Discordance between pain specialists and patients on the perception of dependence on pain medication: A multi-centre cross-sectional study.

AIM: Patients with chronic non-cancer pain are referred to pain centres to improve their pain treatment. The discontinuation of pain medications in case of poor efficacy can be difficult to accept for patients, particularly opioid analgesics. Previous research has described that from the patients' perspective, the psychological relief of a negative effect of chronic pain and withdrawal symptoms of prescription opioids represent drivers of persistent use and first stage of opioid use disorder, despite insufficient pain relief. There is no validated tool to investigate this psychological dependence. This study aimed to assess discordance between patients and pain specialists in their perception of dependence on pain medication and investigate associations with characteristics of patients, type of pain and iatrogenic pharmacodependence. METHODS: Self-administered questionnaires (patients and physicians) were administered in six pain centres in France. A question on perceived dependence on pain medications was addressed to the patient and the physician in a matched pair. Discordance between them was evaluated by the Cohen kappa coefficient. Demographics, pain, anxiety and depression, pain medication withdrawal symptoms, diverted use, and craving represented variables studied in a multivariate model as potentially associated with patient-physician discordance. RESULTS: According to the 212 pairs of completed questionnaires, a perceived dependence was reported by the majority of patients (65.6%) and physicians (68.4%). However, the concordance was fair (kappa=0.38; CI [95%]: 0.25-0.51). Almost all patients (89.3%) were treated with an opioid analgesic. A higher likelihood of discordance was observed when patients suffered from nociplastic pain (odds ratio [OR]: 2.72, 95% [CI]: 1.29-5.84). CONCLUSION: Medical shared-decision for changing pain treatment could be improved by taking into account the perception of patient dependence on medications for pain relief and or psychoactive effects, particularly in nociplastic pain for which the treatment is challenging.

Trim33 masks a non-transcriptional function of E2f4 in replication fork progression.

Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql. Replicative stress blunts Trim33-dependent ubiquitination of E2f4, which stimulates transient Recql recruitment to chromatin and facilitates recovery of DNA synthesis. In contrast, deletion of Trim33 induces chronic genome-wide recruitment of Recql and strongly accelerates DNA replication under stress, compromising checkpoint signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis controls progression of DNA replication forks along transcriptionally active chromatin to maintain genome integrity.

Comparative Effects of 30 Antipsychotics on Risk of Catatonia: An Analysis of the WHO Pharmacovigilance Database.

Objective: Catatonia is a life-threatening psychomotor syndrome that occurs in approximately 10% of patients with acute psychiatric illnesses. Although some case reports have argued that first generation antipsychotics (FGAs) are more likely to induce catatonia than second generation antipsychotics (SGAs), no large observational study has confirmed this hypothesis. We investigated whether FGAs were associated with an increased risk of reporting catatonia when compared with SGAs.Methods: A pharmacovigilance study was performed within VigiBase to compare the cases of catatonia syndromes reported in patients exposed to FGAs with those reported in patients exposed to SGAs. This approach is similar in concept to case-control study, but adapted to a pharmacovigilance database, and allows the estimation of reporting odds ratios (RORs) with 95% confidence intervals.Results: We identified 60,443 adverse effects reported in patients who received FGAs and 253,067 adverse effects reported in patients treated with SGAs. Compared with SGAs, the use of FGAs was associated with an increased risk of reporting catatonia syndromes (ROR = 2.2; 95% CI, 2.0-2.3). Consistent results were observed when the analysis was restricted to reports generated from physicians, reports from the US, and reports with the highest completeness score. The highest RORs were found for molindone (6.0; 95% CI, 3.1-10.4) and haloperidol (3.8; 95% CI, 3.5-4.0).Conclusions: In this large pharmacovigilance study of patients exposed to antipsychotics, the use of FGAs was associated with an increased risk of reporting catatonia syndromes compared to the use of SGAs. This increased risk is consistent with the pharmacodynamic hypothesis of antipsychotic-induced catatonia. Our results warrant replication in population-based studies.

