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We aimed to assess the efficacy and patient satisfaction of subcutaneous tocilizumab (SC TCZ) in patients previously treated with intravenous tocilizumab (IV TCZ) during the COVID-19 pandemic.We conducted a single-centre retrospective study at the Rheumatology Day Care at the Rheumatology Institute, Rambam Health Care Campus, Israel. Clinical and laboratory data of IV TCZ treated patients who switched to SC TCZ were retracted and analysed. Data were collected from the last two visits before switching to SC treatment and two visits afterwards. A telephone call conversation was conducted for all patients who continued SC treatment and did not come to follow-up visits.Forty patients (age 53.03 (± 15.7)) treated with IV TCZ were switched to SC TCZ in April-May 2020. Three patients were excluded from the study. Most of the patients were treated with TCZ for 6.35 (±2.89) years and had low disease activity. 26/37 (70%) patients discontinued SC TCZ therapy and switched back to IV TCZ. The majority of discontinuations were due to flare up of the underlying disease reflected by increased number of tender and/or swollen joints, prolongation of morning stiffness or increased pain VAS score. Two patients were hospitalised for IV glucocorticoids and 1 patient underwent knee arthrocentesis. 11/37 (30%) patients continued SC TCZ treatment. 3/11 (27%) expressed less satisfaction with SC TCZ therapy.More than half of the patients who switched from IV TCZ to SC TCZ showed signs of flare of their underlying disease or were less satisfied with SC treatment.

The aim of the study was to evaluate the interrelationship between the micro- and macrovasculature. This is a cross-sectional study that examined SSc patients and fibromyalgia (FM) patients as controls. We assessed forearm peripheral vascular status and nailfold capillaroscopy. We evaluated the association between nailfold capillaroscopy pattern of microvasculopathy reflected as microangiopathy evolution score and macrovascular changes in the forearm vessels examined by color Doppler ultrasound. We assessed relevant clinical and laboratory data, as well as intima-media thickness (IMT) and internal diameter (ID) in the radial and ulnar arteries in millimeters, and calculated the ratio IMT\ID peak systolic velocity and end-diastolic velocity were used for the calculation of the resistance index. We examined 73 patients: 50 patients with SSc and 23 patients with FM. Ten patients with SSc had arterial occlusions compared to 1 among FM patients (p = 0.082). The SSc group had a statistically significantly higher mean IMT to ID ratio (p

The clerkship of internal medicine is pursued in the 2nd semester of the 4th year at the Technion Medical School. Following the COVID-19 outbreak, frontal and bedside teaching was interrupted. Therefore, we decided to provide distant teaching until having the opportunity to resume clinical bedside teaching. A team of tutors composed a course of weekly units, each week assigned to a different subject in internal medicine. A total of 120 students were divided into 15 groups of 8 students, each group guided by a personal tutor. The format of each unit included online pretest, clinical virtual cases and two separate 2 hour ZOOM sessions with the tutor. The pretest was based on 1-3 chapters from Harrison's Internal Medicine textbook, 20th edition, and consisted of both clinical reasoning and knowledge questions. During ZOOM sessions with the tutor, the students practiced clinical problem solving. In addition, all the students were granted free access to the commercial "Aquifer" case-based virtual course for more practice. The students' feedback at the end of the learning period revealed that, although frustrated in being away from the clinics, the overall level of satisfaction from the course was good (rated 5 or 4/5 by 65% of responders) and the time was used efficiently. In conclusion, the students received a positive proactive learning experience of both theoretical aspects and clinical reasoning skills in internal medicine. There is no doubt that bedside teaching in medicine is invaluable and can't be replaced by any other means, however, given the circumstances, our format provided a reasonable temporary alternative.

The coronavirus disease-2019 (COVID-19) pandemic forced drastic changes in all layers of life. Social distancing and lockdown drove the educational system to uncharted territories at an accelerated pace, leaving educators little time to adjust.To describe changes in teaching during the first phase of the COVID-19 pandemic.We described the steps implemented at the Technion-Israel Institute of Technology Faculty of Medicine during the initial 4 months of the COVID-19 pandemic to preserve teaching and the academic ecosystem.Several established methodologies, such as the flipped classroom and active learning, demonstrated effectiveness. In addition, we used creative methods to teach clinical medicine during the ban on bedside teaching and modified community engagement activities to meet COVID-19 induced community needs.The challenges and the lessons learned from teaching during the COVID-19 pandemic prompted us to adjust our teaching methods and curriculum using multiple online teaching methods and promoting self-learning. It also provided invaluable insights on our pedagogy and the teaching of medicine in the future with emphasis on students and faculty being part of the changes and adjustments in curriculum and teaching methods. However, personal interactions are essential to medical school education, as are laboratories, group simulations, and bedside teaching.

