Israel Medical Association Journal

Background: The use of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs) is emerging for lowering low-density lipoprotein cholesterol (LDL-C). However, real-world data is lacking for their use among elderly patients.

Objective: To define the characteristics of elderly patients treated with PCSK9 mAbs and to evaluate the efficacy and tolerability compared with younger patients.

Methods: We conducted a retrospective cohort study of elderly patients (≥ 75 years at enrollment) treated with PCSK9 mAbs for primary and secondary cardiovascular prevention. Data were retrieved for demographic and clinical characteristics; indications for treatment; agents and dosages; concomitant lipid lowering treatment; LDL-C levels at baseline, 6, 12 months, and at the end of follow up. Data also included achieving LDL-C target levels and adverse effects.

Results: The cohort included 91 elderly patients and 92 younger patients, mean age 75.2 ± 3.76 and 58.9 ± 7.4 years (P < 0.0001). Most patients (82%, 80%) were in high/very high-risk categories. For almost all (98%, 99%), the indication was statin intolerance, with PCSK9 mAb monotherapy the most prevalent regimen. The average follow-up was 38.1 ± 20.5 and 30.9 ± 15.8 months (P = 0.0258). Within 6 months the LDL-C levels were reduced by 57% in the elderly group and by 59% in the control group (P = 0.2371). Only 53% and 57% reached their LDL-C target levels. No clinically significant side effects were documented.

Conclusion: PCSK9 mAbs have similar effects and are well tolerated among elderly patients as in younger patients.

Background: Trabecular bone score (TBS) reflects vertebrae microarchitecture and assists in fracture risk assessment. The International Society of Clinical Densitometry postulates that the role of TBS in monitoring antiresorptive therapy is unclear. Whether changes in TBS correlate with bone resorption measured by bone turnover markers is not known.

Objectives: To determine whether longitudinal changes in TBS correlate with C-terminal telopeptide (CTX) of type I collagen.

Methods: Examinees with two bone mineral density (BMD) measurements were detected via the institutional database. Over 5.8% change in TBS was considered least significant and patients were grouped accordingly (increment, decrement, or unchanged). CTX, BMD, co-morbidities, incident fractures, and medication exposure were compared between the groups by Kruskal-Wallis. The correlation between TBS and BMD change and CTX in a continuous model was analyzed by Pearson's correlation coefficient.

Results: In total, 110 patients had detailed medical records. In 74.5%, TBS change was below least significant change. Two other TBS categories, fracture incidence or medication exposure, did not differ by CTX. In the continuous model, BMD and TBS change was positively correlated (r = 0.225, P = 0.018). A negative correlation was observed between BMD change and CTX. The decrease in BMD level was associated with higher CTX (r = -0.335, P = 0.004). No correlation was observed between CTX and TBS.

Conclusions: No correlation between TBS dynamics and bone resorption marker was found. Clinical interpretation and implication of longitudinal TBS changes should be further explored.

Background: Fibromyalgia syndrome (FMS) is characterized by widespread musculoskeletal pain and tenderness with associated neuropsychological symptoms such as fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression. Osteoporosis is defined as a reduction of bone density. Previous studies to determine an association of FMS with osteoporosis showed mixed results, partially due to small sample sizes and lack of statistical power.

Objectives: To evaluate the association of FMS with osteoporosis.

Methods: We conducted a case-control study utilizing the database from Israel’s largest health maintenance organization. FMS patients were compared to age- and sex-matched controls. Data were analyzed using chi-square and t-tests. Multivariable logistic regression models assessed the association between osteoporosis and FMS. Spearman’s rho test was used for correlation.

Results: We utilized data from 14,296 FMS patients and 71,324 age- and sex-matched controls. Spearman's rho test showed a significant correlation between FMS and osteoporosis (correlation coefficient 0.55, P < 0.001). A logistic regression for osteoporosis showed an odds ratio [OR] of 1.94 (95% confidence interval [95%CI] 1.83–2.06, P < 0.001) for FMS compared to controls and found higher body mass index to be slight protective (OR 0.926, 95%CI 0.92–0.93, P < 0.001).

