Jean-Luc Cracowski

Background: Treatment of Raynaud phenomenon(RP) with oral vasodilators(calcium channel blockers and phosphodiesterase type 5 inhibitors) has shown moderate efficacy, may not benefit to all patients, and adverse effects often compromise long-term treatment. In addition, a large placebo effect may jeopardize the assessment of treatment benefits. Pharmaconutritional strategies aiming at increasing nitric oxide bioavailability (beetroot juice and L-citrulline) may be promising alternatives, and we further hypothesized that patient preference for a treatment could be a driver of the response. Methods: This study consisted of a series of randomized, double-blind, N-of-1 trials conducted in outpatients with primary or secondary RP. Each patient underwent a multiple crossover design with repeated blocks of randomized treatments periods: 2 weeks of placebo, 2 weeks of active treatments, and 1 week of washout. Outcomes included the Raynaud Condition Score(RCS), frequency and daily duration of attacks. Each patient prespecified its preferred primary outcome, efficacy threshold and preferred treatment, which was used for stratified randomization. Generalized linear mixed-effects models were used to determine individual and aggregated efficacy. Results: Twenty-one patients completed 2 to 8 treatment blocks. Seventeen patients tested L-citrulline, 17 beetroot juice and 13 both treatments. Ten patients selected RCS as a primary outcome, 6 patients the number of attacks and 5 the duration of attacks. Median threshold for considering treatment efficacy chosen by patients was 50% (min-max 20% to 75%) reduction of symptoms. Using individual criteria to define efficacy neither L-citrulline nor beetroot juice showed significant efficacy compared to baseline. Based on the aggregated data, our results show no significant difference between L-citrulline and the L-citrulline-based placebo, nor between beetroot juice and nitrate-depleted beetroot juice, with the exception of the daily duration of RP attacks with beetroot juice (p=0.002). Finally, there was a marked placebo response, notably when patients received their preferred treatment. Conclusions: Our study did not show significant beetroot juice or L-citrulline efficacy in RP. However, we found that individual preference for one treatment over another maximizes responses to both placebo and active treatments, particularly with regard to the frequency and duration of RP attacks, thus suggesting that a real and modifiable placebo effect exists in RP. Trial registration: NCT03749577 Funding: Primary Funding Source: Grenoble Alpes University Hospital & Association des Sclérodermiques de France (academic funding).

BACKGROUND: BCR-ABL (fusion between the Abelson [Abl] tyrosine kinase gene at chromosome 9 and the break point cluster [Bcr] gene at chromosome 22) tyrosine kinase inhibitors (TKIs) have been increasingly linked to pulmonary arterial hypertension (PAH) since 2009, although supporting evidence is limited. Our objective was to evaluate the risk of PAH associated with second- and third-generation BCR-ABL TKIs compared with imatinib in adults. METHODS: We employed a prevalent new-user design that emulates a randomized trial within the French national health care database population between 2008 and 2024. Thus, subjects initiating a second- and third-generation BCR-ABL TKI were matched on time and propensity score with users of the first-generation BCR-ABL TKI, imatinib. Patients were followed to occurrence of the primary outcome (ie, new onset of PAH), switch to another BCR-ABL TKI, death from any cause, end of registration within the database, or end of the study period, whichever came first. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression models, and incidence rates and corresponding 95% CIs were calculated using the Poisson distribution. RESULTS: Six thousand six hundred twenty-five dasatinib (age 59.7±15.2 years, 44.0% women), 5205 nilotinib (age 55.4±15.0 years, 44.2% women), 2421 bosutinib (age 63.8±14.2 years, 42.1% women),1358 ponatinib (age 57.3±14.9 years, 46.1% women), and 922 asciminib (age 64.3±13.8 years, 43.7% female) new users were each matched with the maximum of available imatinib users on time-conditional propensity score and on duration of prior imatinib use (prevalent users). Dasatinib use was associated with a 9-fold increased risk of PAH compared with imatinib (1829 versus 43 events per million persons per year; HR=8.89 [95% CI, 5.30–14.92]). Bosutinib and ponatinib were associated with HRs of 10.76 (95% CI, 4.68–24.73) and 7.74 (95% CI, 2.33–25.70) respectively, with most cases occurring in patients previously exposed to dasatinib. Nilotinib and asciminib were not associated with an increased risk of PAH. CONCLUSIONS: This study, designed to emulate a randomized trial, suggests that, in French patients with chronic myeloid leukemia treated with BCR-ABL TKIs, dasatinib use is associated with a higher risk of PAH compared with imatinib, while bosutinib and ponatinib exposure may aggravate or trigger a recurrence of PAH in patients with preexisting dasatinib exposure. Whether bosutinib and ponatinib could induce PAH without preexposure to dasatinib remains to be explored.

