Characteristics and outcomes of gemcitabine-associated pulmonary hypertension.

Background: Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. The objective of the present study was to assess the association between gemcitabine and PH. Methods: We identified incident cases of precapillary PH confirmed by right heart catheterisation in patients treated with gemcitabine from the French PH Registry between January 2007 and December 2022. The aetiology, clinical, functional, radiological and haemodynamic characteristics of PH were reviewed at baseline and during follow-up. A pharmacovigilance disproportionality analysis was conducted using the World Health Organization (WHO) pharmacovigilance database. Results: We identified nine cases of pulmonary arterial hypertension, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (range 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L·min-1·m-2 and a pulmonary vascular resistance of 6.3 (3.1-12.6) Wood units. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Six patients showed clinical improvement upon discontinuation of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine. Conclusion: Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH. The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained dyspnoea.

Negative pressure wound therapy with instillation and dwell time in debridement of fibrinous leg ulcers.

OBJECTIVE: In conjunction with appropriate wound care, negative pressure wound therapy with instillation and dwell time (NPWTi-d) may be used as an adjunct therapy for acute or hard-to-heal (chronic) wounds, especially when infected. However, there are very few data on the use of NPWTi-d in the treatment of fibrinous wounds that are difficult to debride mechanically. The main objective of this study was to describe changes in the fibrin area of such wounds, before and after treatment with NPWTi-d. METHOD: This was a monocentric, observational, prospective pilot study evaluating the NPWTi-d medical device. Eligible patients included in the study were those with hard-to-heal lower limb ulcers who had previously undergone unsuccessful specific debridement treatment for their wound, with failure of manual mechanic debridement for at least six weeks' duration, and whose wounds had a fibrinous surface area of >70% of the total wound surface area. The primary endpoint was the difference in the percentage of fibrinous surface area before and after treatment. RESULTS: A total of 14 patients who received treatment for lower limb ulcers between October 2017 and August 2019 were included in the study. There was a significant shrinkage rate of the fibrinous wound surface between the start and end of treatment (83.6±14.5% and 32.2±19.7%, respectively; p<0.001). CONCLUSION: This study showed a significant decrease in fibrin area in wounds treated with NPWTi-d, with good tolerance. We believe that NPWTi-d has its place in the multidisciplinary management of patients with hard-to-heal ulcers. Additional randomised studies are required to confirm these findings. DECLARATION OF INTEREST: The authors have no conflicts of interest.

Controlled human infection trials: Legitimacy and conditions of implementation in France.

This round table is the result of an observation. The observation being that controlled human infection clinical trials (also called "infectious challenge" trials or "Controlled Human Infection Models", "CHIM") recommended or even encouraged in the context of vaccine developments in particular, are not carried out in France. However, there are no formal prohibitions within regulations or ethical principles, which point to the prior assessment of risks and benefits for individuals and for society. The participants in this Round Table thus wished to examine, through the prism of their respective disciplines, the scientific and medical relevance of conducting such trials in France and, if possible, to imagine the conditions under which they would be carried out, thus resulting in recommendations on (1) the advisability of their conduct in France (2), the conditions under which they would be implemented in terms of logistics and regulations, and (3) their social acceptability. The recommendations on which the participants of the Round Table came to an agreement are presented as the analysis progresses.

The Christmas adverse event syndrome: An analysis of the WHO pharmacovigilance database.

OBJECTIVES: We hypothesized that during the Christmas season the safety profile and the toxicity of some drugs may be exacerbated. We therefore assessed and characterized changes in drug safety profiles over the Christmas period. DESIGN: We performed a retrospective longitudinal analysis of adverse events reported in the World Health Organization (WHO) pharmacovigilance database between April 1st 2017 to March 31th 2023. SETTING: We extracted cases reported by the 5 main contributors' countries of the WHO pharmacovigilance database with a Christmas tradition: USA, France, Germany, Italy and UK. PARTICIPANTS: We analyzed 4,999,459 individual case safety reports from USA (n=3,498,961), France (n=419,018), Germany (n=398,763), Italy (n=251,641) and UK (n=431,076), reported between April 1st 2017 to March 31th 2023. MAIN OUTCOME MEASURES: Monthly reports of adverse events were analyzed. Time trend, seasonal effect a Christmas effect (December-January) were explored. RESULTS: We found 91 adverse events significantly more frequently reported during the Christmas period, independently after controlling for winter effect and general tendency. The main type of adverse events were psychiatric disorders, infections and skin and subcutaneous disorders. The highest numbers of attributable cases to Christmas were found for drug dependence, emotional distress, and drug withdrawal syndrome. The most involved drugs were oxycodone in psychiatric disorders (n=47,527), docetaxel in skin disorders (n=9440) and social circumstances (n=1940), olmesartan in gastrointestinal disorders (n=1263), fentanyl in cardiac disorders (n=929), adalimumab in infections (n=11,316) and immune system disorders (n=3781), and collagenase clostridium histolyticum in reproductive system disorders (n=318). CONCLUSIONS: Our study shows that a range of drugs adverse events are more frequently reported at Christmas compared to other periods of the year, notably psychiatric disorders, infections, and skin disorders.

