Vitamin K antagonist anticoagulation in the antiphospholipid syndrome: time in therapeutic range and clinical outcomes.

BACKGROUND: Thrombosis in the antiphospholipid syndrome is still frequently treated with vitamin K antagonists with a target international normalized ratio of 2-3. Time in therapeutic range of international normalized ratio of ≥ 70% is considered optimal. Time in therapeutic range among antiphospholipid syndrome patients is not well documented and the clinical consequences of poor international normalized ratio control are uncertain. AIMS: To determine the proportion of vitamin K antagonist -treated antiphospholipid syndrome patients achieving time in therapeutic range ≥ 70%, to define the features associated with poor control and to determine its association with thrombotic and bleeding events. METHODS: This medical records review included antiphospholipid syndrome patients treated with vitamin K antagonists, between 2012-2023. The proportion of patients achieving a time in therapeutic range≥ 70% was determined and thrombotic and bleeding events were compared between patients with time in therapeutic range ​​≥ 70% versus < 70%. RESULTS: 67 antiphospholipid syndrome patients were studied. 29.9% achieved time in therapeutic range ≥ 70%. 9.1% of patients with 3 or more comorbidities achieved time in therapeutic range values ≥ 70% compared to 40% of patients with less than 3 comorbidities. Fewer recurrent arterial and overall thrombotic events occurred with time in therapeutic range ​​≥ 70%. CONCLUSIONS: A minority of antiphospholipid syndrome patients treated with vitamin K antagonist s achieve optimal anticoagulation and are at risk for recurrent thrombotic events, particularly arterial. Presence of multiple comorbidities is associated with poor international normalized ratio control. Careful monitoring of this patient population is warranted.

Alpha-1 antagonist treatment for eyelid retraction in patients with thyroid eye disease-a prospective pilot study.

BACKGROUND: Sympathetic overstimulation of Müller's muscle is a suggested mechanism underlying upper eyelid retraction in thyroid eye disease (TED). We examined the effect of tamsulosin, an alpha-1 antagonist, on eyelid retraction in patients with TED. METHODS: A single-centre prospective study. Patients with TED and associated eyelid retraction were treated with oral 0.4 mg/day tamsulosin for 3 months. Upper eyelid margins-to-reflex distance (MRD1), vertical palpebral fissure height (PFH), subjective improvement, signs and symptoms of dry eye, and lubricants use were assessed at baseline and at each subsequent visit. RESULTS: Eleven suitable patients (mean age 47.5 ± 9.68, 8 females) enrolled in the study. Three patients discontinued the drug due to mild adverse effects (dizziness, bradycardia, nausea, and gastrointestinal distress), which resolved immediately upon stopping treatment. The other eight patients tolerated the drug well and reported no side effects. Five patients experienced an objective improvement in eyelid position and subjective improvement in eye discomfort. The mean MRD1 decreased by -1.04 ± 0.81 mm (P = 0.015), and mean PFH decreased by -1.46 ± 1.33 mm (P = 0.039). Mean duration of tamsulosin treatment was 84.63 ± 71.9 days. Patients discontinued the drug due to no improvement in MRD1 (n = 3), referral for eyelid surgery with stable inactive TED (n = 2), treatment with intravenous methylprednisolone due to worsening active TED (n = 2), and patient choice after 5 months of treatment with spontaneous resolution of symptoms (n = 1). CONCLUSIONS: Tamsulosin is a safe potential treatment for eyelid retraction in TED and can be used as a temporary alternative therapeutic approach for patients unsuitable for surgery.

Pregnancy Outcomes in Grand Multiparity Women With Antiphospholipid Antibodies.

