Israel Medical Association Journal

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.

Behçet’s disease (BD) is a systemic inflammatory disorder characterized by a protean clinical spectrum and an enigmatic pathogenesis. After being classified as an autoimmune disorder, spondyloarthritis and vasculitis, today BD is considered at the crossroad between autoimmune and auto-inflammatory syndromes. Many pathogenetic, clinical and therapeutic clues support this recent interpretation, enabling novel treatment choices such as interleukin (IL)-1 inhibition. Thus, in the last decade the IL-1 receptor antagonist anakinra and the anti-IL-1β monoclonal antibody canakinumab were increasingly administered in BD patients resistant to standard therapies, leading to interesting results and new intriguing pathogenetic implications. However, further studies are essential to both establish how the innate and acquired immune systems interact in BD patients and identify the best way of administering anti-IL-1 agents with regard to dosage, interval of administration and organ response.

Autoimmune rheumatic diseases (ARD) affect mainly young women during their reproductive years. Fertility is usually not diminished but the time it takes to conceive is usually longer. Factors related to an ARD or to its treatment are responsible for this effect. In addition, contraception counseling is required to prevent negative fetal outcome and exacerbation of disease symptoms. In recent years, advances in therapies, clarification of risk factors for adverse pregnancy outcomes, and a multidisciplinary approach have vastly improved obstetric management, increasing the possibility of successful pregnancy with a high likelihood of favorable outcome.

Psoriatic arthritis (PsA) is a chronic inflammatory condition associated with skin psoriasis and manifests a wide clinical phenotype, with proposed differences between sexes. Current treatments are based on traditional disease-modifying anti-rheumatic drugs (DMARD), and biologic agents and studies have reported different clinical response patterns depending on sex factors. We aimed to identify sex differences in drug retention rate in patients with PsA and performed a systematic research on MEDLINE, EMBASE and Cochrane databases (1979 to June 2015) for studies regarding effectiveness (measured as drug retention rate) in PsA in both traditional DMARDs and biologics. Demographic data as well as retention rates between sexes were extracted. From a total 709 retrieved references, we included 9 articles for the final analysis. Only one study reported data regarding DMARDs, while eight studies reported retention rate for anti-tumor necrosis factor (TNF) biologics, mainly infliximab, adalimumab and etanercept. No differences were reported in retention rates between sexes for methotrexate, while women manifested lower retention rates compared to men with regard to anti-TNF. We highlight the need to include sex differences in the management flow chart of patients with PsA.

Autoimmune diseases are classic examples of multifactorial disorders in which a large number of genes interact with environmental factors to form the final phenotype. Identification of the genes involved in these diseases is a daunting challenge. Initially the search involved the candidate approach where polymorphisms in suspected genes were tested for association in large cohorts of patients and controls. Today, the most widely used method is genome-wide association studies (GWAS), a method based on screening large panels of patients and controls with hundreds of thousands of single nucleotide polymorphisms (SNPs), with microarray-based technology. Unique families in which autoimmune diseases are caused by single genes are another alternative. The identification of candidate genes is often followed by studies that provide biologic plausibility for the findings. The widely expanding list of genes involved in autoimmune conditions show that the same genes frequently underlie the pathogenesis of different autoimmune diseases. Despite all available resources, the main void of heritability in autoimmune conditions is yet to be discovered. Identification of these genes will help define new biological pathways and identify novel targets for the development of new therapeutic drugs.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with a high degree of variability at onset, making it difficult to reach a correct and prompt diagnosis.

Objectives: To present the difficulties faced by the clinician in making a SLE diagnosis, based on the characteristics at study entry of an Italian cohort of SLE patients with recent onset as compared to two similar cohorts.

Methods: Beginning on 1 January 2012 all patients with a diagnosis of SLE (1997 ACR criteria) and a disease duration less than 12 months were consecutively enrolled in a multicenter prospective study. Information on clinical and serological characteristics was collected at study entry and every 6 months thereafter.