Migraine and large artery atherosclerosis in young adults with ischemic stroke.

INTRODUCTION: Migraine is a risk factor for ischemic stroke, but the mechanisms of stroke associated with migraine are debated. The aim of this study was to investigate the association between migraine and large artery atherosclerosis (LAA) in young adults with ischemic stroke. METHODS: Patients aged between 18 and 54 years consecutively treated for first acute ischemic stroke in a university hospital stroke unit between January 2017 and December 2019 were included in this cross-sectional study. Migraine status was systematically assessed by the same headache specialist. Stenotic and nonstenotic LAA of extracranial and intracranial cerebral arteries were evaluated and graded using the ASCOD (atherosclerosis, small-vessel disease, cardiac pathology, other causes, dissection) criteria. We adjusted the association between migraine and LAA for traditional risk factors. RESULTS: A total of 415 patients were included (mean age [standard deviation], 43.9 [8.7] years; 258/415 [62.2%] men). Migraine with aura (MWA) was diagnosed in 76 patients, and migraine without aura (MWoA) in 68 patients. Patients with migraine had fewer traditional cardiovascular risk factors. Stenotic LAA (10/144 [6.9%] vs. 42/271 [15.5%]; p < 0.001) and LAA of any grade (35/144 [24.3%] vs. 138/271 [50.9%]; p < 0.001) were significantly less frequent in patients with migraine than in patients without migraine, respectively. Multivariable analysis adjusting for age, sex, overweight, tobacco use, hypertension, diabetes, and hyperlipidemia showed a negative association between migraine and LAA of any grade (odds ratio [OR] = 0.44, 95% confidence interval [CI: 0.254-0.78], p = 0.005). This negative association was found for both MWoA (OR = 0.42, 95% CI [0.204-0.88], p = 0.020) and MWA (OR = 0.47, 95% CI [0.228-0.96], p = 0.037) compared to no migraine. CONCLUSION: In this study of young adults with ischemic stroke, migraine had a negative association with LAA. This negative association was independent of traditional vascular risk factors and was found for both MWA and MWoA.

Factors associated with drug-free remission at 5-year in early onset axial spondyloarthritis patients: Data from the DESIR cohort.

OBJECTIVES: To assess the frequency of patients in drug-free remission at 5 years in a cohort of early axial SpA, and the factors associated with this remission. METHODS: Patients: patients included in the DESIR (DEvenir des Spondyloarthropathies Indifférenciées Récentes) cohort undergoing the 5-year visit were selected for this analysis. Definition of 5-year drug-free remission: (1) all patients in ASAS partial remission and/or ASDAS<1.3 at 5 year visit and (2) taking no disease modifying anti-rheumatic drugs at the 5-year visit and (3) with an ASAS-NSAID score≤25 at the 5-year visit. DATA ANALYSIS: the proportion of patients in drug-free remission was described. The association between demographic, clinical, biological and imaging characteristics and drug-free remission at 5 years was assessed by logistic regression. RESULTS: Of the 412 patients included in this analysis, 73 (18%) were in drug-free remission at the 5-year visit. The baseline clinical factors associated with the chances to be in drug-free remission at the 5-year visit were symptom duration (OR=0.66 [95%CI%: 0.44-0.97]), lower HAQ-AS score (OR=0.32 [0.12-0.78]), lower ASDAS score (OR=0.55 [95%CI: 0.34-0.86]), ASAS-NSAID score (OR=0.91 [95%CI: 0.82-0.99]). Furthermore, anti-TNF use (OR=0.20 [95%CI: 0.08-0.42]) during the follow-up decreased the chances of being in 5-year drug-free remission. CONCLUSION: The probability of being in drug free remission at 5 year when beginning an axial SpA is low and is associated with lower baseline disease activity and functional scores, while starting an anti-TNF is associated with poor chances of later being in drug-free remission. NCT01648907.

Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin-7.