OBJECTIVE: In recent years antiphospholipid syndrome (APS) as well as antiphospholipid antibodies (aPL) prevalence has demonstrated an upward trend in women during reproductive age. There is a lack of data concerning its effects on women with grand multiparity (GMP) (parity ≥5). Hence, this study aimed to assess pregnancy outcomes among GMP aPL/APS patients. STUDY DESIGN: We retrospectively assembled the births of GMP women with aPL/APS, between 2017 and 2022 in the Sheba Medical Center. We compared their deliveries with those of two control groups: (1) the "aPL/APS-controls"-of pregnant women with aPL/APS and parity <5. (2) The "GMP-controls"- parity ≥5 without aPL/APS. We examined demographics, aPL characteristics, pregnancy, and neonatal outcomes between the groups. RESULTS: In total, 42 deliveries in the study group were compared to 461 deliveries in the "aPL/APS-controls" group and 84 deliveries of the "GMP-controls." Most parameters were similar across groups. However, the study group had a higher rate of obstetric APS diagnosis (64.64% vs. 83.33%, p < 0.01) and showed significant differences such as older maternal age, higher BMI, more polyhydramnios cases, and larger babies compared to controls (33.91 vs. 36.19, p = 0.05; 23.2 vs. 28.89, p = 0.02; 3.68 vs. 11.9, p = 0.01; and 2.17 vs. 14.28, p < 0.01, respectively). CONCLUSIONS: Our findings reveal that perinatal outcomes in aPL/APS GMP women are comparable and not inferior to those in aPL/APS women with <5 pregnancies or in comparison to the general GMP population. The minor differences observed may all be related to GMP women's older age and higher BMI.

Peanut allergen characterization and allergenicity throughout development.

Introduction: Peanut allergy (PA) in children is a major concern. There is a need for better biological material for both diagnosis and oral immunotherapy (OIT) treatments. The unique state of seeds at early reproductive stages may affect the allergenicity of storage proteins, and impact clinical diagnostic and OIT protocols. The objective of this study was to evaluate the major allergen content in sequential seed developmental stages and monitor allergenicity via specific IgE binding quantification and skin prick testing. Methods: Seeds were collected from peanut plants and sorted into five developmental stages: initial (S1), developing (S2), full-size without coloration (S3), full-size with coloration (S4), and fully mature (S5) seeds. Samples were characterized by RNA-Seq, ELISA, and immunohistochemistry. Lyophilized, ground preparations were used for evaluation of skin test responses in sixty challenge-proven PA children. Results: Gene expression, protein content, and specific IgE binding of allergenic proteins increased throughout seed maturation and development. An expression bias towards the less allergenic A-genome copy of the major allergen Ara h 2 was found in earlier stages, especially in stage S2. Immunohistochemical staining showed that Ara h 2 is more dispersed in the cell and less accumulated within organized bodies at stage S2 versus stage S4. Significant differences were found in mean wheal responses between the commercial peanut extract (equivalent to stage S5) and stages S1 and S2, but not with stage S4, upon skin prick testing in subjects with PA. Discussion: The observed decrease in peanut-specific IgE binding of immature peanut seeds may be a result not only of decreased amounts of allergenic proteins, but also of profound changes in seed composition and conformation. This may be significant for developing a safer and more effective peanut OIT protocol.

Outcomes of IVF treatments in women with antiphospholipid antibodies or antiphospholipid syndrome.

BACKGROUND: Ovulation induction for in vitro fertilization (IVF) may increase intravascular thromboses among patients with antiphospholipid autoantibodies (aPLs) or antiphospholipid syndrome (APS) due to the high estrogen levels. While natural or modified natural IVF treatment cycles (MNC) are sometimes used instead of stimulated cycles with empiric anticoagulant treatment among these infertile patients, their efficacy is unclear. MATERIALS AND METHODS: A retrospective cohort study including all IVF cycles of patients diagnosed with aPLs or APS in a tertiary, university-affiliated hospital between 2012 and 2022. The outcomes of stimulated cycles with anticoagulants and MNC and natural IVF cycle attempts were compared. RESULTS: 121 oocyte retrievals from 38 women were analyzed: 93 stimulated and 28 MNC or natural IVF cycles. The rates of cycle cancellation (0 % vs. 17.9 %, p < 0.001) and cycles in which no oocytes were retrieved (0 % vs. 43.5 %, p < 0.001) were significantly lower following stimulated cycles vs. natural and MNC. In parallel, positive ß-hCG (31.9 % vs. 10.9 %, p = 0.03), clinical pregnancy rate (23.6 % and 3.6 %, p < 0.001) and live birth rates (18.1 % vs. 3.6 %, p = 0.01) were significantly higher following stimulated cycles. No thrombotic events or bleeding occurred in any cycle. CONCLUSION: Ovarian stimulation for IVF is more effective for successful pregnancy and delivery than natural cycles and MNC and can be safely undertaken in aPLs or APS women undergoing IVF. Rates of complication from hormonal treatment are not increased when treated with LMWH during ovarian stimulation.

