An "On Demand" canakinumab regimen for treating children with Colchicine-Resistant familial Mediterranean fever - A multicentre study.

OBJECTIVES: Canakinumab, a human monoclonal antibody targeted at interleukin-1 beta, has demonstrated safety and efficacy in preventing familial Mediterranean fever (FMF) attacks among individuals with colchicine-resistant (crFMF). The manufacturer orders prescribe monthly subcutaneous injections. However, a subset of our patients is treated with an "canakinumab on demand " (COD) strategy, with wider intervals between drug administrations. Therefore, we aimed to compare disease activity and drug safety between COD and "canakinumab fixed frequency" (CFF) policies. METHODS: This retrospective study collected data from three Israeli paediatric rheumatology centres, of children with crFMF who were treated with canakinumab. Epidemiological and clinical parameters, cumulative drug dosages, and adverse events were compared between children treated by both policies. RESULTS: Twenty-five (49 %) children were treated according to COD policy and 26 according to CFF policy. Demographic parameters and most of the disease features did not differ significantly between the groups. Both groups showed significant reduction in attacks after canakinumab introduction. The median number (interquartile range) of attacks per month did not differ significantly between the COD and CFF groups (0.33 (0.08, 0.58) and 0.13 (0, 0.5), respectively, p = 0.485 (even though, per definition, COD patients presumably had an attack before receiving the second canakinumab dose). The mean monthly dose was lower for the COD than the CFF group (1.13 ± 1.13 vs. 3.16 ± 1.46 mg/kg, p < 0.001). Adverse events were similar between the groups. CONCLUSION: For individuals with crFMF, COD compared to CFF policy can achieve similar efficacy and safety, with a lower accumulated canakinumab dose, rendering it less immunosuppressive and less expensive.

Clinical Outcomes of Patients with HER2 Positive Metastatic Breast Cancer to the Brain, with First-Line Trastuzumab, Pertuzumab and Chemotherapy, in a Real-World Setting.

Background: In this observational study, we analyzed the treatment patterns and clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) who developed brain metastases during their disease in a 2.7 million-member public health-provider in Israel. Methods: Newly diagnosed patients with mBC who initiated first-line treatment between January 2013 and June 2021 were identified. Time on treatment (ToT) and overall survival (OS) were assessed at a minimum of 6 months follow-up (cutoff: December 2021). Results: We identified a total of 61 patients: 98.4% females, median age 50 years (IQR = 44-63), 85% invasive ductal tumors, 44% hormone receptor positive, 51% performance status 0-1. The median duration of follow-up was 6.2 years. All patients initiated a combination treatment of trastuzumab, pertuzumab, and chemotherapy (TPC), and 72% moved to second-line treatment during the study follow-up period (82% ado-trastuzumab emtansine). The median ToT for first-line and second-line treatments were 16.9 months (95% CI = 13.9-27.7) and 7.9 months (95% CI = 5.6-10.9), respectively. The median overall survival (OS) was 45.5 months (95% CI = 35.4-71.2) from the initiation of first-line treatment. When considering the timing of brain metastases, the median OS was 36.3 months (95% CI = 10.0-NR) for those diagnosed upfront (n = 15, 25%), 59.1 months (95% CI = 32.5-NR) for those diagnosed while on TPC (n = 25, 41%), and 40.8 months (95% CI = 35.4-NR) for those diagnosed at a later stage (n = 21, 34%). The median OS from brain metastases diagnosis was 25.1 months (95% CI = 17.0-34.6). Conclusion: Patients with upfront brain involvement at the time of mBC diagnosis had shorter survival compared to those who started TPC without brain metastases. Nonetheless, the overall results from this study compare favorably with previous studies and contribute to understanding the value of traditional treatment options, which will serve as a baseline for future treatment strategies in the real-world setting.

