Israel Medical Association Journal

The pathogenesis of atherosclerosis is multifactorial, mainly driven by complex inflammatory processes. Colchicine is an anti-inflammatory drug used in a variety of clinical settings. The purpose of this review is to evaluate the role of colchicine in atherosclerotic vascular disease and more specifically, its promising impact on the outcome of patients with stable and acute coronary syndrome and to review its effect in patients undergoing angioplasty. A literature review was performed using the search terms colchicine, coronary heart disease, or acute coronary syndrome, stable coronary disease. We accessed PubMed, Google scholar, and the Cochrane Library databases to search for studies. Patients with chronic coronary disease may benefit from treatment with low dose colchicine to reduce the occurrence of a cardiovascular event. Among patients with a recent myocardial infarction, colchicine treatment was associated with reduced ischemic cardiovascular events, although without a meaningful difference in mortality. Colchicine was found to be a promising agent that can be potentially integrated into the armamentarium of treatments for patients with atherosclerotic coronary disease pending careful patient selection

Background: There is a lack of real-life clinical data for biosimilar etanercept, an anti-TNF blocking fusion protein. We describe the comparable efficacy and safety of originator and biosimilar etanercept in rheumatoid arthritis (RA) patients in a real-life clinical setting. Our data confirm that a biosimilar etanercept can be safely used as first-line treatment as well as in patients switched from a previous originator compound.

Objectives: To compare the efficacy and safety of originator and biosimilar etanercept in a cohort of RA patients attending two Italian hospitals.

Methods: The study involved 81 consecutive adult RA patients treated for at least 6 months with originator or biosimilar etanercept and considered their clinical and laboratory data, concomitant medications, and adverse events at baseline, and after 3 and 6 months of treatment.

Results: Group 1 included 51 patients taking originator etanercept; group 2 included 30 taking biosimilar etanercept, including 19 who had been switched from the reference product. Despite a significant baseline difference in clinical disease activity, one-way analysis of variance showed that the two groups were clinically comparable after 6 months of treatment, and the same was true when only those receiving etanercept as first-line biological treatment were considered. Nine patients discontinued the treatment due to inefficacy or adverse events, which were never serious and were only reported in group 1.

Conclusions: The efficacy and safety profiles of originator and biosimilar etanercept are comparable in RA patients in a real-life clinical setting. Further studies are needed to confirm these preliminary findings

Background: Behçet’s disease (BD) is an inflammatory disorder potentially leading to life- and sight-threatening complications. No laboratory marker correlating with disease activity or predicting the occurrence of disease manifestations is currently available.

Objectives: To determine an association between serum amyloid-A (SAA) levels and disease activity via the BD Current Activity Form (BDCAF), to evaluate disease activity in relation to different SAA thresholds, to examine the association between single organ involvement and the overall major organ involvement with different SAA thresholds, and to assess the influence of biologic therapy on SAA levels.

Methods: We collected 95 serum samples from 64 BD patients. Related demographic, clinical, and therapeutic data were retrospectively gathered.

Results: No association was identified between SAA levels and BD disease activity (Spearman's rho = 0.085, P = 0.411). A significant difference was found in the mean BDCAF score between patients presenting with SAA levels < 200 mg/L and those with SAA levels > 200 mg/L (P = 0.027). SAA levels > 200 mg/L were associated with major organ involvement (P = 0.008). A significant association was found between SAA levels > 150 mg/dl and ocular (P = 0.008), skin (P = 0.002), and mucosal (P = 0.012) manifestations. Patients undergoing biologic therapies displayed more frequently SAA levels < 200 mg/L vs. patients who were not undergoing biologic therapies (P = 0.012).

Conclusions: Although SAA level does not represent a biomarker for disease activity, it might be a predictor of major organ involvement and ocular disease relapse at certain thresholds in patients with BD.

Background: Non-infectious uveitis (NIU) leads to severe visual impairment, potentially impacting on health-related quality of life (QoL). 

Objectives: To investigate the impact of NIU on QoL.

Methods: Eighty NIU patients and 23 healthy controls completed the 36-item Short-Form Health Survey (SF)-36. The SF-36 values were statistically analyzed to evaluate differences between patients and healthy controls and to identify correlations between SF-36 subscores and clinical/demographic data. 