Results: Our cohort consisted of 122 patients, of whom 103 were females. Among the manifestations included in the 1997 American College of Rheumatology (ACR) criteria, cutaneous, articular and hematologic symptoms were the most prevalent symptoms at study entry.

Conclusions: Data from the literature confirm that the diagnosis of SLE is challenging, and that SLE is a severe disease even at onset when a prompt diagnosis is necessary for initiating the appropriate therapy.

Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix®, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1)pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed “black box” attitude towards all vaccines. The focus of this review article is to revisit this “black box” using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine.

Background: The role of autoimmune factors in the etiology of coronary artery disease (CAD) was suggested in numerous studies but has not been definitively determined.

Objectives: To assess the possible influence of antiphospholipid and antinuclear antibodies on atherosclerosis development in young patients after myocardial revascularization procedures.

Methods: The study group included 39 patients younger than 45 years with coronary artery disease (CAD) who underwent myocardial revascularization. Serum levels of antiphospholipid (aPL), antinuclear (ANA) and antineutrophil cytoplasmatic (ANCA) antibodies were tested within 1 month after the procedure.

Results: All three types of aPL were significantly higher in CAD patients when compared to healthy controls: anti-β2-glycoprotein I (aβ2GPI), both immunoglobulin (Ig)G and IgM classes (median 4.10 SGU, range 3.45–21.63 vs. 0.76, 0.12–6.01, P < 0.001, and 2.82 SGU, 1.44–11.70 vs. 1.08, 0.44–3.64, P < 0.001, respectively); anticardiolipin antibodies (aCL) both IgG and IgM classes (3.13 GPL, 1.32–14.03 vs. 2.42, 0.96–18.45, P = 0.0037, and 6.94 MPL, 1.90–26.40 vs. 4.32, 1.9–28.73, P < 0.008, respectively); and lupus anticoagulant (LA) (27.7% vs. 0%, P = 0.005). ANA were elevated in one patient and ANCA in 23 (60%). The levels of aPL did not correlate with the presence of a clot in a coronary vessel detected during angiography or with exacerbation of coronary artery atherosclerosis.

Conclusions: In young patients with CAD who underwent myocardial revascularization the levels of aPL were significantly higher than in young healthy subjects. Thus, besides the classic risk factors for CAD, autoimmunity may play an important role in atherosclerotic plaque formation and progression.

Background: Balneotherapy is one of the most commonly used non-pharmacological approaches for osteoarthritis (OA). Recent data indicate that some biomarkers could be useful to predict OA progression and to assess therapeutic response.

Objectives: To evaluate the effects of mud-bath therapy on serum biomarkers in patients with knee OA. 

Methods: The study group comprised 103 patients with primary symptomatic bilateral knee OA who were randomly assigned to receive a cycle of mud-bath therapy over a period of 2 weeks or to continue their standard therapy alone. Clinical and biochemical parameters were assessed at baseline and after 2 weeks. Clinical assessments included global pain score on a Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities Index (WOMAC) subscores for knee OA. Cartilage oligomeric matrix protein (COMP), C-terminal cross-linked telopeptide type II collagen (CTX-II), myeloperoxidase (MPO) and high sensitivity C-reactive protein (hsCRP) serum levels were assessed by ELISA.

Results: At the end of mud-bath therapy we observed a statistically significant improvement in VAS and WOMAC subscores. Serum levels of COMP, MPO and hsCRP did not show any significant modification in both groups, while a significant increase (P < 0.001) in CTX-II serum levels was observed in the mud-bath group after the treatment.

Conclusions: A cycle of mud-bath therapy added to usual treatment had a beneficial effect on pain and function in patients with knee OA. The evaluation of serum biomarkers showed only a significant increase of CTX-II, perhaps due to an increase of cartilage turnover induced by thermal stress.

Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. The choice of treatment is based on the severity of systemic involvement, clinical presentation and the site affected, and includes corticosteroids, azathioprine, interferon, cyclophosphamide, methotrexate or tumor necrosis factor-alpha and interleukin-1 blockers. We present a case series of four refractory BD patients successfully treated with intravenous immunoglobulins (IVIG). All patients fulfilled International Study Group criteria. The patients’ mean age was 38.75 ± 12.09 years and mean disease duration 10.25 ± 8.5 years. Human leukocyte antigen B51 was positive in two of four patients. In addition to oral aphthosis, all patients suffered from genital ulcers and cutaneous BD-related manifestations; central nervous system involvement and arthralgia were found in two patients. Peripheral nervous system, gastrointestinal and eye involvement occurred in 25% of cases. In all patients, previously treated according to EULAR recommendations without reaching satisfactory results, IVIG induced immediate and sustained response over time without incurring any side effects. We propose IVIG administration as an additional effective and safe treatment option in patients with severe and resistant BD.

Background: Resective epilepsy surgery is an accepted treatment option for patients with drug-resistant epilepsy (DRE). Presurgical evaluation consists of a phase 1 non-invasive evaluation and a phase 2 invasive evaluation, when necessary.

Objectives: To assess the results of phase 1 evaluation in patients with focal DRE.

Methods: This observational retrospective study was performed in all consecutive DRE patients admitted to our clinic from January 2001 to July 2010, and who underwent a presurgical evaluation which included at least magnetic resonance imaging (MRI) scan and long-term video EEG monitoring (LTVEM).

Results: A total of 253 consecutive patients with a diagnosis of DRE (according to the ILAE recommendations) who underwent presurgical evaluation were extracted from our clinic and department registry. In 45 of these patients either imaging or ictal video EEG data were missing; the final analysis therefore involved 208 patients. The combined result of the LTVEM and the MRI scan were as follows: 102 patients (49% of the cohort) had a lesion on the MRI scan, in 77 patients (37% of the cohort) the LTVEM results were localizing and congruent with the MRI findings, and in 25 patients (12% of the cohort) the LTVEM results were either non-localizing or incongruent with the MRI findings. In 106 patients (51% of the cohort) the MRI scan was normal or had a non-specific lesion. The LTVEM was localizing in 66 of these patients (31.7% of the cohort) and non-localizing in 40 (19.2% of the cohort).

Conclusions: Although some of the patients with focal DRE can be safely treated with resective surgery based solely on the findings of phase 1 evaluation, a substantial percent of patients do need to undergo a phase 2 evaluation before a final surgical decision is made.

 

Background: Atherosclerosis is a systemic disease. Nevertheless, the role of specific biomarkers as indicators for both coronary and carotid diseases is debatable.

Objectives: To evaluate the association of biomarkers with coronary and carotid disease.

Methods: We studied 522 consecutive patients with stable angina. All underwent coronary angiography and carotid duplex study on the same day. Patients with no apparent carotid plaques were evaluated for carotid intima-media thickness (CIMT) using an automated system that sampled over 100 samples in each carotid artery. Biochemical markers of cardiovascular disease risk were obtained at the time of coronary angiography, including serum lipid levels, hemoglobin A1C (HbA1c), white blood cell count, fibrinogen and high sensitivity C-reactive protein (hs-CRP).

Results: The mean age of the patients was 66 ± 11; 73% were males. Significant carotid stenosis was associated with higher hs-CRP (9.4 ± 17 vs. 6.3 ± 13 mg/L, P = 0.001), while high HbA1c (6.7 ± 1.6 vs. 5.8 ± 0.8%, P < 0.001) and low high density lipoprotein levels (40 ± 9 vs. 47 ± 14 mg/dl, P < 0.001) were linked with advanced coronary artery disease severity. In contrast, CIMT was not related to any of the biomarkers evaluated.

Conclusions: Although atherosclerosis is considered a systemic disease, different biomarkers are associated with coronary and carotid artery disease. Identifying the specific biomarkers for each disease is important for both prevention and for exposing the underlying pathophysiologic mechanism.

