Tzippy Shochat

Objective: Cushing syndrome (CS) is associated with depression and anxiety. This study compared treated mood and anxiety disorders between patients with CS and controls, assessing differences by etiology and remission status. Methods: A retrospective matched-cohort study of patients with endogenous CS (2000-2024) from the Clalit Health Services database. Each patient was matched with 5 controls by age, sex, socioeconomic status, and BMI. Mood and anxiety disorders were identified through affective drug dispensations (ADD). Drug discontinuation was defined as ≥1 month without dispensations. Results: The cohort included 540 patients with CS (mean age 47.79 ± 17.01 years; 64.44% women) and 2517 controls, with a median follow-up of 13.20 years (IQR 8.41-18.42). At baseline, patients with CS had nearly twice the odds of receiving ADD than controls (OR = 1.93, 95% CI,1.39-2.66), with a significant excess in women (12.93% vs. 6.93%, OR = 1.99, 95% CI, 1.38-2.87). During the entire follow-up, drug discontinuation rates did not differ (HR = 0.72, 95% CI, 0.50-1.04), whereas the risk of new-onset ADD was 2-fold higher in CS (HR = 2.23, 95% CI, 1.89-2.62). This increased risk was observed in both Cushing disease (HR = 2.44, 95% CI, 1.90-3.13) and adrenal CS (HR = 2.17, 95% CI, 1.64-2.88). Using a 2-year landmark analysis initiated 2 years after diagnosis, the increased risk persisted in patients who achieved remission (HR = 2.10, 95% CI, 1.59-2.78) and in those who did not (HR = 2.38, 95% CI, 1.60-3.55). Conclusion: Endogenous CS is associated with a persistently increased risk of treated affective disorders at diagnosis and throughout long-term follow-up, underscoring the need for ongoing psychological care.

Background: Patients with Cushing syndrome (CS) have a high prevalence of cardiovascular disease and other recognized risk factors for atrial fibrillation/flutter (AF/AFL); however, the prevalence of AF/AFL has not been well characterized in this population. Methods: We conducted a retrospective matched-cohort study using the Clalit Health Services database, including patients with CS and 1:5 matched controls. We assessed the risk of new-onset AF/AFL overall and according to disease etiology and remission status. Pre-existing AF/AFL was defined as >30 days before CS, and new-onset as within 30 days or thereafter. Results: The cohort included 609 patients with CS and 3,018 controls. Pre-existing AF/AFL was more common among patients with CS than controls (3.6% vs. 2.1%; OR 1.70, 95% CI 1.04–2.78). During a mean follow-up of 15 years, patients with CS had a significantly higher risk of developing new-onset AF/AFL compared with controls (HR 1.55, 95% CI 1.19–2.03). This increased risk was observed in both Cushing’s disease (CD) (HR 1.53, 95% CI 1.01–2.32) and adrenal CS (HR 1.70, 95% CI 1.06–2.74). AF/AFL risk did not significantly differ according to remission status, although a trend toward lower risk was observed. Multivariate analysis identified older age at diagnosis, male sex, hypertension, vascular disease and higher BMI as predictors for new-onset AF/AFL. Conclusion: CS is associated with an increased risk of AF/AFL. This elevated risk is observed across both CD and adrenal CS and persisted despite disease remission, underscoring the need for heightened awareness and close cardiovascular surveillance in this population. The increased risk of AF/AFL appears to be primarily driven by coexisting cardiovascular comorbidities rather than cortisol excess or other CS-specific features.

Background Patients with Cushing’s syndrome (CS) have higher weight and body mass index (BMI) compared to matched controls. We aimed to assess reversibility of weight gain (absolute weight and BMI decrease) following treatment for CS and identify predictors for weight loss. Methods A retrospective study using the Clalit Health Services database analyzed a cohort of patients with CS and age-, sex- and BMI-matched controls (up to five controls per case). Weight and BMI were assessed at baseline, one-year post-diagnosis and at the end of follow-up. Patients taking GLP-1 have been excluded from the analysis. Results The cohort included 308 CS patients (67.2% female, mean age 51.6 ± 17.4 years) and 1,020 controls (69.7% female, mean age 54.8 ± 16.9 years). After one year, CS patients who achieved remission experienced significant weight reduction from 85.1 ± 21.0 to 80.8 ± 22.7 kg and BMI decrease from 31.6 ± 7.4 to 29.9 ± 7.4 kg/m² (p < 0.01). By the end of 8.6 years of follow-up, CS patients continued to show significant reductions in both weight (85.0 ± 22.3 to 81.3 ± 22.8 kg, p < 0.01) and BMI (31.2 ± 7.6 to 29.9 ± 7.6 kg/m², p < 0.01), while controls showed slight increases in both. Among patients in remission by the end-of-follow-up, 44.0% (77/175) achieved ≥ 5% and 30.3% (53/175) achieved ≥ 10% weight loss. Patients with persistent CS exhibited no significant weight changes. Multivariate analysis identified female gender, baseline BMI ≥ 30 and a BMI decrease ≥ 1 kg/m² at one year, as predictors for ≥ 5% weight loss. Conclusion Approximately half of CS patients in remission achieved at least 5% decrease in BMI with long-term follow-up, and a third achieved more than 10% decrease. Disease remission, female gender, baseline BMI ≥ 30, and early BMI reduction, predicted a clinically significant weight loss.

