI: 1.55–3.38) and 6.21 (CI: 2.67–14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.

Autologous Myoblasts for the Treatment of Fecal Incontinence: Results of a Phase 2 Randomized Placebo-controlled Study (MIAS)

Objective: The aim of this study was to evaluate the efficacy of intrasphincteric injections of autologous myoblasts (AMs) in fecal incontinence (FI) in a controlled study. Summary of Background Data: Adult stem cell therapy is expected to definitively cure FI by regenerating damaged sphincter. Preclinical data and results of open-label trials suggest that myoblast therapy may represent a noninvasive treatment option. Methods: We conducted a phase 2 randomized, double-blind, placebo-controlled study of intrasphincteric injections of AM in 24 patients. The study compared outcome after AM (n = 12) or placebo (n = 12) injection using Cleveland Clinic Incontinence (CCI), score at 6 and 12 months. Patients in the placebo group were eligible to receive frozen AM after 1 year. Results: At 6 months, the median CCI score significantly decreased from baseline in both the AM (9 vs 15, P = 0.02) and placebo (10 vs 15, P = 0.01) groups. Hence, no significant difference was found between the 2 groups (primary endpoint) at 6 months. At 12 months, the median CCI score continued to ameliorate in the AM group (6.5 vs 15, P = 0.006), while effect was lost in the placebo group (14 vs 15, P = 0.35). Consequently, there was a higher response rate at 12 months in the treated than the placebo arm (58% vs 8%, P = 0.03). After delayed frozen AM injection in the placebo group, the response rate was 60% (6/10) at 12 months. Conclusions: Intrasphincteric AM injections in FI patients have shown tolerance, safety, and clinical benefit at 12 months despite a transient placebo effect at 6 months.

How do GP practices and patient characteristics influence the prescription of antidepressants? A cross-sectional study

BackgroundUnder-prescription of antidepressants (ADs) among people meeting the criteria for major depressive episodes and excessive prescription in less symptomatic patients have been reported. The reasons influencing general practitioners’ (GPs) prescription of ADs remain little explored. This study aimed at assessing the influence of GP and patient characteristics on AD prescription.MethodsThis cross-sectional study was based on a sample of 816 GPs working within the main health care insurance system in the Seine-Maritime district of France during 2010. Only GPs meeting the criteria for full-time GP practice were included. The ratio of AD prescription to overall prescription volume, a relative measure of AD prescription level, was calculated for each GP, using the defined daily dose (DDD) concept. Associations of this AD prescription ratio with GPs’ age, gender, practice location, number of years of practice, number of days of sickness certificates prescribed, number of home visits and consultations, number and mean age of registered patients, mean patient income, and number of patients with a chronic condition were assessed using univariate and multivariate analysis.ResultsThe high prescribers were middle-aged (40–59) urban GPs, with a moderate number of consultations and fewer low-income and chronic patients. GPs’ workload (e.g., volume of prescribed drug reimbursement and number of consultations) had no influence on the AD prescription ratio. GPs with more patients with risk factors for depression prescribed fewer ADs, however, which could suggest the medications were under-prescribed among the at-risk population.ConclusionsOur study described a profile of the typical higher AD prescriber that did not include heavy workload. In future work, a more detailed assessment of all biopsychosocial components of the consultation and other influences on GP behavior such as prior training would be useful to explain AD prescription in GP’s practice.

Copy Number Variations in DCC/18q and ERBB2/17q are Associated with Disease-Free Survival in Microsatellite Stable Colon Cancer.

We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in Stage II–III microsatellite stable (MSS) colon cancer. A total of 401 patients were included from 01/2004 to 01/2009. The CNVs in 8 selected target genes, DCC/18q, EGFR/7p, TP53/17p, BLK/8p, MYC/8q, APC/5q, ERBB2/17q and STK6/20q, were detected using a quantitative multiplex polymerase chain reaction of short fluorescent fragment (QMPSF) method. The primary end‐point was the impact of the CNVs on the 4‐year disease‐free survival (DFS). The recurrence rate at 4 years was 20.9%, corresponding to 14% Stage II patients versus 31% Stage III patients (p < 0.0001). The 4‐year DFS was significantly decreased in patients with a loss at DCC/18q (p = 0.012) and a gain at ERBB2/17q (p = 0.041). The multivariate analysis demonstrated that Stage III, a loss at DCC/18q and a gain at ERBB2/17q were independent factors associated with DFS. A combination of DCC/18q and ERBB2/17q was also associated with relapse, with the hazard ratio increasing from 1 to 2.4 (95% confidence interval (CI), 1.5–4.1) and 3.1 (95% CI, 1.2–8.4) in the presence of 0, 1 or 2 alterations, respectively (p = 0.0013). CNVs in DCC/18q and ERBB2/17q are significantly associated with DFS in Stage II–III MSS colon cancer.