Israel Medical Association Journal

Background: Maternal cardiac arrest during gestation constitutes a devastating event. Training and anticipant preparedness for prompt action in such cases may save the lives of both the woman and her fetus. 

Objectives: To address a previous Jewish guideline that a woman in advanced pregnancy should not undergo any medical procedure to save the fetus until her condition is stabilized. 

Methods: Current evidence on perimortal cesarean section shows that immediate section during resuscitation provides restoration of the integrity of the mother’s vascular compartment and increases her probability of survival. We analyzed Jewish scriptures from the Talmud and verdicts of the oral law and revealed that the Jewish ethical approach toward late gestational resuscitation was discouraged since it may jeopardize the mother. 

Results: We discuss the pertinent Jewish principles and their application in light of emerging scientific literature on this topic. An example case that led to an early perimortem cesarean delivery and brought about a gratifying, albeit only partially satisfying outcome, is presented, albeit with only a partially satisfying outcome. The arguments that were raised are relevant to such cases and suggest that previous judgments should be reconsidered.  

Conclusions: The Jewish perspective can guide medical personnel to modify and adapt the concrete rules to diverse clinical scenarios in light of current medical knowledge. With scientific data showing that both mother and fetus can prosper from immediate surgical extrication of the baby during resuscitation of the advanced pregnant woman, these morals should dictate training and practice in urgent perimortal cesarean sections whenever feasible. 

 

Background: The goals of treatment for rheumatoid arthritis (RA) are remission and low disease activity (LDA). However, many patients do not reach or maintain these targets with regard to disease control. 

Objective: To identify predictive factors of remission/LDA in a cohort of RA patients who started treatment with first line tumor necrosis factor-inhibitors (TNF-i). 

Methods: We included 308 RA patients treated with first line TNF-i for 2 years to evaluate remission/LDA based on the 28-joint disease activity score (DAS28). Predictive factors considered for achievement of remission/LDA were: gender, age at the time of TNF-i treatment, early arthritis, baseline C-reactive protein (CRP) and erythrocyte sedimentation rate levels, RF/anti-citrullinated protein antibody positivity, good/moderate European League Against Rheumatism response at 6 months, co-morbidities, and concomitant disease modifying antirheumatic drugs (DMARDs). Intention to treat, receiver operating characteristic curve, and univariate and multivariate analyses by logistic regression were performed. 

Results: Positive predictors of remission/LDA in both the univariate and the multivariate analyses were: male gender, age at the time of TNF-i treatment ≤ 54 years, negative baseline CRP, and concomitant DMARDs. The presence of any co-morbidity resulted to be a negative predictor of remission/LDA in both the univariate and the multivariate analyses. 

Conclusions: Demographic and clinical features were identified as reliable predictors of both the achievement and the maintenance of treatment targets in a cohort of RA patients treated for 2 years with first line TNF-i. 

 

Background: Evidence has shown that pregnancy failure (PF) in women with systemic sclerosis (SSc) consists mainly of preterm delivery (PD) and intrauterine growth restriction (IUGR). Thyroid dysfunction (TD) and Hashimoto's thyroiditis (HT) represent a common feature of SSc. Since TD has been associated with PF, its presence in SSc women may potentially affect pregnancy outcome. 

Objectives: To analyze the interplay between TD and PF in a cohort of SSc women. 

Methods: SSc women (n=77) and age-matched controls from the general obstetric population (n=50) were included. Clinical/biochemical/instrumental data exploring TD and the visceral involvement were collected in the context of a clinical practice setting. Pregnancy outcome was assessed by registering the history of primary infertility, recurrent spontaneous abortion, PD (≤ 37 gestational week), IUGR, and intrauterine fetal death. 

Results: A higher prevalence of PD/IUGR was recorded in the SSc cohort than the controls (P = 0.04). SSc women with PF showed a higher prevalence of diffuse SSc than women without PF (P = 0.03). Scl-70 positive SSc women had a higher prevalence of PF than women with anti-centromere positivity (P = 0.01). A higher prevalence of HT was recorded in SSc women with PF than in patients without (P = 0.04). 

Conclusions: Our findings support the evidence that women with SSc can have successful pregnancies despite a higher prevalence of PD/IUGR. Diffuse SSc and Scl-70 positivity may predispose SSc women to PF. Routine thyroid workup may be included in the multi-specialist monitoring of SSc women for the early detection of thyroid dysfunctions.

 

Background: Non-infectious uveitis (NIU) leads to severe visual impairment, potentially impacting on health-related quality of life (QoL). 

Objectives: To investigate the impact of NIU on QoL.