Results: NIU patients showed a decrease in the physical component summary score (P < 0.0001) compared to healthy controls, while no difference was highlighted in the mental component summary score (P = 0.97). NIU patients showed a decrease in physical functioning (P = 0.008), role-physical (P = 0.003), bodily pain (P = 0.0001), general health (P < 0.0001), and social functioning (P = 0.01). Physical functioning was lower in patients with acute anterior uveitis (AAU) than in those with panuveitis (P = 0.003). No differences were found between patients with bilateral or unilateral NIU, isolated NIU, or NIU associated with systemic diseases and with or without ocular activity. No correlations were identified between best-corrected visual acuity and SF-36 subscores. Physical functioning (P = 0.02), bodily pain (P = 0.004), and social functioning (P = 0.02) were reduced in males versus females. 

Conclusions: QoL is impaired in individuals with NIU, particularly in the physical domains, general health, and social functioning. AAU affects physical functioning more than panuveitis. NIU seems to affect per se QoL disregarding inflammatory activity, visual impairment, and presence of associated systemic diseases.

 

Biomarkers are important for guiding the clinical and therapeutic management of all phases of rheumatoid arthritis because they can help to predict disease development in subjects at risk, improve diagnosis by closing the serological gap, provide prognostic information that is useful for making therapeutic choices and assessing treatment responses and outcomes, and allow disease activity and progression to be monitored. Various biomarkers can be used to identify subjects susceptible to the disease and those with pre-clinical rheumatoid arthritis before the onset of symptoms such as rheumatoid factor and anti-citrullinated protein antibodies. They can be correlated with a risk of developing rheumatoid arthritis and can predict more bone erosions and severe disease progression. Biomarkers such as the erythrocyte sedimentation rate and C-reactive protein levels provide information about disease activity, while predictive biomarkers allow clinicians to assess the probability of a treatment response before starting a particular therapy particularly in the era of biological drugs. This move from traditional approaches to patient stratification and targeted treatment should greatly improve patient care and reduce medical costs.

Background: The evidence on the use of dexamethasone implants in the treatment of Behçet’s disease (BD)-related uveitis is limited to a few cases. 

Objectives: To evaluate the efficacy of dexamethasone implants on ocular functional, morphological, and clinical parameters in BD patients with severe refractory uveitis. 

Methods: Five eyes from five BD patients were enrolled. A single intravitreal dexamethasone injection was applied to each eye. Best corrected visual acuity (BCVA), central macular thickness (CMT) assessed with optical coherence tomography, retinal vasculitis assessed by fluorescein angiography, vitreous haze score (Nussenblatt scale), intraocular pressure (IOP), and lens status (LOCS III, Lens Opacities Classification System III) were recorded at baseline and at 1, 3, and 6 month follow-up visits.

Results: At baseline, all eyes showed marked macular edema and 4/5 had concomitant active retinal vasculitis. Mean BCVA was increased from baseline at each control visit with a mean improvement of 0.26 ± 0.18 lines at 6 months follow-up. Mean CMT decreased from baseline at each control visit with a mean improvement at 6 months follow-up of 198.80 ± 80.08 µm. At the end of the study, none of the eyes showed macular edema and the mean CMT was 276.80 ± 24.94 µm. Retinal vasculitis resolved in all eyes. One eye experienced an IOP spike during treatment that resolved spontaneously, and one eye developed a clinically significant lens opacity at 6 months follow-up. 

Conclusions: Treatment with a dexamethasone implant in BD-uveitis and inflammatory macular edema was safe and effective as an additional treatment combined with systemic immunomodulatory drugs.

 

Long-term extension studies and observational drug registers have revealed an increased risk of serious infections in patients treated with anti-tumor necrosis factor agents, particularly infliximab, etanercept and adalimumab. The same may be true for the newer biological drugs rituximab, tocilizumab and abatacept, although this has yet to be confirmed by long-term observational studies. We review the risk of tuberculosis, herpes zoster and other opportunistic infections, and the recommendations for screening for tuberculosis and hepatitis B and C infections in patients affected by rheumatoid arthritis, with the aim of informing patients and encouraging greater awareness among physicians.

Background: Serum lactate dehydrogenase (LDH) is elevated in various diseases. 

Objectives: To analyze serum LDH as a distinguishing clinical biomarker and as a predictor of in-hospital outcome in admitted medical patients.

Methods: We analyzed a cohort of all 158 patients with very high isolated LDH (LDH ≥ 800 IU/ml – without concomitant elevations of alanine aminotransferase and aspartate aminotransferase) – admitted to our internal medicine department during a 3 year period. Epidemiologic and clinical data, as well as the final diagnosis and outcome were recorded and compared with those of a cohort of all 188 consecutive control patients.