L’efficacité des médicaments est évaluée par les essais cliniques. Cependant, ceux-ci ne sont pas conçus pour identifier les effets indésirables, en particulier lorsqu’ils sont rares. Ceci justifie un système robuste de pharmacovigilance, pour les évaluer après la commercialisation des médicaments, complété au besoin par des études pharmacoépidémiologiques. Les bénéfices des médicaments s’expriment en valeur relative ou absolue, et varient en fonction du risque associé à la maladie (sa sévérité, son risque de complications ou de progression) et de son incidence pour le bénéfice populationnel. Ce n’est pas le cas des effets indésirables, qui dépendent des caractéristiques intrinsèques du médicament et de la population traitée. Dans ce contexte, peut-on réellement mettre en balance les avantages et les risques des médicaments ? L’expérience de la Covid-19 illustre la complexité de cette notion. Elle met clairement en évidence la nécessité d’une analyse conjointe des essais cliniques, du suivi de pharmacovigilance, des études pharmacoépidémiologiques et de la détection des interactions médicamenteuses potentielles. Enfin, l’acculturation du grand public à l’évaluation de l’efficacité et de la sécurité des médicaments est indispensable pour permettre à chacun d’interpréter correctement cette notion complexe de balance bénéfices-risques, d’éviter les simplifications, et de lutter contre la désinformation.

Background: Statin‐induced liver injury is frequent and usually not severe. The aim of the present study was to describe the safety of statin rechallenge after atorvastatin‐induced liver injury because it is poorly documented. Methods: Cases of liver injury involving atorvastatin were selected from the French pharmacovigilance database. Inclusion criteria were a documented atorvastatin or any other statin reintroduction and an available follow‐up of at least 2 weeks to define negative rechallenge. Results: Twenty‐six cases of atorvastatin liver injury with further statin reintroduction met our criteria. Median time to onset (TTO) of the first episode was 27 days (IQR: 4–43), with a cholestatic pattern in 11 (42.3%) cases, cytolytic in nine (34.6%), and mixed in six (23.1%); severity ranked Grade 2 in 11 (42.3%). Atorvastatin rechallenge was positive in 12 of 16 patients with the same dose (11 of 13) or a reduced dose (1 of 3), and the TTO was shorter (median 11 days). Rechallenge with an alternative statin was performed in 10 patients, of whom two experienced recurrence with rosuvastatin and simvastatin. No recurrence was observed after rechallenge of rosuvastatin in five, pravastatin in two, and simvastatin in one. Conclusion: Our study evidenced frequent recurrence of drug‐induced liver injury after atorvastatin rechallenge, whereas subsequent administration of a hydrophilic statin was well tolerated. By combining our data and published cases, we suggest that rosuvastatin or pravastatin carries the lowest risk of recurrence. Study limitations include a focus solely on atorvastatin, a retrospective design, and potential underreporting to the pharmacovigilance system.

Systemic sclerosis (SSc) is a complex connective tissue disease characterized by excessive extracellular matrix deposition and endothelial dysfunction leading to skin fibrosis and vascular complications. To investigate the contribution of fibroblasts to SSc-associated vasculopathy, we generated 3D vascularized skin organoids incorporating patient-derived fibroblasts and healthy endothelial cells. Comparative analyses revealed that SSc fibroblasts alone induce microvascular alterations, including giant capillaries and early fibrotic responses at the secretome level. These findings demonstrate that fibroblasts are a central driver of vascular remodeling in SSc and highlight their key crosstalk with endothelial cells. This SSc-specific organoid model offers a valuable platform for studying disease mechanisms and therapeutic interventions without relying on animal models.

