Anti-NMDA receptor encephalitis and vaccination: A disproportionality analysis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an auto-immune neurological disorder characterized by the presence in the cerebrospinal fluid (CSF) of antibodies against the GluN1 subunit of NMDA receptors in the brain. The etiology of the disease remains largely unknown. In this study, we aimed to investigate the possible existence of pharmacovigilance signals relating to a link between vaccination and the occurrence of anti-NMDAR encephalitis. We performed a case/non-case study using data from the World Health Organization pharmacovigilance database (VigiBase) up to 31 December 2021. All individual case study reports (ICSRs) linked to a vaccine and coded with the MedDRA Lower Level Term (LLT) "anti-NMDA receptor encephalitis" were analysed. We calculated the Reporting Odds Ratio (ROR) and 95% Confidence Interval (CI) for each type of vaccine. A total of 29,758,737 ICSRs were registered in VigiBase, of which 70 were coded under the selected LLT, and 29/70 (41.4%) involved a vaccine. Of these cases, 53.8% involved children aged younger than 15 years. The median time to onset of anti-NMDAR encephalitis after vaccination was 4 days (range 0-730). The highest RORs were observed for the diphtheria/polio/tetanus/pertussis vaccine [54.72 (95% CI 26.2-114.3)], yellow fever vaccine [50.02 (95% CI 15.7-159)] and human papillomavirus vaccine [32.89 (15.8-68.7)]. All cases were coded as serious; 13 patients did not recover, or were left with permanent sequelae. Nine patients recovered without sequelae or are on the path to recovery, and one patient died. In summary, pharmacovigilance signals were observed for anti-NMDAR encephalitis and vaccination. Clinicians need to be aware of this potential risk, and encourage to report any case of anti-NMDAR encephalitis occurring after vaccination.

Psoriasis risk after beta-blocker exposure: Description of a pharmacovigilance signal.

AIM: We aimed to investigate French pharmacovigilance data. The objective was to characterize psoriatic conditions that occurred after beta-blocker (BB) exposure and bring to light a possible pharmacovigilance signal. METHODS: Spontaneous reports of psoriatic conditions recorded in the French National Pharmacovigilance Database (FPVD) between 1985 and 2019 were extracted. We performed a retrospective, descriptive analysis of reports linked to BB exposure. Association between psoriasis risk and BB exposure was assessed using a case/noncase study. RESULTS: Two hundred and twenty-five reports of psoriatic conditions after BB exposure were recorded in the FPVD during the study period. Both cardioselective and noncardioselective, topical and systemic BBs are involved. Therapeutic indication of BB was mainly hypertension. Mean time to onset was 5 months and outcome was favourable in 68% after BB discontinuation. These features were concordant with those of literature reports. The reporting odds ratio (ROR) was 8.95 (95% confidence interval 7.75-10.33). CONCLUSION: We highlighted a statistically significant disproportionality which constitutes a pharmacovigilance signal. Psoriasis risk with BBs is a class effect. Increasing surveillance during the first year of BB exposure is needed.

Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity.

PURPOSE: Pembrolizumab is a humanized monoclonal antibody that binds to the programmed cell-death protein-1 (PD-1) on immune T-cells, thus blocking PD-1 activity. Pembrolizumab is indicated for the treatment of advanced melanoma, metastatic non-small-cell lung cancer, and head and neck squamous cell carcinoma. However, it is associated with immune-related adverse events. METHODS: We investigated the association between pembrolizumab and immune-mediated necrotizing myopathy (IMNM). We analyzed reports in the World Health Organization's global individual case safety report database, Vigibase, up to January 2020 with the MedDRA lower level term "IMNM." The association between exposure to pembrolizumab and occurrence of the adverse event was estimated by disproportionality analysis. The reporting odds ratio (ROR) was calculated with 95% confidence intervals (CIs). We analyzed the criteria of diagnosis of the adverse reaction. RESULTS: Five-hundred sixty-seven notifications were identified as IMNM of which 14 with pembrolizumab. The ROR was 17.59 (95% CI: 9.4-32.9). CONCLUSION: The diagnosis of IMNM does not always take into account recent criteria for the diagnosis of this pathology. This study highlights the existence of a signal, as well as the need for collaboration between oncologists and neurologists for these neurological pathologies.

Drug induced stuttering: pharmacovigilance data.