OBJECTIVE: Restoring anti-JC virus (JCV) immunity is the only treatment of progressive multifocal leukoencephalopathy (PML). Interleukin-7 is a cytokine that increases number and function of T cells. We analyzed a population of PML patients who received recombinant human IL-7 (rhIL-7) to estimate survival and its determinants. METHODS: After exclusion of patients with missing data or receiving other immunotherapies, findings from 64 patients with proven PML who received rhIL-7 between 2007 and 2020 were retrospectively analyzed. Logistic regression was used to analyze variables associated with one-year survival. RESULTS: Underlying conditions were HIV/AIDS (n = 27, 42%), hematological malignancies (n = 16, 25%), primary immunodeficiencies (n = 13, 20%), solid organ transplantation (n = 4, 6%) and chronic inflammatory diseases (n = 4, 6%). One-year survival was 54.7% and did not differ by underlying condition. Survival was not associated with baseline characteristics, but with a >50% increase in blood lymphocytes (OR 4.1, 95%CI 1.2-14.9) and CD4+ T cells (OR 5.9, 95%CI 1.7-23.3), and a > 1 log copies/mL decrease in cerebrospinal fluid JCV DNA (OR 7.6, 95%CI 1.6-56.1) during the first month after rhIL-7 initiation. Side effects were mainly local and flu-like symptoms (n = 8, 12.5%) and PML-immune reconstitution inflammatory syndrome (IRIS) (n = 5, 8%). INTERPRETATION: In this non-controlled retrospective study, survival did not differ from that expected in HIV/AIDS patients, but might have been improved in those with hematological malignancies, primary immunodeficiencies and transplant recipients. RhIL-7 might have contributed to the increase in blood lymphocytes and decrease in CSF JCV replication that were associated with better survival. ANN NEUROL 2022;91:496-505.

What predicts poor outcome after successful thrombectomy in early time window?

BACKGROUND: Half of the patients with large vessel occlusion (LVO)-related acute ischemic stroke (AIS) who undergo endovascular reperfusion are dead or dependent at 3 months. We hypothesize that in addition to established prognostic factors, baseline imaging profile predicts outcome among reperfusers. METHODS: Consecutive patients receiving endovascular treatment (EVT) within 6 hours after onset with Thrombolysis In Cerebral Infarction (TICI) 2b, 2c and 3 revascularization were included. Poor outcome was defined by a modified Rankin scale (mRS) 3-6 at 90 days. No mismatch (NoMM) profile was defined as a mismatch (MM) ratio ≤1.2 and/or a volume <10 mL on pretreatment imaging. RESULTS: 187 patients were included, and 81 (43%) had a poor outcome. Median delay from stroke onset to the end of EVT was 259 min (IQR 209-340). After multivariable logistic regression analysis, older age (OR 1.26, 95% CI 1.06 to 1.5; p=0.01), higher National Institutes of Health Stroke Scale (NIHSS) (OR 1.15, 95% CI 1.06 to 1.25; p<0.0001), internal carotid artery (ICA) occlusion (OR 3.02, 95% CI 1.2 to 8.0; p=0.021), and NoMM (OR 4.87, 95% CI 1.09 to 22.8; p=0.004) were associated with poor outcome. In addition, post-EVT hemorrhage (OR 3.64, 95% CI 1.5 to 9.1; p=0.04) was also associated with poor outcome. CONCLUSIONS: The absence of a penumbra defined by a NoMM profile on baseline imaging appears to be an independent predictor of poor outcome after reperfusion. Strategies aiming to preserve the penumbra may be encouraged to improve these patients' outcomes.

Personality Related to Quality-of-Life Improvement After Deep Brain Stimulation in Parkinson's Disease (PSYCHO-STIM II).

