Safety of the BNT162b2 mRNA COVID-19 vaccine in patients with familial Mediterranean fever.

OBJECTIVES: Evidence suggests a possible association between the COVID-19 vaccine and autoimmune disease flares or new onset of various autoinflammatory manifestations, such as pericarditis and myocarditis. The objective of this study was to assess the safety of an mRNA-based BNT162b2 anti-COVID-19 vaccine in individuals with FMF, a prototypic autoinflammatory disease. METHODS: Patients participating in this study fulfilled the criteria for diagnosis of FMF, were older than 18 years and received at least one dose of the vaccine. Data on baseline characteristics, features of FMF, post-vaccination side effects, and disease flares were acquired using electronic medical files and telephone interviews. RESULTS: A total of 273 FMF patients were recruited for the study. >95% were vaccinated with two doses of the vaccine. The rates of local reactions following the first and second vaccine doses were 65.5% and 60%, respectively, and 26% and 50.4%, respectively, for systemic adverse events. These rates are lower than those reported for the general population from real-world and clinical trial settings. Postvaccination FMF activity remained stable in most patients. None of the patients reported an attack of pericarditis or myocarditis, considered the most serious vaccine-associated adverse events. Patients with a more active FMF disease and patients harboring the M694V mutation had a significantly higher rate of post-vaccination systemic side effects and attacks. CONCLUSION: The BNT162b2 mRNA COVID-19 vaccine is safe in patients with FMF. Our results support the administration of this vaccine to FMF patients according to guidelines applicable to the general population.

CHA2DS2-VASC Score Predicts the Risk of Stroke in Patients Hospitalized to the Internal Medicine Department Without Known Atrial Fibrillation.

BACKGROUND: The CHA2DS2-VASC score is used to assess the risk of cerebrovascular accident (CVA) in patients with atrial fibrillation (AF) or atrial flutter (AFL). OBJECTIVES: We aimed to determine whether this score can determine the risk of CVA during the first year after hospitalization, in patients without known AF/AFL. DESIGN: Single-center retrospective cohort. PATIENTS: We included all patients aged ≥ 50 who were hospitalized between January 1, 2008, and December 31, 2018, to the internal medicine departments at the Chaim Sheba Medical Center, Israel. Exclusion criteria included history or new diagnosis of CVA, TIA, and AF/AFL and use of anticoagulation at any time. MAIN MEASURES: Patients were stratified into 3 groups according to their CHA2DS2-VASC score (0-1, 2, or ≥ 3). The primary outcome was hospitalization with CVA/TIA within one year of the index hospitalization. KEY RESULTS: Of the patients, 52,206 were included in the study. CVA/TIA occurred in 0.7%, 1.3%, and 1.7% of patients with a CHA2DS2-VASC score of 0-1, 2, and ≥ 3, respectively. Compared to a CHA2DS2-VASC score of 0-1, the HR for CVA/TIA occurrence for CHA2DS2-VASC scores of 2 and ≥ 3 was 1.77 (CI 1.42, 2.22) and 2.33 (CI 1.9, 2.85), respectively (p < 0.001 for both comparisons). Each additional CHA2DS2-VASC point increased the probability for readmission with CVA/TIA within 1-year by 26% (HR 1.26, CI 1.19, 1.32, p < 0.001). Similar trends were seen in subgroup analyses by gender, age, and renal function. CONCLUSIONS: The CHA2DS2-VASC score is a predictor for CVA/TIA during the first year after hospitalization in patients without AF. High CHA2DS2-VASC scores warrant work-up for occult AF/AFL and other risk factors for CVA/TIA.

