Israel Medical Association Journal

Background: While the routine performance of terminal ileum (TI) intubation during colonoscopy procedures is perceived to have a low yield, its utility during colonoscopies performed for specific indications have not been well studied.

Objectives: To assess the diagnostic yield of an indication-based ileoscopy in real-life practice.

Methods: The authors reviewed endoscopic reports of patients who underwent colonoscopies over an 8-year period (2011–2018) and had routine ileoscopy during these procedures. Demographic data, indications for colonoscopy, and endoscopic findings were documented. Diagnostic yield and odds ratio for TI findings were calculated.

Results: Over 30,000 colonoscopy reports performed during the study period were reviewed. Ilesocopy was performed in 1800 patients, 216 patients had findings in the TI (ileitis or ulcers). TI findings were more prevalent in younger ages (38.3 ± 17.6 vs. 43.6 ± 20, P < 0.05). The greatest yield of ileoscopy was evident when performed for the evaluation of chronic abdominal pain and diarrhea (14.4% vs. 9.3%, odds ratio [OR] 1.62, P < 0.05). Positive fecal occult blood test (FOBT) (OR 0.1, 95% confidence interval [95%CI] 0.02–0.5, P = 0.005) and constipation (OR 0.44, 95%CI 0.2–0.9, P = 0.04) were negatively associated with TI findings.

Conclusions: Ileoscopy may have the greatest utility in evaluating suspected inflammatory bowel disease (IBD) patients, but may not add value to the evaluation of constipation and positive FOBT

In this review we described the values of commonly available HScore laboratory markers in patients with coronavirus-19 (COVID-19)-pneumonia associated cytokine storm syndrome (CPN-CSS) and compared results with those of other forms cytokine storm syndrome (O-CSS) to determine a pattern for CPN-CSS. Twelve CPN-CSS studies and six O-CSS studies were included. CPN-CSS typically obtained a single HScore value (e.g., aspartate transaminase > 30 U/L) while failing all other HScore criteria. A typical pattern for CPN-CSS was revealed when compared to O-CSS: lymphopenia vs. pancytopenia and increased vs. decreased fibrinogen. Findings, other than HScore commonly found in CPN-CSS studies, showed elevated lactate dehydrogenase, D-dimer, and C-reactive protein. Although CPN-CSS studies describe severely ill patients, the HScore markers are typically less toxic that O-CSS

Background: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management.

Objectives: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu.

Methods: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies.

Results: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2–6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed.

Conclusions: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

Despite advances in therapeutic modalities, especially with biologic treatments, the number of hospitalizations due to complications for Crohn's disease did not decrease. We examined the prevalence and possible predictive factors of hospitalizations in Crohn's disease. A systematic literature search was conducted until 31 October 2018. Relevant studies were screened according to established protocol. Retrospective cohort studies describing hospitalizations of Crohn's disease patients were included. Meta-analysis was performed by using comprehensive meta-analysis software. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated for the number of patients hospitalized. Twelve studies published before 31 March 2018 fulfilled the inclusion criteria and were comprised of 23 data-sets and included 4421 patients from six countries. A funnel plot demonstrates a moderate publication bias. We reported the event rates for the number of patients hospitalized, in a follow-up survey of 20,987 patient-years, and for the patients who underwent surgery in a follow-up of 5061 patient-years, with ORs of 0.233 with 95%CI 0.227–0.239, and 0.124 with 95%CI 0.114–0.135 (P < 0.001), respectively. Thus, when collecting the data from 12 cohort studies we found that hospitalization takes place in 23.3% of the patients, and operation in 12.4% along their disease duration. Patients with Crohn's disease may be hospitalized due to exacerbation of their inflammatory disease, because of non-inflammatory disease (such as fistula or stricture), or due to medical complications. The goal of therapy should be to keep the Crohn's disease patients in their natural environment and out of the hospital and to prevent surgery as much as possible.

Background: The incidence of Clostridium difficile-associated diarrhea (CDAD) is increasing and is associated with significant morbidity and mortality. Therefore, there is a need to find new tools to determine the severity of the disease.

Objectives: To investigate the prognostic values of inflammatory markers such as mean platelet volume (MPV), neutrophil-lymphocyte ratio (NLR), and C-reactive protein (CRP) in patients with CDAD.

Methods: The study comprised of 100 patients diagnosed with CDAD. The study included an additional control group of 69 patients with diarrhea who were negative for C. difficile toxin. The control group was age- and sex-matched and hospitalized at the same time period. NLR and MPV were obtained from complete blood count results. Serum CRP levels were measured by the latex particle enhanced immunoturbidimetric assay. Blood samples for all inflammatory markers were collected at time of diagnosis and prior to initiating the antibiotic therapy. Demographic, clinical, laboratory, and prognostic data were collected from medical records for a period of 90 days from the initial diagnosis of CDAD.

Results: The mean age of the CDAD group was 68.6 ± 21.5 years compared to 65.6 ± 24.5 in the control group (P = 0.29). Our findings show that patients with CDAD had significantly higher NLR, MPV and serum CRP levels compared to the control group (P < 0.001)). Moreover, significantly higher levels were observed when CDAD was fatal (P < 0.001).