Use of Bisphosphonates and the Risk of Skin Ulcer: A National Cohort Study Using Data from the French Health Care Claims Database.

INTRODUCTION: Previous pre-clinical and pharmacovigilance disproportionality analyses highlighted a safety signal of cutaneous ulcer with bisphosphonate use. Therefore, our objective is to evaluate this risk and assess whether unmeasured confounding factors could explain this association. METHODS: This study is a population-based cohort study from a representative sample (1/97th) of the French health insurance claims database: Echantillon Généraliste des Bénéficiaires (EGB) from 2006 to 2019. To limit the impact of our study design and methodological choices on any association between skin ulceration and exposure to bisphosphonates, we used several methods: a Cox proportional hazards analysis and a prior event rate ratio (PERR) analysis, using two propensity matched control groups, and either the first episode of incident ulceration or multiple event-time outcomes. RESULTS: There were 7402 individuals newly exposed to bisphosphonates matched to 29,605 unexposed individuals on propensity score. The primary outcome was skin ulcer occurrence assessed by at least 2 deliveries of wound dressing during the period of one month. Among 6911 individuals newly exposed to bisphosphonates and 28,072 unexposed individuals with no previous skin ulcer, the Cox regression yielded a hazard ratio (HR) of 1.40 (95% CI 1.26-1.56) for newly exposed individuals. Among 7402 exposed and 29,605 unexposed individuals, the PERR analysis found a non-significant HR of 1.03 (95% CI 0.87-1.24). Results were similar on the different sensitivity analyses. CONCLUSION: No association between bisphosphonate and skin ulcers was found in the French population. The association observed in previous pharmacovigilance studies and in the Cox regression analysis is likely due to unmeasured confounding factors.

Assessment of digital perfusion as a surrogate outcome in Raynaud's phenomenon clinical trials.

OBJECTIVES: Measurement of digital perfusion, sometimes coupled with a cold challenge, has been widely used as an objective outcome in trials evaluating drug therapies in Raynaud's Phenomenon (RP), in addition to patient-reported outcomes or to establish the proof-of-concept in preliminary studies. However, whether digital perfusion is a valid surrogate for clinical outcomes in RP trials has never been explored. The principal aim of this study was to evaluate the potential surrogacy of digital perfusion, by combining individual-level and trial-level data. METHODS: We used individual data from a series of n-of-1 trials, and trial data from a network meta-analysis. We estimated individual-level surrogacy through coefficients of determination between digital perfusion and clinical outcomes (R2ind). We further calculated the coefficients of determination between treatment effect on the clinical outcomes and on digital perfusion, at the individual level (R2TEInd) and at the trial level (R2trial), using non-weighted linear regression, with their 95% CI calculated through bootstrapping. RESULTS: Results from 33 patients and 24 trials were included in the final analysis. At the individual level, there was no correlation between digital perfusion and clinical outcomes at rest and in response to various cooling tests (the highest R2ind was 0.03 [-0.07; 0.09]), and R2TEinf was also very low 0.07 [0; 0.29]. At the trial level, the highest value of R2trial was 0.1 [0; 0.477]. CONCLUSIONS: Digital perfusion, at rest or in response to a cold challenge, and whatever the method used, does not fulfill the criteria of a valid surrogate for existing patient-reported outcomes in RP trials.

Exploring the feelings of being at risk of vaccine related adverse effects: A cross-sectional survey in France.