The prevalence of sacroiliitis on abdominal MRI examinations of patients with Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TA), a systemic large-vessel vasculitis, was reported to have high incidence of spondyloarthropathy. PURPOSE: To evaluate the prevalence of inflammatory sacroiliitis in patients with TA that underwent abdominal/pelvic magnetic resonance imaging (MRI) examinations as part of their vasculitis work-up. MATERIAL AND METHODS: Consecutive abdominal/pelvic MRI examinations of 34 patients with TA fulfilling the 1990 ACR criteria and 34 age- and gender-matched controls performed between 2008 and 2020 were retrospectively reviewed for the presence sacroiliitis. The presence of active and structural lesions was scored twice (with a one-month interval between reads) by one reader. Structural lesions were also evaluated on computed tomography, when available, and correlated to MRI findings. Clinical data were extracted from the patients' clinical files. MRI scores were compared between the study and control groups and correlated with the clinical data. RESULTS: Sacroiliitis was evident in 11.7% of the TA group examinations compared to 0.3% in the control group (P = 0.6). Participants with TA had significantly more erosions and fat deposition compared to the control group (Study: 0.01/0.03, Control: 0/0, P = 0.03/0.003, respectively). However, mean sacroiliitis score was not significantly different (Study: 1.06, Control: 0.78, P = 0.015). Of the four patients with TA and sacroiliitis, 3 (75%) had a diagnosis of inflammatory bowel disease (IBD). CONCLUSION: Sacroiliitis was detected in 11.7% of abdominal MRI examinations of patients with TA, 75% of which had associated IBD, suggesting that both IBD and sacroiliitis should be routinely screened in the TA population as their presence may influence treatment decisions.

The frequency of sacroiliitis on MRI in subjects over 55 years of age.

OBJECTIVE: To evaluate the frequency of sacroiliitis in older subjects. MATERIALS AND METHODS: Consecutive MRI examinations of the sacroiliac joints (SIJs) performed for suspected sacroiliitis (2005-2019) in patients ≥ 18 years were retrospectively evaluated for the presence of active/structural lesions and were categorized for the presence/absence of sacroiliitis. Clinical and imaging parameters were compared between subjects with sacroiliitis according to age groups < 40 years, 40-55, and > 55 years. Clinical parameters including inflammatory back pain (IBP) and other spondyloarthritis (SpA) features were retrieved from the medical records. RESULTS: A total of 431 patients with SIJs MRI were evaluated: median age, 44 [IQR 35-54]; female:male 267(62%):164(38%). Sacroiliitis was diagnosed in 89 (20.6%) subjects-median age, 41 years [IQR 32-54], 52% females- and was equally prevalent among the different age groups: > 40 years old, 23.6%; 40-55, 20%; and > 55 years old, 17%, p = 0.43, with active/structural lesions equally dispersed. Older patients (> 55) started suffering from back pain at an older age and had a longer delay in diagnosis. Gender distribution, the presence of IBP, and other SpA features were no different in patients < 45 and > 55 years of age. CONCLUSIONS: The frequency of sacroiliitis on SIJs-MRI in subjects > 55 years is similar to its frequency in younger subjects and is associated with the same type and magnitude of active and structural MRI lesions. Clinical parameters such as IBP and additional SpA features are similarly prevalent in older and younger subjects suggesting they suffer from the same disease and differing only in age of presentation.

Anakinra for colchicine refractory familial Mediterranean fever: a cohort of 44 patients.

OBJECTIVE: FMF is an autoinflammatory disease of genetic origin. Colchicine is the mainstay of treatment for the prevention of attacks and long-term complications but 5-10% of FMF patients are resistant to colchicine therapy. The aim of our study was to investigate the real-life safety and efficacy of anakinra in a cohort of patients with colchicine-resistant FMF. METHODS: In this retrospective study, patients treated with anakinra for colchicine-resistant FMF between 2010 and 2018 were identified using the computerized database of Sheba Medical Center and enrolled in the study. Data from structured clinical files were analysed to evaluate the efficacy and safety outcomes. To assess efficacy, we used the Global Assessment Score (GAS), a measure comprised of three different domains: number of attacks per month, duration of attacks and number of sites involved in the attacks. Reported adverse events were compiled. RESULTS: A total of 44 patients (24 female) were treated with anakinra. Of these patients, 75% were homozygous for the M649V mutation. The mean duration of treatment was 18 months. The GAS decreased significantly from 6.6 (IQR 5.3-7.8) before treatment to 2 (IQR 0-4.2) while on treatment (P < 0.001). During anakinra treatment, six hospitalizations were reported (three due to related adverse effects). In addition, 11 patients suffered from injection site reactions (5 ceased treatment). Twelve patients reported mild side effects. CONCLUSION: Treatment with anakinra is beneficial for the majority of colchicine-resistant FMF patients and is relatively safe.

Effect of interleukin-1 inhibition in a cohort of patients with colchicine-resistant familial Mediterranean fever treated consecutively with anakinra and canakinumab.