Assessing the diagnostic utility of the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system using real-world data.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive condition associated with clinical features such as splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone abnormalities. Three clinical forms of GD have been defined based on the absence (type 1, GD1) or presence (types 2 and 3) of neurological signs. Early diagnosis can reduce the likelihood of severe, often irreversible complications. The aim of this study was to validate the ability of factors from the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system to discriminate between patients with GD1 and controls using real-world data from electronic patient medical records from Maccabi Healthcare Services, Israel's second-largest state-mandated healthcare provider. METHODS: We applied the GED-C scoring system to 265 confirmed cases of GD and 3445 non-GD controls matched for year of birth, sex, and socioeconomic status identified from 1998 to 2022. The analyses were based on two databases: (1) all available data and (2) all data except free-text notes. Features from the GED-C scoring system applicable to GD1 were extracted for each individual. Patients and controls were compared for the proportion of the specific features and overall GED-C scores. Decision tree and random forest models were trained to identify the main features distinguishing GD from non-GD controls. RESULTS: The GED-C scoring distinguished individuals with GD from controls using both databases. Decision tree models for the databases showed good accuracy (0.96 [95% CI 0.95-0.97] for Database 1; 0.95 [95% CI 0.94-0.96] for Database 2), high specificity (0.99 [95% CI 0.99-1]) for Database 1; 1.0 [95% CI 0.99-1] for Database 2), but relatively low sensitivity (0.53 [95% CI 0.46-0.59] for Database 1; 0.32 [95% CI 0.25-0.38]) for Database 2). The clinical features of splenomegaly, thrombocytopenia (< 50 × 109/L), and hyperferritinemia (300-1000 ng/mL) were found to be the three most accurate classifiers of GD in both databases. CONCLUSION: In this analysis of real-world patient data, certain individual features of the GED-C score discriminate more successfully between patients with GD and controls than the overall score. An enhanced diagnostic model may lead to earlier, reliable diagnoses of Gaucher disease, aiming to minimize the severe complications associated with this disease.

Trends of Diagnosis, Disease Course, and Treatment of Atopic Dermatitis 2012-2021: Real-World Data from a Large Healthcare Provider.

In the last decade, new treatments for atopic dermatitis (AD) have emerged. We aimed to describe trends of the diagnosis, disease course, and treatment of AD over a decade (2012-2021) using data from Maccabi Healthcare Services (a 2.7-million-member healthcare provider in Israel). The AD prevalence was stable (4.0% on 31 December 2021 vs. 4.3% on 31 December 2012). The annual AD incidence was also stable (5.8/1000 in 2012 and 5.7/1000 in 2021). AD-related treatment use was highest in the first year post-diagnosis, and it included, among children (n = 87,414) vs. adults (n = 36,865), low-potency topical corticosteroids (TCS) (41.8% vs. 27.1%), mid-potency TCS (30.1% vs. 28.1%), high-potency TCS (34.9% vs. 60.3%), topical calcineurin inhibitor (10.8% vs. 10.1%), phosphodiesterase-4-inhibitor (0.3% vs. 0.7% overall; approved in 2019), phototherapy (0.1% vs. 2.3%), and systemic/biologic treatments (13.0% vs. 13.3%). Among children diagnosed in 2012 and followed through to 2021 (n = 5248), 21.5% had ≥1 AD diagnosis/treatment 10 years later (among 3223 adults: 38.3%). We conclude that the incidence and prevalence rates of AD were comparable to those in similar database studies and remained relatively stable over the past decade. The results underscore the burden of medication use among children and adults, particularly in the first year after AD diagnosis, and the low rate of AD diagnosis among patients originally diagnosed as children 10 years earlier.

Calcium score of the entire thoracic aorta is an independent predictor of all-cause mortality in patients referred to chest computed tomography.

BACKGROUND: Thoracic arterial calcifications (TAC) are not routinely reported or quantified in chest CT scans. We aimed to evaluate the association between TAC of the entire thoracic aorta and all-cause mortality (ACM) in patients referred to standard chest CT. METHODS: A retrospective analysis of consecutive standard chest CT scans (non-gated, non-contrast) for the quantification of TAC, CAC and aortic valve calcification. TAC was divided into 4 sample-derived categories (TAC 1 = 0, TAC 2 = 1-65, TAC 3 = 66-439 and TAC 4 ≥ 440). Data regarding ACM was retrieved from the health care provider database. Multivariate Cox proportional regression models were used to assess associations between the TAC categories and ACM. RESULTS: The study cohort included 415 patients (mean age 67 years, 52% male); 107 ACM events were recorded during a median follow-up of 9 years (inter-quartile range: 7.4-10.4). The rate of ACM was 13%, 25%, 32%, 41% according to TAC category (p < 0.001). The highest TAC category (≥ 440) was a strong and independent predictor of ACM [HR = 1.69 (1.13-2.52; 0.01)] in multivariate analysis. Other independent predictors of ACM included age [HR = 1.07 (1.04-1.10; p < 0.001)], male sex [HR = 2.27 (1.49-3.46; 0.001)] and malignancy [HR = 2.21 (1.49-3.23; < 0.001)]. CONCLUSIONS: Severe TAC (≥ 440) was found to be an independent predictor of ACM. Thus, we suggest that documenting and quantifying TAC should be routinely incorporated into standard chest CT reports.

