Israel Medical Association Journal

Background: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are chronic conditions with overlapping pathogenic mechanisms. The genetic predisposition and inflammatory pathways common to both diseases suggest a syndemic relationship. While some evidence points to a connection between the two conditions, other reports do not support this link.

Objectives: To investigate the association between AS and the subsequent incidence of IBD. To identify potential risk factors and effect modifiers that contribute to this relationship.

Methods: Utilizing the Chronic Disease Registry of Clalit Health Services, we conducted a retrospective cohort study of individuals diagnosed with AS between January 2002 and December 2018. We compared these patients with age- and sex-matched controls, excluding those with a prior diagnosis of IBD. Statistical analyses included chi-square and t-tests for demographic comparisons, and Cox proportional hazards models for evaluating the risk of IBD development, with adjustments for various co-morbidities and demographic factors.

Results: The study included 5825 AS patients and 28,356 controls. AS patients demonstrated a significantly higher incidence of IBD with hazard ratios of 6.09 for Crohn's disease and 2.31 for ulcerative colitis, after multivariate adjustment. The overall incidence of IBD in the AS cohort was significantly higher compared to controls.

Conclusions: AS patients exhibit a markedly increased risk of developing IBD. These findings advocate for heightened clinical vigilance for IBD symptoms in AS patients and suggest the need for a multidisciplinary approach to patient care. Further research into the shared pathogenic pathways is needed to develop personalized treatment strategies and improve patient management.

Background: Patients with inflammatory bowel disease (IBD) are at increased risk after percutaneous coronary intervention (PCI).

Objectives: To compare the clinical outcomes within 30 days, one year, and five years of undergoing PCI.

Methods: We conducted a retrospective cohort study of adult patients with IBD who underwent PCI in a tertiary care center from January 2009 to December 2019.

Results: We included 44 patients, 26 with Crohn’s disease (CD) and 18 with ulcerative colitis (UC), who underwent PCI. Patients with CD underwent PCI at a younger age compared to UC (57.8 vs. 68.9 years, P < 0.001) and were more likely to be male (88.46% of CD vs. 61.1% of UC, P < 0.03). CD patients had a higher rate of non-steroidal treatment compared to UC patients (50% vs. 5.56%, P < 0.001). Acute coronary syndromes (ACS) and/or the need for revascularization (e.g., PCI) were the most common clinical events to occur following PCI, in both groups. Of patients who experienced ACS and/or unplanned revascularization within 5 years, 25% of UC vs. 40% of CD had target lesion failure (TLF) due to in-stent restenosis and 10% of CD had TLF due to stent thrombosis.

Conclusions: We observed higher rates of TLF in IBD patients compared to the general population as well as differences in clinical outcomes between UC and CD patients. A better understanding of the prognostic factors and pathophysiology of these differences may have clinical importance in tailoring the appropriate treatment or type of revascularization for this high-risk group.

Paraneoplastic syndromes are reported in 8–15% of patients diagnosed with cancer [1]. They are defined as syndromes that occur due to an underlying malignancy, which has yet to be diagnosed, or at the time of the diagnosis and less frequently following the diagnosis of a malignancy. Several mechanisms are involved including autocrine and paracrine mediators, hormones, peptides, cytotoxic lymphocytes, and cytokines [1,2].

Anti-tumor necrosis factor-alpha (anti-TNFα) medications are the most frequently used biologicals to treat inflammatory bowel disease (IBD). Little is known about the ocular side effects of this drug category. We present a case series of six young patients with Crohn disease (CD) and no previous ophthalmologic manifestations who developed blepharitis after commencing treatment with anti-TNFα therapy. Six otherwise healthy patients with CD, with no history of allergies or prior ocular complaints, developed blepharitis at a median of 7.5 months after the initiation of anti-TNFα therapy. All ophthalmic findings were treated topically. The ocular symptoms of two of the patients resolved shortly after discontinuation of the anti-TNFα treatment. The other four presented with relapsing-remitting symptoms. Blepharitis is a common ocular disease in the general population and an extra-intestinal manifestation in patients with IBD. It may be an adverse effect of anti-TNFα therapy in this patient population.

