Main Cause Of Discontinuation Research Articles

Incidence and factors associated with PrEP discontinuation in France.

HIV pre-exposure prophylaxis (PrEP) is effective in preventing HIV, but some seroconversions occur due to poor adherence or PrEP discontinuation. Our objective was to estimate the incidence of PrEP discontinuation and describe the reasons and factors associated with discontinuations. A retrospective cohort was conducted in three French hospitals between January 2016 and June 2022. PrEP users who attended at least twice within 6 months during study period were included and followed up until December 2022. The incidence rate of PrEP discontinuation was estimated by censoring lost to follow up individuals. Factors associated with PrEP discontinuations were identified using a multivariate Cox model. A total of 2785 PrEP users were included, with 94% men and 5% transgender people. Median age was 35 years. By December 2022, 653 users had stopped PrEP (24%). The incidence rate was 10.8 PrEP discontinuations for 100 person-years (PY). The main causes of discontinuation were being in a stable relationship (32%), and not judging the treatment useful anymore (12%). Individuals who discontinued PrEP were younger [<29, HR = 1.45 (1.17-1.80)], and more likely to be women [HR = 2.44 (1.50-3.96)] or sex workers [HR = 1.53 (0.96-2.44)]. They were more likely to report PrEP side effects [HR = 2.25 (1.83-2.77)] or ≥2 sexually transmitted infections [HR = 1.87 (1.53-2.27)] during the last year. The incidence of PrEP discontinuations was quite low compared to rates observed in other cohorts. Users who stopped PrEP were sometimes still exposed to HIV, emphasizing the need for targeted interventions to prepare and support PrEP discontinuations and limit seroconversion risk.

Abstract PO1-03-05: Tolerance of adjuvant radiotherapy combined with pembrolizumab for triple negative breast cancer

Abstract BACKGROUND AND PURPOSE: The current standard-of-care management of locally advanced triple negative breast cancer (TNBC) is based on neoadjuvant chemo-immunotherapy with pembrolizumab, surgery, radiotherapy and adjuvant pembrolizumab. However, the safety of combining pembrolizumab with adjuvant breast radiotherapy has never been evaluated. This study evaluated the tolerance profile of concurrent pembrolizumab (P) with adjuvant radiotherapy (RT) in locally advanced TNBC patients. METHODS: This bicentric ambispective study included the first prospectively registered patients with non-metastatic TNBC treated with the KEYNOTE-522 regimen in our institution. They received P in combination with carboplatin and paclitaxel chemotherapy and a second chemotherapy with doxorubicin and cyclophosphamide, followed by surgery and locoregional RT with or without P as adjuvant treatment. RT was normo- or hypofractionated, for the breast or chest wall, with or without lymph node irradiation according to institutional guidelines. Adjuvant P was administered at a total dose of 1800 mg at 200 mg once every 3 weeks or 400 mg once every 6 weeks. The safety profile was evaluated during and after the end of RT (until the last contact) with CTCAE V.5 scale. RESULTS: A total of 55 patients (pts) were prospectively included between July 2021 and March 2023. The median age was 49 years (29-69). The median follow-up was 12 months ( range, 10-26). Of them, 27 (49%) did not receive P concomitantly with RT (RT-only group) because of neo-adjuvant treatment related toxicities, and 28 (51%) received P concomitantly with RT (P-RT group). There was no statistical difference in population and toxicity between the RT-only group and the P-RT group. Nine patients were diagnosed with cardiac toxicities before the beginning of the RT and did not receive P during the RT. No RT-induced grade ≥4 toxicities were observed. Early toxicities were mainly grade 1-2. Two grade 3 toxicities occurred (1 case of axillary pain in the P-RT group and 1 radiodermatitis in the RT-only group). No cardiac or pulmonary toxicities ≥grade 2 were observed with adjuvant therapy. The toxicity profile is given in table 1. DISCUSSION: In these series, the main cause of discontinuation of pembrolizumab was related to suspicion of cardiac adverse events occurring during the neoadjuvant treatment and related to the injection of pembrolizumab or of the chemotherapy. All myocarditis happened before radiotherapy and did not affect the administration of radiotherapy. In this context, the optimal radiotherapy technique and cardiac dose constraints after ICI-induced myocarditis is unknown and late cardiotoxicity studies will be needed to precise these points. Cardiac sparing techniques, such as deep-inspiration breath hold, proton therapy, or alternative positioning (such as isocentric lateral decubitus) could be considered. CONCLUSION: Adjuvant radiotherapy can be combined with pembrolizumab for TNBC patients without increasing the risk of radiation-induced adverse events, allowing maintaining a systemic treatment in these high-risk patients. Longer follow-up and prospective studies are needed to validate these results. Adjuvant treatment-related adverse events Citation Format: Youlia Kirova, Thaïs Tison, Pierre Loap, Emilie ARNAUD, Kim Cao, Solène Bringer, Manon Kissel, Safia Maaradji, Juliette Mainguene, Jean-Yves Pierga, Florence Lerebours, Anne Salomon, Mariana Mirabelle, Delphine Loirat, Francois-Clement Bidard. Tolerance of adjuvant radiotherapy combined with pembrolizumab for triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-05.