Background: Stuttering is a speech disorder characterized by poor fluency of speech despite the speech production organs being normal. Numerous factors contribute to stuttering, and it may also be an iatrogenic effect of certain drugs. The aim of this study was to investigate the association between stuttering and drug exposure.Research design and methods: We investigated the association between drugs and stuttering. We analyzed reports in the World Health Organization global individual case safety reports database (Vigibase) up to 31 May 2020 with the MedDRA lower level terms 'stutter' and 'stuttering.' The association between a drug and the occurrence of the adverse drug reaction was estimated by disproportionality analysis. Reporting odds ratios (ROR) were calculated with 95% confidence intervals.Results: In total, 724 notifications were identified using the MedDRA terms selected. The main drugs implicated were methylphenidate (ROR = 19.58; 95% CI: 13.3-28.8), topiramate (ROR = 12.5; 95% CI: 7.1-22.1), olanzapine (ROR = 12; 95% CI: 8-17.9) and golimumab (ROR = 10.2; 95% CI: 5.5-19.1).Conclusions: When stuttering occurs in a patient treated by drugs affecting neurotransmission, a drug-induced origin of the stutter should be considered.

Calcium channel blocker exposure and psoriasis risk: Pharmacovigilance investigation and literature data.

INTRODUCTION: Evidence regarding a possible association between psoriatic manifestations and use of calcium channel blockers (CCBs) is sparse. Currently, psoriatic manifestations are not listed in the summary of product characteristics (SmPC) of CCBs. In this context, we aimed to investigate the association between psoriasis and CCB exposure. METHODS: We reviewed spontaneous reports recorded in the French national pharmacovigilance database (FPVD) between 1985 and 2019. The association between CCB exposure and risk of psoriasis was assessed using the case/non-case method. We also analyzed literature data. RESULTS: Ninety-four reports of psoriatic manifestations after CCB exposure were recorded in the FPVD. Both induction and exacerbation cases were observed. Time to onset was less than 2 years in 64% of reports and outcome was favorable in 71% of reports after CCB discontinuation. These features were concordant with those of literature reports. The reporting odds ratio (ROR) was 2.45 (95% CI 1.99-3.02). Concomitant use of betablockers or angiotensin II receptor blockers did not interact with the association between CCB exposure and psoriasis risk. The ROR for the stratum "use of angiotensin converting enzyme inhibitors" (ACEI) was 2.14 (95% CI 1.29-3.55), while the ROR for the stratum ACEI non-use was 0.12 (95% CI 0.10-0.15). Large-scale epidemiologic studies were focused only on first diagnoses and did not include exacerbations; psoriasis risk was therefore probably underestimated. CONCLUSION: We found a statistically significant association between CCB exposure and psoriasis risk, which constitutes a safety signal. This risk is a class effect, time to onset is mostly less than 2 years and outcome is favorable after CCB discontinuation. Psoriasis should be mentioned in the SmPCs of all CCBs, and healthcare workers should be aware of this risk. Attention should be paid to patients taking CCB and ACEI concomitantly.

Psoriasis After Exposure to Angiotensin-Converting Enzyme Inhibitors: French Pharmacovigilance Data and Review of the Literature.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) can induce or aggravate psoriasis. This risk is not specified in the Summary of Product Characteristics (SmPC) of some drugs of this class, such as captopril or enalapril. We aimed to investigate the association between psoriasis and ACEI exposure. METHODS: We analyzed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD) from 1985 to 31 December 2018. The association between psoriasis and ACEI exposure was assessed using the case/non-case method. We also reviewed literature reports. RESULTS: One hundred reports of psoriasis after ACEI exposure were registered in the FPVD. The reporting odds ratio (ROR) was 2.40 (95% CI 1.96-2.95). Time to onset was < 1 year in 67% of reports. Outcome was favorable in 73% of reports after ACEI discontinuation. Almost all ACEIs were concerned. In the literature, we found 21 published reports of psoriasis with ACEIs. Time to onset ranged from 1 week to 4 months. Outcome was also favorable after ACEI discontinuation in over half of the literature reports. CONCLUSIONS: We found a statistically significant association between psoriasis and ACEI, which constitutes a potential safety signal. The risk of psoriasis is a class effect, time to onset is less than 1 year, and outcome is favorable after ACEI discontinuation. Psoriasis should be mentioned in the SmPCs of all ACEIs, and healthcare professionals should be informed about this risk.

Methylphenidate and stuttering.