BackgroundThe registration trials of messenger RNA (mRNA) vaccines against SARS-CoV-2 did not address patients with inflammatory rheumatic diseases (IRD).ObjectiveTo assess the humoral response after two doses of mRNA vaccine against SARS-CoV-2, in patients with IRD treated with immunomodulating drugs and the impact on IRD activity.MethodsConsecutive patients treated at the rheumatology institute, who received their first SARS-CoV-2 (Pfizer) vaccine, were recruited to the study, at their routine visit. They were reassessed 4–6 weeks after receiving the second dose of vaccine, and blood samples were obtained for serology. IRD activity assessment and the vaccine side effects were documented during both visits. IgG antibodies (Abs) against SARS-CoV-2 were detected using the SARS-CoV-2 IgG II Quant (Abbott) assay.ResultsTwo hundred and sixty-four patients with stable disease, (mean(SD) age 57.6 (13.18) years, disease duration 11.06 (7.42) years), were recruited. The immunomodulatory therapy was not modified before or after the vaccination. After the second vaccination, 227 patients (86%) mounted IgG Ab against SARS-CoV-2 (mean (SD) 5830.8 (8937) AU/mL) and 37 patients (14%) did not, 22/37 were treated with B cell-depleting agents. The reported side effects of the vaccine were minor. The rheumatic disease remained stable in all patients.ConclusionsThe vast majority of patients with IRD developed a significant humoral response following the administration of the second dose of the Pfizer mRNA vaccine against SARS-CoV-2 virus. Only minor side effects were reported and no apparent impact on IRD activity was noted.

BackgroundThe registration trials of mRNA vaccines against SARS CoV2 did not address patients with autoimmune inflammatory rheumatoid diseases (AIRD).AimsTo assess the humoral response to mRNA vaccine against SARS CoV2, in AIRD patients treated with immunomodulating drugs and the impact on AIRD activity.MethodsConsecutive patients treated at the rheumatology institute who received their first SARS-CoV-2 (Pfizer) vaccine were recruited to the study, at their routine visit. The patients were invited for serology test 4-6 weeks after receiving the second dose of vaccine. IgG Antibodies (Ab) against SARS COV2 virus were detected using the SARS-Cov-2 IgG II Quant (Abbott) assayResultsOne hundred fifty-six consecutive patients (76% females) treated at a single rheumatology center (mean age (range) 59.1 (21-83) years), mean (range) disease duration 10.8 (1-55) years), were recruited to the study. Thirty-five percents of patients received conventional synthetic (cs)DMARDs only, 64% biological/targeted synthetic (b/ts) DMARDs, 34% received combined treatment with csDMARDs and b/tsDMARDs and 32% corticosteroids (mean dose(range) 5.8mg(2.5-20mg) prednisone). One hundred thirty-seven patients (88%) were seropositive for IgG Ab against SARS CoV2 virus (median 2832.5 AU/ml, range 58-29499). Nineteen (12%) patients had negative tests, 11/19 were treated with B cell depleting agents. The reported side effects of the vaccine were minor (muscle sore, headache, low grade fever). The rheumatic disease remained stable in all patients.ConclusionsThe vast majority of AIRD patients developed a significant humoral response following the administration of the second dose of the Pfeizer mRNA vaccine against SARS CoV2 virus. Only minor side effects were reported and no apparent impact on AIRD activity was noted.

