Maccabi Institute for Health Services Research

To investigate the impact of living in a war zone on acceleration of skeletal maturation and development of permanent teeth. A total of 272 Israeli children and adolescents aged 9-15 years participated in this study. The Gaza group included 106 participants from the Gaza envelope area (within 7 km of the Gaza Strip border), while the central group consisted of 166 participants from central Israel. Skeletal maturation and dental development were assessed using lateral cephalometric and panoramic radiographs, respectively. Significant differences were observed in all maturation variables, including skeletal maturation as well as maturation of the upper and lower second molars (right and left) and upper canines. The Gaza envelope group exhibited more advanced and accelerated maturation than the central group (P < .0005). Positive correlations were identified among tooth maturation, chronological age, and skeletal development (0.519 < r < 0.599). Linear regression analysis revealed that the maturation of the lower left second molar accounted for 47.8% of variance in skeletal maturation. In this study, we confirm that children living under the stress of a conflict zone exhibited earlier skeletal maturation and accelerated eruption of permanent second molars and upper canines than their peers. The early eruption of second molars and canines, particularly the lower left second molar, may serve as a predictive marker for pubertal progression.

Abstract Background The increased lymphoma risk in IBD has been traditionally attributed to immunosuppressive therapy. Previous studies lacked power to explore whether the risk is confounded by disease severity. In this two nationwide cohort study, we aimed to estimate lymphoma rates among patients exposed to different treatments, and to adjust for disease severity. Methods Federated learning methods were used to enable multi-center analyses from Israel and Sweden (2005-2023) without sharing individual-level data; the models run from a shared server as if using a single combined dataset while preserving patient privacy. Treatment exposure was classified as naïve, thiopurines, anti-TNF, or combotherapy with anti-TNF+thiopurines. Lymphoma incidence-rates with age and sex adjusted hazard-ratios (aHR) were calculated by treatment group using a once-exposed-always-exposed approach. Disease load was assessed using hierarchical-clustering of laboratory tests annually. Time-varying Cox models, adjusted for age, sex, and year of IBD diagnosis evaluated the impact of disease severity and treatments on lymphoma. Results We included 97,464 patients with IBD and 644,556 non-IBD matched controls, with a median follow-up of 7.6 years (IQR 3.7-11.9). Overall, 304 IBD patients (0.32%; incidence rates 3.97/10,000) and 1,246 controls (0.19%; 2.42/10,000) developed lymphoma (aHR 2.18 [95%CI 1.9-2.5]). The risk was higher for both non-Hodgkin lymphoma (aHR 2.1 [95%CI 1.8-2.4]) and Hodgkin disease (aHR 2.9 [2.1-4.1]; Figure 1). Treatment-naïve patients had higher hazard of lymphoma than non-IBD controls (aHR 1.51[95%CI 1.26–1.81]). Among IBD patients, anti-TNF-monotherapy (aHR 1.61[95%CI 1.17–2.42]), and combotherapy (aHR1.86 [1.13–3.07]) had increased risk of lymphoma vs. naïve patients. Separately, higher disease severity over time was independently associated with an increased risk of lymphoma (HR 1.36 [1.14-1.63]). In a combined model including treatments and disease severity, adjusted for age and sex, the only independent variables were combotherapy (HR 2.22 [1.28-3.85]) and disease severity (HR 1.36 [1.13-1.62], while treatment with thiopurines and anti-TNF alone were not associated with lymphoma (Table 1). Conclusion IBD was associated with higher risk of lymphoma compared with controls even in untreated patients. The associations of thiopurines and anti-TNF with lymphoma were confounded by disease severity, whereas combotherapy remained independently associated with higher risk. Conflict of interest: Mrs. Lujan, Rona: No conflict of interest Atia, Ohad: No conflict of interest Everhov, Åsa H: No conflict of interest Friss, Chagit: No conflict of interest Focht, Gili: Other: Received in the past 3 years consultation fee from Lilly Sokolik, Menachem: No conflict of interest Voghera, Siri: No conflict of interest Söderling, Jonas: No conflict of interest Osooli, Mehdi: No conflict of interest Ludvigsson, Jonas: No conflict of interest Ben-Tov, Amir: No conflict of interest Zacay, Galia: No conflict of interest Matz, Eran: No conflict of interest Zekaria, Shir: No conflict of interest Waterman, Matti: Personal Fees: Consultant and speaker fees from Abbvie, Janssen, Neopharm, Takeda, Pfizer Paid advisory board participation: Janssen, Takeda, BMS, Abbvie, Pfizer Consultant: Medtronic Turner, Dan: Consultation fee: Janssen, Pfizer, Ferring, Abbvie, Takeda, Prometheus Biosciences, Lilly, SorrisoPharma, Boehringer Ingelheim, Galapagos, BMS, AlfaSigma, Merck, Gentech Research support: Janssen, Abbvie, Takeda, Pfizer Royalties: Shaare Zedek Medical Center, Hospital for Sick Children Olen, Ola: Karolinska Institutet has received research grants from Pfizer, Janssen, AbbVie, Takeda, Ferring, Bristol Myers Squibb, and Alfasigma for projects led by Olén. Ola Olén has also received fees for lectures from Pfizer, Janssen, Bristol Myers Squibb, and Takeda.