Methods: Eighty NIU patients and 23 healthy controls completed the 36-item Short-Form Health Survey (SF)-36. The SF-36 values were statistically analyzed to evaluate differences between patients and healthy controls and to identify correlations between SF-36 subscores and clinical/demographic data. 

Results: NIU patients showed a decrease in the physical component summary score (P < 0.0001) compared to healthy controls, while no difference was highlighted in the mental component summary score (P = 0.97). NIU patients showed a decrease in physical functioning (P = 0.008), role-physical (P = 0.003), bodily pain (P = 0.0001), general health (P < 0.0001), and social functioning (P = 0.01). Physical functioning was lower in patients with acute anterior uveitis (AAU) than in those with panuveitis (P = 0.003). No differences were found between patients with bilateral or unilateral NIU, isolated NIU, or NIU associated with systemic diseases and with or without ocular activity. No correlations were identified between best-corrected visual acuity and SF-36 subscores. Physical functioning (P = 0.02), bodily pain (P = 0.004), and social functioning (P = 0.02) were reduced in males versus females. 

Conclusions: QoL is impaired in individuals with NIU, particularly in the physical domains, general health, and social functioning. AAU affects physical functioning more than panuveitis. NIU seems to affect per se QoL disregarding inflammatory activity, visual impairment, and presence of associated systemic diseases.

 

Background: Cytomegalovirus (CMV) infection during pregnancy is the most common cause of intrauterine infection, and is a common cause of sensorineural hearing loss and mental retardation. 

Objectives: To evaluate trends in amniocentesis and pregnancy outcome in women with suspected cytomegalovirus (CMV) infection during the first trimester.

Methods: All blood tests for CMV immunoglobulin M (IgM) done between 2008 and 2009 on pregnant women who were enrolled in the Maccabi Healthcare Services were retrieved from laboratory database. Immunoglobulin G (IgG) avidity was measured and women were classified according to the risk of acquiring CMV infection. For each patient, performance of amniocentesis and whether pregnancy came to term were recorded.

Results: Of 109,439 pregnant women evaluated during the study period, 76,712 (70.1%) were tested for CMV IgM, and 792 (1.03%) were found to be positive. Among women with positive IgM, only 205 (25.9%) underwent amniocentesis. When compared with women with negative CMV IgM, the rate of pregnancy cessation was doubled in women with positive CMV IgM (28.3% vs. 14.3%, P < 0.05) and mostly elevated in women with a high risk of acquiring CMV (42.3% pregnancy cessation). Among women with positive CMV IgM, those who did not undergo amniocentesis were more likely to abort than those who performed amniocentesis (35.6% vs. 7.3%, P < 0.05). 

Conclusions: More women with suspected CMV infection during the first trimester of pregnancy aborted before all means of detection were utilized to rule out or confirm fetal infection with CMV.

 

Background: Vitamin D insufficiency is associated with autoimmune and chronic inflammatory diseases such as tuberculosis and sarcoidosis. 

Objectives: To evaluate the vitamin D-dependent mechanisms of immunity and autoimmunity in different forms of pulmonary tuberculosis and sarcoidosis.

Methods: We measured the serum levels of 25(OH)D and 1,25(OH)2D, individual autoimmune profiles, plasma concentrations of cathelicidin, several hormones, and production of nine cytokines in patients with short- and long-duration tuberculosis and sarcoidosis.

Results: The level of 25(OH)D was significantly decreased in all patients. Concentration of 1,25(OH)2D was elevated only in sarcoidosis, prolactin content was augmented only in tuberculosis. We saw no expected increase of cathelicidin levels in tuberculosis and sarcoidosis. The individual mean immune reactivity levels of autoantibodies to 24 antigens were significantly lower in tuberculosis and sarcoidosis patients compared to healthy controls. Pronounced deviations from individual mean immune reactivity levels were found for several autoantigens in all patients. The induced production of interferon gamma-γ, interleukin (IL) 2, 17, and 8 by peripheral blood mononuclear cells was significantly increased in patients of both tuberculosis groups, but spontaneous production of tumor necrosis factor-α, IL-2, and IL-6 was lower in the tuberculosis patients than in healthy controls. We registered marked differences in the groups of tuberculosis patients. 

Conclusions: We demonstrated the role of vitamin D deficiency in poor cathelicidin response in  tuberculosis and sarcoidosis. Both diseases are accompanied by significant changes in the autoimmune profile, probably related to the status of vitamin D and cytokine regulation. 