OBJECTIVES: The literature on vaccine hesitancy has widely commented on the various factors leading some to feel particularly at risk of disease infection while others do not. But little attention has been paid to whether we also see such differences regarding people's assessment of their personal vulnerability towards vaccine adverse events (AEs). METHODS: We designed two cross-sectional online surveys among representative samples of the French mainland population (n = 2015 and 3087). We asked participants if they felt, more than others, at risk of severe vaccine related side effects and to explain why. We performed two separate mixed effect binomial regressions models: 1) to explore the link between the feeling of being particularly at risk of severe vaccine related AEs and socio-demographic characteristics, source of information, trust in health agencies and partisan orientation; 2) to explore the link between the fear of side effects and vaccine hesitancy. RESULTS: We found that 15% of respondents felt to be, more than others, at risk of severe vaccine-related adverse events and that this feeling was associated to negative attitudes to vaccines. This feeling was particularly prevalent among women, those with a lower income, lower educational attainment and lower trust in public health institutions. The vast majority of the reasons given by responders are unrelated to genuine risk factors of vaccine related adverse events. CONCLUSIONS: These findings suggest that vaccine hesitancy is at least partly grounded in a feeling of vulnerability towards vaccine adverse events.

Assessment of Reported Adverse Events After Interchanging Between TNF-α Inhibitor Biosimilars in the WHO Pharmacovigilance Database.

BACKGROUND AND OBJECTIVE: Observational studies have shown that a significant proportion of patients interchanging between tumor necrosis factor-α inhibitor biosimilars withdraws from the new treatment because of adverse effects. We aim to analyze adverse events related to interchanging from tumor necrosis factor-α (TNF-α) inhibitor reference products to biosimilars and between biosimilars reported in the World Health Organization pharmacovigilance database. METHODS: We extracted all cases reporting the Medical Dictionary for Regulatory Activities term "Product substitution issue (PT)" for TNF-α inhibitors. Then, we analyzed and categorized all adverse events reported in more than 1% of cases. We compared the adverse events reported according to reporter qualification, type of switch, and type of TNF-α inhibitor using Chi2 tests. We conducted a network analysis coupled with a clustering approach to identify syndromes of co-reported adverse events. RESULTS: In the World Health Organization pharmacovigilance database, 2543 cases and 6807 adverse events related to TNF-α inhibitor interchangeability have been reported up to October 2022. Injection-site reactions were the most reported adverse events with 940 cases (37.0%), followed by modifications in drug effect in 607 cases (23.9%). Musculoskeletal, cutaneous, and gastrointestinal disorders linked to the underlying disease were reported in 505 (20.0%), 145 (5.7%), and 207 (8.1%) cases, respectively. Adverse events non-related to the underlying disease were nonspecific (n = 458, 18.0%), neurologic (n = 224, 8.8%), respiratory (n = 132, 5.2%), and psychological disorders (n = 64, 2.5%). Injection-site reactions and infection-related symptoms (e.g., nasopharyngitis, urinary tract infection, lower respiratory tract infection) were more reported by non-healthcare professionals while adverse events related to reduced clinical efficacy (e.g., drug ineffective, arthralgia, psoriasis) were more reported by healthcare professionals. The proportions of injection-site reactions were higher when switching between biosimilars of the same reference product, but the proportions of adverse events related to reduced clinical efficacy (e.g., psoriasis, arthritis, psoriatic arthropathy) were more reported when switching from a reference product. The main differences in the proportions of reported cases between adalimumab, infliximab, and etanercept were driven by symptoms related to the underlying targeted diseases, except for a higher reporting rate of injection-site pain with adalimumab. Adverse events evocative of hypersensitivity reactions were reported in 192 (7.6%) cases. Most of the network clusters concerned non-specific adverse events or were related to reduced clinical efficacy. CONCLUSIONS: This analysis highlights the burden of patient-reported adverse events when interchanging between TNF-α inhibitor biosimilars, notably injection-site reactions, non-specific adverse events, and symptoms related to reduced clinical efficacy. Our study also highlights differences in reporting patterns between patients and healthcare professionals and depending on the type of switch. The results are limited by missing data, the lack of precision of the coded Medical Dictionary for Regulatory Activities terms, and by the variability of reporting rate of adverse events. Thus, incidence rates of adverse events cannot be inferred from these results.

Investigating the link between drug consumption and adverse events reporting in France.