BACKGROUND: Deep brain stimulation of the sub-thalamic nucleus (DBS-STN) reduces symptoms in Parkinson's disease (PD) patients with motor fluctuations. However, some patients may not feel ameliorated afterwards, despite an objective motor improvement. It is thus important to find new predictors of patients' quality of life (QoL) amelioration after DBS-STN. We hypothesized that personality dimensions might affect QoL after DBS-STN. OBJECTIVE: To evaluate associations between personality dimensions and QoL improvement one year after DBS-STN. METHODS: DBS-STN-PD patients (n = 303) having answered the "Temperament and Character Inventory" (TCI) before surgery and the PDQ-39 before and one year after surgery were included, from the cohort study PREDI-STIM. Linear regression models were used to evaluate associations between TCI dimensions and change in PDQ-39 scores after DBS-STN. RESULTS: Novelty Seeking and Cooperativeness scores before surgery were positively associated with PDQ-39 scores improvement after DBS-STN (FDR-adjusted p < 0.01). Moreover, paradoxically unimproved patients with deterioration of their PDQ-39 scores after DBS-STN despite improvement of their MDS-UPDRS-IV scores had lower Cooperativeness scores, while paradoxically improved patients with amelioration of their PDQ-39 scores despite deterioration of their MDS-UPDRS-IV scores had higher Reward Dependence scores. CONCLUSION: Some presurgical personality dimensions were significantly associated with QoL amelioration and discrepancy between motor state and QoL changes after DBS-STN in PD. Educational programs before DBS-STN should take in account patient personality dimensions to better deal with their expectations.

Botulinum toxin injections as an effective treatment for patients with intertriginous Hailey-Hailey or Darier disease: an open-label 6-month pilot interventional study.

BACKGROUND: Patients with Hailey-Hailey and Darier diseases present with disabling inflammatory lesions located in large skin folds, which are often exacerbated or induced by sweating. Quality of life is highly impaired because of pain and recurrent skin infections. An improvement in skin lesions after botulinum toxin A injections has previously been reported in some patients but no prospective interventional studies are available. The aim of this open-label, 6-month, interventional pilot study (NCT02782702) was to evaluate the effectiveness and safety of botulinum toxin A for patients with moderate to very severe skin lesions located in folds. RESULTS: Thirty patients (26 Hailey-Hailey/4 Darier) were included. Botulinum toxin A proved effective within the first month in two-thirds of patients, taking all study parameters (itchiness, cutaneous pain, sweating and odour, infections, psychosocial impairment and quality of life) into account and persisted during the 6-month follow-up period. No patient was classed as a BtxA non-responder, but 11 (37%) Hailey-Hailey patients (the most severe ones), experienced a relapse during the study. No serious side effects were reported. Mild transient clear fluid discharge at the site of the injections was reported for 27% of patients. CONCLUSIONS: Botulinic toxin seems to be an effective and safe treatment for Hailey-Hailey and Darier diseases. Nevertheless, it may prove insufficient for the severest of Hailey-Hailey cases and could be considered as supplementary to other conventional treatments. Further studies are required to confirm our results on larger Darier cohorts.

Psychiatric Disorders and Hydroxychloroquine for Coronavirus Disease 2019 (COVID-19): A VigiBase Study.

INTRODUCTION: In the stressful context of the coronavirus disease 2019 (COVID-19) pandemic, some reports have raised concerns regarding psychiatric disorders with the use of hydroxychloroquine. In this study, we reviewed all psychiatric adverse effects with hydroxychloroquine in COVID-19 patients, as well as in other indications, reported in VigiBase, the World Health Organization's (WHO) global database of individual case safety reports. METHODS: First, we analyzed all psychiatric adverse effects, including suicide, of hydroxychloroquine in COVID-19 patients reported to 16 June 2020. We also performed disproportionality analysis to investigate the risk of reporting psychiatric disorders with hydroxychloroquine compared with remdesivir, tocilizumab, or lopinavir/ritonavir prescribed in COVID-19 patients. We used reporting odds ratios (RORs) and their 95% confidence intervals (CIs) to calculate disproportionality. Second, we sought to examine the psychiatric safety profile of hydroxychloroquine in other indications (before 2020). RESULTS: Among the 1754 reports with hydroxychloroquine in COVID-19 patients, we found 56 psychiatric adverse effects. Half of these adverse effects were serious, including four completed suicides, three cases of intentional self-injury, and 12 cases of psychotic disorders with hallucinations. Compared with remdesivir, tocilizumab, or lopinavir/ritonavir, the use of hydroxychloroquine was associated with an increased risk of reporting psychiatric disorders (ROR 6.27, 95% CI 2.74-14.35). Before 2020, suicide was the main cause of death among all adverse drug reactions reported with hydroxychloroquine, followed by cardiac adverse effects (cardiomyopathy) and respiratory failure. CONCLUSIONS: This pharmacovigilance analysis suggests that COVID-19 patients exposed to hydroxychloroquine experienced serious psychiatric disorders, and, among these patients, some committed suicide. Further real-world studies are needed to quantify the psychiatric risk associated with hydroxychloroquine during the COVID-19 pandemic.