Background: Diabetic foot ulcers (DFUs) represent a serious public health problem associated with significant morbidity and health costs. Despite optimal etiologic treatment and local care, amputation is frequent, stressing the need for new treatments. The benefit of systemic administration of vasodilators, such as prostacyclin analogues, has proven efficacy in other types of skin ulcers, but it is counterbalanced by potentially serious vasodilation‐induced, concentration‐dependent, adverse effects. Experimental data has shown the feasibility of local administration of treprostinil on the wound using iontophoresis. Objective: We aimed to assess the safety of the local iontophoretic administration of treprostinil in patients with DFU through a single ascending dose safety study. Methods: We conducted a prospective single ascending dose phase I study. Patients received a single dose of treprostinil applied via iontophoresis at a current density of 0.2 mA/cm ² for 30 min. Local and systemic adverse effects were monitored, and plasma treprostinil concentrations were measured over an 8‐h follow‐up period. Results: Four patients were included, and received single doses of 0.025, 0.05, 0.1, and 0.25 mg/L at 0.2 mA/cm ² during 30 min, and were followed‐up for 8 h. All patients did not present any significant adverse effect. Plasma concentration was below < 1.8 ng/mL 8 h after the administration. Conclusions: Our results suggest that iontophoresis of treprostinil is a safe procedure at 0.25 mg/mL, without systemic adverse effect, suggesting its potential as a targeted treatment for DFUs.

Objectives: To evaluate whether patients with systemic lupus erythematosus (SLE) have different nailfold videocapillaroscopy (NVC) findings compared with healthy controls (HCs) and whether there is an association between NVC abnormalities and disease activity, clinical and/or laboratory features in SLE. Methods: This is an observational, multicentre, international, matched case–control study. 381 subjects (203 patients with SLE and 178 HCs) were enrolled from 16 centres in 10 countries. Clinical and laboratory data were collected using ad hoc forms. 5861 NVC images were acquired, coded and uploaded for central blinded analysis. Results: A normal NVC pattern was observed in most patients with SLE (86.6%) and, a significantly higher frequency of NVC abnormalities such as enlarged and giant capillaries, microhaemorrhages and irregular nail bed architecture (p<0.001) were found in the remaining patients. Multiple correspondence analysis outlined two NVC patterns, one of which, the more severe (cluster 2), present in 12% of patients, was characterised by a higher prevalence of lower capillary density, abnormally shaped and enlarged capillaries and irregular nail bed architecture. NVC cluster 2 had significantly higher disease activity compared with cluster 1 for both Systemic Lupus Erythematosus Disease Activity Index cut-off points ≥3 and ≥4 (p=0.016 and p=0.028, respectively). SLE with ‘more severe’ NVC pattern (cluster 2) have a significantly higher frequency of arthritis, renal involvement and ongoing glucocorticoid therapy, whereas serositis was significantly associated with ‘less severe’ NVC pattern (cluster 1). Conclusions: This study has shown that changes in NVC patterns are associated with important aspects of SLE disease activity. Future prospective studies are needed to further support the use of NVC in SLE monitoring. Trial registration number: NCT02801812.

Introduction: Drug efficacy and effectiveness are assessed respectively through clinical trials and pharmaco-epidemiological studies. However, relative and absolute benefits of drugs are distinct measures that must be considered in relation to the baseline risk of disease incidence, complication or progression. On the other hand, adverse drug reactions are independent of the basic risk but depend on the characteristics of the population treated. Given these prerequisites, how can we balance the benefits and risks of drugs? Areas covered: We use the example of therapeutics evaluated during Covid to describe how assessing the benefit-risk balance of drugs is a complex process. Expert opinion: Clinical trials are not designed to identify rare adverse events, underscoring the necessity for a pharmacovigilance system. Evaluating the balance between the benefits and risks of drugs is an ongoing process, demanding the simultaneous analysis of data from clinical trials, potential drug-drug interactions, pharmacovigilance monitoring and pharmaco-epidemiological studies, to identify potential safety concerns. In addition, pharmacologists must play a major role in educating the general public about drugs, aiding in the accurate interpretation of the benefit-risk balance and preventing misinformation.