Results: Very high isolated LDH was a distinguishing biomarker for the presence of cancer (27% vs. 4% in the LDH group and controls respectively, P < 0.0001), liver metastases (14% vs. 3%, P < 0.0001), hematologic malignancies (5% vs. 0%, P = 0.00019), and infection (57% vs. 28%, P < 0.0001). Very high isolated LDH was a marker for a severe prognosis, associated with more admission days (9.3 vs. 4.1, P < 0.0001), significantly more in-hospital major complications, and a high mortality rate (26.6% vs. 4.3%, P < 0.0001). Finally, very high isolated LDH was found in a multivariate regression analysis to be an independent predictor of mortality.

Conclusions: The presence of very high isolated LDH warrants thorough investigation for the presence of severe underlying disease, mostly metastatic cancer, hematologic malignancies and infection. Moreover, it is a marker for major in-hospital complications and is an independent predictor of mortality in admitted medical patients. 

Background: The VEGFR/PDGFR inhibitor sunitinib was approved in Israel in 2008 for the treatment of metastatic renal cell carcinoma (mRCC), based on an international trial. However, the efficacy of sunitinib treatment in Israeli mRCC patients has not been previously reported.

Objectives: To report the outcome and associated factors of sunitinib treatment in a large cohort of Israeli mRCC patients.

Methods: We conducted a retrospective study of an unselected cohort of mRCC patients who were treated with sunitinib during the period 2006–2013 in six Israeli hospitals. Univariate and multivariate analyses were performed to determine the association between treatment outcome and clinicopathologic factors.

Results: We identified 145 patients; the median age was 65 years, 63% were male, 80% had a nephrectomy, and 28% had prior systemic treatment. Seventy-nine percent (n=115) had clinical benefit (complete response 5%, n=7; partial response 33%, n= 48; stable disease 41%, n=60); 21% (n=30) were refractory to treatment. Median progression-free survival (PFS) was 12 months and median overall survival 21 months. Factors associated with clinical benefit were sunitinib-induced hypertension: [odds ratio (OR) 3.6, P = 0.042] and sunitinib dose reduction or treatment interruption (OR 2.4, P = 0.049). Factors associated with PFS were female gender [hazard ratio (HR) 2, P = 0.004], pre-sunitinib treatment neutrophil to lymphocyte ratio ≤ 3 (HR 2.19, P = 0.002), and active smoking (HR 0.19, P < 0.0001). Factors associated with overall survival were active smoking (HR 0.25, P < 0.0001) and sunitinib-induced hypertension (HR 0.48, P = 0.005). To minimize toxicity, the dose was reduced or the treatment interrupted in 39% (n=57). 

Conclusions: The efficacy of sunitinib treatment for mRCC among Israeli patients is similar to that of international data.

Objectives: To investigate the results of PVS after MI, according to date of completion.

Methods: PVS results were interpreted according to the mode of MI management in 801 asymptomatic patients: 301 (group I) during the period 1982–1989, 315 (group II) during 1990–1999, and 185 (group III) during 2000–2010. The periods were chosen based on changes in MI management. Angiotensin-converting enzyme (ACE) inhibitors had been given since 1990; primary angioplasty was performed routinely since 2000. The PVS protocol was the same throughout the whole study period.

Results: Group III was older (61 ± 11 years) than groups I (56 ± 11) and II (58 ± 11) (P < 0.002). Left ventricular ejection fraction (LVEF) was lower in group III (36.5 ± 11%) than in groups I (44 ± 15) and II (41 ± 12) (P < 0.000). Monomorphic VT < 270 beats/min was induced as frequently in group III (28%) as in group II (22.5%) but more frequently than in group I (20%) (P < 0.03). Ventricular fibrillation and flutter (VF) was induced less frequently in group III (14%) than in groups I (28%) (P < 0.0004) and II (30%) (P < 0.0000). Low left ventricular ejection fraction (LVEF) and date of inclusion (before/after 2000) were predictors of VT or VF induction on multivariate analysis.

Conclusions: Induction of non-specific arrhythmias (ventricular flutter and fibrillation) was less frequent than before 2000, despite the indication of PVS in patients with lower LVEF. This decrease could be due to the increased use of systematic primary angioplasty for MI since 2000. 