Which Method for Diagnosing Small Fiber Neuropathy?

Introduction: Small fiber neuropathies (SFN) induce pain and/or autonomic symptoms. The diagnosis of SFN poses a challenge because the role of skin biopsy as a reference method and of each neurophysiological test remain to be discussed. This study compares six methods evaluating small sensory and autonomic nerve fibers: skin biopsy, Quantitative Sensory Testing (QST), quantitative sweat measurement system (Q-Sweat), Laser Evoked Potentials (LEP), Electrochemical Skin Conductance (ESC) measurement and Autonomic CardioVascular Tests (ACVT). Methods: This is a single center, retrospective study including patients tested for symptoms compatible with SFN between 2013 and 2016 using the afore-mentioned tests. Patients were ultimately classified according to the results and clinical features as "definite SFN," "possible SFN" or "no SFN." The sensitivity (Se) and specificity (Sp) of each test were calculated based on the final diagnosis and the best diagnostic strategy was then evaluated. Results: Two hundred and forty-five patients were enrolled (164 females (66.9%), age: 50.4 ± 15 years). The results are as follows: skin biopsy: Se = 58%, Sp = 91%; QST: Se = 72%, Sp = 39%; Q-Sweat: Se = 53%, Sp = 69%; LEP: Se = 66%, Sp = 89%; ESC: Se = 60%, Sp = 89%; Cardiovascular tests: Se = 15%, Sp = 99%. The combination of skin biopsy, LEP, QST and ESC has a Se of 90% and a Sp of 87%. Conclusion: Our study outlines the benefits of combining skin biopsy, ESC, LEP and QST in the diagnosis of SFN.

Personality Dimensions Are Associated with Quality of Life in Fluctuating Parkinson's Disease Patients (PSYCHO-STIM).

BACKGROUND: Parkinson's disease (PD) negatively affects patients' Quality of Life (QoL) which depends on both objective criteria such as physical health and subjective ones such as worries and norms according to personal believes. Therefore, QoL could be also associated to personality dimensions in chronic neurological diseases such as PD. OBJECTIVE: Our objective was thus to study the potential association between personality dimensions and QoL in PD patients with motor fluctuations before Deep Brain Stimulation of the Sub-Thalamic Nucleus (DBS-STN). METHODS: Data were obtained from the French multicentric cohort study Predi-Stim. All PD patients awaiting DBS-STN and responding to the inclusion criteria at the time of the study were included. All participants answered the "Temperament and Character Inventory" (TCI) and the PDQ-39 before surgery. Analyses were made using adjusted univariate generalized linear regression models to evaluate a potential association between TCI dimensions and PDQ-39 scores. RESULTS: Three hundred thirty-three consecutive patients were included. The temperament Harm Avoidance was negatively associated with QoL (p = 1e-4, R2= 0.33), whereas the character Self-Directedness was positively associated with mental component of QoL (p = 2e-4, R2= 0.33) in PD patients with motor fluctuations awaiting DBS-STN. CONCLUSIONS: PD patients with motor fluctuations, with lower Harm Avoidance and higher Self-Directedness scores have the best QoL mainly at an emotional and social level. Therapeutic education of these PD patients focusing on their personal resources may thus be important to improve their well-being.

Are potentially inappropriate and anticholinergic medications being prescribed for institutionalized elderly subjects?