Retention rate of biologic and targeted synthetic anti-rheumatic drugs in elderly rheumatoid arthritis patients: data from GISEA registry.

An increased number of elderly individuals affected by rheumatoid arthritis (RA) has been reported, including both patients with RA onset in advanced age and patients aged with the disease. In this registry-based study, we aimed to analyze the retention rate and cause of discontinuation of biologic (b) and targeted synthetic (ts)-disease-modifying anti-rheumatic drugs (DMARDs) in RA patients over 65 year old. RA patients enrolled in the Italian GISEA registry and starting a b- or a ts-DMARD over 65 years of age were included. Demographic, clinical, serologic, and therapeutic features were collected. A total of 1,221 elderly RA patients were analyzed (mean age 71.6 ± 5.2 years). RA was diagnosed before 65 years in 72.5% of cases, a 60.6% of patients experienced a previous b- or ts-DMARD. In patients older than 65 initiating a new b- or ts-DMARDS, tumor necrosis factor alpha inhibitors (TNFi) were prescribed in 29.6% of patients, abatacept in 24.8%, anti-interleukin 6 receptor antagonists (anti-IL6R) in 16.3%, Janus kinases inhibitors (JAKi) in 24.9%, and rituximab in 4.4%. The main causes of discontinuation were primary or secondary inadequate responses (66.1%). The median retention rate for all treatments was 181.3 weeks. A statistically higher retention rate was observed for abatacept when compared to TNFi (p = 0.02), JAKi (p < 0.001), and anti-IL6R (p < 0.001), and for TNFi vs. JAKi (p = 0.013). We described, in a real-life setting, elderly RA patients treated with a biologic or a ts-DMARD in Italy. Loss of efficacy was the main cause of discontinuation, and the DMARD safety profile suggests that age does not contraindicate their use. Our study reinforced that the control of disease activity is mandatory.

Outcomes of CLL Patients Exposed to Venetoclax+/-R after Ibrutinib in France: The Resist Retrospective Study from the Filo-CLL Group

Background: In chronic lymphocytic leukemia (CLL), despite the fact that Bruton tyrosine kinase inhibitors (BTKi) are increasingly used 1st or 2nd line therapy, and the Bcl-2 inhibitor (Bcl-2i) venetoclax +-rituximab (VEN-R) relapses, based on the good results of the MURANO trial (although it did not include BTKi-exposed patients [pts]), multicentric retrospective studies describing the real world outcomes of BTKi exposed pts under Bcl-2i treatment are still lacking. Most of the data published so far, extracted from USA databases, lack granularity to explain which clinical or biological factors define prognosis in the modern therapeutic era of CLL. Here, results of the experience gathered by 10 FiLO-CLL-affiliated centers in France are presented, monitored by physicians in charge of the pts. The RESIST registry assembled outcomes from 150 pts, among whom 117 are presented here as a first efficacy analysis (the complete set of pts will be presented at the congress). Results: Analysis of these 117 pts shows a predominance of men (68%) and a median age of 59 years (29-85). A median of two previous lines of treatment (range 1-5] was given before initiating VEN, with a majority of immunochemotherapy (FCR) in first line and progressive increase of ibrutinib use. As expected, the rate of complete response (CR) decreased over the lines, yet remained over 30%. Intolerance to ibrutinib was the main cause for discontinuation in 27.4%, and 66.7% were refractory or relapsed patients (45% presenting with BTK mutations before VEN, the other patients stopped due to other causes). At the time of VEN treatment (75% VEN-R), 35.3% of the pts had bulky disease, 63% elevated lactate dehydrogenase and 24.8% a bad performans status (3-4). High risk cytogenetic was found in nearly all patients: 63.8% del(17p) and/or TP53 mutation and 94% unmutated IGHV status. The sequence of VEN therapy was terminated as planned for 56.3% of the pts, while it was stopped for progression/relapse in 27.6% and for intolerance in 16.1%. The most common grade ≥ 3 adverse events observed with VEN, reported in 92 pts, were hematological (30.4%), gastro-intestinal (8.7%), infectious (3.3%) and cutaneous (4.4%). Tumor lysis syndrome during the ramp-up phase was infrequent (grade 1 = 8.4%, grade 2 = 1.9% and grade 3 = 0.9%). At the time of analysis, the best response was CR for 69% of the pts (CR+Cri+PR: 95%). MRD assessment was done in 52 pts, 50% of which obtained MRD undetectable responses. With a median follow-up of 37.7 months (mo; 95% confidence interval [CI] 32.7-40.1), 27.6% of the pts had progressed. The mPFS is 35.9 mo (95%CI 29.8-53), mOS 59.4 mo (95%CI 44-Not Reached) and median time to next treatment (TNTT) 45.9 mo (95%CI 31.7-58.8), while in the 7-year update of the VenR arm of the MURANO trial the latter outcomes were much higher (54.7 mo, not reached, and 63 mo respectively). On univariate and multivariate analyses, only TP53 mutations tended to be significantly associated with worse PFS (HR = 1.83 [0.99; 3.38], p=0.05) and OS (HR = 2.11 [0.91; 4.86], p=0.07). A total of 44 patients relapsed after VEN, with a median time to next treatment-2 of 18.0 mo (95%CI 5.5-21.1). The updated results of this subset of patients will be presented at the congress. Conclusion: Although slightly improved as compared to other real-life series in Italy or in the US, these data indicate that VEN or VEN+R after progression, relapse or intolerance to BTKi is moderately efficient with only about 35.9 months median PFS (in spite of undetectable MRD in 26/52 available patients). TP53 abnormalities were confirmed to be an important risk factor, yet not BTK mutations, or. This work is important to help designing clinical trials aiming at improving the outcomes with next generation BTKi/Bcl-2i, or even CAR-T cells.