Drug fever-an immune-mediated delayed type hypersensitivity reaction to Vinca alkaloids in pediatric oncology patients, possibly mediated by cysteinyl leukotrienes.

Background: Drug hypersensitivity reactions are common in pediatric hemato-oncology patients due to multiple factors including immune compromise and pharmacological complexities. Fever can signify severe delayed-type hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). The etiology of fever as an isolated hypersensitivity reaction to chemotherapeutic agents not fully understood. Here, we report three children with intracranial neoplasms experiencing recurrent febrile reactions following Vinca alkaloid-based chemotherapy, mitigated by cysteinyl leukotriene receptor antagonist therapy. Methods: We present a series of pediatric patients with diverse intracranial neoplasms who developed recurrent fever episodes after multiple courses of Vinca alkaloid-based chemotherapy. Treatment involved prophylactic and post-chemotherapy administration of a cysteinyl leukotriene receptor antagonist to prevent fever episodes and enable completion of chemotherapy regimens without protocol modifications or desensitization. Results: All three patients experienced fever consistent with delayed-type hypersensitivity reactions to Vinca alkaloids. Prophylactic use of the leukotriene antagonist Montelukast successfully prevented fever recurrence, allowing uninterrupted completion of chemotherapy courses. Conclusion: Our findings suggest that Montelukast, a leukotriene antagonist, may be beneficial in managing fever as a delayed-type hypersensitivity reaction to Vinca alkaloids in pediatric patients. Further research is warranted to elucidate the underlying mechanisms and leukotriene pathways involved in drug-induced fever reactions.

Mindfulness-based stress reduction (MBSR) for fibromyalgia patients: The role of pain cognitions as mechanisms of change.

BACKGROUND: Fibromyalgia (FM) is a pain condition characterized by physical and psychological difficulties. This randomized controlled trial aimed to evaluate the effects of a mindfulness-based stress reduction (MBSR) on FM patients and identify the role of two pain cognitions: psychological inflexibility in pain (PIPS) and pain catastrophizing (PCS), as mechanisms of change. METHODS: 95 FM patients (Mean ± SD: 49.18 ± 13.26 years) were randomly assigned to MBSR group therapy (n = 49) or a waitlist (WL) control group (n = 46). An adapted MBSR protocol for FM was employed. A series of measures were taken, covering FM symptoms, depression, perceived stress (PSS), PIPS and PCS. Three measurements were conducted: pre-intervention, post-intervention and 6-months follow up. RESULTS: Compared to WL controls, the MBSR group showed greater improvements in FM symptoms (F(1,78) = 2.81, p < 0.05), PSS (F(1,78) = 4.38, p < 0.05) and Depression (F(1,78) = 21.12, p < 0.001), with mostly medium effect sizes. Improvements in PSS (F(2,68) = 7.75, p < 0.05) and depression (F(2,68) = 15.68, p < 0.05) remained stable over six months. The effect of MBSR on FM and PSS was mediated by one's reported change in PIPS. The effect of MBSR on depression was mediated by one's reported change in PCS. CONCLUSIONS: These results reveal the significant therapeutic potential of MBSR for FM patients, due to the emphasis on non-judging and acceptance of negative inner states. Furthermore, this research identified two important pain-related cognitions as mechanisms of change, suggesting that MBSR contributes to cognitive change, which enables the reduction of physical and psychological distress. TRIAL REGISTRATION NUMBER: NCT04304664.

Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

Omalizumab withdrawal outcomes in chronic spontaneous urticaria are linked with baseline IgE and eosinophil levels.

Background: Chronic Spontaneous Urticaria (CSU) is an immune-mediated skin disease that may require prolonged treatments. Currently, there are no recommendations for treatment discontinuation once CSU symptoms are controlled, particularly among patients primarily diagnosed with severe CSU. Objective: In this real-life study we aimed to describe our experience of omalizumab (Oma) treatment withdrawal in CSU and define biomarkers related to these outcomes. Methods: CSU patients followed at our allergy clinic from January 2016 to December 2022 were included. Response to Oma therapy, and Oma-withdrawal outcomes among patients who reached complete remission for >6 months were analyzed. Results: During the study period 192/335(%) CSU patients were categorized as severe-CSU and entitled to receive Oma according to our country's regulations. Of them, 131/192(68%) were considered "Oma-responders", and 95/131(72.5%) patients underwent gradual treatment withdrawal. Successful Oma-withdrawal was documented in 47/95(49.5%) whereas 48/95(50.5%) patients experienced flare and were defined as unsuccessful OMA-withdrawal. The first was associated with shorter disease duration 7.1 ± 7.4 years vs. 10.7 ± 9.4 (P = 0.042), lower baseline-IgE 81.6 ± 84.1IU/ml vs. 324.7 ± 555.9 (P = 0.005), and lower baseline-eosinophils count 131.4 ± 110.5 vs. 195.6 ± 98.4 (P = 0.043) in comparison to failure of Oma-withdrawal group. Conclusion: OMA may be successfully withdrawn in up to 50% of severe CSU patients following complete remission of disease symptoms, utilizing a gradual withdrawal protocol. Oma-withdrawal failure was linked with longer duration of disease as well as high IgE and eosinophil counts prior to initiation of Oma therapy. These parameters may enable the design of a treatment withdrawal algorithm.

Elevated serum thyroid stimulating immunoglobulin linked to failure of first-line intravenous methylprednisolone monotherapy in moderate-to-severe thyroid eye disease.

PURPOSE: To assess factors associated with failure of intravenous methylprednisolone (IVMP) monotherapy as the first-line treatment for thyroid eye disease (TED) and to identify patients who might benefit from supplementing mycophenolate mofetil (MMF) to IVMP. METHODS: Data for all patients with TED treated with IVMP according to the EUGOGO protocol in our center between 2016-2021 were retrospectively analysed. RESULTS: Forty-seven patients (mean age 51.32 ± 14 years, 27 females) were enrolled. The mean time from first reported symptoms to first IVMP treatment was 12.1 ± 5.59 months (range 0-120). The mean clinical activity score (CAS) before treatment and at a mean of 5 and 12.2 weeks after treatment initiation was 6.00, 2.96, and 1.81, respectively (P < 0.01). Twenty-one patients (44.68%) were recommended second-line treatment: nine due to no response or worsening of CAS, six due to partial response, four with good response but early relapse after completion of treatment, and one due to late relapse. Eighteen of those 21 patients received second-line treatment which included rituximab (n = 7), MMF (n = 6), a second course of IVMP (n = 4), and tocilizumab (n = 1). Serum thyroid-stimulating immunoglobulin (TSI) levels were higher in patients who received second-line treatment compared with patients who responded well to first-line IVMP monotherapy at presentation (2135% vs 1159%, P = 0.05) and after completion of first-line treatment (2201% vs. 986%, P = 0.043). DISCUSSION: TED patients requiring second-line treatment after failed IVMP monotherapy had higher baseline and post-first-line treatment serum TSI levels. Those with elevated TSI may benefit from dual therapy (IVMP and MMF) and require closer monitoring.

Nsaids Linked to IgA-Mediated Hypersensitivity Vasculitis and Purpura Fulminans-Like Eruption.