OBJECTIVES: To evaluate the efficacy of IL-1 blockers in a cohort of patients with colchicine-resistant familial Mediterranean fever (crFMF) treated consecutively with anakinra and canakinumab. METHODS: Patients with crFMF treated with anakinra and canakinumab in any order were identified using the computerised database of Sheba Medical Centre. Background characteristics of the patients, reason for switching IL-1 inhibitor, and frequency of attacks under colchicine only, anakinra, and canakinumab were extracted from the computerised patient files. Patients were then interviewed for patient-reported outcomes. RESULTS: A total of 46 patients in our clinic were prescribed canakinumab for crFMF after previous anakinra treatment, whereas no patients who switched treatment from canakinumab to anakinra were identified. Of those, 23/46 patients (50%) discontinued anakinra due to inadequate response (11 of them with secondary failure after a good initial response). Frequency of flares was significantly decreased following switch to canakinumab from anakinra treatment (p<0.01). After the switch to canakinumab, the median duration of flares, the severity of pain during a flare, and the patient's global assessment of disease activity were all significantly decreased (p≤0.01), according to the reports from the patients. CONCLUSIONS: Canakinumab is an effective treatment for FMF after failure of anakinra due to any cause.

The risk for severe COVID 19 in patients with autoimmune and/or inflammatory diseases: First wave lessons.

Data regarding the risk for severe COVID19 in patients with autoimmune or inflammatory diseases are scarce. To estimate the risk of those patients to develop a more severe COVID19 infection All active patients and those with dermatologic and/or rheumatologic autoimmune/inflammatory diseases were identified in a single tertiary center. The charts of those tested positive for COVID19 between 1 March 2020 and 31 May 2020 reviewed including demographics, co-morbidities, and medications. COVID19 outcome of those with dermatologic and/or rheumatologic autoimmune/inflammatory diseases were compared to COVID19 infected matched controls without an autoimmune/inflammatory background. Overall, 974 of 381 268 active patients were tested positive for COVID19, including 35 out of 13 225 with dermatologic and/or rheumatologic autoimmune/inflammatory diseases. No statistically significant difference in severity of COVID19 infection or mortality rate was found. The rate of asymptomatic, mild, moderate, severe/critical and fatal COVID19 infection was 11.4%, 37.1%, 22.8%, 11.4%, and 17.1%, respectively, for the patients with autoimmune diseases and 17.8%, 45.8%, 10.9%, 6.8%, and 18.4%, respectively for the controls . Patients with autoimmune/inflammatory diseases seem not to develop a more severe COVID19 infection than controls.

[A CLINICAL DISCUSSION: FEVER OF UNKNOWN ORIGIN IN THE MODERN ERA - MORE QUESTIONS THAN ANSWERS].

INTRODUCTION: In this case report we discuss a patient who suffers from recurrent bouts of fever and as part of the clinical workup for autoinflammatory diseases was genetically tested for mutations in 26 genes related to autoinflammatory disease with a next generation sequencing test. We discuss the benefits and pitfalls of using this test.

[IS THERE A CORRELATION BETWEEN CARRIAGE OF AN MEFV MUTATION AND GOUT?]

INTRODUCTION: Gout is an inflammatory condition mediated by Interleukin-1-beta (IL-1ß). A mutation in the MEFV gene (the gene related to Familial Mediterranian fever) may cause an elevation in IL-1ß, and is associated with a variety of inflammatory conditions. Reports in the literature are inconsistent as to whether a mutated MEFV gene is related to the phenotype of gout. OBJECTIVES: To assess whether a carriage state of a mutation in the MEFV gene correlates with the expression and severity of gout. METHODS: A total of 73 patients, 50 with gout and 23 with hyperuricemia were examined for an MEFV mutation. Carriage rate was compared between hyperuricemic and gout patients, and disease activity measures were compared between MEFV mutation carriers and non-carriers. RESULTS: We did not find a statistically significant difference in the carriage rate of an MEFV mutation between gout patients and hyperuricemic patients without gout, nor did we find a correlation between MEFV mutation carriage and gout severity. CONCLUSIONS: Further large-scale studies should be conducted in order to determine a possible correlation between MEFV mutation carriage and gout.

The PET-CT Radiological Appearance of Facial Cosmetic Injections: A Pitfall in the Evaluation of the Oncological Patient.