We previously reported an increase in overall cancer risk in patients with endogenous Cushing’s syndrome (CS), mainly during the 10-year period following CS diagnosis. To identify predictors of cancer in patients with CS, we conducted this retrospective nationwide cohort study of patients with CS, diagnosed between 2000 and 2023 in Israel. The cohort comprised 609 patients with CS (age at diagnosis, 48.1 ± 17.2 years; 65.0% women) and 3,018 age-, sex-, socioeconomic status-, and body mass index-matched controls (1:5 ratio). Patients were grouped according to the occurrence of any malignancy within 10-years after the diagnosis of CS. Cox proportional hazards models, with death as a competing event, were used to identify predictors of cancer development. Independent predictors of cancer development in patients with CS included age ≥60 years (HR 1.75, 95% CI 1.01–2.68), male gender (HR 1.67, 95% CI 1.04–3.05), and adrenal-origin CS (HR 1.66, 95% CI 1.01–2.73). Baseline urinary-free cortisol levels were not associated with cancer development. Patients with ≥4 CS-associated comorbidities had a higher cancer risk (HR 1.76, 95% CI 1.03–3.02; age- and sex-adjusted). The overall 10-year risk of malignancy was twice as high in patients with CS compared to matched controls, with cancer developing, on average, 5 years earlier in patients with CS (62.3 ± 15.0 vs 67.2 ± 12.3 years). Cancer-related mortality at 10-years was twice as high in deceased patients with CS, compared to deceased controls. In conclusion, age ≥60 years at CS diagnosis, male gender, and adrenal-origin CS are independent predictors of cancer diagnosis within 10-years of initial confirmation of CS.

Objectives: To evaluate the discordance between patients’ global assessments (PGA) and evaluators’ global assessments (EGA) in psoriatic arthritis (PsA), and to explore the association of clinical variables, patient-reported outcomes (PROs) and ultrasound (US) factors with this discordance. Methods: Consecutive PsA patients (CASPAR criteria) were prospectively recruited and evaluated by a comprehensive clinical examination, PROs and sonographic assessment (including 52 joints, 40 tendons and 14 entheses). EGA was scored by rheumatologists blinded to the PGA. Discordance between PGA and EGA was considered significant if the delta was ≥3. The US assessor was blinded to the clinical data. The concordant and discordant groups were compared, and factors associated with discordance were evaluated through a multivariate regression analysis. Results: Of the 158 PsA patients who were included, 88 (55.7%) patients were considered discordant, with the mean difference between PGA and EGA of 3.3. The discordant group had significantly higher tender joint counts (TJC), enthesitis, C-reactive protein (CRP) and lower working status rates compared with the concordant group (P < 0.05). US scores were similar between the groups. Patients with discordance had significantly higher PsA activity scores, a higher prevalence of fibromyalgia and worse PROs, including pain, depression, fatigue and measures of quality of life (P < 0.05). On multivariate regression, higher TJC, lower swollen joint counts and depression were associated with greater discordance (OR 1.07, OR 0.85 and OR 1.05, respectively, P < 0.05). Conclusion: The discrepancy between PGA and EGA in PsA is characterized by worse disease activity scores and worse subjective measures but not by sonographic measures.