Adolescent Body Mass Index and Early Chronic Kidney Disease in Young Adulthood.

Importance: Despite increasing obesity rates in adolescents, data regarding early kidney sequelae are lacking. Objective: To assess the association between adolescent body mass index (BMI) and early chronic kidney disease (CKD) in young adulthood (<45 years of age). Design, Setting, and Participants: This cohort study linked screening data of mandatory medical assessments of Israeli adolescents to data from a CKD registry of a national health care system. Adolescents who were aged 16 to 20 years; born since January 1, 1975; medically evaluated for mandatory military service through December 31, 2019; and insured by Maccabi Healthcare Services were assessed. Individuals with kidney pathology, albuminuria, hypertension, dysglycemia, or missing blood pressure or BMI data were excluded. Body mass index was calculated as weight in kilograms divided by height in meters squared and categorized by age- and sex-matched percentiles according to the US Centers for Disease Control and Prevention. Follow-up started at the time of medical evaluation or January 1, 2000 (whichever came last), and ended at early CKD onset, death, the last day insured, or August 23, 2020 (whichever came first). Data analysis was performed from December 19, 2021, to September 11, 2023. Main Outcomes and Measures: Early CKD, defined as stage 1 to 2 CKD by moderately or severely increased albuminuria, with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher. Results: Of 629 168 adolescents evaluated, 593 660 (mean [SD] age at study entry, 17.2 [0.5] years; 323 293 [54.5%] male, 270 367 [45.5%] female) were included in the analysis. During a mean (SD) follow-up of 13.4 (5.5) years for males and 13.4 (5.6) years for females, 1963 adolescents (0.3%) developed early CKD. Among males, the adjusted hazard ratios were 1.8 (95% CI, 1.5-2.2) for adolescents with high-normal BMI, 4.0 (95% CI, 3.3-5.0) for those with overweight, 6.7 (95% CI, 5.4-8.4) for those with mild obesity, and 9.4 (95% CI, 6.6-13.5) for those with severe obesity. Among females, the hazard ratios were 1.4 (95% CI, 1.2-1.6) for those with high-normal BMI, 2.3 (95% CI, 1.9-2.8) for those with overweight, 2.7 (95% CI, 2.1-3.6) for those with mild obesity, and 4.3 (95% CI, 2.8-6.5) for those with severe obesity. The results were similar when the cohort was limited to individuals who were seemingly healthy as adolescents, individuals surveyed up to 30 years of age, or those free of diabetes and hypertension at the end of the follow-up. Conclusions and Relevance: In this cohort study, high BMI in late adolescence was associated with early CKD in young adulthood. The risk was also present in seemingly healthy individuals with high-normal BMI and before 30 years of age, and a greater risk was seen among those with severe obesity. These findings underscore the importance of mitigating adolescent obesity rates and managing risk factors for kidney disease in adolescents with high BMI.

Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy.

Importance: Increasing use of second-line noninsulin antidiabetic medication (ADM) in pregnant individuals with type 2 diabetes (T2D) may result in fetal exposure, but their teratogenic risk is unknown. Objective: To evaluate periconceptional use of second-line noninsulin ADMs and whether it is associated with increased risk of major congenital malformations (MCMs) in the infant. Design, Setting, and Participants: This observational population-based cohort study used data from 4 Nordic countries (2009-2020), the US MarketScan Database (2012-2021), and the Israeli Maccabi Health Services database (2009-2020). Pregnant women with T2D were identified and their live-born infants were followed until up to 1 year after birth. Exposure: Periconceptional exposure was defined as 1 or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, or insulin (active comparator) from 90 days before pregnancy to end of first trimester. Main Outcomes and Measures: Relative risks (RRs) and 95% CIs for MCMs were estimated using log-binomial regression models, adjusting for key confounders in each cohort and meta-analyzed. Results: Periconceptional exposure to second-line noninsulin ADMs differed between countries (32, 295, and 73 per 100 000 pregnancies in the Nordics, US, and Israel, respectively), and increased over the study period, especially in the US. The standardized prevalence of MCMs was 3.7% in all infants (n = 3 514 865), 5.3% in the infants born to women with T2D (n = 51 826), and among infants exposed to sulfonylureas was 9.7% (n = 1362); DPP-4 inhibitors, 6.1% (n = 687); GLP-1 receptor agonists, 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); and insulin, 7.8% (n = 5078). Compared with insulin, adjusted RRs for MCMs were 1.18 (95% CI, 0.94-1.48), 0.83 (95% CI, 0.64-1.06), 0.95 (95% CI, 0.72-1.26), and 0.98 (95% CI, 0.65-1.46) for infants exposed to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, respectively. Conclusions and Relevance: Use of second-line noninsulin ADMs is rapidly increasing for treatment of T2D and other indications, resulting in an increasing number of exposed pregnancies. Although some estimates were imprecise, results did not indicate a large increased risk of MCMs above the risk conferred by maternal T2D requiring second-line treatment. Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.

