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.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) are new antidiabetic drugs that are recommended by current guidelines as a class I novel glucose-lowering treatment that improves cardiovascular outcome in type 2 diabetes mellitus (T2DM), particularly in patients with cardiovascular disease.

Objectives: To evaluate adherence to the current guidelines for treatment with SGLT2i and GLP1-RA drugs in patients referred to ambulatory consultant cardiology clinics with pre-existing T2DM.

Methods: We studied consecutive new patients with a pre-existing diagnosis of T2DM who were referred to the Clalit Health Services ambulatory consultant cardiology clinic over a 6-month period. The recorded information included demographics, co-morbidities, and prescribed drugs at patient admission.

Results: During the study period, 1782 patients visited our outpatient cardiology clinic. At screening, T2DM was present in 428 patients (24%); 77 (18%) were being treated with SGLT2i, and 39 (9.1%) with GLP1-RA. Patients receiving SGLT2i and GLP1-RA were younger and had more coronary artery disease, lower mean left ventricular ejection fraction, and higher mean estimated glomerular filtration rates than those who were not receiving these drugs. HbA1C was > 7 in 205 (47.9%) patients and > 7.5 in 136 patients (31.8%). Body mass index was > 30 kg/m² in 231 (54%) patients.

Conclusions: GLP1-RA and SGLT2i drugs were found to be administered more frequently than previously reported, but they are not yet satisfactorily prescribed.

The coronavirus disease-2019 (COVID-19) and its management in patients with epilepsy can be complex. Prescribers should consider potential effects of investigational anti-COVID-19 drugs on seizures, immunomodulation by anti-seizure medications (ASMs), changes in ASM pharmacokinetics, and the potential for drug-drug interactions (DDIs). The goal of the Board of the Israeli League Against Epilepsy (the Israeli Chapter of the International League Against Epilepsy, ILAE) was to summarize the main principles of the pharmacological treatment of COVID-19 in patients with epilepsy. This guide was based on current literature, drug labels, and drug interaction resources. We summarized the available data related to the potential implications of anti-COVID-19 co-medication in patients treated with ASMs. Our recommendations refer to drug selection, dosing, and patient monitoring. Given the limited availability of data, some recommendations are based on general pharmacokinetic or pharmacodynamic principles and might apply to additional future drug combinations as novel treatments emerge. They do not replace evidence-based guidelines, should those become available. Awareness to drug characteristics that increase the risk of interactions can help adjust anti-COVID-19 and ASM treatment for patients with epilepsy

Background: Guidelines recommend initiation of parenteral biologic or oral target-specific disease-modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) in rheumatoid arthritis (RA) patients who do not adequately respond to conventional DMARDs.

Objectives: To compare the preferred route of administration of bDMARDs or tsDMARDs in RA patients who were previously treated with at least one type.

Methods: A cross-sectional survey was conducted of consecutive RA patients previously prescribed bDMARDs or tsDMARDs. We analyzed the factors associated with patients' preferred route of administration.

Results: The cohort included 95 patients, mostly female (72.6%), seropositive (81.05%), mean age 63.4 ± 11.9 years. The oral route was preferred by 39 patients (41%) and 56 (59%) preferred the parenteral route. Most patients (65.9%) preferred to continue with their current route (P < 0.001). Switching from a current route was less common with patients who were currently using the oral route (13.3% vs. 38.2%, P = 0.04). Many patients (53.8%) who preferred the oral route had never experienced it before, while this was rare (3.6%) regarding the parenteral route (P = 0.0001). Employment status was associated with preference of the subcutaneous route over the intravenous route of bDMARDs (P = 0.01). Of the 21 patients who had previously experienced both parenteral and oral treatment, 16 (76.2%) preferred the oral route.

Conclusions: RA patients preferred to continue treatment with an administration route they have already experienced. However, when choosing an unexperienced route, significantly more patients preferred the oral route. Our results strengthen the understanding of patient preferences, which could improve drug adherence, compliance, and disease outcome.