Temporal evolution of antiretroviral therapy (2017-2021): analysis of treatment change and its economic impact

To analyze the modifications of antiretroviral therapy (ART) and their economic impact on daily clinical practice. Observational, retrospective study of patients who started ART between 01/2017-12/2021 (follow-up until 12/2022). Variables collected: prescribed ART, duration, the reason for the change, and treatment costs. A total of 280 patients initiated ART therapy. The median durability of 1st line was: 19.9 months in 2017 (95%CI 13.9-25.9), 12.2 months in 2018 (95%CI 4.7-19.7), 27.4 months in 2019 (95%CI 6.8-48.1) and the median was not reached for the years 2020 and 2021 (p<0.001). Triple therapy with protease inhibitors was changed in 63.8% (81/127) of cases, followed by integrase inhibitors 52.1% (159/305), while dual therapy (DTG/3TC) only in 8.3% (7/84). The main cause of discontinuation was simplification/optimization 47.5% (124/261), followed by adverse effects 21.8% (57/261), with 2017 being the only year where simplification/optimization was at the same level as adverse effects. The economic impact of ART changes resulted in an average cost reduction of 34.0€ [-391.4 to +431.4] per month per patient. The year 2019 stands out as the only year where these changes were associated with an increase in mean additional cost (23.4€ [-358.3 to +431.4]). Optimization/simplification accounts for almost half of the reasons for TAR change, with an economic impact that, despite the inflection point of 2019, each year manages to exceed the previous one, achieving a progressive cost reduction maintained over time.

Current Insights into Cellular Determinants of Peritoneal Fibrosis in Peritoneal Dialysis: A Narrative Review

Peritoneal fibrosis is the final process of progressive changes in the peritoneal membrane due to chronic inflammation and infection. It is one of the main causes of discontinuation of peritoneal dialysis (PD), apart from peritonitis and cardiovascular complications. Over time, morphological changes occur in the peritoneal membranes of patients who use PD. Of those are mesothelial-to-mesenchymal transition (MMT), neoangiogenesis, sub-mesothelial fibrosis, and hyalinizing vasculopathy. Several key molecules are involved in the complex pathophysiology of peritoneal fibrosis, including advanced glycosylation end products (AGEs), transforming growth factor beta (TGF-β), and vascular endothelial growth factor (VEGF). This narrative review will first discuss the physiology of the peritoneum and PD. Next, the multifaceted pathophysiology of peritoneal fibrosis, including the effects of hyperglycemia and diabetes mellitus on the peritoneal membrane, and the promising biomarkers of peritoneal fibrosis will be reviewed. Finally, the current and future management of peritoneal fibrosis will be discussed, including the potential benefits of new-generation glucose-lowering medications to prevent or slow down the progression of peritoneal fibrosis.

Natalizumab treatment of multiple sclerosis - a Danish nationwide study with 13 years of follow-up.

Natalizumab is a widely used high-efficacy treatment in multiple sclerosis (MS). Real-world evidence regarding long-term effectiveness and safety is warranted. We performed a nationwide study evaluating prescription patterns, effectiveness, and adverse events. A nationwide cohort study using the Danish MS Registry. Patients initiating natalizumab between June 2006 and April 2020 were included. Patient characteristics, annualized relapse rates (ARRs), confirmed Expanded Disability Status Scale (EDSS) score worsening, MRI activity (new/enlarging T2- or gadolinium-enhancing lesions), and reported adverse events were evaluated. Further, prescription patterns and outcomes across different time periods ("epochs") were analysed. In total, 2424 patients were enrolled, with a median follow-up time of 2.7 years (interquartile range (IQR) 1.2-5.1). In recent epochs, patients were younger, had lower EDSS scores, had fewer pre-treatment relapses and were more often treatment naïve. At 13 years of follow-up, 36% had a confirmed EDSS worsening. On-treatment ARR was 0.30, corresponding to a 72% reduction from pre-initiation. MRI activity was rare, 6.8% had activity within 2-14 months from treatment start, 3.4% within 14-26 months, and 2.7% within 26-38 months. Approximately 14% of patients reported adverse events, with cephalalgia constituting the majority. During the study, 62.3% discontinued treatment. Of these, the main cause (41%) was due to JCV antibodies, while discontinuations due to disease activity (9%) or adverse events (9%) were less frequent. Natalizumab is increasingly used earlier in the disease course. Most patients treated with natalizumab are clinically stable with few adverse events. JCV antibodies constitute the main cause for discontinuation.