Abstract Background The concept of dual biologics therapy (DBT) in inflammatory bowel diseases (IBD) generates growing interest. Small-scale studies suggest its effectiveness, but data from unselected cohorts remain scarce. This nationwide study aimed to evaluate the effectiveness and durability of DBT in IBD. Methods We utilized data from the epi-IIRN cohort that includes data from all four health maintenance organizations (HMOs) in Israel, covering 98% of the population. Medication data are highly accurate since they are being dispensed and subsidized via the HMO. Patients with IBD who received concurrent biologic or small-molecule therapy in parallel for at least one month were included. We further evaluated the time to discontinuation of combination therapy and the time to initiation of corticosteroid treatment. Results Among 74,372 patients with IBD, 63 patients (0.08%) had documented DBT, including 65% with Crohn’s disease and 35% with ulcerative colitis with a median follow-up of 5.5 months since starting DBT [IQR 3.85-12.5]. While 57% of patients had pediatric-onset disease, most DBT (65%) were initiated during adulthood (mean age 31.9 years). The most commonly used agents were anti-TNF (n = 42) and vedolizumab (n = 38), with the most frequent combination being anti-TNF+vedolizumab (n = 23; 36.5%), followed by anti-TNF+ustekinumab (n = 14; 22%), ustekinumab+vedolizumab (n = 7; 11%), tofacitinib+vedolizumab (n = 6; 9.5%), and upadacitinib+ustekinumab (n = 5; 7.9%). Rapid decline in treatment durability was observed during the first six months, with a median DBT duration of 6.3 months (95% CI, 5.0-12.5). By the end of follow-up, 27% (17/63) of patients remained on DBT (none required corticosteroids); 47.6% (30/63) discontinued one biologic yet continued without steroid treatment, and 25.4% (16/63) discontinued one biologic and subsequently required systemic or locally active corticosteroids (Figure). No meaningful differences were observed between Crohn’s disease and ulcerative colitis; at 6 months, systemic and locally active steroid use was similar (8-9 percent for systemic and 9-16 percent for locally active; log-rank p &amp;gt; 0.7). Conclusion In this nationwide study, DBT was infrequently used and typically discontinued within months. Nevertheless, the low rates of subsequent corticosteroid use might suggest that DBT discontinuation reflected disease improvement rather than treatment failure. Alternatively, the early discontinuation could, in part, reflect clinicians’ caution regarding the safety of combination therapy. These findings provide further real-world evidence supporting the potential role of short-term DBT in IBD management and highlight the need for further evaluation of both its efficacy and safety. Conflict of interest: Yuval Bar-Asher, Shira: No conflict of interest Sokolik, Menachem: No conflict of interest Ben-Tov, Amir: No conflict of interest Zacay, Galia: No conflict of interest Matz, Eran: No conflict of interest Zekaria, Shir: No conflict of interest Dotan, Iris: No conflict of interest Turner, Dan: No conflict of interest