Idiopathic inflammatory myopathies (IIM) are a group of rare, autoimmune, systemic diseases with a large spectrum of clinical phenotypes. The diagnosis and management of myositis demand an integrated evaluation of different clinical, laboratory, and pathological findings in various organs. Recent developments in IIM research, especially in the serological testing and pathology fields, has led to a new classification and better recognition of patients with early or extra-muscular disease, with improvement in clinical care and prognosis.

Recognizing myocarditis is a diagnostic and therapeutic challenge due to the heterogeneity of its clinical presentation and the wide range of etiologies. There is a lack of uniformity among position papers and guidelines from various professional societies regarding the definition and diagnostic workout, including recommendations for performing endomyocardial biopsy (EMB) and medical management, especially the use of immunosuppressive regimens [1-3]. Moreover, there is significant variability among medical centers in Israel in the diagnostic and therapeutic approaches to acute myocarditis. The purpose of this position paper is to present ways to standardize the management of acute myocarditis in Israel [4] by providing up-to-date definitions of the clinical categories of myocarditis, diagnostic criteria, and therapeutic approaches that correspond to the realities of our healthcare system.

In the position statement on the definition and diagnosis of acute myocarditis on page XXX of this issue of the Israel Medical Association Journal (IMAJ), we discussed contemporary criteria for definition of acute myocarditis and inflammatory cardiomyopathy [1-6]. We also addressed current diagnostic methods including indications for endomyocardial biopsy (EMB) [7-21]. In this position statement, we discuss the management approaches during hospitalization and following hospital discharge, including specific forms of myocarditis and recommendations for returning to physical activity after myocarditis [21-36].

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.

Fever of unknown origin (FUO) is defined as the repeated occurrence of elevated body temperature above 38.3°C (101°F) lasting for at least 3 weeks with no clear diagnosis despite a thorough investigation of more than one-week duration. FUO cases could be categorized into three major etiologies: infectious, neoplastic, and systemic inflammatory. Despite novel diagnostic modalities, clinicians still encounter a significant number of unresolved FUO cases, accounting for as many as 50% of cases [1]. Prolonged futile FUO investigations may be a source of frustration for many clinicians [2]. We described a unique cause for FUO that shares the complexity of the diagnostic workup and emphasizes the importance of ¹⁸F-fluorodeoxyglucose positron-emission tomography/computed tomography (PET/CT) modality in the process of investigating FUO.

Background: The two cerebral hemispheres influence the immune response differently. While the left hemisphere enhances cellular immunity, the right hemisphere inhibits it.

Objectives: To determine whether immune and inflammatory markers correlated with stroke severity and hospitalization duration as a function of stroke side.

Methods: The study included 137 patients with unilateral ischemic stroke. The medical records were reviewed for demographic and clinical laboratory data, including C-reactive protein (CRP), white blood cell (WBC) count, its differential stroke side and stroke severity according to the National Institute of Health Stroke Scale (NIHSS), and length of hospital stay (LOS). We examined differences between right side (RS) and left side (LS) stroke on immune and inflammatory markers and compared correlations between these markers and NIHSS and LOS as a function of stroke side.

Results: RS stroke patients had higher CRP and monocytes than LS stroke patients. In RS stroke patients, CRP, total WBC, and lymphocyte levels positively correlated with both NIHSS and LOS, whereas levels of neutrophils were positively correlated with NIHSS alone. No correlations were found for LS stroke patients.

Conclusions: Immune-inflammatory markers correlated with stroke severity and LOS only in patients with RS stroke. Neuroimmunological processes influence short-term clinical outcomes after stroke, especially considering the differential effects of the hemispheres on immunity. Prospective studies that evaluate long-term clinical outcomes are needed. Testing the effects of anti-inflammatory treatments on prognosis of RS stroke patients should be considered.