Methylphenidate (MPH) is a piperidine similar to amphetamines, and is indicated for attention deficit hyperactivity disorder. Studies concerning stuttering occurring with MPH are contradictory. We investigated the association between MPH and stuttering. We analysed reports in the World Health Organization global individual case safety reports database, Vigibase, up to 31 December 2018, with the MedDRA preferred term "dysphemia" and the lower level terms "stutter" and "stuttering". The association between exposure to MPH and occurrence of the adverse drug reaction was estimated by disproportionality analysis. Reporting odds ratios (RORs) were calculated with 95% confidence intervals (CIs). In total, 2975 cases of dysphemia were reported, of which 46 reports were associated with MPH. For the Preferred Term "dysphemia", the ROR was 7.3 (95% CI: 5.4-9.8). With the Lower Level Term "stuttering", 584 cases were registered in the database of which 17 involved MPH. The ROR was 13.9 (95% CI: 8.6-22.5). This study found a signal for stuttering with MPH.

Psoriasis during angiotensin receptor blocker exposure: an underestimated adverse drug reaction.

BACKGROUND: Angiotensin receptor blockers (ARBs) can induce or exacerbate psoriasis. Psoriasis is unlisted in the Summary of Product Characteristics (SmPC) of ARBs. We aimed to investigate the association between psoriasis and ARB exposure. METHODS: We reviewed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD). The association between psoriasis and ARB exposure was assessed using the case/non-case method. We also analyzed literature reports. RESULTS: We identified 89 reports of psoriasis during ARB exposure in the FPVD. Time to onset was most often less than 1 year. Outcome was favorable in 67% of reports after ARB discontinuation. Almost all ARBs were concerned. The reporting odds ratio (ROR) for psoriasis with this therapeutic class was 4.86 (95%CI 3.92-6.03). In the literature, we found 14 published reports of psoriasis with ARB exposure. Time to onset ranged from 6 weeks to 9 months. Outcome was also favorable after ARB discontinuation in the literature. CONCLUSIONS: This underestimated adverse drug reaction is a class effect, time to onset is most often less than 1 year and outcome seems favorable after ARB discontinuation. The case/non-case approach highlights a potential safety signal. The SmPC of ARBs should be updated, increased awareness among healthcare professionals is warranted.

Overview of Social Cognitive Dysfunctions in Rare Developmental Syndromes With Psychiatric Phenotype.

Rare neurodevelopmental syndromes often present social cognitive deficits that may underlie difficulties in social interactions and increase the risk of psychosis or autism spectrum disorders. However, little is known regarding the specificities of social cognitive impairment across syndromes while it remains a major challenge for the care. Our review provides an overview of social cognitive dysfunctions in rare diseases associated with psychiatric symptoms (with a prevalence estimated between 1 in 1,200 and 1 in 25,000 live births: 22q11.2 deletion syndrome, Angelman syndrome, Fragile X syndrome, Klinefelter syndrome, Prader-Willi syndrome, Rett syndrome, Smith-Magenis syndrome, Turner syndrome, and Williams syndrome) and shed some light on the specific mechanisms that may underlie these skills in each clinical presentation. We first detail the different processes included in the generic expression "social cognition" before summarizing the genotype, psychiatric phenotype, and non-social cognitive profile in each syndrome. Then, we offer a systematic review of the social cognitive abilities and the disturbed mechanisms they are likely associated with. We followed the PRISMA process, including the definition of the relevant search terms, the selection of studies based on clear inclusion, and exclusion criteria and the quality appraisal of papers. We finally provide insights that may have considerable influence on the development of adapted therapeutic interventions such as social cognitive training (SCT) therapies specifically designed to target the psychiatric phenotype. The results of this review suggest that social cognition impairments share some similarities across syndromes. We propose that social cognitive impairments are strongly involved in behavioral symptoms regardless of the overall cognitive level measured by intelligence quotient. Better understanding the mechanisms underlying impaired social cognition may lead to adapt therapeutic interventions. The studies targeting social cognition processes offer new thoughts about the development of specific cognitive training programs, as they highlight the importance of connecting neurocognitive and SCT techniques.

Eosinophilic pneumonia induced by non-steroidal anti-inflammatory drugs: An underestimated risk.