 

Biomarkers are important for guiding the clinical and therapeutic management of all phases of rheumatoid arthritis because they can help to predict disease development in subjects at risk, improve diagnosis by closing the serological gap, provide prognostic information that is useful for making therapeutic choices and assessing treatment responses and outcomes, and allow disease activity and progression to be monitored. Various biomarkers can be used to identify subjects susceptible to the disease and those with pre-clinical rheumatoid arthritis before the onset of symptoms such as rheumatoid factor and anti-citrullinated protein antibodies. They can be correlated with a risk of developing rheumatoid arthritis and can predict more bone erosions and severe disease progression. Biomarkers such as the erythrocyte sedimentation rate and C-reactive protein levels provide information about disease activity, while predictive biomarkers allow clinicians to assess the probability of a treatment response before starting a particular therapy particularly in the era of biological drugs. This move from traditional approaches to patient stratification and targeted treatment should greatly improve patient care and reduce medical costs.

Ovarian cancer is a major cause of cancer death among women worldwide, and particularly in Israel. Although the disease at stage IA has 5 year survival rates of over 90%, early detection methods are not sufficiently accurate. Consequently, ovarian cancer is typically diagnosed late, which results in high fatality rates. An excellent candidate for early ovarian cancer detection would be in vivo magnetic resonance spectroscopy (MRS) because it is non-invasive and free of ionizing radiation. In addition, it potentially identifies metabolic features of cancer. Detecting these metabolic features depends on adequate processing of encoded MRS time signals for reconstructing interpretable information. The conventional Fourier-based method currently used in all clinical scanners is inadequate for this task. Thus, cancerous and benign ovarian lesions are not well distinguished. Advanced signal processing, such as the fast Padé transform (FPT) with high-resolution and clinically reliable quantification, is needed. The effectiveness of the FPT was demonstrated in proof-of-concept studies on noise-controlled MRS data associated with benign and cancerous ovaries. The FPT has now been successfully applied to MRS time signals encoded in vivo from a borderline serous cystic ovarian tumor. Noise was effectively separated out to identify and quantify genuine spectral constituents that are densely packed and often overlapping. Among these spectral constituents are recognized and possible cancer biomarkers including phosphocholine, choline, isoleucine, valine, lactate, threonine, alanine, and myoinositol. Most of these resonances remain undetected with Fourier-based in vivo MRS of the ovary. With Padé optimization, in vivo MRS could become a key method for assessing ovarian lesions, more effectively detecting ovarian cancer early, thereby improving survival for women afflicted with this malignancy.

Background: Abatacept acts as a co-stimulation modulator preventing activation of T cells. Although it is approved for the treatment of rheumatoid arthritis (RA), its effects on adaptive immune response have not been fully elucidated. 

Objectives: To observe, in a cohort study, based on a clinical practice setting, the variation of peripheral blood T cells, immunoglobulin levels, and autoantibodies in the serum of RA patients during abatacept therapy. 

Methods: Our study comprised 48 RA patients treated with abatacept. All clinical data were collected at baseline and after 3 months of treatment. Clinical and laboratory tests included erythrocyte sedimentation rate, C-reactive protein, 28-joint disease activity score, RF, anti-citrullinated protein antibody, total immunoglobulins, immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), and lymphocyte sub-population. 

Results: Total immunoglobulin serum levels significantly decreased after 3 months of treatment and correlated positively with disease activity both at baseline and after 3 months of abatacept treatment. A reduction of serum IgM, IgG, IgA and RF was also demonstrated. The absolute number and percentage of cytotoxic (CD8+) T cells significantly decreased after 3 months of abatacept treatment, in particular the percentage of cytotoxic (CD8+) T cells significantly decreased only in patients responding to the treatment.

Conclusions: Our results highlight a different role of abatacept in the modulation of the adaptive immune response in RA by the reduction of polyclonal B-cell activation and cytotoxic T cells. 

 

Background: The evidence on the use of dexamethasone implants in the treatment of Behçet’s disease (BD)-related uveitis is limited to a few cases. 

Objectives: To evaluate the efficacy of dexamethasone implants on ocular functional, morphological, and clinical parameters in BD patients with severe refractory uveitis. 

Methods: Five eyes from five BD patients were enrolled. A single intravitreal dexamethasone injection was applied to each eye. Best corrected visual acuity (BCVA), central macular thickness (CMT) assessed with optical coherence tomography, retinal vasculitis assessed by fluorescein angiography, vitreous haze score (Nussenblatt scale), intraocular pressure (IOP), and lens status (LOCS III, Lens Opacities Classification System III) were recorded at baseline and at 1, 3, and 6 month follow-up visits.

