Israel Medical Association Journal

Background: Serum ferritin is a sensitive inflammatory biomarker reflecting cell damage and oxidative stress in inflammatory rheumatic diseases. The use of ferritin for assessment of systemic sclerosis (SSc) activity, severity, and prognosis has not been fully elucidated.

Objectives: To assess the correlation between serum ferritin levels and SSc disease parameters, complications, and outcome.

Methods: Demographic, clinical, and laboratory data, including blood levels of ferritin, were collected from files of patients with SSc who were treated at the Rheumatology Institute at Rambam Health Care Campus from January 2004 to July 2021. The study compared SSc patients with elevated levels of ferritin to those with normal levels.

Results: We extracted data of 241 SSc patients (80% female, 60% with diffuse SSc, mean age 54 ± 15.4 years, mean disease duration 6.8 ± 4.5 years). During follow-up, 39% died. Elevated ferritin levels positively correlated with male sex; short disease duration; lung, heart, and kidney involvement; higher modified Rodnan skin score; anemia; elevated levels of creatinine kinase, C-reactive protein, creatinine, and troponin; reduced pulmonary function tests (forced vital capacity and diffusion capacity of the lung for carbon monoxide); and left ventricular ejection fraction. There were no correlations between ferritin levels and pulmonary hypertension or gastrointestinal involvement. Levels of ferritin negatively correlated with anti-centromere antibodies.

Conclusions: In SSc, ferritin can serve as a marker for ongoing systemic inflammation and prognosis, particularly in patients with lung and heart involvement. Further studies on serial ferritin measurement in the management of SSc patients are warranted.

Background: The parasympathetic system and its main neurotransmitter, acetylcholine, contributes to homeostasis of inflammation. Cholinergic dysregulation is thought to contribute to the pathogenesis of inflammatory rheumatic diseases. Cholinesterase activity in patients with psoriatic arthritis (PsA) has not been investigated.

Objectives: To compare the cholinesterase activity in patients with PsA and immunocompetent controls and to explore the correlation between cholinergic status (CS) and PsA disease activity.

Methods: Serum acetylcholinesterase (AChE) and total cholinesterase activity were measured in patients with PsA (n=88) and matched controls (n=84). Cholinergic activity before and 3–6 months after the initiation of a biologic treatment was evaluated in seven patients with PsA.

Results: The levels of AChE and CS were similar in both PsA patients and controls. PsA patients treated with biologics had significantly lower levels of AChE and CS compared to patients treated with non-biologics: 447.4 vs. 526 substrate hydrolyzed/min/ml, P = 0.005, and 1360.9 vs. 1536, P = 0.029, respectively. We found an association between C-reactive protein levels, AChE activity (r = 0.291, P = 0.008), and cholinergic status (r = 0.247, P = 0.026) in patients with PsA but not in controls. No correlation between AChE activity, cholinergic status, and the indices of PsA disease activity was found. After initiating or switching biologic treatment in 7 patients, AChE levels remained stable.

Conclusions: We demonstrated similar cholinesterase activity in patients with psoriatic arthritis and controls, highlighting a potential effect of biologic treatment on cholinergic activity in patients with PsA.

Background: Jejunal disease is associated with worse prognosis in Crohn's disease. The added value of diffusion weighted imaging for evaluating jejunal inflammation related to Crohn's Disease is scarce.

Objectives: To compare diffusion weighted imaging, video capsule endoscopy, and inflammatory biomarkers in the assessment of Crohn's disease involving the jejunum.

Methods: Crohn's disease patients in clinical remission were prospectively recruited and underwent magnetic resonance (MR)-enterography and video capsule endoscopy. C-reactive protein and fecal-calprotectin levels were obtained. MR-enterography images were evaluated for restricted diffusion, and apparent diffusion coefficient values were measured. The video capsule endoscopy-based Lewis score was calculated. Associations between diffusion weighted imaging, apparent diffusion coefficient, Lewis score, and inflammatory biomarkers were evaluated.

Results: The study included 51 patients, and 27/51 (52.9%) with video capsule endoscopies showed jejunal mucosal inflammation. Sensitivity and specificity of restricted diffusion for video capsule endoscopy mucosal inflammation were 59.3% and 37.5% for the first reader, and 66.7% and 37.5% for the second reader, respectively. Diffusion weighted imaging was not statistically associated with jejunal video capsule endoscopy inflammation (P = 0.813).

Conclusions: Diffusion weighted imaging was not an effective test for evaluation of jejunal inflammation as seen by video capsule endoscopy in patients with quiescent Crohn's disease.

Optic neuritis is an inflammation of the optic nerve and has several causes. The hallmarks of clinical manifestation are pain on movement of the eyes and decreased vision. Typical optic neuritis is an idiopathic demyelinating condition that is often associated with multiple sclerosis, affects young women, is unilateral, and has a good prognosis.