Time on Treatment and Survival Outcomes for Patients Treated With First-line Osimertinib vs. Other Tyrosine Kinase Inhibitors, for EGFR Mutation-positive Metastatic Non-small Cell Lung Cancer: Real-world Experience Data.

BACKGROUND/AIM: In this observational study, we analyzed the time on treatment (ToT) and overall survival (OS) of patients with metastatic non-small cell lung cancer (mNSCLC) in a 2.7-million-member public health provider in Israel. PATIENTS AND METHODS: Newly diagnosed patients with mNSCLC who initiated first-line tyrosine kinase inhibitor (TKI) therapy between Jan 2017-Dec 2020 were identified from the National Cancer Registry and Maccabi Healthcare Services database. Outcomes were assessed at a minimum of 23 months of follow-up (cutoff: 30th November 2022). All analyses compared first-line treatment osimertinib vs. standard TKIs (erlotinib, afatanib or gefitinib). RESULTS: A total of 165 patients (59% female, median age 68 years) were identified, including 58% smokers, 95% with adenocarcinomas, 33% with brain metastases, and 62%/15%/23% with 0-1/2-4/unknown performance status (PS). Of these, 77 (47%) were treated with standard TKI drugs and 88 (53%) with osimertinib as first-line treatment. The median duration of follow-up was 33.6 months (95%CI=29.9-37.3) and 58.5 months (95%CI=52.5-64.4) for patients who received osimertinib and standard TKIs, respectively. The median ToT (in months) was significantly (p<0.0001) longer with osimertinib (17.6; 95%CI=13.71-23.9) vs. standard TKIs (9.40; 95%CI=7.17-12.1). The 24-month survival rate was 58.0% among patients who received osimertinib and 50.6% among those who received standard TKI therapy (p=0.18). From second-line treatment initiation, 43.8% of those who received second-line osimertinib and 17.7% of those that received other second-line treatment were still alive at 24 months. CONCLUSION: Compared to standard TKIs, first-line osimertinib treatment was associated with a significantly longer ToT, and a longer OS. Our cohort also included patients with PS 2-4 who would not necessarily be included in clinical trials, allowing analysis of a real-world population.

Adherence to the Mediterranean diet is associated with decreased Fecal Calprotectin Levels in Children with Crohn's Disease in Clinical Remission under biological Therapy.

BACKGROUND AND AIM: Adherence to the Mediterranean diet (MD) was shown to be associated with decreased disease activity in adult patients with Crohn's disease (CD). Nevertheless, data on its association with fecal calprotectin (FC), particularly in children, remain limited. This study aims to assess the association between adherence to the MD and FC as an indicator of mucosal healing (MH), in patients who are predominantly in remission while undergoing biological therapy. METHODS: This was a cross-sectional study among children with CD. Adherence to MD was evaluated using both the KIDMED questionnaire and a food frequency questionnaire (FFQ). Israeli Mediterranean Diet Adherence Screener (I-MEDAS) score was calculated, and FC samples were obtained. RESULTS: Of 103 eligible patients, 99 were included (mean age 14.3±2.6 years; 38.4% females); 88% were in clinical remission and 30% presented with elevated FC. The mean KIDMED score was higher among patients who had FC<200 µg/g compared to patients with FC>200µg/g (5.48±2.58 vs. 4.37±2.47, respectively; p=0.04). A moderate correlation between the KIDMED score and the I-MEDAS score was observed (r=0.46; p=0.001). In a multivariate regression analysis, adherence to MD was associated with decreased calprotectin levels, OR 0.75[95%CI: 0.6-0.95], p=0.019. Vegetable consumption was found to be inversely associated with elevated FC (0.9 portion/day [0.3-2.9] in FC>200µg/g vs. 2.2 portions/day [0.87-3.82] in FC<200µg/g; p=0.049). CONCLUSIONS: In children with CD who are mostly in clinical remission under biological therapy, high adherence to MD is associated with decreased FC levels. Encouraging vegetable consumption, especially during remission, may benefit these patients.