Effectiveness and Safety of Acitretin for the Treatment of Hidradenitis Suppurativa, Predictors of Clinical Response: A Cohort Study

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the hair follicle which presents with painful nodules, abscesses, and fistulae in apocrine gland-bearing areas of the skin. Approved treatments include antibiotics and biologic drugs such as adalimumab. Despite these treatments, HS management is challenging. Acitretin is an oral retinoid used for its management as 3rd or 4th line therapy. There is little evidence regarding the effectiveness and safety of acitretin treatment for HS, and no reports have previously explored the potential clinical predictors associated with the response to the treatment. Methods: Retrospective cohort study to assess the effectiveness and safety of acitretin treatment in HS patients who failed to respond to topical therapies. Results: Sixty-two patients with moderate to severe HS were included. A significant decrease in the International HS Severity Scoring System (IHS4) score was found over time. Higher basal IHS4 score, family history of HS, follicular phenotype, and history of follicular plugging conditions were potential predictors of response. Most patients did not suffer any adverse events, and no severe side effects were observed. The main cause of discontinuation was lack of efficacy. Conclusion: Acitretin can be considered as a therapeutic option for patients with HS. The presence of follicular phenotype or a history of components of follicular occlusion syndrome is associated with better outcomes.

Improving long-term adherence to sublingual immunotherapy. Results of a proactive patient-centered management planning.

Background. Long-term adherence to sublingual immunotherapy (SLIT) results very poor in real-life studies. Effective actions are needed. Key point of any policy aimed to overcoming non-cost related barriers to medication long-term adherence is to actively support patients' needs and preferences starting from shared decisions making. Objective. To explore SLIT related viewpoints, needs and preferences of a homogeneous group of patients. To assess their priority order and to what extent each of them could affect SLIT adherence. To find a rational basis for a proactive action-plan to support patients' needs and preferences and assess results on SLIT long-term adherence. Patients and methods. Preferences and viewpoint of patients in treatment-related decisions and their health-related needs have been explored by structured, direct interview of 65 adult patient. The activities of the hospital outpatient clinic were rearranged to support needs and requests shared by all patients, and to allow tailored interventions integrating them into routine practice. Adherence to SLIT was studied on a different group of 129 patients aged 14 to 42 years and defined as number of patients who completed three years of therapy. Results. SLIT was completed by 98 patients (76%). Main cause of discontinuation for 31 remaining patients have been pregnancy (16%), change of work residence (19%), side-effects (10%), perceived inefficacy (26%), and non-compliance (29%). Conclusions. To improve adherence, it is necessary to investigate patient-related factors to find a common ground to take actions aimed to remove barriers to long-term SLIT-adherence that virtually can work for all patients, but flexible enough to allow patient-tailored interventions. The substantial differences on disease's perception between patients with only allergic rhinitis and those with asthma entail the necessity of differentiated approaches. Management strategy based on shared decision making followed by proactive and ongoing interventions to support patients' needs and preferences proves effective to ensure a good long-term adherence to SLIT in real-life.

The Use of Ibrutinib in Italian CLL Patients Treated in a Real-World Setting (EVIDENCE): A Preliminary Report

IntroductionIbrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant survival benefit vs chemo- and /or immunotherapy in multiple phase 3 studies of patients (pts) with chronic lymphocytic leukemia (CLL). It has profoundly changed the treatment landscape of CLL with the longest follow-up. However, seven years (yrs) after ibrutinib was approved in Italy by regulatory agencies for CLL treatment, available data on the patterns of care of such pts in the setting of clinical practice is limited.Herein we present the first interim analysis (IA) of EVIdeNCE (ClinicalTrials.gov Identifier: NCT03720561), a multicenter, observational clinical study designed to describe the current management of pts receiving ibrutinib in real-world setting in Italy in terms of retention rate: the study's primary end point.MethodsEVIDENCE 312 treatment-naïve (TN) 38% and relapsed/refractory (R/R) 62% pts with CLL according to the iwCLL diagnosis criteria observed at 39 Italian hematological institutions in the period between November 2018 and October 2019. Inclusion criteria were treatment with ibrutinib according to the European Summary of Product Characteristics as per routine clinical practice started within the previous 3 months. The purpose of this IA is to provide demographics and disease characteristics at baseline and a preliminary evaluation of ibrutinib retention rate after one year of follow-up, along with its safety profile.ResultsThe median age of pts at the time of ibrutinib initiation was 71.0 yrs (range 41.0-89.0), with 60% ≥70 yrs, 63.2% male, and 90% with Eastern Cooperative Oncology Group (ECOG) performance 0-1. Baseline Rai stage 0-I, II, and III-IV accounted for 18.3%, 29.7% and 52.1% pts, respectively. Patients in stage IV were observed in 40% of the R/R and 27% in TN subgroup. Considering 120 pts with known mutational status, del(17p) and/or TP53 mutation were present in 50.0% of pts (TN=52.1%, R/R=48.6%), while IGHV was unmutated in 35.0% (TN=33.3% and R/R=36.15) and mutated in 15.0% (TN=14.6%, R/R=15.3%). At baseline, 62.9% of pts had comorbidities and 30.6% presented with a history of cardiovascular diseases (CVDs). A CIRS score ≥6 was observed in 28.5% of pts. The median time from CLL diagnosis to the start of ibrutinib was 5.1 yrs (TN 1.75 yrs vs R/R 7.27 yrs).At least 1 treatment-emergent adverse event (TEAE) of any grade was experienced by 70.7% of pts. Frequencies were as follows: infections (30.8%; COVID-19 infections 3.2%), arthralgia (10.8%), neutropenia (9.3%), fatigue (8.4%), diarrhea (7.7%), atrial fibrillation (7.4%; grade 3-4, 4.2%), fever (7.1%), rash (6.4%), anemia (6.1%) and hypertension (4.2%). Mild bleeding TEAEs were reported in 16.1% of pts with no major bleeding event. TEAEs were more frequent in the elderly (≥65 yrs) while no significant differences in the rate of TEAEs were recorded in TN and R/R pts (69.7% vs 71.4%, respectively). Serious TEAEs were reported in 21.9% of pts.Overall in intention to treat (ITT), 32 deaths (10%) were observed (TN=8, R/R=24). The most common causes of death were infections (3.5%) and progressive disease (PD) (1.9%).Permanent discontinuation was observed in 56 (18%) of the pts (TN=17.2%, R/R=18.7%) and it mostly occurred within the first 6 months. Main causes of discontinuation were toxicity (6.1%), PD (3.8%) or death (3.5%). Temporary interruptions (≤ 3 months without therapy and/or dose modifications) during the whole observation period occurred in 30.3% (TN=35.3%, R/R=27.2%) and 37.7% (TN=37.5%, R/R=37.8%) of pts, respectively, mainly determined by toxicity and clinical judgment.Finally, in this first IA after 17.3 months (range 1.1 - 27.0) median follow-up, the ibrutinib retention rate (calculated as the ratio between the number of patients who retained ibrutinib treatment over the total number of patients at risk) at 1-year was 81.9% [95% confidence interval (CI), 77.2% - 86.1%] with no difference between TN 83.2% (95% CI, 75.2% - 89.4%) and R/R 81.2% pts (95% CI, 74.9% - 86.4%).ConclusionsEVIDENCE is the first real-world study of ibrutinib use in CLL clinical practice in Italy. Ibrutinib retention rate at one-year suggests a better knowledge and expertise of hematologists in the management of ibrutinib-related toxicities that may result in an improved long-term outcome of pts with CLL. DisclosuresMolica: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astrazeneca: Honoraria. Scarfo: Astra Zeneca: Honoraria; Abbvie: Honoraria; Janssen: Honoraria, Other: Travel grants. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Frigeri: Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Sanna: Janssen: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy. Coscia: Janssen: Honoraria, Other, Research Funding; AbbVie: Honoraria, Other; AstraZeneca: Honoraria; Gilead: Honoraria. Reda: Abbvie: Consultancy; Astra Zeneca: Consultancy; Beigene: Consultancy; Janssen: Consultancy. Tafuri: Novartis: Research Funding; Roche: Research Funding; Celgene: Research Funding. Grugnetti: Janssen: Current Employment. Magarotto: Janssen: Current Employment. Mauro: Tskeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria, Speakers Bureau.

Safety profile of clozapine: Analysis using national registry data in Japan

Clozapine is the only effective antipsychotic drug used for the treatment of treatment-resistant schizophrenia. Although it has been shown that the frequency of clozapine use is very low in Japan, our previous study revealed that the number of clozapine prescriptions has been increasing in recent years, and that risk factors leading to discontinuation of clozapine were also identified as age ≥40 years, poor tolerability to olanzapine, previous treatment with clozapine, and white blood cell count <6000/mm3. The main cause for discontinuation of clozapine is the occurrence of a wide range of adverse events, including neutropenia/leukopenia and fatal cardiac disorders. In this study, we analyzed the physical details and backgrounds of patients with adverse events that led to clozapine discontinuation using a national registry database of more than 8000 Japanese patients. The physical adverse events that led to discontinuation of clozapine were neutropenia/leukopenia, glucose intolerance, cardiac disorders, gastrointestinal disorders, neuroleptic malignant syndrome, pleurisy, pulmonary embolism, sedation/somnolence, and seizures. Neutropenia/leukopenia had the highest incidence (5.0%). Neutropenia/leukopenia and cardiac disorders tended to occur early in the treatment period, indicating the need for careful monitoring for these adverse events in the early stages of clozapine treatment. Gastrointestinal disorders occurred over a long period of time, suggesting the need for careful observation during the maintenance period. The data obtained in our study will lead to the optimal and safe use of clozapine treatment.

Multicenter Study of Secukinumab Survival and Safety in Spondyloarthritis and Psoriatic Arthritis: SEcukinumab in Cantabria and ASTURias Study.

