Israel Medical Association Journal

The prevalence of difficult-to-treat rheumatoid arthritis (D2T RA) varies between 5% and 25%, with females comprising the majority of patients and no difference in patient age between D2T and non-D2T RA cohorts. While several attempts to subclassify D2T RA patients into defined subgroups have been tried, the inclusion of an individual D2T RA patient to one of the predefined subgroups can be difficult or impossible as multiple factors are usually involved in the mechanisms of rheumatoid arthritis (RA) refractoriness, with the complex interplay of inflammatory, structural, social, and psychological factors being unique for each patient. More severe disease at presentation, including seropositivity and early erosion formation, and insufficiently aggressive initial treatment can both contribute to the eventual development of D2T RA. No single test or study can replace the holistic clinical approach to the diagnosis and understanding of the causation of D2T RA. Traditional in-depth clinical history and thorough clinical examination remain sine qua non in managing D2T RA patients. Multifaceted contributions of inflammatory and non-inflammatory components create the uniqueness of D2T RA and dictate a comprehensive approach to the management, including both pharmacologic and non-pharmacological therapeutic strategies. Mean annual total costs for D2T RA patients have been estimated as being about twice as high as that of patients with non-D2T RA.

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism and manifests as a multisystem disease. Most patients present with oropharyngeal malformations, cardiomyopathies, elevated liver enzymes, and hypoglycemia. Treatment with D-galactose has been shown to improve symptoms. Our patient presented with PGM1 deficiency. She conceived spontaneously. Throughout her pregnancies, our patient was monitored by a multidisciplinary team of cardiologists, endocrinologists, and physicians with experience in high-risk pregnancy. She delivered twice by cesarean section. Our case highlights the importance of a multidisciplinary approach and individualized management of prenatal and postpartum care of a patient with a PGM1 deficiency. To the best of our knowledge, there have been no reports about a PGM1-deficient patient who conceived and delivered.

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.

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: Surgical resection is the only curative option for gastric carcinoma (GC). Minimally invasive techniques are gaining popularity.

Objectives: To present a single-surgeon's experience in transitioning from an open to a minimally invasive approach, focusing on surgical and oncological outcomes.

Methods: We conducted a retrospective analysis including distal gastrectomy patients 2012–2020 operated by a single surgeon. Two cohorts were compared: open (ODG) and laparoscopic distal gastrectomy (LDG).

Results: Overall, 173 patients were referred for gastrectomy during the study years. We excluded 80 patients because they presented with non-GC tumors, underwent proximal or total gastrectomy, or underwent palliative surgery. Neoadjuvant treatment was administered to 62 patients (33.3%). Billroth 1 was the preferred method of reconstruction (n=77, 82.8%), followed by Roux-en-Y (n=12, 13%). Fifty-one patients (54.8%) underwent LDG, 42 (45.2%) underwent ODG. The LDG group had significantly shorter lengths of stay (6 days, interquartile range [IQR] 1–3 5–8 vs. 5 days, IQR 1–3 4–6, P = 0.001, respectively), earlier return to oral feeding (1 day, IQR 1–3 1–3 vs. 2 days, IQR 1–3 1–3.2, P < 0.001), and earlier removal of drains (4 days, IQR 1–3 3–5.2 vs. 5 days, IQR 1–3 3.5–6.7, P < 0.001). Overall lymph node yield was 30 (IQR 1–3 24–39) and was similar among groups (P = 0.647).

Conclusions: Laparoscopic techniques for resection of distal GC are feasible and safe, leading to good perioperative outcomes and adequate lymph node yield.

Acute cholecystitis is a common surgical diagnosis. If not addressed properly, it can potentially lead to sepsis, perforation of the gallbladder, and even death.

The most frequent pathogens isolated from bile cultures of patients with cholecystitis are anaerobes and Enterbacterales such as E. coli, Klebsiella species, and Streptococcus species [1].

Streptococcus gordonii belongs to the Viridians streptococci group of oral bacteria and is commonly associated with dental caries. S. gordonii has been previously reported as the causative pathogen in both endocarditis and spondylodiskitis [2]. However, it has rarely been associated with biliary infections. In this report, we presented a patient diagnosed with cholecystitis associated with S. gordonii infection.

Background: The hepatobiliary system is a sterile micro-environment. Bacterial infection in this system is most commonly associated with anaerobes as well as gram-positive and gram-negative bacteria. Biliary infections with Staphylococcus aureus are poorly characterized.

