Off-label use of rituximab in patients with systemic lupus erythematosus with extrarenal disease activity: a retrospective study and literature review.

Introduction: Off-label rituximab is commonly used for patients with systemic lupus erythematosus (SLE) with extrarenal disease activity. Methods: The outcomes and tolerability of rituximab in adult patients with non-renal SLE treated at our hospital from 2013 to 2020 were described. Patients were followed-up until December 2021. Data were retrieved from electronic medical records. Response was classified into complete, partial or no response according to the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2 K)-based definitions. Results: A total of 44 cycles were administered to 33 patients. Median age was 45 years and 97% were female. Median follow-up was 5.9 years (IQR 3.7-7.2). The most frequent symptoms that motivated rituximab use were thrombocytopenia (30.3%), arthritis (30.3%), neurological manifestations (24.2%) and cutaneous lupus (15.2%). After most treatment cycles a partial remission was achieved. The median SLEDAI-2 K score declined from 9 (IQR 5-13) to 1.5 (IQR 0-4) (p < 0.00001). The median number of flares significantly declined after receiving rituximab. Platelet counts significantly improved in patients with thrombocytopenia and patients with skin disorders or neurological manifestations also had a partial or complete response. Only 50% of patients with a predominant joint involvement had either a complete or a partial response. The median time to relapse after the first cycle was 1.6 years (95% CI, 0.6-3.1). Anti-dsDNA levels decreased significantly after rituximab from a median of 64.3 (IQR 12-373.9) to 32.7 (IQR 10-173), p = 0.00338. The most frequent adverse events were infusion-related reactions (18.2%) and infections (57.6%). All patients needed further treatment to maintain remission or to treat new flares. Conclusion: A partial or complete response was documented after most rituximab cycles in patients with non-renal SLE. Patients with thrombocytopenia, neurolupus, and cutaneous lupus had better response than those with a predominant joint involvement.

Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial.

Background: A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration. Methods: The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with ClinicalTrials.gov, NCT05142553. Findings: From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4+ and CD8+ T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19. Interpretation: Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe. Funding: HIPRA SCIENTIFIC, S.L.U.

European association for clinical pharmacology and therapeutics young clinical pharmacologists working group: a cornerstone for the brighter future of clinical pharmacology.

The European Association for Clinical Pharmacology and Therapeutics (EACPT) is a leading society in Europe serving the European and global Clinical Pharmacology and Therapeutics community. Its specific aims include promotion of the utilisation and divulgation of the utility of clinical pharmacology services in health care delivery. EACPT currently has four active working groups (WGs): Education, Regulatory affairs, Clinical research and Young Clinical Pharmacologists (YCP WG). EACPT YCP WG was established in 2015 with the idea of improving education, research, training and networking/mobility opportunities for YCPs across Europe and globe. The main objective of the present manuscript is to provide detailed information on general characteristics, structure, chronogram, objectives, accomplishments and current/future focus areas of the EACPT YCP WG. Consequently, we tend to notably enhance EACPT YCP WG's visibility, increase the number of its members and mobility/networking options and to expand areas of activity even more. Moreover, by this we can also make clinical pharmacology more attractive to early career fellows and colleagues and empower its position alongside other medical specialties.

Off-Label Use of Rituximab in Patients with Different Types of Nephropathies in a Tertiary Hospital: A Retrospective Study.

Off-label use of rituximab is commonly requested for patients with resistant nephropathies. The outcomes and tolerability of rituximab in adult patients with nephropathy treated at our hospital (from 2013 to 2018) were described. Data were retrieved from electronic medical records. Response was classified as complete remission (CR), partial remission (PR), or no response (NR) according to the KDIGO criteria. A total of 89 requests were received for 61 patients. Median age was 58 years (45.9% female). Idiopathic membranous nephropathy (MN) (n = 30) was the most frequent indication, followed by minimal change disease (MCD) (n = 15) and secondary membranoproliferative glomerulonephritis (MPGN) (n = 12). Three patients with focal segmental glomerulosclerosis (FSGS) were included. After most treatment cycles in MN, a CR or PR was observed; median proteinuria levels significantly decreased for these patients (6000 mg/24h (IQR 3584-10,300) vs. 1468.8 (IQR 500-4604.25), p < 0.01). In MPGN, no response was documented after 46.7% of rituximab cycles. A CR or PR was described with the majority of rituximab cycles in MCD, with a significant decrease in proteinuria (6000 mg/24 h (IQR 4007-11,426) vs. 196.8 (IQR 100-1300), p = 0.013). No cycles produced a response in FSGS. Mean CD19+ B-cell decreased in all types of nephropathy (10.44% vs. 0.29%, p < 0.0001). Eleven patients presented infusion-related reactions, and 17 presented infectious complications. The majority of patients with MN and MCD had complete or partial responses; however, neither MPGN nor FSGS had encouraging results.