Background: The exposure to ambient particulate matter (PM) is associated with increased morbidity and mortality from respiratory, cardiovascular, and other causes. A major contribution to this adverse effect is attributed to particles at the nanoscale range (ultrafine particles [UFP] particles < 100 nm). Most of the information about human exposure to PM has been collected by environmental monitoring of inhaled particles.

Objectives: To evaluate the use of direct measuring of UFP in the sputum as a biomarker for lung inflammation and functional impairment.

Methods: The study population included 121 patients who underwent an induced sputum (IS) test as a part of a clinical evaluation for respiratory symptoms. Cell differential count was performed, and the UFP content was measured in each IS sample. The UFP content in the sputum was compared among patients with different inflammatory phenotypes based on IS granulocytes levels: eosinophilic inflammation (EI) IS eosinophils > 2.7%, neutrophilic inflammation (NI) IS neutrophils > 65%, and mixed granulocytic inflammation (MGI) including both IS eosinophils > 2.7% and IS neutrophils > 65%. The association between the IS-UFP content and pulmonary function test (PFT) parameters was also tested.

Results: Patients with MGI had a distinct profile of particles in IS, which was characterized by the highest percentage of UFP (relative to larger particles) compared to patients with EI, NI, or normal IS cell count. Furthermore, EI and NI were found to have an interaction effect regarding the IS–UFP profile, as demonstrated by the significantly different IS–UFP profile of patients with MGI compared to the profile associated with EI and NI independently. Last, the profile of UFP in the IS samples was also correlated with patient PFT. Reduced forced mid-expiratory flow (FEF) 25–75 or FEV1 were correlated with a higher IS–UFP mean size. Reduced FEF25–75 was correlated with a lower IS–UFP concentration and percentage relative to larger particles.

Conclusions: To the best of my knowledge, this study is the first to report a distinct IS–UFP profile in patients with MGI, which suggest an interaction effect of EI and NI on the IS–UFP content. This finding may further support the consideration of MGI as a distinct inflammatory phenotype, beyond the simple combination of EI and NI independently. In addition, reduced PFT parameters were associated with a specific change in the IS–UFP profile. The results of this study may shed light on the use of IS–UFP content as a biomarker for lungs inflammation and functional impairment. Further prospective studies are needed to establish a cause and effect relationship between lungs inflammation and functional impairment to the IS–UFP content.

Background: Patients with autoimmune disease (AID) and coronavirus disease 2019 (COVID-19) could have higher mortality due to the co-morbidity and the use of immunosuppressive therapy.

Objectives: To analyze the risk factors and outcomes of patients with AID and COVID-19 versus a control group.

Methods: A prospective cohort study included patients with and without AID and COVID-19. Patients were paired by age and sex. Clinical, biochemical, immunological treatments, and outcomes (days of hospital stay, invasive mechanical ventilation [IMV], oxygen at discharge, and death) were collected.

Results: We included 226 COVID-19 patients: 113 with AID (51.15 ± 14.3 years) and 113 controls (53.45 ± 13.3 years). The most frequent AIDs were Rheumatoid arthritis (26.5%), systemic lupus erythematosus (21%), and systemic sclerosis (14%). AID patients had lower lactate dehydrogenas, C-reactive protein, fibrinogen, IMV (P = 0.027), and oxygen levels at discharge (P ≤ 0.0001) and lower death rates (P ≤ 0.0001). Oxygen saturation (SaO₂) ≤ 88% at hospitalization provided risk for IMV (RR [relative risk] 3.83, 95% confidence interval [95%CI] 1.1–13.6, P = 0.038). Higher creatinine and LDH levels were associated with death in the AID group. SaO₂ ≤ 88% and CO-RADS ≥ 4 were risk factors for in-hospital mortality (RR 4.90, 95%CI 1.8–13.0, P = 0.001 and RR 7.60, 95%CI 1.4–39.7, P = 0.016, respectively). Anticoagulant therapy was protective (RR 0.36, 95%CI 0.1–0.9, P = 0.041)

Conclusions: Patients with AID had better outcomes with COVID-19 than controls. Anticoagulation was associated with a lower death in patients with AID.