INTRODUCTION: Eosinophilic pneumonia (EP) is a rare but serious adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: We describe the second published case of EP induced by oral diclofenac. We also reviewed the literature as well as French pharmacovigilance database. Case presentation A 63 year-old woman with polyarthralgia had taken diclofenac for three days for analgesic purposes. Progressively, the patient presented weakness, dyspnea and fever. Computed tomography (CT) scan revealed bilateral interstitial infiltration. Broncho-alveolar lavage (BAL) showed an elevated level of eosinophils. After ruling out all other possible etiologies, drug-induced EP was diagnosed and treatment by corticosteroid was initiated. The patient recovered in three months. RESULTS: In the French pharmacovigilance database, six cases of EP were recorded (3 with naproxen, 2 with ibuprofen, 1 with piroxicam). In the literature, twenty-six cases of EP with NSAIDs were published. The most commonly involved drug was naproxen (n=8), followed by fenbufen (n=4), ibuprofen (n=3) and diclofenac (n=2). A high level of eosinophils was systematically observed in the blood cell count or BAL. Corticosteroid therapy was started in eleven cases. All patients recovered. CONCLUSION: Complete history taking and examination should be done to rule out other etiological diagnoses. BAL is sufficient to diagnose EP. Corticosteroid therapy should be indicated for more severe or refractory cases. This adverse drug reaction is underestimated, healthcare professionals should be informed.

Bisphosphonate-related osteonecrosis of the jaw: data from the French national pharmacovigilance database.

The aim of this study was to describe bisphosphonate-related osteonecrosis of the jaw (BRONJ) in the French national pharmacovigilance database. BRONJ was identified with the standardized MedDRA query (SMQ) 'osteonecrosis' among all data from 1985 to 31 December 2014. Because this SMQ was not specific to the jaw localization, selection of cases based on anatomy was performed after data extraction. For each case, demographic and medical information was analysed, as well as data about notification (year of notification, year of occurrence, outcome, seriousness). Known associated factors for BRONJ were also documented: dentoalveolar surgery, glucocorticoids, chemotherapy, anti-angiogenics, denosumab. Among 1404 SMQ notifications, 663 were located in the jaws and 629 were associated with bisphosphonate use. BRONJ reported in the database mainly affected women (n = 443, 71%) with an oncological indication (n = 440, 70%). BRONJ was considered as serious in 91%. Outcome was unfavourable for 92% of cases. Associated factors were identified for 70% of the patients. A peak of notification was noted in 2014 (13% of all cases), but on analysis by year of occurrence instead of by year of notification, this peak disappeared. SMQ 'osteonecrosis' appears to be an adequate tool to analyse BRONJ in a pharmacovigilance database.

«Cognitus & Moi¼: A Computer-Based Cognitive Remediation Program for Children with Intellectual Disability.

Attentional, visuospatial, and social cognition deficits have a negative impact on children's adaptative and social competences and, as a result, on their ability to achieve a normal functioning and behavior. Until now and despite the frequency of those deficits, there is a lack of children's specific cognitive remediation tools specifically dedicated to attentional and visuospatial areas. The «Cognitus & Moi¼ program involves a variety of exercises in a paper and/or pencil (n = 30) or a computerized format (n = 29) and a strategy coaching approach. Each module of «Cognitus & Moi¼ targets a single impaired cognitive area, within the limits of cognitive domains' overlapping. The little cartoon character named Cognitus, who illustrates the program, is supposed to be very friendly and kind toward children. Cognitus will accompany them throughout the program for an effective and positive reinforcement. The main goal of «Cognitus & Moi¼ is to adjust to children's difficulties in daily life. Moreover, since the cognitive remediation benefit is complex to apply in daily life, the program is based on a metacognitive strategy. After a complete neuropsychological assessment and a psychoeducational session (with the child and the parents), 16 1-h-sessions of cognitive remediation with the therapist are proposed. Each session is composed of three parts: (1) computerized tasks focusing on specific attentional or visuospatial components (20 min). The attentional module targets hearing, visual, and divided attention. A double attention task is also proposed. The visuospatial module targets eye tracking and gaze direction, spatial orientation, visuospatial memory and construction, and mental imagery; (2) pen and paper tasks focusing on the same processes (20 min) and a facial emotion recognition task; (3) a proposal of a home-based task (during 20 min). Weekly, specific attentional and visuospatial home tasks are proposed to the child and analyzed with the parents and the therapist. Indeed, home exercises are useful to promote the transfer of strategies to daily life and their subsequent automation. The heterogeneity of cognitive deficits in intellectual deficiency necessitates an individualized cognitive remediation therapy. In this regard, «Cognitus & Moi¼ seems to be a promising tool.