Conclusions: There is a significant correlation between FMS and osteoporosis. Early detection of predisposing factors for osteoporosis in FMS patients and implementation of suitable treatments and prevention measures (such as dietary supplements, resistance or weight bearing exercise, and bone-mineral enhancing pharmacological therapy) may reduce both occurrence rate and severity of osteoporosis and its complications, such as fractures.

Background: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients.

Objectives: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. 

Methods: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. 

Results: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data.

Conclusions: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported. 

 

Background: Atherosclerosis is a systemic disease. Nevertheless, the role of specific biomarkers as indicators for both coronary and carotid diseases is debatable.

Objectives: To evaluate the association of biomarkers with coronary and carotid disease.

Methods: We studied 522 consecutive patients with stable angina. All underwent coronary angiography and carotid duplex study on the same day. Patients with no apparent carotid plaques were evaluated for carotid intima-media thickness (CIMT) using an automated system that sampled over 100 samples in each carotid artery. Biochemical markers of cardiovascular disease risk were obtained at the time of coronary angiography, including serum lipid levels, hemoglobin A1C (HbA1c), white blood cell count, fibrinogen and high sensitivity C-reactive protein (hs-CRP).

Results: The mean age of the patients was 66 ± 11; 73% were males. Significant carotid stenosis was associated with higher hs-CRP (9.4 ± 17 vs. 6.3 ± 13 mg/L, P = 0.001), while high HbA1c (6.7 ± 1.6 vs. 5.8 ± 0.8%, P < 0.001) and low high density lipoprotein levels (40 ± 9 vs. 47 ± 14 mg/dl, P < 0.001) were linked with advanced coronary artery disease severity. In contrast, CIMT was not related to any of the biomarkers evaluated.

Conclusions: Although atherosclerosis is considered a systemic disease, different biomarkers are associated with coronary and carotid artery disease. Identifying the specific biomarkers for each disease is important for both prevention and for exposing the underlying pathophysiologic mechanism.

 

Background: High density breast mammography has been associated with a greater risk for breast cancer and an increased likelihood of false negative results. 

Objectives: To assess whether the degree of mammographic breast density correlates with an increased risk for the presence of radiographic findings requiring further histological investigation. 

Methods: Included in the study were 2760 consecutive screening mammograms performed in a large volume, early detection mammography unit. All mammograms were complemented by high resolution ultrasound and interpreted by a single expert radiologist. Breast density (BD) was evaluated using a semi-quantitative 5 grade scale and grouped into low breast density (LBD) and high breast density (HBD) mammograms. Demographic and all relevant obstetric, personal and family history of breast cancer data were recorded. 

Results: Of the 2760 mammograms 2096 (76%) were LBD and 664 (24%) were HBD. Mean age of the LBD and HBD groups was 59 ± 10.5 and 50.9 ± 9.3 years respectively (P = 0.001). Breast density significantly correlated with presence of mammographic findings requiring further histological assessment (8.7% and 12.3% for LBD and HBD respectively, P < 0.01). In women younger than 60 years in whom histological assessment was required due to these findings, malignant pathology was significantly more prevalent in the HBD group (2.3% and 4.1% respectively, P = 0.03). Age, parity, patient history and HBD were identified as independent risk factors for any pathological mammographic finding. 

Conclusions: Highly dense mammography, aside from being an indicator of higher risk for breast cancer, appears to be associated with a significantly higher incidence of findings that will prompt further investigation to achieve a definite diagnosis. 

 

Background: While earlier studies indicated that cholesterol levels decrease significantly after an acute myocardial infarction (MI), a more recent study refuted this observation. 

Objectives: To assess changes in plasma lipid levels after onset of acute MI, and determine important predictors of lipid dynamics.