Cancer Risk in Patients with Gaucher Disease Using Real-World Data.

The association between GD and cancer has been uncertain due to ascertainment bias in previously published studies. We analyzed cancer incidence using the Maccabi Healthcare Service (MHS) electronic health records among 264 patients with GD compared to 3440 matched controls. We ascertained cancers diagnosed before and after the index date (i.e., the first documentation of GD in cases and the corresponding date for controls). Before the index date, cancers were diagnosed in 18 individuals, with 11 (4.2%) in the GD group and 7 (0.2%) in the control group. After the index date, cancers were diagnosed in 57 individuals, with 20 (7.9%) in the GD group and 37 (1.1%) in the control group, with a median follow-up of almost 13 years in both groups. The most common cancers diagnosed in GD were non-melanoma skin cancer (NMSC) and hematological malignancies, with a clustering of diagnoses around the time of GD diagnosis. The incidence of cancers (excluding MNSC) was 4.1 (95% CI 2.2-7.1) and 0.7 (95% CI 0.4-0.9) per 1000 patient-years in the GD and control groups, respectively, with an incidence rate ratio of 6.37 (95% CI 3-12.7). Patients with GD underwent more cancer screening tests than their counterparts in the control group. While our study revealed an increased occurrence of cancers in patients with GD, this finding might be partly attributed to the more rigorous surveillance procedures employed in this patient population.

Pulmonary Evaluation in Children with Post-COVID-19 Condition Respiratory Symptoms: A Prospective Cohort Study.

Background: Studies on post-COVID-19 condition (PCC) in adults have shown deterioration in pulmonary function tests (PFTs), mainly a diffusion limitation. Among the pediatric population, data are scarce. Aim: To characterize PFTs in children with PCC, including changes over time. Methods: A prospective longitudinal study of children with defined PCC and respiratory complaints who were referred to a designated multidisciplinary clinic from 11/2020 to 12/2022. Results: Altogether, 184 children with a mean age of 12.4 years (SD 4.06) were included. A mild obstructive pattern was demonstrated in 19/170 (11%) at presentation, as indicated by spirometry and/or positive exercise challenge test and/or reversibility post bronchodilators, only three had a previous diagnosis of asthma. Lung volumes and diffusion were normal in all but one patient (1/134, 0.7%). Exhaled nitric oxide levels were elevated in 32/144 (22%). A total of 33 children who had repeated PFTs had normal or near-normal PFTs on follow-up testing, including seven (21.2%) who had mild obstructive PFTs at presentation. Multivariate analysis identified older age [OR 1.36 (95% CI:1.07-1.75)], specific imaging findings (prominent bronchovascular markings (OR 43.28 (95% CI: 4.50-416.49)), and hyperinflation (OR 28.42, 95% CI: 2.18-370.84)] as significant predictors of an obstructive pattern on PFTs. Conclusions: In children with PCC and respiratory symptoms, the most common impairment was a mild obstructive pattern; most were without a history of asthma. Improvement was witnessed in long-term follow-up. In contrast to the adult population, no diffusion limitation was found. Empirical periodic inhaler therapy may be considered in children with factors associated with PFT abnormalities.

Correlates of Early Dental Implant Failure: A Retrospective Study.