Objective: Patients with endogenous Cushing's syndrome (CS) have elevated mortality, particularly during active disease. A recent meta-analysis reported reduced mortality rates after 2000 in adrenal CS and Cushing disease (CD), though many studies lacked population-matched controls. Methods: Nationwide retrospective study (2000-2023) in Israel using the Clalit Health Services database to assess all-cause mortality in patients with endogenous CS matched 1:5 with controls by age, sex, socioeconomic-status, and body mass index (BMI). Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, impact of hypercortisolism remission, disease source, and mortality risk factors. Results: The cohort included 609 cases with CS (mean age 48.1 ± 17.2 years; 65.0% women) and 3018 matched controls (47.9 ± 17.2 years; 65.4% women). Over a median follow-up of 16 years, 133 cases (21.8%) and 472 controls (15.6%) died (HR = 1.44, 95% CI, 1.19-1.75). Both patients with CD (HR = 1.73, 95% CI, 1.27-2.36) and adrenal CS (HR = 1.31, 95% CI, 1.00-1.81) had increased mortality risk. Patients without remission within 2 years had a higher mortality risk than those achieving remission (HR = 1.44, 95% CI, 1.00-2.17). Mortality was similar for CD and adrenal CS (HR = .83, 95% CI, .56-1.24). Older age, male gender, and prior malignancy were independent risk factors for mortality. Conclusion: This is the largest national cohort study on mortality risk in CS over the past 2 decades, showing a significantly higher risk compared to matched controls in a homogeneous database. While etiology had no impact, remission significantly affected mortality, highlighting the importance of disease control for long-term survival.

Objective: Endogenous Cushing's syndrome (CS) has been linked with an increased risk of cancer. We aimed to evaluate the association between cancer risk and disease remission postsurgery in adrenal CS and Cushing's disease (CD). Design: A nationwide retrospective matched-cohort study of patients with CS diagnosed between 2000 and 2023 in Israel, using Clalit Health Services’ database. Methods: Patients with CS were matched 1:5 with controls by age, sex, socioeconomic status, and BMI. Remission status postsurgery was assessed within 2 years after the diagnosis of CS. The outcome measured was time to first diagnosis of malignancy, at least 3 years post-CS diagnosis, excluding those who died or developed cancer earlier. Malignancy risk, stratified by remission status, was evaluated using Cox proportional hazards with death as a competing event. Results: The cohort comprised 388 cases and 1862 controls [mean age at diagnosis, 47.4 ± 16.8 years; 1534 (68.2%) women]. Among patients with CD, those who did not achieve remission within 2 years postdiagnosis (n = 69) had a higher risk of malignancy compared to those who achieved remission (n = 99) (HR 3.89, 95% CI 1.41-10.75). Cancer risk in patients with CD who achieved remission was similar to that of the controls (HR 0.58, 95% CI .23-1.47). In patients with adrenal CS, the risk of cancer was comparable between those who did not achieve early remission (n = 39) and those who did (n = 113) (HR 1.68, 95% CI .83-3.40). Conclusion: Though cancer risk is higher in both CD and adrenal CS, we have shown that achieving surgical remission within 2 years may attenuate cancer risk in patients with CD, but not in those with adrenal CS.

Context: Leukocytosis frequently noted in Cushing’s syndrome (CS), along with other blood cell changes caused by direct and indirect cortisol effects. Objective: Assess baseline white blood cell (WBC) profile in CS patients compared to controls and WBC changes pre- and post-remission after surgical treatment for CS. Design: A comparative nationwide retrospective cohort study. Setting: Data from Clalit Health Services database. Patients: 297 patients (mean age 51 ± 16.1 years, 73.0% women) with CS and 997 age-, sex-, body mass index-, and socioeconomic status-individually matched controls. Ectopic CS or adrenal cancer patients were excluded. Main outcome measure: Mean WBC, neutrophils, and neutrophil-to-lymphocyte ratio (NLR) two-years before and after pituitary or adrenal surgery. WBC and neutrophils are expressed as Kcells/µl. Results: At baseline, leukocytosis was observed in 21.5% of patients with CS vs. 8.9% of controls (P < 0.001). Patients with CS had significantly higher WBC (8.8 ± 2.88 vs. 7.54 ± 2.45, p < 0.0001), neutrophils (5.82 ± 2.38 vs. 4.48 ± 1.97, p < 0.0001), and NLR (3.37 ± 2.63 vs. 2.27 ± 1.86, p < 0.0001) compared to controls, regardless of pituitary or adrenal source of hypercortisolemia. Post-surgery, patients with CS experienced significant decreases in mean WBC (-0.57 ± 2.56, p < 0.0001), neutrophils (-0.84 ± 2.55, p < 0.0001), and NLR (-0.63 ± 2.7, p < 0.0001). Despite achieving disease remission, patients with CS still had higher WBC (8.11 ± 2.4 vs. 7.46 ± 2.17, p = 0.0004) and neutrophils (4.71 ± 2.10 vs. 4.41 ± 1.87, p = 0.03) compared to controls. Patients with CD and baseline leukocytosis had lower remission rate than those with normal WBC (36.7% vs. 63.9%, p = 0.01). Conclusions: At diagnosis, CS patients have elevated WBC, neutrophils, and NLR compared to controls. Remission does not normalize WBC levels in all patients, and baseline leukocytosis predicts a poorer remission prognosis in CD.