Abstract In recent decades, global crises like the COVID-19 pandemic and natural disasters have significantly challenged the ability to provide care for older adults, highlighting a critical research priority. Israel, with its advanced system of care for older adults and strong community support, performed well during COVID-19. This report describes efforts to maintain care during the June 2025 Israel-Iran war, a period of physical threat, disrupted medical services, psychological distress, and weakened social supports due to displacement and infrastructure damage. We highlight innovative strategies ensuring continuity of medical, mental health, and essential social services for older adults. Israel’s approach to emergency care for older adults rested on three pillars: (i) Leveraging past experience: Protocols from previous emergencies, including COVID-19, were quickly activated. This ensured continuity of care for older adults, especially those evacuated or in unsafe apartments, balancing safety with independence. (ii) Coordinated communication: Ongoing national and municipal collaboration and communication about at-risk older adults, enabled effective and timely, targeted interventions. (iii) Volunteerism and Civil Initiatives: A massive surge of community-led volunteer efforts provided transport, medications, and evacuee assistance, critically addressing urgent needs beyond government capacity. In conclusion, these three pillars – rapid response based on prior experience, a strong national and municipal system of communication and collaboration, and robust volunteerism – enabled continuous, high-quality care for older adults during this major crisis., These lessons can inform other systems aiming to enhance their resilience and capacity to provide care to older adults during emergency situations.

Abstract Background Optimizing low-density lipoprotein cholesterol (LDL-C) is crucial for both primary and secondary prevention in atherosclerotic cardiovascular disease (ASCVD). Clinical guidelines for managing LDL-C recommend lower targets with increasing patient risk level and consideration of appropriate intensification of lipid lowering therapy (LLT). Understanding trends in LLT use can help inform clinical practice and health policy. This study analysed long-term trends in LLT use among patients with ASCVD among the general population within the Maccabi Health Services (MHS, a nationwide payer-provider health plan in Israel, representing one quarter of the population) database. Methods We retrospectively examined deidentified electronic health records and pharmacy data from MHS between 2013 and 2023. We included adults aged 40–79 years with a first non-fatal ASCVD event between January 2006 and December 2023 and assessed annual LLT utilization patterns following index event. Using multivariable logistic regression, we identified factors independently associated with stable LLT utilization at 1, 3, 5, and 8 years of follow-up among patients who experienced their first event in 2013 or later and survived for the corresponding duration. Stable LLT utilization was proxied as the purchase of at least one LLT of any type in each follow-up year. Results Among 44,410 adults experiencing their first ASCVD event, approximately 86% were on any LLT in any of the follow-up years. Among them, we observed a significant decrease in the use of statin monotherapy and increase in combination use of statins and ezetimibe between 2013 and 2023, dropping from 76% to 49% and rising from 4.3% in 2013 to 31.6% in 2023, respectively (p&amp;lt;0.001, Figure 1). The utilization of PCSK9 inhibitors has also grown steadily, from 0.02% in 2016 to 3.15% in 2023, mostly in combination with other LLTs. Across all subgroups, consistent LLT use was independently associated (Figure 2) with male sex, higher socioeconomic status (SES), an index event of an MI (compared to ischemic stroke, PAD or carotid endarterectomy), a history of diabetes, hypertension, or LLT use prior to their index event. Younger age was independently associated with less LLT use. Conclusions We observed steady overall LLT use and increasing combination LLT use over the last decade among patients in MHS following an ASCVD event. Observations underscore the need to target certain groups of patients in guideline directed LLT use following ASCVD events, particularly among the younger population, women, those with lower SES, and those experiencing ischemic stroke or PAD. Targeted, innovative interventions may be needed to address barriers to, continued implementation of, and adherence to, guideline recommended LLT. Further research is warranted to explore the underlying causes of LLT non-utilization and develop effective strategies to mitigate this challenge.