Methods: We prospectively measured lipid levels of patients who presented with an acute MI. Blood samples were drawn on admission to the hospital (day 1), after fasting at least 12 hours overnight (day 2), and on the 4th day of hospitalization (day 4). 

Results: Of 67 acute MI patients, 30 were admitted for ST elevation MI (STEMI) and 37 for non-STEMI. Both total cholesterol and low density lipoprotein cholesterol (LDL-C) levels decreased significantly (by 9%) in the 24 hours after admission and by 13% and 17% respectively on day 4. High density lipoprotein cholesterol (HDL-C) levels as well as triglycerides did not change significantly. Independent predictors of LDL-C decrease were the presence of diabetes mellitus [odds ratio (OR) 6.73, P = 0.01), and elevated cardiac troponin T (cTnT) levels (OR 1.81, P < 0.04).

Conclusions: LDL-C levels decrease significantly after an acute MI. The reduction is correlated with cTnT levels. Diabetes is a strong independent predictor of LDL-C decrease. In acute MI patients only measurements taken within 24 hours of onset should be used to guide selection of lipid-lowering medication.

 

 Background:  Pomegranate extract (POMx) consumption has been shown to reduce the incidence and severity of collagen-induced arthritis in mice.

Objectives:  To investigate whether pomegranate consumption affects disease activity in patients with rheumatoid arthritis (RA), in relation to their serum oxidative status.

Methods:  In this pilot 12 week open-labeled study eight patients with active RA consumed POMx (10 ml/day) for 12 weeks. Patients’ joint status and serum oxidative status (lipid peroxidation, total thiols group, paraoxonase 1 activity) were evaluated at baseline and at week 12.

Results:  Six patients completed the study. POMx consumption significantly (P < 0.02) reduced the composite Disease Activity Index (DAS28) by 17%, which could be related mostly to a significant (P < 0.005) reduction in the tender joint count (by 62%). These results were associated with a significant (P < 0.02) reduction in serum oxidative status and a moderate but significant (P < 0.02) increase in serum high density lipoprotein-associated paraoxonase 1 (PON1) activity. The addition of POMx to serum from RA patients reduced free radical-induced lipid peroxidation by up to 25%.

Conclusions:  The pomegranate consumption reduced DAS28 in RA patients, and this effect could be related to the antioxidative property of pomegranates. Dietary supplementation with pomegranates may be a useful complementary strategy to attenuate clinical symptoms in RA patients.

Background: Several murine models are susceptible to atherosclerosis, such as low density-lipoprotein receptor-deficient (LDLR^-/-) and apolipoprotein E-deficient (apoE^-/-) mice, and are used for studying pathophysiological mechanisms. Atherosclerotic lesions in the aortic valve and thoracic/abdominal aorta are commonly associated with hyperlipidemia. We recently demonstrated the development of large atherosclerotic plaques in Helicobacter pylori-infected heterozygous LDLR^+/- apoE^+/- mice.

Objectives: To measure novel biomarkers related to atherosclerosis, blood coagulation, and oxidative stress in order to investigate their possible pathogenic roles in atherosclerosis-prone mice.

Methods: Mice were fed with a normal chow diet or high-fat diet and sacrificed at different age intervals to measure aortic plaque size. Plasma cholesterol was enzymatically measured. Enzyme-linked immunosorbent assay was used to measure oxidized LDL (oxLDL)/beta-2-glycoprotein I (β2GPI) complexes, immunoglobulin M (IgM) antibodies against native LDL, oxLDL, or oxLDL/β2GPI, and urine 11-dehydro-thromboxane B₂ (11-dhTxB₂) or 8-hydroxy-deoxyguanosine.