The PAAPI project (Optimising Inappropriate Prescriptions in the Elderly) is a multi-disciplinary approach put in place by the Toulouse Pharmacovigilance Centre (CRPV) in order to improve drug prescribing practice in nursing homes. The aim of this study was to analyse the association between polypharmacy, frequency of prescriptions for potentially inappropriate medications (PIMs) and the anticholinergic burden of prescriptions in elderly patients from the PAAPI cohort. We carried out a retrospective study on residents of 24 nursing homes (EHPAD) participating in the PAAPI programme between 1er January 2017 and 31 December. Resident's Data were collected in a single review in a random day. Drug prescriptions were analysed quantitatively and qualitatively. PIMs and anticholinergic drugs were identified by the list EU(7)PIM and the Duran scale, respectively. The total anticholinergic burden was calculated by adding the anticholinergic scores of each drug. We classified the drugs into three categories: no anticholinergic burden (burden = 0), low anticholinergic burden (≥1 ≤ 3) or high anticholinergic burden (burden > 3). A total of 1191 residents living were included, and we analysed 8869 drug prescription lines. The average age of the residents was 87.0 ± 8.3 years, and the majority (71.5%) were female. Nearly half of the residents (49.6%, n = 67) having a prescription with a high anticholinergic burden were taking more than 9 drugs (Fisher exact test P < 0.05). All the prescriptions with more than 5 PIMs (n = 23) had an anticholinergic burden > 0, with the majority (65.2%, n = 15) having a high anticholinergic burden (Kruskal-Wallis test, P < 0.0001). In this cohort, 88% (n = 539) of prescriptions with a low anticholinergic burden and 100% (n = 135) of prescriptions with a high anticholinergic burden included at least one PIM. According to our study, the anticholinergic burden of prescriptions given to residents in the PAAPI cohort is associated with the prescription of PIMs and with polypharmacy. Optimizing the use of medicines remains essential in this population, given the harmful properties of these drugs. It would also be useful for the list of anticholinergic drugs to be updated as new medicines come onto the market.

Abatacept in rheumatoid arthritis and the risk of cancer: a world observational post-marketing study.

OBJECTIVES: We aimed to investigate whether abatacept used in patients for RA was associated with an increased risk of reporting overall cancer and specific cancers, including breast, lung, lymphoma, melanoma and non-melanoma skin cancer when compared with other biologic DMARDs (bDMARDs). METHODS: We performed an observational study within VigiBase, the World Health Organization's global database of individual case safety reports, from 2007 to 2017 to compare the cases of cancer reported in RA patients exposed to abatacept with those reported in RA patients exposed to other bDMARDs. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% CIs of the exposure odds among spontaneous reporting of cancers to the exposure odds among other reported adverse effects. RESULTS: We identified 15 846 adverse effects reported in RA patients who received abatacept and 290 568 adverse effects reported in RA patients treated with other bDMARDs. Compared with other bDMARDs, the use of abatacept was not associated with an increased risk of reporting cancer overall [ROR 0.98 (95% CI 0.91, 1.05)]. Analyses by specific cancer sites showed a significantly increased ROR for melanoma [1.58 (95% CI 1.17, 2.08)], but not for other specific cancer sites. CONCLUSION: Compared with other bDMARDs, exposure to abatacept in RA patients was only significantly associated with an increased risk of reporting melanoma. This increased risk is consistent with the properties of abatacept (CTLA-4 agonist) since it has an opposite action than ipilimumab, an antibody that blocks CTLA-4 and is approved for the treatment of malignant melanoma. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov), NCT03980639.

Drug-induced osteoporosis/osteomalacia: analysis in the French and Spanish pharmacovigilance databases.