Background: The salutary effects of statin therapy in patients with cardiovascular disease (CVD) are well established. Although generally considered safe, statin therapy has been reported to contribute to induction of diabetes mellitus (DM).

Objectives: To assess the risk-benefit of statin therapy, prescribed for the prevention of CVD, in the development of DM.

Methods: In a population-based real-life study, the incidence of DM and CVD were assessed retrospectively among 265,414 subjects aged 40–70 years, 17.9% of whom were treated with statins. Outcomes were evaluated according to retrospectively determined baseline 10 year cardiovascular (CV) mortality risks as defined by the European Systematic COronary Risk Evaluation, statin dose-intensity regimen, and level of drug adherence.

Results: From 2010 to 2014, 5157 (1.9%) new cases of CVD and 11,637 (4.4%) of DM were observed. Low-intensity statin therapy with over 50% adherence was associated with increased DM incidence in patients at low or intermediate baseline CV risk, but not in patients at high CV risk. In patients at low CV risk, no CV protective benefit was obtained. The number needed to harm (NNH; incident DM) for low-intensity dose regimens with above 50% adherence was 40. In patients at intermediate and high CV risk, the number needed to treat was 125 and 29; NNH was 50 and 200, respectively.

Conclusions: Prescribing low-dose statins for primary prevention of CVD is beneficial in patients at high risk and may be detrimental in patients at low CV risk. In patients with intermediate CV risk, our data support current recommendations of individualizing treatment decisions.

Background: Tumor necrosis factor-alpha (TNFα) inhibitors are indicated for patients with psoriatic arthritis (PsA) in whom conventional disease-modifying anti-rheumatic drugs (DMARDs) are insufficient to achieve disease remission. 

Objectives: To determine the value of acute-phase reactant levels at diagnosis of psoriatic arthritis in predicting the need for biologic treatment with TNFα inhibitors.

Methods: We conducted a longitudinal observational study of an inception cohort of 71 consecutive patients diagnosed with psoriatic arthritis. C-reactive protein (CRP) was assayed for all patients at their first visit.

Results: All patients were treated with one or more DMARDs, mainly methotrexate (81.6%). Thirty-seven patients (52.11%) had an inadequate response and received at least one TNF inhibitor. CRP level at diagnosis was positively correlated with need for a TNF inhibitor (P = 0.009, HR 1.8, 95%CI 1.27–1.85). Patients with CRP > 0.9 mg/dl at diagnosis started biologic treatment significantly earlier than patients with a lower level (P = 0.003, HR 2.62, 95%CI 0.393–2.5).

Conclusions: In patients with psoriatic arthritis, CRP ≥ 0.9 mg/dl at diagnosis significantly predicts an earlier need for a TNF inhibitor to achieve disease control.

 

Long-term extension studies and observational drug registers have revealed an increased risk of serious infections in patients treated with anti-tumor necrosis factor agents, particularly infliximab, etanercept and adalimumab. The same may be true for the newer biological drugs rituximab, tocilizumab and abatacept, although this has yet to be confirmed by long-term observational studies. We review the risk of tuberculosis, herpes zoster and other opportunistic infections, and the recommendations for screening for tuberculosis and hepatitis B and C infections in patients affected by rheumatoid arthritis, with the aim of informing patients and encouraging greater awareness among physicians.

Objectives: To characterize common obstetric anesthesia practices after cesarean deliveries in Israel in order to standardize postoperative pain relief protocols.

Methods: A questionnaire was completed during an interview with every obstetric anesthesia unit in all 25 delivery wards in Israel. Data were gathered on intraoperative anesthesia and analgesia protocols as well as postoperative pain relief protocols. A sub-analysis compared units whose director completed a formal obstetric anesthesia training program with those whose directors did not.

Results: Neuraxial morphine was used routinely in 12% of hospitals. No unit providing intrathecal morphine complied with American Society of Anesthesiologists guidelines for respiratory monitoring after use of neuraxial opioids. Additionally, non-steroidal anti-inflammatory drugs (NSAIDs) were used routinely in only half the wards, while patient-controlled analgesia was used infrequently. Postoperative verbal analog scores were not recorded routinely in 71% of units on postoperative day 1. The unit director's training significantly influenced the unit protocols.