Objectives: We aimed to evaluate the drug retention rate and safety of secukinumab (SEC) in patients with axial spondyloarthritis (AxSpA) and psoriatic arthritis (PsA) in a real clinical setting.Methods: This multicenter retrospective observational study included all AxSpA and PsA patients who received at least one dose of SEC. Adverse events (AE) and the drug retention rate were the main study outcomes. Drug survival was analyzed by Kaplan-Meier curves while predictive factors of discontinuation were evaluated using a Cox regression analysis. The weight of these associations was estimated by hazard ratio (HR) values.Results: We included 154 patients (59 PsA and 95 AxSpA). Mean disease duration was 6.5 years (IQR 2-8). Sixty-one percent of patients were treated with two or more biologics prior to SEC. The 1 and 2-year retention rates for SEC were 66 and 43%, respectively. The main causes of discontinuation were inefficacy (59%) and AE (36%). The factors associated with lower risk of discontinuation were male gender (HR 0.54, 95% CI 0.38-0.78 p = 0.001), obesity (HR 0.53, 95% CI 0.30-0.93 p = 0.027), hypertension (HR 0.55, 95% CI 0.30-0.93 p = 0.008), and diabetes (HR 0.42 95% CI 0.18-0.99 p = 0.047) while number of previous biologics and depression were predictors of discontinuation (HR 1.18, 95% CI 1.04-1.34 p = 0.011 and HR 2.53, 95% CI 1.61-3.96 p < 0.001).Conclusions: SEC showed a good retention rate in a population previously exposed to several biological therapies. As a novelty, cardiometabolic comorbidities were associated with better drug survival.

Factores involucrados en la adherencia a la inmunoterapia sublingual y subcutánea en pacientes del Servicio de Alergología de una institución de salud en Medellín-Colombia

Introducción. Las enfermedades alérgicas en el mundo han aumentado en el último siglo, requiriendo a su vez nuevos tratamientos que permitan mejorar la calidad de vida de los pacientes; como respuesta, la inmunoterapia ha surgido como una opción terapéutica. El objetivo de este estudio fue identificar aspectos de la adherencia a la inmunoterapia sublingual (ITSL) y subcutánea (ITSC), y los motivos de abandono. Materiales y métodos. Estudio descriptivo retrospectivo de pacientes con enfermedades alérgicas (rinitis, asma o dermatitis atópica) que iniciaron inmunoterapia, por vía subcutánea o sublingual, en el Servicio de Alergología de una institución de salud de la ciudad de Medellín, Colombia. Para el análisis estadístico se utilizaron distribuciones absolutas, relativas, medidas de resumen y la prueba Chi cuadrado de independencia. Resultados. Se incluyeron 144 pacientes (ITSC=84,7%;ITSL=15,3%). El 38,9% de los pacientes fueron considerados adherentes; no se hallaron diferencias significativas en la adherencia según la vía de administración (p=0,833). La razón más importante para la selección de la vía de la inmunoterapia en ambos grupos fue la recomendación médica. De los pacientes no adherentes, el 95,5% (n=84) abandonaron el tratamiento. Las características sociodemográficas de los dos grupos de inmunoterapia fueron relativamente similares, sin diferencias significativas. Se encontró una diferencia significativa entre el servicio prestado por la institución en salud y el abandono al tratamiento, siendo mayor para el grupo tratado con ITSL (38,5%; p=0,007). Conclusión. La principal causa de abandono de la terapia fue la no autorización del tratamiento por parte de las Entidades Promotoras de Salud (53,6%).

Long-term follow-up reveals a low persistence rate of abobotulinumtoxinA injections for idiopathic overactive bladder

Little is known about long-term efficacy and tolerance of intra-detrusor injections of abobotulinumtoxinA for management of idiopathic overactive bladder (OAB). We report long-term efficacy and compliance of abobotulinumtoxinA in patients treated for OAB. All patients treated with abotulinumtoxinA for OAB in a tertiary reference centre between 2005 and 2012 were included in a retrospective analysis. Patients received 150, 250 or 500 U of abotulinumtoxinA as first injection. The primary endpoint was the discontinuation rate at 5 years. Other outcomes of interest were: rate of failure, reasons for discontinuation and subsequent treatment elected in those who did not persist with abobotulinumtoxinA. Fifty-nine patients (50 women and 9 men) were included. Forty-one patients (69.4%) received 250 U of abobotulinumtoxinA as first injection. Thirteen patients (22%) received 500 U and 5 (8.4%) received 150 U of BoNT-A. Median follow-up was 83.6 months [0.3-183.6]. Median number of injections per patient was 2 [1-15] and median reinjection interval was 10.7 [3-86.4] months. The estimated 5-year discontinuation-free survival rate was 23.4%. Fourteen patients (23.7%) experienced persistent improvement of symptoms and 12 patients (20.3%) stopped the injections because of tolerability issues. Main cause of discontinuation was primary failure, which occurred in 21 patients (35.5%). Overall, 59.3% of patients were successfully treated with first abobotulinumtoxinA injection. Although the estimated 5-year discontinuation-free survival rate is low, abobotulinumtoxinA could be considered as an alternative off-labelled in patients not responders to onabotulinumtoxinA after failure of other conservative measures. 3.