 Background: Hemorrhagic radiation cystitis (HRC) is a significant clinical problem that occurs after pelvic radiation therapy and is often refractory.

Objectives: To evaluate the efficacy and safety of hyperbaric oxygen therapy (HBO) for HRC.

Methods: Daily 90 minute sessions of HBO at 2 ATM 100% oxygen were given to 32 HRC patients with American Society of Therapeutic Radiology and Oncology (ASTRO) grades 3-4 hematuria.

Results: The median age was 72.5 (48–88 years). The median time interval between radiation therapy and HBO was 4 years (1–26 years). The patients received a median of 30 HBO sessions (3–53). Hematuria resolved in 27 patients (84%) and persisted in 5. Cystectomy was required in two, and ileal-conduit and bilateral percutaneous nephrostomies were performed in one and two patients, respectively. With a median follow-up of 12 months (5–74 months), the hematuria cleared completely in 16 patients (59%) and mild hematuria requiring no further treatment recurred in 10 others. Another patient with ASTRO grade 4 hematuria needed bladder irrigation and blood transfusions. Complications included eardrum perforation in four patients and transient vertigo and mild hemoptysis in one case each. None of them required HBO discontinuation.

Conclusions: HBO controlled bleeding in 84% of the patients. A durable freedom from significant hematuria was achieved in 96% of the patients. HBO seems to be an effective and safe modality in patients with HRC.

Background: Coronary computed tomography angiography (CCTA) is an established modality for ruling out coronary artery disease. However, it has been suggested that CCTA may be a source of non-negligible radiation exposure.

Objectives: To evaluate the potential degradation in coronary image quality when using prospective gated (PG) CCTA as compared with retrospective gated (RG) CCTA in chest pain evaluation.

Methods: The study cohort comprised 216 patients: 108 consecutive patients in the PG CCTA arm and 108 patients matched for age, gender and heart rate in the RG CCTA arm. Scans were performed using a 64-slice multidetector CT scanner. All 15 coronary segments were evaluated subjectively for image quality using a 5-point visual scale. Dose-length product was recorded for each patient and the effective radiation dose was calculated

Results: The PG CCTA technique demonstrated a significantly higher incidence of step artifacts in the middle and distal right coronary artery, the distal left anterior descending artery, the second diagonal, the distal left circumflex artery, and the second marginal branches. Nevertheless, the diagnostic performance of these scans was not adversely affected. The mean effective radiation doses were 3.8 ± 0.9 mSv vs.17.2 ± 3 mSv for PG CCTA and RG CCTA, respectively (P < 0.0001).

Conclusions: Artifacts caused by the PG CCTA technique (64 MDCT) scanners tended to appear in specific coronary segments but did not impair the overall diagnostic quality of CCTA and there was a marked reduction in radiation exposure. We conclude that 64-slice PG CCTA is suitable for clinical use, especially for acute chest pain "fast track" evaluation targeted at relatively young subjects in a chest pain unit.
 

Background: Many patients present to the emergency department with chest pain. While in most of them chest pain represents a benign complaint, in some patients it underlies a life-threatening illness.

Objectives: To assess the routine evaluation of patients presenting to the ED[1] with acute chest pain via the utilization of a cardiologist-based chest pain unit using different non-invasive imaging modalities.

Methods: We evaluated the records of 1055 consecutive patients who presented to the ED with complaints of chest pain and were admitted to the CPU[2]. After an observation period and according to the decision of the attending cardiologist, patients underwent myocardial perfusion scintigraphy, multidetector computed tomography, or stress echocardiography.

Results: The CPU attending cardiologist did not prescribe non-invasive evaluation for 108 of the 1055 patients, who were either admitted (58 patients) or discharged (50 patients) after an observation period. Of those remaining, 445 patients underwent MDCT[3], 444 MPS[4], and 58 stress echocardiography. Altogether, 907 patients (86%) were discharged from the CPU. During an average period of 236 ± 223 days, 25 patients (3.1%) were readmitted due to chest pain of suspected cardiac origin, and only 8 patients (0.9%) suffered a major adverse cardiovascular event.

Conclusions: Utilization of the CPU enabled a rapid and thorough evaluation of the patients’ primary complaint, thereby reducing hospitalization costs and occupancy on the one hand and avoiding misdiagnosis in discharged patients on the other.
 

[1] ED = emergency department

[2] CPU = chest pain unit

[3] MDCT = multidetector computed tomography

[4] MPS = myocardial perfusion scintigraphy