Results: There was a parallel increase in plaque size, plasma cholesterol, and urinary 11-dhTxB₂ in atherosclerosis-prone mice. In contrast to atherosclerosis-prone strains, an elevation of urinary 11-dhTxB₂ with no significant plaque generation was observed in LDLR^+/- apoE^+/- mice. The atherogenic autoantigen oxLDL/β2GPI complex was detected only in LDLR^-/- mice. These levels seem to depend on plaque size. IgM antibodies against oxLDL in apoE^-/- mice were found, accompanied by atherosclerotic progression.

Conclusions: Progression of atherosclerotic lesions was associated not only with cholesterolemia but also with platelet activation and natural autoimmune-mediated regulatory mechanism(s) in murine models.
 

In recent years the survival of patients with systemic lupus erythematosus has increased markedly. Consequently, long-term complications, such as osteoporosis, are currently of paramount importance. SLE[1] is known to increase the risk of bone fractures, and numerous studies have found that SLE patients have osteoporosis. Of the various risk factors associated with osteoporosis in SLE, disease duration, the use of corticosteroids and chronic disease-related damage are consistently reported, with differences between studies probably due to the different populations studied. The role of chronic inflammation in osteoporosis is also important. On the other hand, little attention has been paid to osteoporotic fractures, especially of the vertebra, which are associated with reduced quality of life, increased mortality rates and increased risk of new vertebral and non-vertebral fractures in the general population.

Background: The introduction of more potent statins such as atorvastatin and rosuvastatin in Israel was accompanied by massive advertising about their superiority.

Objectives: To assess the need for switching therapy from older statins to more potent ones among diabetic patients with uncontrolled hypercholesterolemia.

Methods: Data on all diabetic patients over 30 years old attending two urban clinics were extracted and analyzed. For each patient we checked the last low density lipoprotein-cholesterol measurements for the year 2006, the brand and the dose of cholesterol-lowering medications, prescriptions and actual purchasing over a 4 month period prior to the last LDL-C[1] measurement, and whether treatment changes were necessary to achieve the LDL-C target (100 mg/dl or 70 mg/dl).

Results: The study population comprised 630 patients, age 66.7 ± 12.6 years, of whom 338 (53.6%) were women. Of the 533 (84.6%) patients whose LDL-C was measured in 2006, 45 (8.1%) had levels < 70 mg/dl and 184 (33.3%) had levels of 70 mg/dl < LDL-C < 100 m/dl.  The reasons for LDL-C > 100 mg/dl were patients not prescribed cholesterol-lowering drugs (38.3%), partial compliance (27.2%), and under-dosage of statins (15.4%); only 7.7% needed to switch to a more potent statin. Reasons for LDL-C > 70 mg/dl were patients not prescribed cholesterol-lowering drugs (34.3%), partial compliance (22.0%), and under-dosage of statins (26.6%); only 8.7% needed to switch to a more potent statin.

Conclusions: Only a small minority of diabetic patients with uncontrolled hypercholesterolemia need one of the potent statins as the next treatment step. More emphasis on compliance and dose adjustment is needed to achieve the target LDL-C level.

Background: The imaging parameters that mandate further diagnostic workup in focal asymmetric breast densities are not clearly defined.

Objectives: To identify indications for further workup in FABD[1] by comparing mammographic and ultrasonographic findings with the pathology results of women with FABD.

Methods: Ninety-four women (97 FABD) were referred for core needle biopsy after incidental discovery of FABD on routine mammograms (n=83) or on diagnostic mammograms performed for palpable masses (n=11). Clinical data included patient’s age, use of hormone replacement therapy, family history of breast cancer, and the presence of a palpable mass. Mammograms and sonograms were evaluated for lesion size and location, associated calcifications, architectural distortion, and change from previous examinations when available. Two patient groups emerged according to the pathological findings and the data were compared.

Results: The average age, size and location of the lesions in the malignant (n=5) and benign (n=92) groups were similar. There was a significant difference (P < 0.05) for the presence of a clinically palpable mass (60% vs. 9%, respectively), a cluster of calcifications (60% vs. 12%), associated architectural distortion (exclusively in the malignant group) and a solid mass on sonography (50% vs. 9%). The malignant group had a higher rate of family history of breast cancer and HRT[2] use.