Conclusions: Elevated NLR, MPV, and serum CRP levels may serve as biomarkers for prediction of recurrence and mortality in patients with CDAD.

Background: Crohn’s disease and ulcerative colitis are the two major classic presentations of inflammatory bowel diseases (IBD). Studies have shown a wide variation in the incidence and prevalence attributed to different geographic and ethnic populations.

Objectives: To assess the clinical characteristics of IBD among Arabs in Israel and to compare them to characteristics of IBD among Ashkenazi Jews.

Methods: This retrospective, comparative study compared the clinical characteristics of IBD among 150 Arabs from the Holy Family Hospital and the Nazareth Hospital EMMS, both located in Nazareth, Israel, to those of 97 age- and sex-matched Ashkenazi Jewish patients from Shaare Zedek Medical Center, Jerusalem, Israel.

Results: The Arab cohort, which included 106 patients (70%) with Crohn's disease and 44 (29%) with ulcerative colitis, was compared to 97 Ashkenazi patients (81% with Crohn's disease and 17% with ulcerative colitis) (P < 0.05). Alcohol consumption was found in both groups, but Arabs smoked more (46% vs. 12%, respectively, P < 0.05). Obstructive phenotype was lower in Arabs (10% vs. 32%, P < 0.05). 5-aminosalicylic acid and anti-tumor necrosis factor alpha were prescribed for the Arab and Ashkenazi groups (89% and 21%, respectively). The need for surgical intervention due to disease severity and/or complications was not significant (22% vs. 24%).

Conclusions: Despite similar reports of NOD2/CARD15 mutations, Crohn's disease is more common than ulcerative colitis within the Arab-Israeli population. Increased smoking rates may explain milder disease severities in Arabs, as reflected by lower obstructive pattern and frequent use of milder therapeutic modalities.

Angiogenesis is the outgrowth of new blood vessels from existing ones and is an early occurrence in inflamed joint tissue. It is governed by a tightly controlled balance of pro- and anti-angiogenic stimuli, which promote or inhibit generation and proliferation of new endothelial cells, vascular morphogenesis, and vessel remodeling. At the beginning, capillary formation is crucial in maintaining the supply of various nutrients as well as oxygen to the inflamed tissue. Local and systemic expression of angiogenic factors may indicate a constant remodeling of synovial vasculature. Redox signaling is closely related to angiogenesis and can alter angiogenic responses of synovial cells. In this review we discuss key issues about the endothelial pathology in inflammatory arthritis followed by a review of angiogenic processes and main angiogenic mediators. We discuss the hypoxia-vascular endothelial growth factor (VEGF)-Ang/Tie2 system and its related therapeutic implications in detail with further review of various mediator protein targets and intracellular regulatory pathway targets with their current and potential future role in preclinical or clinical setting whilst ameliorating inflammation.

Background: Multidisciplinary biopsychosocial rehabilitation for patients presenting with rheumatic diseases has been shown to produce better results in a warm climate. Dead Sea Climatotherapy (DSC) has been successfully used for decades to treat many patients with rheumatic diseases.

Objectives: To evaluate the short-term improvement of Norwegian patients who presented with chronic pain following a multidisciplinary biopsychosocial approach to treatment combined with DSC. Both objective and subjective clinical parameters were evaluated.

Methods: This retrospective study included a statistical analysis of 938 patients presenting with rheumatoid arthritis and ankylosing spondylitis (n=105), osteoarthritis (n=342), fibromyalgia (n=374), and other orthopedic conditions (n=117). Clinical assessments were conducted before and after a 3 week treatment program at the Dead Sea.

Results: Six parameters improved significantly in the rheumatoid arthritis and ankylosing spondylitis group as well as in the osteoarthritis group. Five parameters in the fibromyalgia group improved, while two improved in the orthopedic conditions group. Overall, major significant changes occurred in the pain self-assessment, joint motility, and daily activities scores.

Conclusions: A 3-week multidisciplinary biopsychosocial program combined with DSC induced positive changes in the clinical parameters of Norwegian patients presenting with chronic musculoskeletal pain.

Background: Temporal trends in the incidence of inflammatory bowel disease (IBD) in the Arab and Jewish populations in Israel have been poorly described.

Objectives: To compare the annual incidence and prevalence rates of Crohn's disease (CD) and ulcerative colitis (UC) in the Arab and Jewish populations in Israel between the years 2003 and 2008.

Methods: We applied a common case identification algorithm to the Clalit Health Services database to both determine trends in age-adjusted incidence and prevalence rates for IBD in both populations during this period and estimate the burden of IBD in Israel.

Results: The incidence of CD in the Arab population increased from 3.1/100,000 in 2003 to 10.6/100,000 person-years in 2008, compared with a decrease in the Jewish population from 14.3/100,000 to 11.7/100,000 person-years for the same period. The incidence of UC in the Arab population increased from 4.1/100,000 in 2003 to 5.0/100,000 person-years in 2008, a low but stable rate, compared with a decrease from 16.4/100,000 to 9.5/100,000 person-years for the same time period in the Jewish population. The prevalence of both diseases increased due to the accumulation of incident cases but remained much lower among Arabs.