We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23-1.52 and 1.19, 1.12-1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.

ABSTRACTBackgroundThe clinical trials used to approve COVID-19 vaccines excluded pregnant women, and existing safety assessments of COVID-19 vaccination, particularly during early stages of pregnancy, are limited to observational studies prone to various types of potential bias, including healthy vaccinee bias.MethodsThe study includes pregnancies in Israel with last menstruation period (LMP) between March 1, 2016 and February 28, 2022. The main analysis presents observed-to-expected comparisons of the number of eventual fetal losses among pregnant women exposed to mRNA COVID-19 vaccination (almost all Pfizer) during gestational weeks 8-13 and 14-27, respectively. Women vaccinated for influenza during gestational weeks 8-27, as well as women vaccinated prior to pregnancy for COVID-19 or influenza, were used as comparative controls. Cohort-specific expected number of fetal losses are established based on estimates from a regression model trained on historical data from 2016-2018 that incorporates individual-level risk factors and gestational week of each pregnant woman included in the cohort.ResultsAnalysis of 226,395 singleton pregnancies in Israel from 2016 to 2022 indicates that COVID-19 vaccination with dose 1 during weeks 8-13 was associated withhigher-than-expectedobserved number of fetal losses of approximately 13 versus 9 expected for every 100 exposed pregnancies, i.e., nearly 3.9 (95% CI: [2.55-5.14]) additional fetal losses above expected per 100 pregnancies Most of the excess fetal losses occurred after gestational week 20 and nearly half occurred after gestational week 25. Similarly, women vaccinated with dose 3 during weeks 8-13 exhibited ahigher-than-expectednumber of fetal losses with nearly 1.9 (95% CI: 0.39-3.42]) additional fetal losses above expected per 100 pregnancies. In contrast, pregnant women vaccinated for influenza during weeks 8-27 exhibited a consistentlylower-than-expectedobserved number of fetal losses, likely the result of healthy vaccinee bias. Women vaccinated for COVID-19 or influenza prior to pregnancy exhibitedaccording-to-expectedorlower-than-expectednumbers of fetal losses.ConclusionThe results provide evidence for a substantiallyhigher-than-expectednumber of eventual fetal losses associated with COVID-19 vaccination during gestational weeks 8-13.

RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between rheumatoid arthritis and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD) with a view to updating FRAX. The resource comprised 1,909,896 men and women, aged 20-116 years, from 29 prospective cohorts in which the prevalence of RA was 3% or less (primary analysis) and an additional 17 cohorts with a prevalence greater than 3% (supplementary analysis). The association between RA and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. In the primary analysis, RA was reported in 1.3% of individuals. During 15,683,133 person-years of follow-up, 139,002 fractures occurred, of which 27,518 were hip fractures. RA was associated with an increased risk of any clinical fracture (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.35-1.65). The HRs were of similar magnitude for osteoporotic fracture and MOF but higher for hip fracture (HR = 2.23; 95% CI 1.85-2.69). For hip fracture, there was a significant interaction with age with higher HRs at younger ages. HRs did not differ between men and women and were independent of exposure to glucocorticoids and femoral neck BMD. Lower HRs were observed in the supplementary analysis cohorts, particularly in those with a high apparent prevalence of RA, possibly from conflation of RA with osteoarthritis. A diagnosis of RA confers an increased risk of fracture that is largely independent of BMD, sex, and corticosteroids. RA should be retained as a risk factor in future iterations of FRAX with updated risk functions to improve fracture risk prediction.

Not available.