Safety and survival associated with biologic therapies: first report of the Biobadaguay on the Paraguayan-Uruguayan registry of adverse events with biologic therapies

ObjectiveAnalyze adverse events (AE) and survival associated with biologic therapies (BT) in the BIOBADAGUAY, the Paraguayan Uruguayan registry of adverse events. MethodsProspective, observational study of undetermined duration. Patients on biologic therapy at initiation and controls were included. Clinical, biological and treatment variables were registered. Results826 registers were entered (650 BT and 176 controls). 70.9% were women and rheumatoid arthritis (RA) was the most frequent diagnosis (63.2%). The BT most often used was adalimumab and the main cause of discontinuation was loss of efficacy (42.1%). The incidence of AE of patients on BT was 143.9 (128.8–160.8) per 1000 patients/year. In the comparative study of AE related to diagnosis, juvenile idiopathic arthrosis (JIA) was associated with a higher overall number of AE (RTI = 2.3, 95% confidence interval [CI] 1.6–3.4; P = 4.27 e-06), whereas RA was associated with a higher number of serious AE (RTI = 2.2, 95% CI 1.2–4.1; P = 1.17 e-0.2). On the other hand, treatment with tocilizumab was associated with a higher rate of AE (RTI = 2.69, 95% CI 1.9–3.82; P = 3.13 e-08). In JIA, treatment with corticosteroids and number of previous BT was associated with a decrease in BT survival. ConclusionIn this first report of the BIOBADAGUAY registry, the main cause of BT discontinuation was loss of efficacy. In terms of the diagnosis involved, RA and JIA were associated with a higher risk of AE. In this registry, variables related to a shorter survival of BT were identified.

Real-World Effectiveness and Safety of Apremilast in Older Patients with Psoriasis.

Apremilast is a drug recently developed for psoriasis. Few data are available on its use in the elderly. We evaluated the tolerance and effectiveness of apremilast used in daily practice for psoriasis treatment in older patients. We performed a multicenter, retrospective study involving patients aged ≥ 65years who had received apremilast as a psoriasis treatment. Demographic data and details regarding psoriasis and adverse events (AEs) were collected from patient medical records. 135 patients were included (mean age: 73.5years). Treatment was stopped in 74 patients (54.8%) for AEs (n = 43, 56.6%), primary failures (n = 18, 23.4%), and relapses (n = 7, 9.2%). When patients were stratified by age at treatment initiation, the main cause of discontinuation in patients ≥ 75years was AEs, whereas in patients aged 65-74years it was primary failures (28.3%). Sixty-one patients reported AEs, mainly digestive (n = 49). Regarding effectiveness, 45.2% of patients reached PGA 0/1 between 3 and 6months after treatment initiation. One-year apremilast continuation rates were better in the 65-74 and 75-84years subgroups than in the > 85years subgroup (p = 0.01). Apremilast seems to be an effective and safe therapeutic option for psoriasis in the elderly. The main AEs reported by patients did not seem to differ from those reported previously in younger populations. However, AEs were more frequent in patients > 75years old leading to more frequent discontinuation of apremilast compared with younger patients, suggesting a higher level of vigilance is needed in the elderly.

Why do we Discontinue Biologic Agents? A Retrospective Study of 11 Years

Introduction: Biologic agents acquired a growing relevance in dermatology, however, adverse events (AE) and reasons to discontinue therapy are not completely known. The objective of this study is to analyse the reasons behind the discontinuation of biologics and characterize the AE in this population of patients.&#x0D; Material and Methods: Descriptive observational study, including patients over 18-years-old under treatment with biologic agents in the Dermatology Department of Hospital de Santarém, Portugal, between January/2007 and December/2017. We analysed reasons for therapeutic discontinuation, defined as the omission of at least 2 consecutive administrations, whatever the reason implicated and whether or not proposed by the dermatologist.&#x0D; Results: A total of 262 cycles of treatment were performed, in 138 patients (59.4% male, 40.6% female). Psoriasis was the most prevalent diagnosis (93.5% of the patients). Cycles of treatment with 8 biologic agents were analysed: etanercept (46.6%), adalimumab (31.3%) and ustekinumab (12.6%) were the most represented. During the study period, 167 suspensions were registered, for which 170 justifications were indicated. The most prevalent causes were: primary or secondary therapeutic failure (35,3%), AE (31.2%), factors related to the patient/noncompliance (17.1%), surgical intervention (7.1%) and excellent clinical response/absence of lesions (6.5%). Among therapeutic discontinuations motivated by AE (n=53), infections were the most frequent cause (35.8%, n=19), followed by malignancies (15.1%, n=8), hematological abnormalities (13.2%, n=7), neurological symptoms (9.4%, n=5) and local reactions at the injection site (5.7%, n=3).&#x0D; Discussion: The main cause for discontinuation of biologics was therapeutic failure, immediately followed by AE. Two different patterns of discontinuation were apparent: definitive suspension, commonly decided by the physician due to primary or secondary therapeutic failure, and temporary discontinuation, frequently without formal medical indication, due to AE, later resuming the same drug. We found a higher percentage of therapeutic cycles discontinued due to AE than reported in the literature. Temporary suspensions of the biologics due to AE, often not sufficiently valued by the dermatologist, are probably under-recognized and contribute to a suboptimal pattern of use of biologics and worse clinical outcomes.