The aim of the study was to evaluate the interrelationship between the micro- and macrovasculature.This is a cross-sectional study that examined SSc patients and fibromyalgia (FM) patients as controls. We assessed forearm peripheral vascular status and nailfold capillaroscopy. We evaluated the association between nailfold capillaroscopy pattern of microvasculopathy reflected as microangiopathy evolution score and macrovascular changes in the forearm vessels examined by color Doppler ultrasound. We assessed relevant clinical and laboratory data, as well as intima-media thickness (IMT) and internal diameter (ID) in the radial and ulnar arteries in millimeters, and calculated the ratio IMT\ID peak systolic velocity and end-diastolic velocity were used for the calculation of the resistance index.We examined 73 patients: 50 patients with SSc and 23 patients with FM. Ten patients with SSc had arterial occlusions compared to 1 among FM patients (p = 0.082). The SSc group had a statistically significantly higher mean IMT to ID ratio (p 0.001). There was no correlation between microangiopathy evolution score for both hands, RI, or mean IMT/ID ratio. Total microangiopathy evolution score was not associated with arterial occlusions.Our study demonstrated a high prevalence of macrovascular disease in SSc; no correlation was found between microvasculopathy and macrovascular disease, suggesting that different pathogenic mechanisms might operate in different vessels size. Key Points • This study demonstrated a high prevalence of macrovascular arterial forearm disease in systemic sclerosis patients. • This study found no correlation between capillaroscopic microangiopathy evolution score (MES) and macrovascular abnormalities. • Our findings suggest that different pathogenic mechanisms might operate in different vessels size.

BackgroundIntestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency.ObjectiveTo genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.MethodsFamily-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function.ResultsWe identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein’s transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected.ConclusionsBiallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP’s importance in EC barrier function in the gut.

Background:Transient osteoporosis (TOP) or transient bone marrow edema syndrome is an enigmatic condition of unknown etiology first described in pregnant women. Though usually self limited, TOP causes pain and debilitation and predisposes the patient to avascular necrosis or fractures. The course can be protracted and patient may suffer relapses. Diagnostic method of choice is magnetic resonance imaging (MRI). Based on small case series and expert opinion, several therapeutic approaches have been proposed to hasten the recovery, including bisphosphonates, calcitonin, teriparatide. However, the literature is scarce and additional experience is needed to promote the understanding of this condition.Objectives:To present our experience with TOP, including patient’s characteristic, approach to diagnosis, prognosis and therapyMethods:It is retrospective, single center study, conducted in Rambam healthcare campus, Haifa, Israel. All the medical files of patients referred to Rheumatology unit between years 2010-2020 were screened for diagnosis of TOP. Search words included: “osteoporosis”, “bone marrow edema”, “transient osteoporosis”. The files were reviewed for patient’s characteristics, modality of diagnosis, duration until full recovery, treatments and relapses.Results:Eight patients with at least one episode of TOP were identified using the search words. Six patients (75%) were female. Three female patients developed TOP during or shortly after pregnancy. Two patients – one male and one non pregnant female suffered from TOP after bariatric surgery. One pregnant woman had a strong family history of TOP. The most frequent involved site in order of frequency were: hip (4/8), ankle (3/8) and knee (2/8). Six patients presented with more than one simultaneous site of TOP (hips, knees and ankles). Blood count, liver and Kidney function tests, markers of bone resorption, rheumatoid factor, Anti cyclic citrullinated peptide, Antinuclear antibodies were negative in all of the patients. C-reactive protein was elevated in 4/8 patients, Erythrocyte sedimentation rate was elevated in 2/8 patients. All patients had vitamin D deficiency. The diagnosis was confirmed by MRI. All the patients were treated with vitamin D and intra-venous Pamidronate, one patient with addition of calcitonin and one patient with addition of intra venous Iloprost. Time to recovery ranged from 1.2 to 6 months. The time to recovery was the same in pregnancy related TOP. Recovery was confirmed with follow-up MRI in all the patients. Relapses occurred in 4/8 patients and only one them had pregnancy related TOP. All the patients were treated by multidisciplinary team, including orthopedic surgeon, physiotherapist and psychologist when needed.Conclusion:Our experience with TOP was enriched in patients presenting with more than one site of disease probably representing referral bias. Pregnancy related TOP was associated with lower risk of relapse. In terms of time to recovery there was no trend between pregnancy related and non related TOP or one site versus several sited TOP. None of the patients developed fracture, advocating in favor of adding bisphosphonates to therapy. Multidisciplinary approach is an essential part of TOP treatment strategy.Disclosure of Interests:Sami Giryes: None declared, Katya Dolnikov: None declared, Alexandra Balbir-Gurman Consultant of: Novartis, Daniela Militianu: None declared, Natalia Puchkov: None declared, Yolanda Braun-Moscovici: None declared