A 64-year-old male, with antineutrophil cytoplasmic antibody-associated vasculitis was being treated with methotrexate and low dose prednisone. He arrived at the clinic with bluish discoloration of the toes. Inflammatory markers and urine were normal. No history of chilblains or Raynoud's phenomena was noted. He recovered recently from mild coronavirus disease 2019 (COVID-19). A diagnosis of COVID toes (COVID digits) was made [Figure 1].

Backgrounds: Behçet's disease (BD) is a chronic vasculitic multi-systemic disease of unknown etiology. BD is characterized by recurrent attacks of oral aphthae, genital ulcers, and uveitis. BD is a multisystemic disorder and as such it may provoke various psychiatric manifestations, including depression.

Objectives: To evaluate the association between BD and depression, adjusting for established risk factors for depression.

Methods: We executed a cross-sectional study based on the Clalit Health Services database, the largest healthcare organization in Israel, serving over 4.4 million members. For this study 873 BD patients were detected and matched with 4369 controls by age and sex.

Results: The rate of depression was higher among the BD patients compared with the control group (9.39% vs 5.49%, respectively, odds ratio [OR] 1.79, 95% confidence interval [95%CI] 1.37–2.31, P < 0.001). An association between BD and depression was also observed on multivariable analysis (OR 1.83, 95%CI 1.39–2.39, P < 0.001). When stratifying the data, according to established risk factors, the association between BD and depression was prominent in the youngest age group (18–39 years of age), low and high socioeconomical status, and non-smokers.

Conclusions: Establishing the association between BD and depression should influence the attitude and the treatment of BD patients, as this relationship requires a more holistic approach and a multidisciplinary treatment regimen for all patient needs.

Background: The CHA₂DS₂-VASc score has been shown to predict systemic thromboembolism and mortality in certain groups in sinus rhythm (SR), similar to its predictive value with atrial fibrillation (AF).

Objectives: To compare factors of inflammation, thrombosis, platelet reactivity, and turnover in patients with high versus low CHA₂DS₂-VASc score in SR.

Methods: We enrolled consecutive patients in SR and no history of AF. Blood samples were collected for neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), immature platelet fraction (IPF%) and count (IPC), CD40 ligand, soluble P-selectin (sP-selectin) and E-selectin. IPF was measured by autoanalyzer and the other factors by ELISA.

Results: The study comprised 108 patients (age 58 ± 18 years, 63 women (58%), 28 (26%) with diabetes), In addition, 52 had high CHA₂DS₂-VASc score (³ 2 for male and ³ 3 for female) and 56 had low score. Patients with low scores were younger, with fewer co-morbidities, and smaller left atrial size. sP-selectin was higher in the high CHA₂DS₂-VASc group (45, interquartile ratio [IQR] 36–49) vs. 37 (IQR 28–46) ng/ml, P = 0.041]. Inflammatory markers were also elevated, CRP 3.1 mg/L (IQR 1.7–9.3) vs. 1.6 (IQR 0.78–5.4), P < 0.001; NLR 2.7 (IQR 2.1–3.8) vs. 2.1 (IQR 1.6–2.5), P = 0.001, respectively. There was no difference in E-selectin, CD40 ligand, IPC, or IPF% between the groups.

Conclusions: Patients in SR with high CHA₂DS₂-VASc score have higher inflammatory markers and sP-selectin. These findings may explain the higher rate of adverse cardiovascular events associated with elevated CHA₂DS₂-VASc score.

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: Cystic periventricular leukomalacia (cPVL) is a strong indicator of subsequent motor and developmental impairments in premature infants. There is a paucity of publications on biomarkers of cPVL.

Objectives: To determine C-reactive protein (CRP) levels during the first week of life of preterm infants who later developed cPVL and to identify the association between CRP levels with perinatal factors.

Methods: We retrospectively included infants ≤ 32 weeks gestation and/or birth weights ≤ 1500 grams; 17 with a cranial ultrasound diagnosis of cPVL and 54 with normal ultrasounds. Serum CRP levels were measured during days 1-7 (CRP^1–7d) of life and subdivided into two timing groups: days 1–3 (CRP^1–3d) and days 4-7 (CRP^4–7d).

Results: The cPVL group had significantly higher mean CRP^4–7d levels compared to controls (12.75 ± 21.2 vs. 2.23 ± 3.1, respectively, P = 0.03), while CRP^1–3d levels were similar. CRP^1–7d levels were significantly correlated with maximal fraction of inspired oxygen during the first 12 hours of life (FiO₂-12h, r = 0.51, P < 0.001]. Additional risk factors were not associated with CRP levels.

Conclusions: Our finding of elevated CRP^4-7d levels and later development of cPVL supports earlier studies on the involvement of inflammation in the pathogenesis of cPVL. Whether CRP could serve as a biomarker of cPVL and its correlation with outcomes, awaits further trials. Furthermore, the correlation between FiO₂-12h and CRP^1–7d levels suggest that hypoxia and/or hyperoxia may serve as a trigger in the activation of inflammation during the first days of life of preterm infants

Background: Granulomatosis with polyangiitis (GPA) is a rare small vessel vasculitis. It usually involves the respiratory tract and kidney. Rarely, tumor-resembling inflammatory changes ensue.

