Israel Medical Association Journal

Background: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA.

Objectives: To evaluate SC tocilizumab in a real-life clinical setting.

Methods: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed.

Results: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively.

Conclusions: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.

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.

Background: The effect of repeated intravenous amantadine (IVAM) in advanced Parkinsonism has not been studied in depth.

Objectives: To report the experience of our medical center with repeated IVAM infusions in patients with advanced Parkinsonism.

Methods: Thirty patients with advanced Parkinsonism of various etiologies were enrolled in an open-label retrospective study. All patients were treated with IVAM infusions in a neurological daycare center. Treatment was initiated with a loading dose of 200/400 mg per day for 5 days followed by a once-daily maintenance dose of 200/400 mg every 1 to 3 weeks. Patients and their caregivers participated in a structured interview and independently completed a clinical global impression of changes scale questionnaire on various motor and non-motor symptoms.

Results: Patient mean age was 73.3 ± 9.7 years, average disease duration was 6.2 ± 5.7 years, and mean Hoehn and Yahr score was 3.2 ± 0.84. Mean duration of the IVAM treatment was 15.1 ± 11.6 months. An improvement in general function was reported by 91% of the patients and 89% of the caregivers. Most of the patients reported improvement in tremor and rigidity, as well as in gait stability, freezing of gait, and reduced falls. The treatment was safe with few side effects.

Conclusions: Our data suggest that repeated IVAM infusions could be an effective treatment against various motor symptoms and for improvement of mobility in patients with advanced Parkinsonism. Further randomized clinical trials with a larger sample size using objective measures are warranted to validate our results.

Background: The MitraClip procedure is becoming an acceptable alternative for high-risk patients with mitral regurgitation (MR) due to functional (FMR) or degenerative (DMR) disease and suitable mitral anatomy.

Objectives: To evaluate the results of MitraClip at our institute in carefully selected patients.

Methods: We conducted a retrospective analysis of medical records and echocardiography data from January 2012 to December 2017.

Results: A total of 39 MitraClip procedures in 37 patients (aged 75 ± 12 years, 9 women) was performed. Twenty-four patients presented with FMR, 12 with DMR, and 1 with combined pathology. One-day post-procedure MR was moderate to low in 86.1% of patients, with immediate device success in 88.8%. MR at 1 year was moderate to low in 79% at 1 year. Survival at 1 year was 86% and at 2 years 69.4%. Peri-procedural (< 1 week) death and MitraClip failure occurred in one and three patients, respectively. New York Heart Association score improved to class 1 or 2 in 37% of patients at 1 year vs. one patient at baseline. Post-procedural systolic pulmonary pressure was reduced from 53 (range 48–65) to 43 (range 36–52) mmHg at 1 month with a subsequent plateau at follow-up, to 41 (34–57) mmHg at 6 months, and to 47 (38–50) at 12 months.

Conclusions: MitraClip in severe MR resulted in modest improvement in functional status and pulmonary pressure with a small risk of immediate procedural complications. Outcomes are encouraging considering the natural course of MR and the risks of surgical intervention.

Background: The Israel Poison Information Center (IPIC), Rambam Health Care Campus, provides 24-hour telephone consultations on clinical toxicology and drug and reproductive toxicology. It participates in research, teaching and regulatory activities, and provides laboratory services. In 2014, nurse specialists in poison information joined the IPIC.

Objectives: To report the epidemiology of poison exposures in Israel.

Methods: We present computerized queries and a descriptive analysis of the medical records database of the IPIC for 2017.

Results: A total of 39,928 poison exposure cases were recorded, reflecting increases of 226.3% and 26.7% compared with 1995 and 2012, respectively. Children < 6 years of age were involved in 47.0% of cases; 80.4% of calls were made by the public and 17.8% by physicians; 74.2% of exposures were unintentional and 7.3% intentional. Pharmaceuticals were involved in 51.4% of cases, chemicals in 36.9%, bites and stings in 2.2%, and plants and mushrooms in 1.5%. Substances most frequently involved were analgesics, cleaning products, and antimicrobials. Clinical severity was moderate/major in 3.3%, mainly due to insecticides, drugs of abuse, and corrosives. Three fatalities were recorded (due to colchicine, organophosphates, and volatile substance inhalant abuse).

Conclusions: Poison exposures and poisonings have markedly increased in Israel, contributing substantially to morbidity. The IPIC prevented unnecessary referrals to emergency departments. Its database is a valuable national resource for collecting and monitoring poisoning exposure cases. It can be used as a real-time surveillance system for the benefit of public health. It is recommended that reporting to the IPIC become mandatory, and its activities adequately supported by national resources.

Background: Catheter ablation (CA) is a well-established therapeutic option for patients with recurrent symptomatic atrial fibrillation (AF). Data on gender-related differences are limited with regard to baseline characteristics and long-term success rates of catheter ablation for AF.

Methods: We analyzed a cohort of 251 consecutive patients who underwent a first catheter ablation for AF in our institute during the period 2008 through 2015. All patients were followed by regular annual clinic visits, electrocardiograms, periodic 24–48 hour Holter monitoring, and loop recorders. The primary endpoint was first recurrence of AF during 1 year of follow-up.