Background:A growing body of evidence suggests that the gut microbiota plays a significant role in the development of autoimmune diseases. Altered microbiota composition was associated with gastrointestinal and extraintestinal features in systemic sclerosis (SSc) patients.Objectives:To look for differences in gut microbiota between SSc patients regarding disease duration, disease subset and occurrence of digital ulcers (DU).Methods:SSc patients seen at our center were recruited in a prospective study. The exclusion criteria included antibiotic or probiotic treatment during the month prior to recruitment, recent hospitalization, BMI>30, diabetes mellitus or concomitant inflammatory bowel disease. Fecal samples were processed and 16S rRNA gene sequences were analyzed using the QIIME2 packageWeighted (quantitative) and unweighted (qualitative) UniFrac distances, alpha diversity for richness and homogeneity, taxa plots for species and phyla and ANCOM analyses were performed.Results:During July 2018-May 2019, 26 SSc patients (mean age [SD] 53[12.7] years) and disease duration 8.8 [7.1] years) fulfilled the criteria and were willing to participate in the study. Thirteen patients had diffuse SSc, 16 patients had active DU, 8 patients had Raynaud’s phenomenon only without DU, 2 patients had past DU. The microbiota was significantly more similar between patients without active DU compared to those with active DU (P=0.024), but species richness did not differ. Patients with SSc duration less than 6 years had significantly different microbiota compared to long-lasting SSc (unweighted PCoA – q=0.031). Significant variations concerning quantitative and qualitative UniFrac distances (q=0.063, q=0.005) and species richness (q=0.009) were found among patients with diffuse compared to limited SSc. Limited SSc was associated with greater species richness. Taxa plot analysis revealed higher relative abundance of Firmicutes in diffuse disease and of Actinobacteria and Bacteroidetes in limited SSc.Conclusion:Disease duration, disease subset and active DU were associated with shifts in the microbiome of SSc patients. The impact of these changes on disease progression needs further elucidation.Figure:Disclosure of Interests:Yolanda Braun-Moscovici: None declared, Shira Ben Simon: None declared, Katya Dolnikov: None declared, Sami Giryes: None declared, Doron Markovits: None declared, Yonit Tavor: None declared, Kohava Toledano: None declared, Alexandra Balbir-Gurman Consultant of: Novartis, Omry Koren: None declared

Intestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (To genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.Family-based whole exome sequencing was performed based on an autosomal recessive inheritance model.We identified a rare homozygous variant (NM_031310.2:c.101TC;p.Leu34Pro) inBiallelic missense variants in

Because previous findings showed that in human embryonic stem cell-derived cardiomyocytes (hESC-CM) the machinery for Ca2+-induced release of calcium is immature, we tested the hypothesis that hESC-CM contain functional 1,4,5-inositol triphosphate (IP3)-operated intracellular Ca2+ ([Ca2+]i) stores. We investigated the effects of angiotensin II (AT-II) and endothelin 1 (ET-1), which activate the 1,4,5-IP3 pathway, on [Ca2+]i transients and contractions in hESC-CM. Our major findings were that in hESC-CM, both AT-II (10(-9)-10(-7) M) and ET-1 (10(-9)-10(-7) M) exert inotropic and lusitropic effects. The involvement of 1,4,5-IP3-dependent intracellular Ca2+ release in AT-I-induced effects was supported by these findings: the effects of AT-II were blocked by 2-aminoethoxyphenyl borate (2-APB, a 1,4,5-IP3 receptor blocker) and U73122 (a phosopholipase C blocker); and hESC-CM express AT-II type 1 and IP3 type I and II receptors as determined by fluorescence immunostaining. In conclusion, hESC-CM exhibit functional AT-II and ET-1 signaling pathways, as well as 1,4,5-IP3-operated releasable Ca2+ stores.