Conclusions: Intrathecal morphine, the gold standard of care in cesarean deliveries, is rarely used, mainly due to shortage of staff and lack of formal obstetric anesthesia training. In addition, NSAIDs are also underused. There is a need for more formal training for obstetric anesthesiologists in Israel.

Objectives: To determine the outcome of RA with respect to disease activity and the rate of remission, as measured by the DAS-28, in a real-world inception cohort.

Methods: We conducted an observational cross-sectional study of a single-center real-world inception cohort of 101 consecutive patients being treated for RA in 2009–2010 in a rheumatology outpatient clinic. Patients were managed at the discretion of the attending rheumatologist with the goal of achieving remission. DAS-28 scores were calculated and analyzed by clinical and treatment variables derived from the medical files.

Results: Mean patient age was 58.6 ± 13.4 years and mean duration of disease 10.7 ± 7.9 years. Disease remission (DAS-28 < 2.6) was achieved in 26.7% of patients and low disease activity (> 2 .6 DAS-28 < 3.2) in 17%. Monotherapy with a conventional disease-modifying anti-rheumatic drug (C-DMARD, 21% of patients at last follow-up) was associated with a significantly lower mean DAS-28 score and C-reactive protein level than combined C-DMARD treatment (79% of patients), and with shorter disease duration than combined treatment with C-DMARDs or C-DMARD(s)+biological DMARD (40% of patients). Rheumatoid factor and anti-cyclic citrullinated peptide positivity had no effect on DAS-28 scores. Time from diagnosis was inversely correlated with DAS-28 scores.

Conclusions: The achievement of low disease activity and remission in a significant portion of our inception cohort of patients with RA suggests that the treat-to-target strategy is feasible and effective in routine clinical practice. 

The DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), also known as DIHS (drug-induced hypersensitivity syndrome), presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, producing damage in several systems, especially kidney, heart, lungs, and pancreas. The pathogenesis is related to specific drugs (especially the aromatic anticonvulsants), altered immune response, sequential reactivation of herpes virus, and association with some HLA alleles. Glucocorticoids are the basis for the treatment of the syndrome, which may be given with intravenous immunoglobulin and, in selected cases, ganciclovir. This article reviews current concepts regarding the interaction of drugs, viruses and immune responses during this complex adverse-drug reaction.
 

Background: Intravitreal injections of the anti-vascular endothelial growth factor (VEGF) drugs bevacizumab (Avastin®) and ranibizumab (Lucentis®) became the mainstay of treatment for various retinal pathologies, but there is no consensus among ophthalmologists on the precise use of these drugs.

Objectives: To describe the current application of anti-VEGF[1] drugs among retinal specialists in Israel.

Methods: A questionnaire was sent via email to all 62 members of the Israeli Society of Retinal Specialists. The survey included 34 questions on various aspects of the use of anti-VEGF drugs: diagnosis, treatment, follow-up of different retinal pathologies, and the measures taken for ensuring sterile administration of the intravitreal injections.

Results: Fifty members (80%) completed the survey. Most of them (56%) offered both bevacizumab and ranibizumab to their patients for age-related macular degeneration, but 70% were influenced by the patient’s socioeconomic status. Three consecutive monthly injections were usually recommended (58%) for the first 3 months, and treatment was extended as long as subretinal or intraretinal fluids persisted (57%). Over two-thirds (68%) switched the drugs after the 3-monthly series if the first one yielded no improvement in fluid status. The routine practice for intravitreal injection (> 80%) involved the wearing of sterile gloves, using an eyelid speculum, and administering povidone-iodine pretreatment and topical antibiotics after treatment.

Conclusions: Intravitreal VEGF administration varies widely among Israeli retinal specialists. The current survey is intended to assist Israeli ophthalmologists in establishing their own treatment strategy for patients with retinal pathologies.