Results: The cohort comprised 26% women (n=65), who were older (62.1 ± 9.6 vs. 54.4 ± 11.3 years, P < 0.01) and had a higher proportion of diabetes mellitus (23.1 vs. 5.4%, P < 0.001) than male patients. No other significant differences were evident. At 1 year follow-up, the cumulative survival free of AF was significantly higher in women compared with men (83% vs. 66%, respectively, log rank P value = 0.021). Subgroup analysis showed an interaction between female and small indexed left atrial diameter (LADi < 23 mm/m²).

Conclusions: Our findings suggest that women experience a significantly lower rate of AF recurrence post-CA compared with men. This gender-related advantage appears to be restricted to women without significant left atrial enlargement. It further implies that left atrial enlargement has a stronger negative impact on post-CA AF recurrence in females than in males. Due to the relatively small sample number of females further research is warranted to validate our conclusions.

Background: The aggregation of autoimmune diseases in relatives (AID-R) of patients with systemic sclerosis (SSc) has been reported.

Objectives: To analyze the prevalence of autoimmune diseases in SSc relatives and to compare their features to those of SSc patients without AID-R (controls).

Methods: A case-control analysis compared SSc patients with AID-R to those without AID-R (25 patients) with similar disease duration.

Results: Among 322 patients, 25 (7.7%; 21 females, 41.4 ± 15.6 years of age, disease duration 11 ± 8.6 years) had AID-R (21 had a first-degree relative, 4 had a second-degree relative, and 2 had both). Fourteen patients (56%) and five controls (20%) had an additional autoimmune disease (P < 0.009). Diffuse SSc (48% vs. 24%) and arthritis (72% vs. 28%) were more frequent among the patients with AID-R than the controls (P < 0.05). No significant differences were found regarding lung, heart, vascular, and digestive system involvement. The mean number of additional autoimmune diseases was 0.84 ± 0.94 in AID-R vs. 0.24 ± 0.52 in controls (P < 0.038). The mean number of autoantibodies was 2.8 ± 1.5 and 2.2 ± 0.9 (P < 0.047). Five patients died during follow-up, four of whom had AID-R. Relatives of SSc patients had diverse autoimmune diseases; the prevalence of SSc in scleroderma relatives was 1.86% (2 in first-degree and 6 in second-degree relatives). SSc patients with AID-R had an obvious tendency to polyautoimmunity.

Conclusion: A precise family history is an important clue in prognosis and prediction of autoimmune diseases in SSc patients and their relatives.

Background: The lack of organs for liver transplantation has prompted transplant professionals to study potential solutions, such as the use of livers from donors older than 70 years. This strategy is not widely accepted because potential risks of vascular and biliary complications and recurrence of hepatitis C.

Objectives: To examine the efficacy and safety of liver grafts from older donors for transplantation.

Methods: A retrospective analysis of data on 310 adults who underwent deceased donor liver transplantation between 2005 and 2015 was conducted. We compared graft and recipient survival, as well as major complications, of transplants performed with grafts from donors younger than 70 years (n=265, control group) and those older than 70 years (n=45, older-donor group), followed by multivariate analysis, to identify risk factors.

Results: There was no significant difference between the control and older-donor group at 1, 5, and 10 years of recipient survival (79.5% vs. 73.3%, 68.3% vs. 73.3%, 59.2% vs. 66.7%, respectively) or graft survival (74.0% vs. 71.0%, 62.7% vs. 71.0%, 54.8% vs. 64.5%, respectively). The rate of biliary and vascular complications was similar in both groups. Significant risk factors for graft failure were hepatitis C (hazard ratio [HR] = 1.92, 95% confidence interval [95%CI] 1.16–2.63), older donor age (HR = 1.02, 95%CI 1.007–1.031), and male gender of the recipient (HR = 1.65, 95%CI 1.06–2.55).

Conclusion: Donor age affects liver graft survival. However, grafts from donors older than 70 years may be equally safe if cold ischemia is maintained for less than 8 hours.

Background: Recurrence of tracheoesophageal fistula (TEF) is reported in 8–20% patients. Factors that may influence recurrence of fistula beyond the postoperative period are not clear.

Objectives: To evaluate possible factors associated with recurrence of TEF beyond the immediate postoperative period.

Methods: A single center, retrospective comparison of patients with and without recurrence of TEF was conducted. Medical records of patients previously operated for TEF who were followed in our pediatric pulmonary institute between January 2007 and December 2016 were reviewed.

Results: The medical records of 74/77 patients previously operated for TEF were evaluated. Nine patients (12%) had a recurrence of TEF and 65 did not. These groups had similar age and gender distribution and similar prevalence of VACTERL association. In addition, they had similar length of atretic gap, rates of thoracoscopic surgery, rates of prolonged need for respiratory assistance post-surgery, and frequency of gastrointestinal symptoms. Notably, the patients who had recurrent TEF had significantly more hospitalizations for respiratory symptoms (P = 0.011) and significantly more episodes of clinical bronchiolitis per patient (P < 0.0001). In addition, the patients with recurrent TEF had significantly more episodes of positive polymerase chain reaction for viruses (P = 0.009).

Conclusions: Hospitalizations for respiratory symptoms as well as clinical and/or viral bronchiolitis are associated with recurrence of TEF. Even though cause and effect cannot be established, these patients should undergo meticulous evaluation for the possibility of recurrence of TEF.