On the basis of previous findings suggesting that in human embryonic stem cell-derived cardiomyocytes (hESC-CM) the sarcoplasmic reticulum Ca2+-induced release of calcium machinery is either absent or immature, in the present study we tested the hypothesis that hESC-CM contain fully functional 1,4,5-inositol trisphosphate (1,4,5-IP3)-operated intracellular Ca2+ ([Ca2+]i) stores that can be mobilized upon appropriate physiological stimuli. To test this hypothesis we investigated the effects of angiotensin-II (AT-II) and endothelin-1 (ET-1), which activate the 1,4,5-IP3 pathway, on [Ca2+]i transients and contractions in beating clusters of hESC-CM. Our major findings were that in paced hESC-CM both AT-II and ET-1 (10−9 to 10−7 M) increased the contraction amplitude and the maximal rates of contraction and relaxation. In addition, AT-II (10−9 to 10−7 M) increased the [Ca2+]i transient amplitude. The involvement of 1,4,5-IP3-dependent intracellular Ca2+ release in the inotropic effect of AT-II was supported by the findings that (a) hESC-CM express AT-II, ET-1, and 1,4,5-IP3 receptors determined by immunofluorescence staining, and (b) the effects of AT-II were blocked by 2 μM 2-aminoethoxyphenyl borate (a 1,4,5-IP3 receptor blocker) and U73122 (a phospholipase C blocker). In conclusion, these findings demonstrate for the first time that hESC-CM exhibit functional AT-II and ET-1 signaling pathways, as well as 1,4,5-IP3-operated releasable Ca2+ stores. Disclosure of potential conflicts of interest is found at the end of this article.

Since cardiac transplantation is limited by the small availability of donor organs, regeneration of the diseased myocardium by cell transplantation is an attractive therapeutic modality. To determine the compatibility of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) (7 to 55 days old) with the myocardium, we investigated their functional properties regarding intracellular Ca2+ handling and the role of the sarcoplasmic reticulum in the contraction. The functional properties of hESC-CMs were investigated by recording simultaneously [Ca2+]i transients and contractions. Additionally, we performed Western blot analysis of the Ca2+-handling proteins SERCA2, calsequestrin, phospholamban, and Na+/Ca2+ exchanger (NCX). Our major findings are, first, that hESC-CMs displayed temporally related [Ca2+]i transients and contractions, negative force-frequency relations, and lack of post-rest potentiation. Second, ryanodine, thapsigargin, and caffeine did not affect the [Ca2+]i transient and contraction, indicating that at this developmental stage, contraction depends on transsarcolemmal Ca2+ influx rather than on sarcoplasmic reticulum Ca2+ release. Third, in agreement with the notion that a voltage-dependent Ca2+ current is present in hESC-CMs and contributes to the mechanical function, verapamil completely blocked contraction. Fourth, whereas hESC-CMs expressed SERCA2 and NCX at levels comparable to those of the adult porcine myocardium, calsequestrin and phospholamban were not expressed. Our study shows for the first time that functional properties related to intracellular Ca2+ handling of hESC-CMs differ markedly from the adult myocardium, probably due to immature sarcoplasmic reticulum capacity.

Regeneration of the diseased myocardium by cardiac cell transplantation is an attractive therapeutic modality. Yet, because the transplanted cardiomyocytes should functionally integrate within the diseased myocardium, it is preferable that their properties resemble those of the host. To determine the functional adaptability of human embryonic stem cell-derived cardiomyocytes (hESC-CM) to the host myocardium, the authors investigated the excitation-contraction (E-C) coupling and the responsiveness to common physiological stimuli. The main findings are: (1) hESC-CM readily respond to electrical pacing and generate corresponding [Ca(2+)](i) transients (measured by fura-2 fluorescence) and contractions (measured by video edge detector). (2) In contrast to the mature myocardium, hESC-CM display negative force-frequency relations. (3) The hESC-CM contraction is dependent on [Ca(2+)](o) and blocked by verapamil. (4) Surprisingly, ryanodine, the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin, and caffeine do not affect the [Ca(2+)](i) transient or contraction. Collectively, these results indicate that at the developmental stage of 45 to 60 days, the contraction is largely dependent on [Ca(2+)](o) rather than on sarcoplasmic reticulum (SR) Ca(2+) stores. The results show for the first time that the E-C coupling properties of hESC-CM differ from the adult myocardium, probably due to immature SR function. Based on these findings, genetic manipulation of hESC-CM toward the adult myocardium should be considered.