INTRODUCTION: Osteomalacia and osteoporosis are two metabolic bone disorders that increase the risk of fracture due to several causes. In terms of drugs, apart from corticosteroids, which are known to induce bone disorders, several other drugs used in chronic disease management have also been linked with an increased risk of osteoporosis and osteomalacia. PURPOSE: The aim of this study was to describe spontaneous reports of drug-induced osteoporosis and osteomalacia in the French (FPVDB) and Spanish (SPVDB) pharmacovigilance databases. METHODS: Data were provided by the FPVDB and SPVDB. All reports of osteoporosis and osteomalacia recorded from 1985 up to 31 December 2015 inclusive were selected. Taking the time to onset of bone loss into account, all cases occurring in less than 1 month were excluded. RESULTS: A total of 369 reports (44 cases of osteomalacia, 325 cases of osteoporosis) were registered in the FPVDB and 64 (22 cases of osteomalacia, 42 cases of osteoporosis) in the SPVDB. In France, the top 5 drugs involved in the onset of osteoporosis were corticosteroids accounting for approximately half of the reports (n = 170) followed by systemic antiviral (n = 87), antacid (n = 29), antiepileptic (n = 27) and antithrombotic (n = 24) drugs. The 2 main classes of drugs implicated in osteomalacia were systemic antiretroviral drugs for half of the reports (n = 21) and antiepileptic drugs (n = 15). In Spain, corticosteroids were involved in 35.7% of reported cases of osteoporosis (n = 15) followed by systemic antiviral drugs (n = 12). There was no spontaneous report for antacid drugs. For osteomalacia, the 2 main drug classes were systemic antiretroviral drugs (n = 18, 81.8%) followed by antiepileptics (n = 2, 9.0%). In both countries, concomitant administration of systemic corticosteroids with other suspected drugs did not significantly modify the time to onset of drug-induced osteoporosis. CONCLUSION: Despite some differences between the French and Spanish PVDBs, our data consistently show that bone loss is not only restricted to glucocorticoids but also involves antivirals, antiepileptic drugs, antacid drugs or antidepressants. Further analysis might prove useful in exploring the characteristics of drug-induced bone loss on a larger scale.

Breast cancer and spironolactone: an observational postmarketing study.

INTRODUCTION: Recent studies have discussed the risk of breast cancer with antihypertensive drugs. For spironolactone, data are conflicting. The present paper investigates this potential signal in VigiBase®, the World Health Organization Global Individual Case Safety Report (ICSR) database. METHODS: In VigiBase®, we performed a case/non-case study using data registered from 1981 (spironolactone's marketing authorization) to December 31, 2017. Among women ≥ 50 years, we measured the risk of reporting "Breast malignant tumors" compared with all other adverse drug reactions (as a crude and adjusted (a) reporting odds ratio (ROR 95% CI)) for spironolactone compared with first, all other drugs and second, pseudo aldosterone antagonists (amiloride, triamterene). ROR were adjusted for age, year of report, continent of report, number of drug prescribed, and completeness score. Sensitivity analyses were performed after exclusion of drug competitors (i.e., drugs like estroprogestative therapy and progestogens that could mask a putative signal) and reports from health professionals. RESULTS: During the study period, 125 ICSRs reported spironolactone exposure and breast malignant cancer in women ≥ 50 years. We failed to find a positive association between spironolactone exposure and breast cancer in comparison with exposure to other drugs (aROR = 0.63 95% CI [0.52-0.75]) or pseudo aldosterone antagonists (amiloride, triamterene) (0.56 [0.44-0.72]). Similar trends were found after exclusion of drug competitors and/or reports from health professionals. CONCLUSION: This study did not find evidence for breast cancer associated with spironolactone.

Enlarged perivascular spaces and florbetapir uptake in patients with intracerebral hemorrhage.