 

Background: Recent studies show that vaccination of health care workers (HCW) might reduce influenza transmission and mortality among hospitalized patients. No studies have compared the incidence of laboratory-proven influenza in vaccinated versus unvaccinated hospital HCW. 

Objectives: To evaluate the effectiveness of influenza vaccination among hospital HCW and to examine the attitudes of this population towards influenza vaccination.

Methods: We performed a prospective cohort study between 1 January and 30 April 2014 of 1641 HCW at our medical center; 733 were vaccinated and 908 not vaccinated. A random sample of 199 subjects was obtained: 97 vaccinated and 102 non-vaccinated. Participating individuals were contacted on a weekly basis during the flu season and were asked to report any respiratory or flu symptoms and, if positive, to undergo a polymerase chain reaction (PCR) test for influenza. 

Results: In the general HCW population, vaccination was more frequent among physicians 298/498 (58%) than among nurses (324/862 (38%) and among males than females. Flu symptoms were reported by 20 of 199 participants, 13 in the non-vaccinated group (12.7%) and 7 in the vaccinated group (7.2%). A positive PCR test for influenza A virus was present in 4 of 20 people tested (20%). All positive cases were from the non-vaccinated group (P = 0.0953). 

Conclusions: Non-vaccinated HCW showed a higher, although not statistically significant, tendency for contracting laboratory-proven influenza than the vaccinated population. The main reasons for vaccination and non-vaccination were personal beliefs and habits. Education efforts are needed to improve compliance. Larger studies could further clarify this issue.

 

Background: The popularity of bicycle riding for recreation, exercise and transportation has grown enormously in recent years, which has led to an increased incidence of bicycle-related injuries. While these injuries involve mainly the musculoskeletal system, data on shoulder-specific injuries incurred while bike riding are lacking. Classifying these shoulder injuries may provide insight and assistance in the creation and implementation of effective protective gear and measures. 

Objectives: To investigate the types and mechanisms of shoulder injuries among cyclists.

Methods: This study retrospectively examined all cyclists who incurred shoulder injuries while riding and were admitted to the emergency department and shoulder clinic between January 2008 and November 2013. The study included 157 subjects with various bicycle-related shoulder injuries treated with either conservative or surgical measures. 

Results: Eighty-four percent of injuries were caused by a direct blow to the shoulder, 7% by falling on an outstretched hand, 6% were traction injuries, and 3% were due to hyper-abduction. Nine different clinical types of injury were observed; the most common injuries were clavicle fractures (32%), followed by acromioclavicular joint dislocations (22%), rotator cuff tears (22%), and humeral fractures (8%). Fifty-one percent of subjects were managed with conservative care and the remaining patients required surgical interventions. 

Conclusions: The shoulder injuries incurred while riding a bicycle span the entire spectrum of shoulder injuries and often result in debilitating conditions. Although the use of helmets is increasing, there is currently no effective protective gear or measures to prevent riders from suffering shoulder injuries. 

 

Background: Selection of appropriate reference charts for fetal biometry is mandatory to ensure an accurate diagnosis. Most hospitals and clinics in Israel use growth curves from the United States. Charts developed in different populations do not perform well in the Israeli population.

Objectives: To construct new reference charts for fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), using a large sample of fetuses examined at 14–42 weeks gestational age in a medical center and a community ultrasound unit located in two different regions of Israel. 

Methods: Data from the medical center and the community clinic were pooled. The mean and standard error of each measure for each week was calculated. Based on these, reference charts were calculated using quantiles of the normal distribution. The performance of the reference charts was assessed by comparing the new values to empirical quantiles.

Results: Biometric measurements were obtained for 79,328 fetuses. Growth charts were established based on these measurements. The overall performance of the curves was very good, with only a few exceptions among the higher quantiles in the third trimester in the medical center subsample.

Conclusions: We present new local reference charts for fetal biometry, derived from a large and minimally selected Israeli population. We suggest using these new charts in routine daily obstetric practice.