Objectives: To report three unique cases of GPA presenting with tumor-like lesions in various organs.

Methods: We presented three cases of GPA. Case 1 presented with typical upper respiratory symptoms of GPA and a mediastinal mass. Case 2 presented with low back pain, a large retroperitoneal mass, and nodular skin lesions. Case 3 presented with epigastric pain and a paravertebral inflammatory mass.

Results: The patients were treated successfully with rituximab.

Conclusions: Clinicians should be aware of this presentation of granulomatosis with polyangiitis, which is known as Tumefaction Wegener’s granulomatosis

Background: Heart failure with preserved ejection fraction (HFpEF) is a common clinical entity, with a mechanism that appears to involve endothelial dysfunction of the cardiac microcirculation. Endothelial progenitor cells (EPC) are bone marrow derived cells that are able to differentiate into functional endothelial cells and participate in endothelial surface repair.

Objectives: To compare the level and function of EPCs in patients with HFpEF compared with heart failure with reduced ejection fraction (HFrEF) and control subjects.

Methods: We enrolled 21 patients with HFpEF (LVEF ≥ 50%, age 74.5 ± 9.9 years, 43% men, 48% diabetes), 20 patients with HFrEF (LVEF < 40%, age 70 ± 11.5 years, 90% men, 60% diabetes), and 11 control subjects with cardiovascular risk factors (age 53.3 ± 6.1years, 90% men, 64% diabetes). Circulating EPC levels were evaluated by expression of vascular endothelial growth factor receptor-2 (VEGFR-2), CD34, and CD133 by flow-cytometry. EPCs colony forming units (CFUs) were quantified after 7 days in culture.

Results: The proportion of cells that co-expressed VEGFR-2 and CD34 or VEGFR-2 and CD133 was similar among the HFpEF and HFrEF groups, and significantly lower than in the control group. The number of EPC-CFUs was also similar among the two heart failure groups and significantly lower than the control group.

Conclusions: Patients with HFpEF, like HFrEF, have significant reduction in EPC level and function.

Background: Patients with type 2 diabetes mellitus (T2DM) have a high rate of cardiovascular disease (CVD). The Mediterranean diet is preferred for CVD prevention. Endothelial dysfunction is demonstrated early in T2DM.

Objectives: To study the effects of dietary intervention of T2DM patients without known CVD on endothelial function and vascular inflammation.

Methods: A prospective study enrolled 22 patients with T2DM. Patients were divided randomly into two groups: an intervention group with 12 patients (55 ± 7 years old, 6 women) and a control group with 10 patients (59 ± 10 years old, 5 women). Clinical evaluation included body mass index (BMI) and endothelial function measured by the flow mediated percent change (FMD%). Fasting blood was drawn on entry to the study and 3 months later, measuring C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), total cholesterol, triglycerides, and glycosylated hemoglobin (HbA1C%). The intervention was based on weekly telephone calls by a clinical dietitian for 3 months.

Results: In the intervention group CRP and ICAM-1 were reduced (from 4.2 ± 3.3 mg/dl to 0.4 ± 0.5 mg/dl, P = 0.01 and from 258.6 ± 98.3 ng/ml to 171.6 ± 47.7 ng/ml, P = 0.004). Endothelial function (FMD%) was improved (from 0.5 ± 8.0% to 9.5 ± 11.5%, P = 0.014). No change was observed in BMI, HbA1C%, total cholesterol, and triglycerides levels in either group.

Conclusions: Patients with T2DM on the Mediterranean diet who received a weekly telephone call for 3 months improved their endothelial function with reduction of markers of inflammation.

In the absence of definitive anti-viral therapy, there is considerable interest in mitigating against severe inflammatory reactions in coronavirus disease-2019 (COVID-19) pneumonia to improve survival. These reactions are sometimes termed cytokine storm. PDE4 inhibitors (PDE4i) have anti-inflammatory properties with approved indications in inflammatory skin and joint diseases as well as chronic obstructive pulmonary disease (COPD). Furthermore, multiple animal models demonstrate strong anti-inflammatory effects of PDE4i in respiratory models of viral and bacterial infection and also after chemically mediated lung injury. The rationale for PDE4i use in COVID-19 patients comes from the multimodal mechanism of action with cytokine, chemokine, and other key pathway inhibition all achieved with an excellent safety profile. We highlight how PDE4i could be an overlooked treatment from the rheumatologic and respiratory armamentarium, which has potential beneficial immune-modulation for treating severe COVID-19 pneumonia associated with cytokine storms. The proposed use of PDE4i is also supported by age-related immune changes in inflammation severity in PDE4i modifiable pathways in primate coronavirus disease. In conclusion, over-exuberant anti-viral immune responses in older patients with COVID-19 may pose a substantial risk to patient survival and mitigation against such hyper-inflammation with PDE4i, especially with anti-viral agents, is a strategy that need to be pursed, especially in older patients