Establishing and Evaluating a Study Questionnaire on Knowledge and Attitudes of Healthcare Professionals Towards Recreational and Medical Cannabis Across Europe.

BACKGROUND AND OBJECTIVE: The present survey was a preliminary to a European research project on the attitude and knowledge of healthcare professionals towards the use of medical cannabis. The objective was to evaluate the readability, understandability, and relevance of a first version of the study questionnaire before preparing the finalized questionnaire, which will be subsequently proposed to European healthcare professionals on a large scale. METHODS: A cross-sectional study was conducted between December 2019 and May 2020. We established an electronic evaluation questionnaire relating to the study questionnaire. This evaluation questionnaire was proposed to multidisciplinary experts from all over Europe. Feedback from the evaluation questionnaire was considered for improving and finalizing the study questionnaire. RESULTS: 66 evaluation questionnaires were collected from nine European countries (Cyprus, France, Germany, Italy, Lithuania, Portugal, Spain, Sweden, United Kingdom), which corresponded to a participation rate of 41.5%. Most participants were women (65.2%, n = 43). The mean age was 39.5 years ± 11.6. Each participant could specify several occupations. There were 25 pharmacologists, 24 physicians, ten pharmacists, four university teachers, three epidemiologists or public health experts, one nurse, one biotechnologist, one microbiologist, and one police researcher. Overall, 84.8% of participants were interested in the topic of the survey on the knowledge and attitudes of healthcare professionals towards recreational and medical cannabis across Europe. Participants were satisfied with all but six of the proposed questions. In addition, two additional questions were subject for comments despite a high level of satisfaction. Consequently, the concerned questions (n = 8) were modified. CONCLUSION: This evaluation survey was a necessary step to improve the quality of the future research project. The positive feedback encourages the authors to proceed with the project on a European scale, scheduled for 2021.

COVID-19 in Solid Organ Transplantation: A Matched Retrospective Cohort Study and Evaluation of Immunosuppression Management.

BACKGROUND: The epidemiological and clinical characteristics of solid organ transplant (SOT) patients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic remains unclear. We conducted a matched retrospective cohort study to compare clinical outcomes among SOT recipients with the general population and to assess immunosuppression management. METHODS: Adult SOT recipients with laboratory polymerase chain reaction-confirmed SARS-CoV-2 infection admitted to a tertiary-care hospital in Barcelona, Spain, from March 11 to April 25, 2020, were matched to controls (1:4) on the basis of sex, age, and age-adjusted Charlson's Index. Patients were followed for up to 28 days from admission or until censored. Primary endpoint was mortality at 28 days. Secondary endpoints included admission to the intensive care unit and secondary complications. Drug-drug interactions (DDI) between immunosuppressants and coronavirus disease 2019 (COVID-19) management medication were collected. RESULTS: Forty-six transplant recipients and 166 control patients were included. Mean (SD) age of transplant recipients and controls was 62.7 (12.6) and 66.0 (12.7) years, 33 (71.7%) and 122 (73.5%) were male, and median (interquartile range) Charlson's Index was 5 (3-7) and 4 (2-7), respectively. Mortality was 37.0% in SOT recipients and 22.9% in controls (P = 0.51). Thirty-three (71.7%) patients underwent transitory discontinuation of immunosuppressants due to potential or confirmed DDI. CONCLUSIONS: In conclusion, hospitalized SOT recipients with COVID-19 had a trend toward higher mortality compared with controls, although it was not statistically significant, and a notable propensity for DDI.