The objective of this study is to examine the potential association between drug use and adverse event reporting in France. A number of drug users and cases reported were extracted from the French Health Care Insurance database (Open Medic) and the French pharmacovigilance database. We performed two separate mixed-effect models (with a drug used or reporting rate as dependent variables) with a random intercept for drug classes. We selected 62 drugs from 10 drug classes, for which 177 364 cases were reported in the French pharmacovigilance database in 2020. The results showed a strong association between drug users and the number of reported cases in France among each drug class (P < 0.01). Within a drug class, the number of reported cases is, therefore, a proxy for the exposure to a given drug in the population. This finding could be useful to approximate and compare drug exposure from pharmacovigilance databases.

[COVID-19 and adenovirus vaccines: French experience of enhanced pharmacovigilance]. / COVID-19 et vaccins à adénovirus : expérience française de suivi renforcé de pharmacovigilance.

As part of the COVID-19 vaccination campaign, the National Agency for the Safety of Medicines and Health Products and all 31 regional pharmacovigilance centers were mobilized in an exceptional reinforced vaccine pharmacovigilance surveillance system. Concerning adenovirus vaccines, Vaxzévria® and Jcovden®, this national system, based on the daily analysis of notified cases of adverse events, has allowed the early identification of safety signals, some of which have been validated, others still under analysis, common to mRNA vaccines or more specific of adenovirus vaccines such as Vaccine Induced Immune Thrombocytopenia. Complementing european and international actions, this follow-up has contributed to a better definition of the safety profile of these vaccines and has led to redefine the vaccine strategy in our country. Although today these two vaccines have no longer place in the national vaccine strategy, they are still used in other countries, where the experience acquired could be useful and will contribute to fuel the reflection on future therapies involving viral vectors.

Individualized Net Benefit estimation and meta-analysis using generalized pairwise comparisons in N-of-1 trials.

BACKGROUND: The Net Benefit (Δ) is a measure of the benefit-risk balance in clinical trials, based on generalized pairwise comparisons (GPC) using several prioritized outcomes and thresholds of clinical relevance. We extended Δ to N-of-1 trials, with a focus on patient-level and population-level Δ. METHODS: We developed a Δ estimator at the individual level as an extension of the stratum-specific Δ, and at the population-level as an extension of the stratified Δ. We performed a simulation study mimicking PROFIL, a series of 38 N-of-1 trials testing sildenafil in Raynaud's phenomenon, to assess the power for such an analysis with realistic data. We then reanalyzed PROFIL using GPC. This reanalysis was finally interpreted in the context of the main analysis of PROFIL which used Bayesian individual probabilities of efficacy. RESULTS: Simulations under the null showed good size of the test for both individual and population levels. The test lacked power when being simulated from the true PROFIL data, even when increasing the number of repetitions up to 140 days per patient. PROFIL individual-level estimated Δ were well correlated with the probabilities of efficacy from the Bayesian analysis while showing similarly wide confidence intervals. Population-level estimated Δ was not significantly different from zero, consistently with the previous Bayesian analysis. CONCLUSION: GPC can be used to estimate individual Δ which can then be aggregated in a meta-analytic way in N-of-1 trials. GPC ability to easily incorporate patient preferences allow for more personalized treatment evaluation, while needing much less computing time than Bayesian modeling.

Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis.

OBJECTIVES: To mine the serum proteome of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and to detect biomarkers that may assist in earlier and more effective diagnosis and treatment. METHODS: Patients with limited cutaneous SSc, no extensive interstitial lung disease and no PAH-specific therapy were included. They were classified as cases if they had PAH confirmed by right heart catheterisation (RHC) and serum collected on the same day as RHC; and as controls if they had no clinical evidence of PAH. RESULTS: Patients were mostly middle-aged females with anticentromere-associated SSc. Among 1129 proteins assessed by a high-throughput proteomic assay (SOMAscan), only 2 were differentially expressed and correlated significantly with pulmonary vascular resistance (PVR) in SSc-PAH patients (n=15): chemerin (ρ=0.62, p=0.01) and SET (ρ=0.62, p=0.01). To validate these results, serum levels of chemerin were measured by ELISA in an independent cohort. Chemerin levels were confirmed to be significantly higher (p=0.01) and correlate with PVR (ρ=0.42, p=0.04) in SSc-PAH patients (n=24). Chemerin mRNA expression was detected in fibroblasts, pulmonary artery smooth muscle cells (PA-SMCs)/pericytes and mesothelial cells in SSc-PAH lungs by single-cell RNA-sequencing. Confocal immunofluorescence revealed increased expression of a chemerin receptor, CMKLR1, on SSc-PAH PA-SMCs. SSc-PAH serum seemed to induce higher PA-SMC proliferation than serum from SSc patients without PAH. This difference appeared neutralised when adding the CMKLR1 inhibitor α-NETA. CONCLUSION: Chemerin seems an interesting surrogate biomarker for PVR in SSc-PAH. Increased chemerin serum levels and CMKLR1 expression by PA-SMCs may contribute to SSc-PAH pathogenesis by inducing PA-SMC proliferation.