BACKGROUND: Facial rejuvenation using different dermal and sub-dermal injectable compounds is a popular cosmetic procedure which may pose a diagnostic dilemma to the radiologist. OBJECTIVES: To describe the appearance of cosmetic facial fillers on PET-CT. METHODS: All PET-CT exams performed between January 2015 and May 2017 in which findings suggestive of prior facial filler procedures was evident and where anamnestic confirmation with the patient was possible were reviewed. RESULTS: We describe five females who had undergone facial filler procedures leading to calcifications around the mouth and nasolabial triangle. CONCLUSIONS: Familiarity with the appearance of such cosmetic procedures on PET-CT is of paramount importance in order to avoid misinterpretation of the findings leading to unnecessary apprehension and work-up.

Adverse cardiovascular events in rheumatoid arthritis patients treated with JAK inhibitors: An analysis of postmarketing spontaneous safety reports.

OBJECTIVES: The ORAL Surveillance trial, a postmarketing safety clinical trial, found an increased risk of adverse cardiovascular events and venous thromboembolism (VTE) in patients treated with Janus Kinase (JAK) inhibitors compared to tumor necrosis factor (TNF) inhibitors. However, additional studies yielded mixed results and data on other JAK inhibitors are limited. METHODS: A retrospective, pharmacovigilance study using the FDA adverse event reporting system (FAERS) to assess reporting of adverse cardiovascular events following treatment with JAK inhibitors in rheumatoid arthritis (RA) patients between January 2015 and June 2023. To identify disproportionately increased reporting, an adjusted reporting odds ratio (adj.ROR) was calculated with a multivariable logistic regression model. RESULTS: We identified safety reports of 75,407 RA patients treated with JAK inhibitors (tofacitinib, n = 52,181; upadacitinib, n = 21,006; baricitinib, n = 2,220) and 303,278 patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs; TNF inhibitors, rituximab, and tocilizumab). The mean age was 61.2(±12) and 59.0(±13), respectively; 82 % and 81 % were women. Compared to bDMARDs, JAK inhibitors were associated with an increased reporting of VTE [n = 1,393, adj.ROR=2.11 (1.97-2.25)], stroke [n = 973, adj.ROR=1.25 (1.16-1.34)], ischemic heart disease [IHD, n = 999, adj.ROR=1.23 (1.13-1.33)], peripheral edema [n = 2699, adj.ROR=1.22 (1.17-1.28)], and tachyarrhythmias [n = 370, adj.ROR=1.15 (1.00-1.33)]. Most of the events occurred in the first year after treatment initiation. When different JAK inhibitors were compared, VTE, stroke, and IHD were more frequently reported with upadacitinib and baricitinib than tofacitinib. When stratified by age category, all safety signals were statistically significant in patients aged≤65 years. CONCLUSION: In this global postmarketing study, JAK inhibitors are associated with increased reporting of VTE, stroke, IHD, and tachyarrhythmias. These adverse events were reported following all JAK inhibitors that were studied, suggesting a class effect.

The effect of air permeability characteristics of protective garments on the induced physiological strain under exercise-heat stress.

OBJECTIVES: The high values of thermal resistance (Rct) and/or vapor resistance (Ret) of chemical protective clothing (CPC) induce a considerable thermal stress. The present study compared the physiological strain induced by CPCs and evaluates the relative importance of the fabrics' Rct, Ret, and air permeability in determining heat strain. METHODS: Twelve young (20-30 years) healthy, heat-acclimated male subjects were exposed fully encapsulated for 3h daily to an exercise-heat stress (35°C and 30% relative humidity, walking on a motor-driven treadmill at a pace of 5 km h(1) and a 4% inclination, in a work-rest cycle of 45 min work and 15 min rest). Two bipack CPCs (PC1 and PC2) were tested and the results were compared with those attained by two control suits-a standard cotton military BDU (CO1) and an impermeable material suit (CO2). RESULTS: The physiological burden imposed by the two bilayer garments was within the boundaries set by the control conditions. Overall, PC2 induced a lower strain, which was closer to CO1, whereas PC1 was closer to CO2. Air permeability of the PC2 cloth was almost three times higher than that of PC1, enabling a better heat dissipation and consequently a lower physiological strain. Furthermore, air permeability characteristic of the fabrics, which is associated with its construction and weave, significantly correlated with the physiological strain, whereas the correlation with Rct, Ret, and weight was poor. CONCLUSIONS: The results emphasize the importance of air permeability in reducing the physiological strain induced by CPCs.