Levodopa-Carbidopa Intestinal Gel Infusion Therapy Discontinuation: A Ten-Year Retrospective Analysis of 204 Treated Patients.

BackgroundParkinson’s disease (PD) is the second most common progressive neurodegenerative disease. In the advanced stages, the continuous delivery of levodopa (LD) as levodopa-carbidopa intestinal gel (LCIG) has demonstrated significant improvement of motor and nonmotor complications and improvement of the patients’ quality of life (QoL). Despite the growing global experience with this treatment, anumber of unsolved practical issues remain, and currently, the data on the reasons that can lead to the discontinuation of LCIG are scarce.ObjectiveIn the present study, we aimed to analyze the causes that led to the discontinuation of LCIG therapy.MethodsIn this retrospective study, after 10 years of experience with LCIG as a therapeutic option in advanced PD, we analyzed the data of all dropout cases among the 204 patients that initiated LCIG therapy in two Romanian centers.ResultsOf the 204 patients enrolled, 43 patients dropped out. Disease duration until LCIG infusion was significantly longer (11.67±4.98 vs 9.44±3.44) and the overall clinical picture more sever (both regarding motor symptoms and cognitive decline) in dropout patients (compared to patients who continued treatment). The dropout patients also presented significant differences regarding the incidence of polyneuropathy (32.5% vs 11.18%). The main cause of discontinuation was death.ConclusionThe causes of discontinuation from LCIG therapy in Romanian patients are similar to those from other centers; however, the rate of dropouts is somewhat lower. The clinician’s experience in selecting and treating the patients in advanced stages of PD can increase therapeutic adherence. Also, the presence of a well-trained caregiver along with the availability of a proper aftercare system is mandatory for maintaining the long-term benefits of the therapy and the overall best outcome possible. Targeted prospective studies are needed to confirm whether a more severe stage of the disease and cognitive impairment at the time of initiation, respectively, the association of polyneuropathy can be considered as predictive factors for dropout.

First-line treatment of pelvic organ prolapse and discontinuation of pessary treatment.

The primary objective of this study was to investigate the percentages of women choosing watchful waiting, pessary use or surgery as first-line treatment of pelvic organ prolapse (POP). Second, the rate and cause of discontinuation of pessary use were investigated. A retrospective chart review was conducted on 794 patients referred with POP at a Danish tertiary center for urogynecology at Aalborg University Hospital between 1 January 2014 and 31 December 2015. The following data were registered: age, BMI, previous use of a pessary, total number of births, vaginal births, cesarean sections, previous hysterectomy, prolapse surgery and incontinence surgery, smoking, menopause, sexual status and POP-Q stage in the three vaginal compartments. Pessary treatments were evaluated after 3months. Additional visits, reason for discontinuation and secondary treatment were noted. First-line treatment was surgery in 50%, watchful waiting in 33% and pessary use in 17% of patients. Characteristics associated with choosing surgery instead of a pessary were age < 65years, previous prolapse surgery, prolapse in the anterior or posterior compartment, and POP-Q stage > 2. Characteristics associated with choosing watchful waiting instead of a pessary were age < 65 years and prolapse in the posterior compartment. A total of 33% discontinued pessary treatment within the first 3months. Discontinuation was associated with age < 65years, previous hysterectomy and pelvic surgery, and additional visits. Expulsion of the pessary and pain/discomfort were the main causes of discontinuation. This study showed that 50% of patients referred with POP were treated with conservative treatment (watchful waiting and pessary) and thus more women could probably be treated in primary care.

Long-term safety, tolerability, and efficacy of magnesium valproate versus sodium valproate in acute seizures

Objectives: To evaluate the safety, tolerability and efficacy of magnesium valproate and sodium valproate as monotherapies in patients with epilepsy in China.Methods: We recruited patients admitted with seizures over a two-year period. All patients underwent early neurological assessments, electroencephalogram testing, and neuroimaging. The treatments received at baseline and at one year of follow-up were compared.Results: In total, 175 patients were included. The retention rates of the magnesium valproate and sodium valproate treatments were 73.1% and 64.2%, respectively. The main cause of discontinuation was the development of intolerable adverse events. The retention rate and total effective rate in the magnesium valproate group were significantly higher than those in the sodium valproate group (73.1% and 70.2% versus 64.2% and 47.2%, respectively). The safety endpoints included 120 patients (magnesium valproate: n = 67; sodium valproate: n = 53). The incidence of adverse events in the magnesium valproate group was significantly lower than that in the sodium valproate group (30% versus 51%).Conclusions: Magnesium valproate treatment shows favorable safety and tolerability and is associated with markedly improved seizure control. Ideally, future large, prospective, randomized, and double-blind studies are needed to confirm these findings.