Conclusions: FABD usually present a benign etiology and can safely be managed by follow‑up. The presence of an architectural distortion, a cluster of malignant‑appearing or indeterminate calcifications, a sonographic mass with features of possible malignancy, or a clinically palpable mass mandates tissue diagnosis.

Background: Hip fracture rates are increasing worldwide, and the risk for a second hip fracture is high. The decision to administer antiresorptive treatment is based mainly on bone mineral density and/or a history of previous osteoporotic fractures.

Objectives: To evaluate the contribution of BMD[1], previous fractures, clinical and laboratory parameters to hip fracture risk assessment.

Methods: The study population included 113 consecutive hip fracture patients, aged 72.5 ± 9.4 years, discharged from the Department of Orthopedic Surgery113 consecutive patients, 87 women and 26 men, aged 50-90 years, mean ag. BMD was assessed at the lumbar spine, femoral neck and total hip. The results were expressed in standard deviation scores as T-scores – compared to young adults and Z-scores – compared to age-matched controls. Plasma or serum levels of parathyroid hormone, 25-hydroxyvitamin 3 and urinary deoxypyridinoline cross-links were evaluated.

Results: We observed T-scores ≤-2.5 in 43 patients (45.3%) at the lumbar spine, in 47 (52.2%) at the femoral neck and in 33 (38%) at the total hip. Twenty-eight patients (29.5%) had neither low BMD nor previous osteoporotic fractures. Using a T-score cutoff point of (-1.5) at any measurement site would put 25 (89%) of these patients into the high fracture risk group. Mean DPD level was 15.9 ± 5.8 ng/mg (normal 4–7.3 ng/mg creatinine). Vitamin D inadequacy was observed in 99% of patients.

Conclusions: Using current criteria, about one-third of elderly hip fracture patients might not have been diagnosed as being at risk. Lowering the BMD cutoff point for patients with additional risk factors may improve risk prediction yield.

Objectives: To examine whether the treatment recommendations given to ischemic heart disease patients at hospital discharge are compatible with the guidelines of the Israeli Medical Societies and the U.S. National Cholesterol Education Program for coronary artery disease prevention; and to study the effects of brief educational sessions on the adherence of physicians with the guidelines.

Methods: We included consecutive IHD[1] patients admitted to four central hospitals in Israel between 1998 and 2000. The study was conducted in two phases. In phase 1, we reviewed discharge letters to document treatment recommendations given to each patient. In phase 2 we educated the practitioners by reviewing the Israeli Medical Societies and the NCEP[2] guidelines and the quality of their recommendations in phase 1, after which we reevaluated the discharge letters.

Results: The study included 2,994 patients: 627 in phase 1 and 2,367 in phase 2. Of the patients who needed cholesterol-lowering according to their low density lipoprotein levels, 37.4% were not prescribed such drugs at discharge (under-treatment group). This proportion was reduced by education to 26.6% (P < 0.001) in phase 2. Of the treated patients, 65.6% did not reach the target LDL[3] goal in phase 1 (under-dosage group) as compared to 60.2% in phase 2 (P = 0.23). In phase 2 there was an increase in the percent of patients reaching LDL levels <130 mg/day (69.3% vs. 63.8% of patients prescribed medication, P = 0.01), but the percent of patients reaching LDL levels <100 was not different in phase 2 after adjusting for age and gender (the odds ratio for reaching target LDL was 1.16, with 95% confidence interval of 0.95–1.43).

Conclusions: Physician recommendations to IHD patients discharged from hospital were suboptimal. We documented a high proportion of under-treated and under-dosage patients. Brief educational sessions have a beneficial effect on the usage of statins; however, additional effort in guideline implementations is needed.