Recurrent exertional rhabdomyolysis: coincidence, syndrome, or acquired myopathy?

The purposes of this report are to review and discuss the issue of recurrent exertional rhabdomyolysis (ER), the return to physical activity after ER, and the possible causes of recurrence, with special consideration to metabolic myopathies and the possibility of an acquired post-ER myopathy. We discuss the medical investigation required prior to return to physical activity after an episode of ER and suggest two possible mechanisms for recurrence of ER in the absence of a known cause: premature return to activity and an acquired post-ER muscular disorder. We also emphasize the need to create proper guidelines for return to physical activity after ER and, for further investigation, the possible mechanisms of ER recurrence in patients without a known metabolic myopathy.

Exertional heat illness: the role of heat tolerance testing.

Exertional heat stroke (EHS) is a common clinical problem for both athletes and warriors; however, evidence-based guidance for return-to-play/duty (RTP/RTD) decisions is limited. Heat tolerance testing (HTT) has been proposed as a potential tool that, when combined with appropriate clinical information, may assist in RTP/RTD decisions. However, currently, no standard of care is available for performing HTT. The Israeli Defense Forces (IDF) HTT protocol, which was developed over decades of careful research, has proven useful for IDF warriors and is utilized by other militaries to assist in RTD decisions. The present case studies are used to discuss the efficacy of the IDF HTT in determining RTD for two warriors who experienced EHS. Strengths and limitations of the IDF HTT, along with current and potential roles in clinical decision-making and in future thermoregulation research, are discussed.

Heat injury prevention--a military perspective.

Heat-related injuries, and specifically exertional heat stroke, are a significant occupational risk in the armed forces, especially for those soldiers who are rapidly deployed from a temperate climate region to hot climate regions. Traditionally, adaptation to heat was considered as a matter of physiological adaptation. It is clear today that these injuries are mostly avoidable when applying proper education and behavioral adaptations. Education on behavioral adaptation for the prevention of heat injuries should be targeted at the individual and the organization level. This article summarizes the issue of proper preventive measures that should be taken to avoid, or at least minimize, the risk of exertional heat related injuries during military operations and training.

Heat tolerance in women--reconsidering the criteria.

INTRODUCTION: Exertional heat stroke (EHS) is the most dangerous heat-related injury. EHS may be followed by a state of heat intolerance. The Israeli Defense Forces (IDF) performs heat tolerance tests (HTT) to all heat injury victims 6-8 wk following injury as part of the "return to duty" process. The HTT protocol and normal values are based on vast experience with young healthy men. Over the last several years an increasing number of female soldiers have been joining combat units. Heat injuries and, thus, HTT among women have become more frequent. Due to potential gender-related physiological and thermoregulatory differences, we examined the necessity for validating the HTT protocol for women. METHODS: Retrospective physiological data from our database on heat injuries and HTT between the years 2008-2010 was compared between 9 female subjects and 170 male subjects who had similar background characteristics. RESULTS: Defining heat intolerance as peak rectal temperature > 38.5 degrees C, peak heart rate > 150 bpm, or the inability to reach equilibrium in these values, we diagnosed 67% of the female subjects as heat intolerant. In the male subjects, only 26% were diagnosed as heat intolerant using the same criteria. CONCLUSIONS: Using the standard HTT criteria, women are more frequently diagnosed as heat intolerant than men. Further studies should be performed in order to re-evaluate the normal values for a "female HTT" in order to optimize the process of safe return to duty of female heat injury victims and to minimize false positive results among female soldiers.

Misdiagnosis of exertional heat stroke and improper medical treatment.

Exertional heat stroke (EHS) is the most complicated and dangerous amongst heat injuries that can lead to irreversible injury and even death. Early diagnosis and treatment are therefore crucial determinants of the patient's prognosis. The following case report depicts a soldier who presented primarily with confusion and behavioral changes during physical exercise and later lost consciousness. He was misdiagnosed by the field physician as suffering from supraventricular tachycardia, was treated as such and only diagnosed as suffering from EHS later in the emergency room. Our main aims are: to highlight the possibility of misdiagnosis of EHS even among trained physicians, to describe the main symptoms of EHS, and to emphasize the importance of early diagnosis and proper treatment.

Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination.

BACKGROUND: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. METHODS: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. FINDINGS: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. INTERPRETATION: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. FUNDING: none.