Objectives: To depict the clinical characteristics and outcome of patients with S. aureus infection of the hepatobiliary system.

Methods: Medical records of patients with bile cultures positive for S. aureus from January 2006 to November 2020 were extracted from the computerized database of a hospital in Israel.

Results: We analyzed the results of 28 cases that were found in the database. The mean age of study patients was 62.2 ± 19 years. Hypertension, dyslipidemia, chronic kidney disease, diabetes, and benign prostatic hypertrophy were the most common co-morbidities (57.1%, 32.1%, 25%, 25%, and 25%, respectively). Fourteen of the methicillin-resistant S. aureus (MRSA) bile cultures (82.3%) were a result of primary S. aureus biliary infections (no other source for S. aureus infection) and the remainder were of a secondary infection. Eight of the MRSA cultures (47.1%) were from hospital acquired infections. Increased hospital mortality in patients with S. aureus hepatobiliary infection was associated with hypertension (P = 0.04), bedridden status (P = 0.01), and nursing home residence (P = 0.003).

Conclusions: Hepatobiliary infection with S. aureus can manifest in a variety of ways. S. aureus should be especially considered in patients who are bedridden, present with hypertension, or live in nursing homes because of their association with in-hospital mortality resulting from this entity.

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: Heart failure (HF) patients with reduced ejection fraction (HFrEF) are frequently treated with sub-optimal doses of angiotensin converting enzyme-inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta blockers (BBs).

Objectives: To determine factors associated with attaining upper-range doses in patients with HFrEF.

Methods: We examined treatment in patients with left ventricular ejection fraction (LVEF) ≤ 40% in a community-based, dedicated heart-failure clinic. Upper-range doses were defined as ≥ 75% of target recommended doses by heart failure society guidelines.

Results: The majority of the 215 patients were men (82%); median age at presentation 73 years (interquartile range [IQR] 65–78) and LVEF of 30% (IQR 25–35%). Following the up-titration program, 41% and 35% of patients achieved upper-range doses of ACE-Is/ARBs and BBs, respectively. Higher body mass index (BMI) was the only parameter found to be associated with achieving upper-range doses of ACE-I/ARBs (odds ratio [OR] 1.13, 95% confidence interval [95%CI] 1.05–1.22, P = 0.001). More patients achieved this target as BMI increased, with a sharp decline in the highest obesity category (BMI ≥ 40 m²/kg). Attaining upper-range doses of BBs was associated with pre-existing diabetes mellitus (DM) (OR 2.6, 95%CI 1.34–5.19, P = 0.005); women were associated with attaining lower BBs doses (OR 0.34, 95%CI 0.13–0.90, P = 0.031).

Conclusions: Achieving upper-range doses of ACE-Is/ARBs and BBs in HFrEF outpatients in a treatment up-titration program were associated with greater BMI and DM, respectively. These findings may serve as benchmarks for up-titration programs.

Background: Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials.

Objectives: To report the first Israeli experience with HSCT for progressive SSc and review the current literature.

Methods: Five SSc patients who were evaluated in our department and were treated by HSCT were included. Medical records were evaluated retrospectively. Demographic, clinical, and laboratory data were recorded. Continuous data are presented as the mean ± standard deviation. Categorical variables are presented as frequencies and percentages.

Results: Five SSc patients were treated with HSCT. Four patients were adults (mean age 53 ± 12 years) and one was a 12-year-old pediatric patient. All patients were female. HSCT was initiated 1.4 ± 0.8 years after diagnosis. Two patients were RNA POLIII positive, two were anti-topoisomerase 1 positive, and one only antinuclear antibodies positive. All patients had skin and lung involvement. The mean modified Rodnan Skin Score was 29 ± 4.7 before HSCT, which improved to 10.4 ± 9.6 after HSCT. The forced vital capacity improved from 68 ± 13% to 90 ± 28%. Diffusing capacity of the lungs for carbon monoxide increased by 6%. Among severe adverse events were cyclophosphamide-related congestive heart failure, antithymocyte globulin-related capillary leak syndrome, and scleroderma renal crisis. All symptoms completely resolved with treatment without sequela. No treatment related mortality was recorded.

Conclusions: HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.

In this review, the authors re-examine the role of aspirin in the primary prevention of cardiovascular disease. They discuss the history of the use of aspirin in primary prevention, the current guidelines, and the recent evidence surrounding aspirin use as primary prevention in special populations such as those with moderate cardiovascular risk, diabetes mellitus, and the elderly