PURPOSE: Enlarged perivascular spaces in the centrum semiovale (CSO-EPVS) have been linked to cerebral amyloid angiopathy (CAA). To get insight into the underlying mechanisms of this association, we investigated the relationship between amyloid-ß deposition assessed by 18F-florbetapir PET and CSO-EPVS in patients with acute intracerebral hemorrhage (ICH). METHODS: We prospectively enrolled 18 patients with lobar ICH (suggesting CAA) and 20 with deep ICH (suggesting hypertensive angiopathy), who underwent brain MRI and 18F-florbetapir PET. EPVS were assessed on MRI using a validated 4-point visual rating scale in the centrum semiovale and the basal ganglia (BG-EPVS). PET images were visually assessed, blind to clinical and MRI data. We evaluated the association between florbetapir PET positivity and high degree (score> 2) of CSO-EPVS and BG-EPVS. RESULTS: High CSO-EPVS degree was more common in patients with lobar ICH than deep ICH (55.6% vs. 20.0%; p = 0.02). Eight (57.1%) patients with high CSO-EPVS degree had a positive florbetapir PET compared with 4 (16.7%) with low CSO-EPVS degree (p = 0.01). In contrast, prevalence of florbetapir PET positivity was similar between patients with high vs. low BG-EPVS. In multivariable analysis adjusted for age, hypertension, and MRI markers of CAA, florbetapir PET positivity (odds ratio (OR) 6.44, 95% confidence interval (CI) 1.32-38.93; p = 0.03) was independently associated with high CSO-EPVS degree. CONCLUSIONS: Among patients with spontaneous ICH, high degree of CSO-EPVS but not BG-EPVS is associated with amyloid PET positivity. The findings provide further evidence that CSO-EPVS are markers of vascular amyloid burden that may be useful in diagnosing CAA.

Adverse Drug Reactions Involving Protein Kinase Inhibitors: A French Pharmacovigilance Database Study Comparing Safety in Younger and Older Patients (≥ 75 years) with Cancer.

BACKGROUND: Despite the increasing incidence of cancers in elderly people, this population remains under-represented in clinical trials. As a result, data describing the safety and efficacy of protein kinase inhibitors (PKIs) specifically in older patients with cancer are lacking. Advanced age may have a significant impact on drug pharmacology, but data on PKI safety in older patients remain poorly described in "real life". OBJECTIVES: We performed an observational study describing adverse drug reactions (ADRs) related to PKIs and compared the results for younger and older (aged ≥ 75 years) patients. METHODS: We extracted all notifications considered to be related to PKIs from our regional pharmacovigilance database between March 2003 and November 2015. Information about patients, drug exposure, and ADRs were captured. After a descriptive analysis of ADRs, we compared their characteristics between older and younger patients. RESULTS: In total, 214 patients experienced 320 ADRs related to PKIs. Slightly over half the patients were male (57%). The mean age was 64.1 years (range 15-90), and 52 (24.3%) patients were aged ≥ 75 years. Cutaneous reactions were the most frequently reported ADRs (22.9%), followed by gastrointestinal (16.8%) and respiratory (12.1%) ADRs. The most often involved PKIs were imatinib [54 patients (25.2%)], dasatinib [25 (11.7%)], sunitinib [25 (11.7%)], erlotinib [25 (11.7%)], and sorafenib [24 (11.2%)], followed by vemurafenib [17 (7.9%)] and everolimus and nilotinib, with 11 patients (5.1%) each. These drugs were administered mostly for three therapeutic indications: chronic myeloid leukemia [56 patients (26.2%)], malignant urinary tract cancer [31 (14.5%)], and bronchial cancer [27 (12.6%)]. Comparison of PKI-related ADRs between older and younger patients showed no significant difference, except for the mean number of coadministered drugs (5.3 vs. 4.2; p = 0.03) and the proportion of vascular ADRs (17.3 vs. 4.3%; p = 0.005), mainly arterial hypertension, which were both significantly more frequent in the older group. CONCLUSIONS: Our work showed that PKI-related ADRs in older patients were similar to those in younger adults, except for vascular ADRs, which were significantly more frequent in the older population. Our results require confirmation by larger studies but could lead physicians to be more vigilant about cardiovascular comorbidities during initiation of PKIs in elderly people.

Tamoxifen and the risk of Parkinsonism: a case/non-case study.

BACKGROUND: Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure. OBJECTIVES: To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018. METHODS: Among women ≥ 55 years, we measured the risk of reporting "Parkinsonism" compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors. RESULTS: During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71-0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33-0.46). CONCLUSION: This study did not find evidence for Parkinsonism associated with tamoxifen.