Mouse models of diabetes-related ulcers: a systematic review and network meta-analysis.

BACKGROUND: Diabetic foot ulcers (DFUs) are a common complication of diabetes, associated with important morbidity. Appropriate animal models of DFUs may improve drug development, and subsequently the success rate of clinical trials. However, while many models have been proposed, they are extremely heterogeneous, and no standard has emerged. We thus propose a systematic review with a network meta-analysis (NMA) to gather direct and indirect evidence, and compare the different mouse models of diabetes-related ulcers. METHODS: The systematic search was performed in Pubmed and Embase. The main outcomes were wound size measurement at days 3, 7, 11 and 15 (±1 day). The risk of bias and methodological quality of all included studies was assessed by using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool. Meta-regressions were done on prespecified variables, including mouse strain, type of ulcer, sex, age, and use of a splint. FINDINGS: We included 295 studies. Among all models, only db/db, ob/ob, streptozotocin (STZ), and STZ + high fat diet mice showed a significantly delayed wound healing, compared with controls, at each time point. Age, sex and ulcer type had influence on wound healing, although not at all time points. INTERPRETATION: In conclusion, the db/db model is associated with the largest delay in wound healing The STZ model also exhibits significantly decreased wound healing. STZ + high fat diet and ob/ob mice may also be relevant models of diabetes-related ulcers, although the results rely on a more limited number of studies. FUNDING: This work was funded by the Agence Nationale de la Recherche (grant ANR-18-CE17-0017).

JAK inhibitors and risk of major cardiovascular events or venous thromboembolism: a self-controlled case series study.

PURPOSE: JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE. METHODS: A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized. RESULTS: Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1-75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5-9.2] for VTE and 6.1 months [IQR: 3.0-8.5] for ATE. An IRR of 8.27 (95% CI 3.41-20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02-21.11]). An IRR of 9.27 (3.68-23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27-31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE. CONCLUSIONS: This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib.

Placebo response in Raynaud's Phenomenon clinical trials: The prominent role of regression towards the mean: Placebo response in Raynaud's Phenomenon.

BACKGROUND: Substantial placebo response has been observed in trials assessing treatments in Raynaud's Phenomenon (RP), which makes any treatment effect difficult to detect. However, whether this response is due to a real placebo effect or to other nonspecific effects, such as regression towards the mean (RTM), has not been explored. Our objectives were to explore and quantify placebo response in RP, and to evaluate the magnitude of RTM contribution. METHODS: We combined trial-level and individual-level data from a series of n-of-1 trials and a network meta-analysis, respectively. Main outcomes were the daily frequency and the mean duration of RP attacks, as well as the Raynaud's Condition Score (RCS). We estimated the placebo response by the mean difference between the placebo period (or arm) and the baseline. RTM was estimated by the relationship between placebo response and baseline, and with Galton squeeze plots. Finally, we simulated the effect of the threshold used for inclusion in clinical trials on RTM. FINDINGS: We observed a large and significant placebo response from both individual and trial data for RCS [-1.20 (-1.63, -0.77) and -0.65 (-0.89, -0.41)] and the daily frequency of RP [-0.61 (-0.85, -0.37) and -0.75 (-0.95, -0.54)]. Outcome at baseline was significantly associated with placebo response, suggesting the presence of RTM. The latter was confirmed on individual data, through Galton squeeze plots. INTERPRETATION: Placebo response is large in RP trials, and likely due to regression towards the mean rather than 'true' placebo effect. This should be carefully considered when designing future trials. FUNDING: This work has been partially supported by MIAI @ Grenoble Alpes (ANR-19-P3IA-0003).