Conclusions: Understanding the factors underlying the differences in incidence and prevalence of IBD in the Jewish and Arab populations may shed light on the genetic and environmental factors associated with these diseases.

Background: Frozen section (FS) is often performed when histopathological evaluations are urgently required for implementation of therapeutic measures. In dermatology, this method is most commonly used to evaluate excision margins of tumors. FS are also routinely employed to differentiate toxic epidermal necrolysis from staphylococcal scalded skin syndrome. However, little is currently known about the performance of FS in the diagnosis of inflammatory dermatoses.

Objectives: To compare histopathological diagnoses in a series of patients with a clinical diagnosis of an inflammatory dermatosis for which FS and paraffin-section (PS) specimens were obtained on the same day.

Methods: We conducted a single-center retrospective analysis of 43 cases. All histological slides were reviewed by a single dermato-pathologist. Concordance was calculated between FS and PS.

Results: Patients were divided into three groups according to diagnosis: papulosquamous diseases (group I), drug eruptions (group II), and a heterogeneous group (group III) that included cases of bullous vasculitis and Sweet syndrome. Among the three groups, the results of FS and of PS were discordant only in five cases (5/43, 11.6%). Compared to PS, FS had a sensitivity of 92.9% [95% confidence interval (95%CI) 64.17–99.63%] and a specificity of 100% in group I, sensitivity of 90.9% (95%CI 57.12–99.52%) and specificity of 100% in group II, and sensitivity of 83.33% (95%CI 60.78–94.16%) and specificity of 100% in group III. The degree of agreement between the results of the FS and of the PS was almost perfect (kappa = 0.95, 0.93 and 0.85 respectively).

Conclusions: This study suggests that FS is a valid approach for the rapid diagnosis of inflammatory dermatoses. This method is as specific as PS, although it is less sensitive.

Background: Erythema nodosum (EN) is the most common type of panniculitis, commonly secondary to infectious diseases.

Objectives: To elucidate the causative factors and the clinical presentation of patients with EN (2004–2014) and to compare their data to those reported in a previous study.

Methods: A retrospective study was conducted of all patients diagnosed with EN who were hospitalized at Soroka University Medical Center (2004–2014). The clinical, demographic, and laboratory characteristics of the patients were compared to those in a cohort of patients diagnosed with EN from 1973–1982.

Results: The study comprised 45 patients with a diagnosis of EN. The most common symptoms of patients hospitalized with EN were arthritis or arthralgia (27% of patients). Patients with EN, compared to those reported in 1987, has significantly lower rates of fever (18% vs. 62% P < 0.001), streptococcal infection (16% vs. 44%, P = 0.003), and joint involvement (27% vs. 66%, P < 0.001). In addition, fewer patients had idiopathic causes of EN (9% vs. 32%, P = 0.006).

Conclusions: In the past decades, clinical, epidemiological, and etiological changes have occurred in EN patients. The lowering in rate of fever, streptococcal infection, and joint involvement in patients with EN are probably explained by improvements in socioeconomic conditions. The significantly decreasing rate of idiopathic causes of EN is possibly due to the greater diagnostic accuracy of modern medicine. The results of the present study demonstrate the impact of improvements in socioeconomic conditions and access to healthcare on disease presentation.

Background: Inflammatory bowel disease (IBD) prevalence is increasing among Bedouin Arabs in Israel. This population is known to have a high rate of consanguinity. NOD2/CARD15 mutations are well-studied in IBD.

Objectives: To investigate the frequency of NOD2/CARD15 mutations in IBD Bedouin patients and their relevance to disease phenotype.

Methods: The IBD-Arab cohort in southern Israel included 68 patients, of which 25 Crohn's disease (CD) patients and 25 ulcerative colitis (UC) patients consented to participate (72%). Blood samples were obtained from all participants who were genotyped for NOD2/CARD15 variants Arg702Trp, Gly908Arg, and Leu1007fsinsC.

Results: The NOD2/CARD15 mutation frequency was higher in Crohn's disease than in ulcerative colitis patients. Carrier frequency for the Gly908Arg mutation in CD and UC patients was 8/25 (32%) and 3/25 (12%), respectively (P = 0.08). Neither the Arg702Trp nor Leu1007fsinsC mutation was found in our cohort. No homozygous/compound heterozygote mutations were found. Genotype-phenotype analysis revealed that CD patients carrying the Gly908Arg mutation were younger at diagnosis, 22.8 ± 4.5 vs. 28.82 ± 9.1 years (P = 0.04). All carriers were males, compared with 41.2% in non-carriers (P = 0.005). NOD2/CARD15 mutation carriers with UC were older, 67.0 ± 24.5 years compared with 41.2 ± 12.3 years (P = 0.006). No other associations regarding disease localization or other clinical parameter were found.

Conclusions: The frequency of NOD2/CARD15 gene mutations is high in CD and UC among Bedouin Arab IBD patients and is associated with younger age at onset in CD and male gender.