PURPOSE: To examine whether patient-level disease diagnoses, drug treatments, and dental clinical factors are correlates of early implant failure. MATERIALS AND METHODS: This historical, nested case-control study used electronic medical records to retrieve patient-level data on individuals with implant failure occurring up to 6 months after implantation, including demographics, clinical information (number, location, and complicated status of implants), underlying diseases (osteoporosis, diabetes, hypertension, inflammatory bowel disease [IBD], myocardial infarction [MI]), and drug purchases (chemotherapy, bisphosphonates, selective serotonin inhibitors, antihypertensive medications, proton pump inhibitors [PPIs], disease-modifying antirheumatic drugs, corticosteroids, and nonsteroidal anti-inflammatory drugs) among adult members of a large, state-mandated health provider in Israel between 2015 and 2020. Individuals with implant extraction occurring up to 6 months after implantation were matched 1:1 to controls. Univariate and adjusted multivariate conditional logistic regression models were used to examine the odds ratios (ORs) of all dental implant risk factors among the patients. RESULTS: A total of 585 individuals with implant failure (mean age, 53 years [42,62], 51.3% females and 49.7% males) were identified among 29,378 eligible patients. Compared to controls, patients who experienced implant failure (ie, cases) were more likely to have smoked in their lifetime (18% vs 11.5%, P = .009), experienced IBD (1.5% vs 0.02%, P = .059), and consumed PPIs within 6 months of the implant surgery (40.0% vs 32.5%, P = .028). Clinical factors, including the number of implants per person (individuals with two implants, OR = 1.53; individuals with at least four implants, OR = 3.33; P < .01), location of implant (maxilla; OR = 1.59; 95% CI: 1.2-2.04), and smoking (OR = 1.57; 95% CI: 1.09-2.26) were significant correlates of early implant failure among the included cases. Crohn's disease, MI, and osteoporosis were found to be borderline significant correlates of early dental implant failure. CONCLUSIONS: Among the factors examined, the number of implants, the location of implants, and smoking history were significant correlates of early implant failure, while Crohn's disease, MI, and osteoporosis were found to not be significant. Larger patient-level studies are needed to examine the individual and combined effects of diseases, medications, and clinical factors on early implant failure.

DXA assessment and fracture prevention in hormone positive breast cancer patients after treatment initiation with aromatase inhibitors: A registry-based cohort study.

Background: Several guidelines have been proposed to prevent aromatase inhibitors induced bone loss (AIBL), but there is scarce data on their endorsement in clinical practice. Aim: To assess bone health evaluation and fracture prevention in postmenopausal women with estrogen receptor (ER)-positive breast cancer after aromatase inhibitors (AI) initiation. Methods: An historical cohort analysis based on data from the cancer and osteoporosis Maccabi Health Services (MHS) registries from Jan 1st 2009 to Dec 31st 2020. Cases of estrogen receptor (ER)-positive breast cancer were extracted. Index date was set as the first aromatase inhibitors (AI) purchase. Variables such as age, BMI, smoking history, alcohol use, rheumatoid arthritis, diabetes, glucocorticosteroid use, previous fractures, BMD T-scores and purchases of AI and anti-resorptive agents were collected. Age under 50, previous cancer, prior major osteoporotic fractures and prior anti-resorptive treatment were exclusion criteria. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 8617 women initiating AI were eligible. The median follow up was 6.1 years. The mean (SD) age at index was 62.8 (9.2), the mean (SD) BMI was 29.1 (5.6). The mean (SD) T-score was -1.3 (1.2) at the lumbar spine, -1.5 (0.9) at the femoral neck and -1.0 (1.0) at the total hip. Twenty percent had type 2 diabetes, 8.1 % were active smokers, 3.8% had rheumatoid arthritis and 1.2% were exposed to glucocorticoids.A total of 37% and 53% underwent a DXA scan at 1 and 2 years from AI initiation, and 12% and 17% were prescribed an anti-resorptive agent at 1 and 2 years from index. Advanced age was associated with a higher rate of evaluation and treatment, while obesity and diabetes were associated with a lower rate. The cumulative incidence of a major osteoporotic fracture was 8.8 and 15.8 % at 5 and 10 years, respectively. Conclusions: Despite the excess risk of fractures, bone health assessment and preventive treatment are still partial and postponed in breast cancer AI treated patients. Strategies to ensure appropriate care are needed.

BNT162b2 mRNA COVID-19 Vaccine Effectiveness in Patients with Coeliac Disease Autoimmunity: Real-World Data from Mass Vaccination Campaign.

BACKGROUND: Data on COVID-19 vaccine effectiveness among patients with coeliac disease are currently lacking because patients with immune conditions were excluded from clinical trials. We used our coeliac disease autoimmunity (CDA) cohort to explore the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in preventing SARS-CoV-2 infection among patients with CDA. METHODS: This retrospective cohort study included patients with positive autoantibodies against tissue transglutaminase (tTG-IgA). In the primary analysis, the cohort included CDA patients who received two vaccine doses against COVID-19 and matched patients in a 1:3 ratio. Patients were divided into subgroups based on their positive tTG-IgA level at diagnosis and their current serology status. RESULTS: The cohort included 5381 vaccinated patients with CDA and 14,939 matched vaccinated patients. The risk for breakthrough SARS-CoV-2 infection evaluated with Kaplan-Meier survival analysis via log-rank tests was similar between groups (p = 0.71). In a Cox regression survival analysis, the hazard ratio for breakthrough infection among patients with CDA compared to matched patients was 0.91 (95% confidence interval = 0.77-1.09). CONCLUSIONS: COVID-19 vaccination is effective in patients with coeliac disease autoimmunity. Vaccine effectiveness was comparable to the reference population.

