Israel Medical Association Journal

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.

We describe the features of nocebo, and its impact in studies of transition from the originator to the respective biosimilar in inflammatory rheumatic diseases. Investigations in healthy volunteers as well as in the neurology and anesthesiology fields demonstrated the involved cerebral areas and the neurotransmitter pathways responsible for the nocebo response. Whether these findings are applicable to patients with inflammatory rheumatic diseases remains to be demonstrated. Nocebo may account for part of the after-switching biosimilar failures. However, in the absence of validated classification or diagnostic criteria, specific neurochemical and neuroimaging studies, the lack of data on serum tumor necrosis factor and drug levels, and the disease improvement after the switching back to the originator biologic observed in some patients, the nocebo diagnosis remains the role of the individual clinician. Investigations on nocebo pathophysiology and diagnosis are required to address its impact in after-transition biosimilar studies in rheumatology.

Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.

Inflammation is the basic mechanism leading to many pathological processes, including degenerative diseases, atherosclerosis, and cancer. We found an interesting link connecting rheumatoid arthritis and atherosclerosis that may explain the high cardiovascular event rate among patients with rheumatoid arthritis, but also may lead to a new way of thinking and a better understanding of atherosclerosis. Rheumatoid arthritis could serve as a model of accelerated atherosclerosis. Understanding the basic mechanisms of rheumatoid arthritis may solve some of the complexity of atherosclerosis.

Rheumatic diseases commonly affect women of childbearing age, when women may be contemplating pregnancy or they discover an unplanned pregnancy. Therefore, specific issues about pregnancy planning and management are commonly encountered in patients during these times. Knowledge of the effect of pregnancy on disease activity is important for counseling. This review summarizes recent data on the course of different rheumatic diseases during pregnancy and the postpartum period. Rheumatoid arthritis and systemic lupus erythematosus are the most commonly investigated diseases. Data are increasing about spondyloarthritis. Sparse data are available for other rheumatic diseases. Despite the differences in these diseases and the various courses these disease take during pregnancy, a common feature is that active maternal disease in the months prior to conception increases the risk of flares during pregnancy, which in turn can lead to adverse pregnancy outcomes. Therefore, maternal and fetal health can be optimized if conception is planned when disease is inactive so that a treatment regimen can be maintained throughout pregnancy.

Serum rheumatoid factors are autoantibodies of different isotypes directed against the Fc fraction of immunoglobulin G (IgG) and represent paradigmatic autoantibodies that have been largely used in clinical practice for decades. Traditionally IgG has been associated with rheumatoid arthritis and more recently included also in the classification criteria for Sjӧgren’s syndrome. Researchers have established that rheumatoid factors are positive in a variety of infectious, autoimmune, and neoplastic disorders, thus requiring a comprehensive evaluation of seropositive patients. Of note, hepatitis B and C viruses represent a crossroad that includes the high rheumatoid factor seroprevalence and chronic inflammatory disease, as well as progression to non-Hodgkin's lymphomas. Chronic antigen stimulation is the likely common ground of these processes and rheumatoid factors may represent mere bystanders or drivers of pathology. Mixed cryoglobulinemia and lymphoproliferative disease are prime examples of the deleterious effects of rheumatoid factor-B cell activity, possibly associated with hepatitis B and C. More importantly, they show a clear association in a physiological host response to infection, chronic inflammation, and the slide toward autoimmunity and malignancy. The association between hepatitis B and C infections and the appearance of serum rheumatoid factors is further supported by prevalence data, which support a coexistence of these markers in a significant proportion of cases, with viral infections being frequent causes of rheumatoid factors in patients without a rheumatic condition. We provide a comprehensive overview of the known connections between hepatitis B and C infections and rheumatoid factors.

Background: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes.

Objectives: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA.

Methods: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394).

Results: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses.

Conclusions: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.

Background: Rheumatic mitral stenosis (MS) is a relatively rare diagnosis in the developed countries and its treatment during pregnancy is challenging due to hemodynamic changes. With the demographic changes due to recent waves of immigration an increase in the prevalence of rheumatic heart disease is expected.

Objective: To evaluate maternal and neonatal complications in patients with mitral stenosis.

Methods: During the years 2006–2017, 22 women who underwent 31 pregnancies were followed at the Sheba Medical Center in Israel. We collected on regarding hemodynamic changes and their clinical course. MS was classified as mild, moderate, or severe according to mitral valve area by echocardiography. Maternal and fetal adverse events were evaluated according to severity of MS and compared by Poisson regression modeling.

Results: MS was severe in 7 pregnancies (22.6%), moderate in 9 (29%), and mild in 15 (48.4%). Twenty patients were managed conservatively and 2 underwent a successful percutaneous mitral balloon valvuloplasty (PBMVP) during pregnancy. All pregnancies ended with a liveborn neonate and with no maternal mortality. Peak and mean mitral pressure gradients increased during pregnancy from 13.3 ± 5.3 to 18.6 ± 5.1 mmHg and from 5.9 ± 2.3 to 9.6 ± 3.4 mmHg respectively (P < 0.05). Eight pregnancies (25.8%) were complicated by pulmonary congestion, 2/15 (13.3%) with mild MS, 2/9 (22.2%) with moderate, and 4/7 (57.1%) with severe MS. The adverse event rate was higher among patients with severe MS compared with moderate and mild MS [hazard ratio (HR) 3.15, 95% confidence interval (95%CA) 1.04–9.52 and HR 4.06, 95%CI 1.4–11.19 respectively, P < 0.05]. Nine of 31 deliveries were vaginal; 6 of 22 cesarean sections (27.3%) were performed for cardiac indications.

Conclusions: The number of total adverse events were higher among patients with severe MS. Patients with moderate and mild MS should be treated attentively, but good obstetric and maternal outcome can be expected.

Background: Patients with rheumatic diseases, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS), encounter significantly higher rates of cardiovascular morbidity and mortality. The renin-angiotensin-aldosterone system maintains hemodynamic stability through blood pressure regulation. When dysregulated, this system has been implicated in various pathological conditions, including cardiovascular events.

Objectives: To investigate the levels of renin and aldosterone in RA and AS patients.

Methods: Three groups were recruited: patients with RA, patients with AS, and healthy controls. Subjects were excluded if they had a diagnosis of hypertension, hyperaldosteronism, or renal artery stenosis, or were taking drugs that might have affected renin levels. Renin and aldosterone levels were measured using commercially available kits. Data were analyzed using univariate analyses and multivariate regression analyses.

Results: Fifty-one subjects were enrolled in the study: 15 with RA, 4 with AS, and 32 healthy controls. At the univariate analysis, the three groups differed in age (P = 0.005), renin levels (P = 0.013), and aldosterone-to-renin ratio (P = 0.019). At the post-hoc tests, both AS and RA patients differed from controls for renin levels and the aldosterone-to-renin ratio. At the multivariate regression analysis, AS patients had lower renin values than controls (beta standardized regression coefficient -0.323, P = 0.022).

Conclusion: Patients with RA tended to have lower levels of plasma renin compared to healthy subjects. This finding indicates that the renin-angiotensin-aldosterone system might not be directly involved in the process that results in increased cardiovascular events in rheumatoid arthritis.