Background:Patients with autoimmune inflammatory rheumatic diseases (AIIRD) are susceptible to pneumococcal infection. Despite The European Alliance of Associations for Rheumatology (EULAR) recommendations for pneumococcal vaccination for most patients with AIIRD [1], the uptake of pneumococcal vaccination remains suboptimal. COVID-19 pandemic has highlighted the importance of vaccination. Yet, its impact on pneumococcal vaccination in AIIRD patients is unknown.Objectives:1.To describe temporal trends in PCV13 vaccination during 2017-2020 in order to explore the impact of the onset of the COVID-19 pandemic on PCV13 vaccination patterns in patients with common AIIRD, using data from Maccabi Healthcare Services [MHS], the 2nd largest of state-mandated health plans in Israel.2.To describe temporal trends in the characteristics of AIIRD patients newly vaccinated with PCV13 in 2017-2020.Methods:A retrospective study was performed using de-identified MHS electronic healthcare data, including adult patients with rheumatoid arthritis (RA; ICD-9: 714.0), psoriatic arthritis (PsA; ICD-9: 696.0), systemic lupus erythematosus (SLE; ICD-9: 710.0), or ankylosing spondylitis (AS, ICD-9: 720.0). PCV13 coverage was described by calendar year among prevalent patients at 4 time points: 31/12/2017, 31/12/2018, 31/12/2019 and 31/12/2020, overall and by demographic and clinical characteristics. Vaccine coverage rates were calculated on 31 December of each calendar year by dividing the number of vaccinated individuals by the total number of prevalent patients. The annual percentage change in vaccination coverage (VC) was calculated (VC minus VC in previous year/ VC in previous year X 100). Characteristics of patients newly-vaccinated with PCV13 were compared across calendar years using Chi-squared and Kruskal-Wallis tests.Results:The study population characteristics are presented in Table 1 (total Ns: 15898 [2017], 16736 [2018], 17731 [2019] and 1878 [2020]). Among the 2020 prevalent population, the median age was 58.6 years (64.9% female) and the median AIIRD duration was approximately 10 years, with 69.0% and 56.4% having previously been treated with DMARDs ever and in the past 5 years, respectively. Across all years, vaccination coverage with PCV13 was highest in the following subgroups: men, age ≥65 years, high socioeconomic status (SES), and RA patients, followed by PsA and SLE in a sequential order (Figure 1). Overall, PCV13 vaccination coverage increased from 2.3% at the end of 2017 to 13.0% at the end of 2019, then reached 31.1% at the end of 2020. Similar trends over time were observed in subgroup analyses by diagnosis and age groups. The annual percentage increase in PCV13 vaccination coverage from 2019 to 2020 was largest among patients with PsA. PCV13 coverage among patients without prior use of anti-rheumatic treatments remained below 2% in 2017-2019, increasing to 7.8% by the end of 2020.Among 5659 patients who were newly vaccinated with PCV13 in 2017-2020, the median age at PCV13 vaccination increased over time from 57 years in 2017-2018 to 61-9 years in 2020. A significant change in SES distribution among PCV13-vaccinated patients was observed over time; while an increasing proportion of vaccinated patients resided in low SES areas (from 2.2% in 2017 to 22.6% in 2019), 2020 was characterized by a relatively higher SES. Overall, 9.7% of PCV-13 vaccinated patients were never treated with DMARDs, with no clear trend observed over time. Over time, smokers and patients with comorbidities, such as diabetes and hypertension, accounted for a relatively higher proportion of PCV13-vaccinately patients. While 2017-2019 was characterized by an increasing prevalence of immunosuppression (from 22.4% to 28.8%), patients vaccinated in 2020 were relatively less likely (26.8%) to be treated with immunosuppressants.Conclusion:The results of the real-world analysis of patients with AIIRD in a large healthcare database in Israel indicate that PCV13 vaccination coverage increased over time across major demographic and comorbidity subgroups, prior to and during 2020, the start of the COVID-19 pandemic.REFERENCES:[1] Furer V. Ann. Rheum. Dis. 79, 39–52 (2020).Acknowledgements:NIL.Disclosure of Interests:Victoria Furer: None declared, Clara Weil: None declared, Sivan Gazit: None declared, Gabriel Chodik: None declared, Shera Ann Slav AbbVie Inc., AbbVie Inc., Shiran Nafterlberg Blonder AbbVie Inc., AbbVie Inc., Ori Elkayam: None declared.