Association of early-life exposure to acid-suppressive therapy and fractures during childhood: a retrospective cohort study.

OBJECTIVES: Increased acid-suppressive therapy (AST) usage during infancy is seen worldwide, while the data on the risk for paediatric fractures associated with these drugs are scarce. We aimed to evaluate the risk for fractures associated with early-life usage of AST. METHODS: This population-based retrospective propensity-matched cohort study included children born between 2005 and 2016 who used AST during the first year of life, and a 3:1 matched unexposed group. Study subjects were followed from the end of the first year of life until the earliest of the following: an outcome event (either fracture or non-fracture injury, separately), age of 10 or August 2022. The cumulative incidence of fractures and the HR of AST for fracture and non-fracture injury as negative control were calculated. RESULTS: A total of 13 894 eligible AST users and 41 418 propensity score-matched non-users were included in the analysis. The cumulative incidence of fracture among children with AST (23.7%) was significantly (p<0.001) higher than non-users (21.7%) corresponding to an HR of 1.11 (95% CI 1.06 to 1.16). The HR for one to two AST purchases versus none was 1.09 (95% CI 1.04 to 1.14) and the HR for 3+ AST purchases versus none was 1.25 (95% CI 1.13 to 1.39). AST was also associated with injuries by an HR of 1.09 (95% CI 1.04 to 1.13). CONCLUSIONS: AST was associated with a small but statistically significant increased incidence of fractures. We cannot exclude reporting bias or residual confounders. The clinical inference is currently unclear.

Pre-morbid Laboratory Tests, Diseases, and Medications in Amyotrophic Lateral Sclerosis in Israel.

BACKGROUND: There is an unmet need for real-world data regarding laboratory results, co-morbidities, and medication use prior to the first symptoms of amyotrophic lateral sclerosis (ALS). Researchers must identify specific subpopulations at risk for developing ALS and understand pathogenic mechanisms preceding the clinical presentation of ALS as well as possible subclinical disease manifestations. OBJECTIVES: To valuate the role of laboratory results, co-morbidities, and medication use prior to the first symptoms of patients with ALS in Israel so that specific subpopulations at risk for developing ALS can be identified and for possible subclinical disease manifestations. To understand pathogenic mechanisms preceding the clinical presentation of ALS. METHODS: At the ALS clinic at Tel Aviv Sourasky Medical Center, 259 ALS patients insured by Maccabi Healthcare Services and seen between January 1998 and December 2017 were included. Comparisons of demographics, co-morbidities, medications taken, history of trauma, and laboratory tests prior to disease onset were performed between patients and 1295 matched controls. RESULTS: Prior to disease presentation, ALS patients had a higher frequency of hypertension and cardiovascular disease; presented more frequently with trauma and viral infections; more frequently used analgesics, non-steroidal anti-inflammatory drugs, narcotics, antibiotics, and antiviral medications; and had higher creatine kinase levels. CONCLUSIONS: ALS patients showed higher frequency of cardiovascular disease prior to diagnosis, as well as higher frequency of trauma, infections, and pain medication usage.

Identifying Profiles of Patients With Uncontrolled Type 2 Diabetes Who Would Benefit From Referral to an Endocrinologist.