Results: At baseline, all eyes showed marked macular edema and 4/5 had concomitant active retinal vasculitis. Mean BCVA was increased from baseline at each control visit with a mean improvement of 0.26 ± 0.18 lines at 6 months follow-up. Mean CMT decreased from baseline at each control visit with a mean improvement at 6 months follow-up of 198.80 ± 80.08 µm. At the end of the study, none of the eyes showed macular edema and the mean CMT was 276.80 ± 24.94 µm. Retinal vasculitis resolved in all eyes. One eye experienced an IOP spike during treatment that resolved spontaneously, and one eye developed a clinically significant lens opacity at 6 months follow-up. 

Conclusions: Treatment with a dexamethasone implant in BD-uveitis and inflammatory macular edema was safe and effective as an additional treatment combined with systemic immunomodulatory drugs.

 

Background: Common variable immunodeficiency (CVID) is the most common symptomatic primary immune deficiency of adulthood. Besides recurrent infections, autoimmune disorders–mainly cytopenias–affect 30% of patients with CVID.

Objectives: To describe the efficacy and safety of facilitated subcutaneous immunoglobulin (fSCIg), which is a combination of 10% [human] SCIg with recombinant human hyaluronidase for the treatment of CVID-linked cytopenias. 

Methods: We describe four women (mean age 54 years) with CVID associated with idiopathic thrombocytopenic purpura (ITP) (n=3) and autoimmune hemolytic anemia (AIHA) (n=1). Diagnosis of CVID was made according to the European Society of Immune Deficiencies / Pan-American Group for Immune Deficiency criteria. All were treated with fSCIg (bi-monthly, 20 g).

Results: After a median follow-up of 22 months, all patients achieved a stable remission from the cytopenias, characterized by increased platelet values in ITP (mean values 93000/mmc), and resolution of anemia. A reduction of the daily prednisone dose was documented in the patient with AIHA. No systemic adverse drug reactions were observed. 

Conclusions: Our preliminary data documented the efficacy and safety of fSCIg in the treatment of CVID associated with autoimmune cytopenias, with a good tolerability. We also noted the role of fSCIg as a steroid sparing agent. It is thus possible to suppose an immunomodulatory role for fSCIg, but linked to different mechanisms than IVIg, due to the peculiar pharmacokinetic and administration route of fSCIg. 

 

Background: Anti-glomerular basement membrane (GBM) antibody disease, or Goodpasture’s disease, is the clinical manifestation of the production of anti-GBM antibodies, which causes rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. Anti-GBM antibody detection is mandatory for the diagnosis of Goodpasture’s disease either from the serum or kidney biopsy. Renal biopsy is necessary for disease confirmation; however, in cases in which renal biopsy is not possible or is delayed, serum detection of anti-GBM antibody is the only way for diagnosis.

Objectives: To assess the predictive value of positive anti-GBM antibodies in a clinical setting. 

Methods: Data from anti-GBM antibody tests performed at one medical center between 2006 and 2016 were systematically and retrospectively retrieved. We recruited 1914 patients for the study. Continuous variables were computed as mean ± standard deviation, while categorical variables were recorded as percentages where appropriate. Sensitivity and specificity of anti-GBM titers were calculated. Kaplan–Meyer analysis was performed, stratifying survival according to the anti-GBM antibody titers.

Results: Of the 1914 anti-GBM test results detected, 42 were positive, 23 were borderline, 142 were excluded, and 1707 results were negative. Male-to-female ratio was 1:1.2. Sensitivity of anti-GBM test was 41.2% while specificity was 85.4%. Concerning the Kaplan–Meyer analysis, overall survival was 1163.36 ± 180.32 days (median 1058 days). 

Conclusions: Our study highlights the lack of sensitivity of serological testing of anti-GBM titers. Comparing survival curves, the survival correlated with anti-GBM titer only in a borderline way. Because highly sensitive bioassays are not routinely used in clinics, renal biopsy is still pivotal for Goodpasture’s disease diagnosis.

 

Hyperbaric oxygen therapy (HBOT) has been investigated as a primary/adjunctive treatment for a number of injuries and medical conditions including traumatic ischemia, necrotizing soft tissue injuries, non-healing ulcers and osteoradionecrosis, but the results are controversial. There is insufficient evidence to support or reject the use of HBOT to quicken healing or to treat the established non-union of fractures. However, in patients with fibromyalgia, HBOT reduces brain activity in the posterior cortex and increases it in the frontal, cingulate, medial temporal and cerebellar cortices, thus leading to beneficial changes in brain areas that are known to function abnormally. Moreover, the amelioration of pain induced by HBOT significantly decreases the consumption of analgesic medications. In addition, HBOT has anti-inflammatory and oxygenatory effects in patients with primary or secondary vasculitis. 

This review analyzes the efficacy and limitations of HBOT in orthopedic and rheumatologic patients.