OBJECTIVE: To compare the outcomes of glycemic uncontrolled diabetes mellitus type 2 patients receiving treatment from endocrinologists with those treated by primary care physicians. Additionally, this research aims to identify patient profiles that would benefit from personalized referral-a novel medical approach that aims to match the most suitable specialist for effectively managing patient while considering the patient's profile. METHODS: This retrospective cohort study uses the Maccabi Healthcare Services diabetes registry to match 508 pairs of glycemic uncontrolled diabetes mellitus type 2 patients treated by endocrinologists (EndoG) and primary care physicians (PcPG). Using a generalized additive model, we analyzed the hemoglobin A1c (HbA1c) trend over 1 year for each group. We employed the odds ratio (OR) from conditional logistic regression to determine the likelihood of favorable outcomes in the EndoG compared to the PcPG, using the entire cohort and subcohort profiles. RESULTS: The generalized additive model comparison indicated an improvement in HbA1c levels in both groups, with the EndoG outperforming the PcPG. Furthermore, the EndoG group had an OR = 2.27 (95% confidence interval, 1.6 to 3.2) for reducing HbA1c by at least 1% within a year and an OR = 1.68 (95% confidence interval, 1.02 to 2.76) for achieving low-density lipoprotein levels< 100 mg/dl. We identified 96 profiles with positive outcomes, all favoring treatment by endocrinologists. CONCLUSIONS: EndoG demonstrated superior HbA1c control over time and achieved better outcomes compared to PcPG. The identification of 96 profiles benefiting from endocrinologist referral emphasizes the potential of personalized referral.

Management and outcome of 500 multiple myeloma patients treated for first relapse outside clinical studies.

Treatment options for multiple myeloma (MM) at 1st relapse are expanding. The current study compared common 2nd line regimens administered in a real-world setting. MM patients registered in Maccabi health care services and treated with second line therapy during 2014-2020 were evaluated, analyzing factors affecting time to third line therapy (TT3T). The study included 500 MM patients, previously treated with proteasome inhibitor (PI)-based induction. Median age at second line treatment was 68.5 years (IQR: 61.6-76.4). Most patients received a triplet based induction composed of PI (n = 471, 94.2%), with (n = 71) or without IMID (n = 400), followed by second line treatment composed of lenalidomide-dexamethasone (RD) (n = 225, 45%) or lenalidomide-dexamethasone-daratumumab (RD-Dara (n = 104, 20.8%)). Multivariable analysis confirmed treatment type (RD-Dara vs. IMID) to be associated with a lower risk to progress to third line therapy; (HR = 0.5, 95% CI 0.3-0.86, p = 0.012). Within a median follow-up period of 22.5 months (intraquartile range 11.1-39.4 m), median TT3T was not reached in patients receiving RD-Dara vs. 32.4 months (95% CI 18.0-46.8 m) with IMID, 18 months (95% CI 10.4-25.6 m) with IMID-PI and 12.1 months (95% CI 5.6-18.7 m) with PI-based regimen. In contrast, PI vs. IMID-based therapy and increased body weight were associated with a higher likelihood of progression (HR = 2.56 (95% CI 1.49-4.42); HR = 1.43, (95% CI 0.96-2.14), p = 0.08). To conclude, second line therapy with RD-Dara was associated with a significantly longer TT3T compared with IMID-based regimen, longer than obtained with PI-IMID and PI-based regimens, in patients treated outside clinical studies and previously exposed to bortezomib.

Real-World Utilization of Molnupiravir during the COVID-19 Omicron Surge in Israel.

Molnupiravir (MOV) was introduced in Israel in January 2022 during the SARS-CoV-2 Omicron surge for high-risk patients contraindicated for nirmatrelvir/ritonavir. This retrospective cohort study aimed to describe characteristics of patients offered COVID-19 antiviral treatment in Maccabi Healthcare Services (antiviral treatment-eligible cohort; n = 5596) between 12 January and 28 February 2022, and the subset of these who were dispensed MOV (MOV-treated cohort; n = 1147), as well as outcomes following MOV dispensation. Median (interquartile range) age in the antiviral treatment-eligible and MOV-treated cohorts were 70.5 (61.1, 77.3) and 74.1 (64.3, 81.7) years, respectively. The MOV-treated cohort (male: 53.2%) had high rates of COVID-19 vaccination (91.4%) and comorbidities, including immunosuppression (40.0%) and chronic kidney disease (67.0%; eGFR < 30 mL/min/1.73 m2: 28.8%), and most used comedications either contraindicated or with major potential for drug-drug interactions with nirmatrelvir/ritonavir (87.3%). At 28 days post-MOV dispensation, the cumulative incidence (95% CI) of COVID-19-related hospitalization and/or all-cause mortality was 3.6% (2.5%, 4.6%), with similar rates across sexes and age groups (18-64 vs. ≥65 years), and lower rates among recently vaccinated and/or recently SARS-CoV-2-infected patients. These data describe the characteristics and outcomes for MOV-treated patients in Israel, whose clinical characteristics may preclude the use of nirmatrelvir/ritonavir to treat their COVID-19 infection.