Background: IgA vasculitis and hypersensitivity reactions following exposure to non-steroidal anti-inflammatory drugs (NSAIDs) are very rarely associated with purpura fulminans (PF). The latter is a coagulation event characterised by decreased levels of protein C and a rapidly progressive purpuric rash, often leading to ischaemia, amputations and death. Case summary: A previously healthy 66-year-old man presented with a vasculitic rash and abdominal pain following exposure to naproxen (NSAID), which quickly deteriorated to purpura fulminans-like eruption and skin necrosis, mainly involving the face and hands. The presence of IgA sediments on skin biopsy and decreased levels of complement as well as protein C pointed to an immune-mediated inflammatory process. Dramatic clinical escalation with immediate risk to organs and life required an aggressive and broad-spectrum therapeutic approach in an intensive care setting. Clinical improvement and complete reconstitution of protein C were achieved following plasma exchange with fresh frozen plasma (FFP) and immunosuppression with glucocorticoids with no persistent organ damage. Conclusions: This rare case illustrates the catastrophic cross links between NSAIDs, IgA-mediated hypersensitivity vasculitis and purpura fulminans-like syndrome. A high index of suspicion is required for the evaluation of environmental exposures such as drugs and infections in patients with vasculitis and/or purpura. A rapid and comprehensive therapeutic approach should be implemented to avoid multi-organ damage, amputations and death. Complete avoidance of the offending agent is key for future prevention of recurrence. LEARNING POINTS: This case illustrates a rare cross link between a commonly used drug (NSAIDs) and severe, life-threatening hypersensitivity reactions (IgA vasculitis and purpura fulminans-like eruption).These events require a high index of suspicion and emphasise the importance of considering environmental exposures such as drugs in the immediate diagnosis of both conditions.In addition to long-term drug avoidance, early and aggressive interventions are required to avoid organ damage, amputations or death.

Heart valve disease in primary antiphospholipid syndrome.

OBJECTIVES: Antiphospholipid syndrome (APS)-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS associated HVD. METHODS: In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group). RESULTS: pAPS-HVD patients had more cerebrovascular events 56.3% vs 25% (p= 0.005) and livedo reticularis 24.2% vs 7.8% (p= 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, p= 0.034), recurrent thrombosis (33.3% vs 4.7%, p< 0.001), and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-B2GPI-IgG. [84.8% vs 63.2% (p= 0.034)], anti-cardiolipin IgG [90.9% vs. 64.8% (p= 0.005)] and triple positive aPL [75.8% vs 56.5% (p= 0.047)] were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis. CONCLUSION: pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as with specific serology namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients.

Smell Function in Schizophrenia During Acute Psychosis and Correlation with Clinical Symptomatology and Length of Hospitalization.

BACKGROUND: While several studies have noted smell impairment in schizophrenia, it is unclear whether this impairment extends to acute psychosis and whether it is associated with more severe illness as expressed in extended hospitalization. OBJECTIVES: To evaluate the olfactory function of patients in an acute psychotic state and correlate it with clinical symptomatology and length of hospitalization. METHODS: Olfactory function was assessed in 20 patients with schizophrenia in their first week of hospital admission for acute psychosis compared with matched controls. Olfaction was evaluated via three stages: threshold, discrimination, and identification of different odors utilizing the Sniffin' Sticks test battery. RESULTS: Schizophrenia patients scored significantly lower on total smell score, discrimination, and identification abilities. A significant association was observed between hospitalization duration and total smell score and smell discrimination. No significant associations between smell and clinical symptomatology were observed. CONCLUSIONS: Study observations confirm impaired sense of smell in schizophrenia patients and suggest that smell impairment may be a potential marker of more serious illness as expressed in longer hospital stay.

An Update in COVID-19 Vaccine Reactions in 2023: Progress and Understanding.

It has been 3 years since the coronavirus disease 2019 (COVID-19) pandemic was initially declared, and 2 years have passed since the first COVID-19 vaccines were introduced. Since then, 13.2 billion COVID-19 vaccine doses have been administered worldwide, largely with multiple doses of messenger RNA vaccines. Although mild local and systemic adverse effects after COVID-19 vaccination are common, serious adverse effects following immunization are rare, particularly when compared with the large number of vaccine doses administered. Immediate and delayed reactions are relatively common and present similarly to allergic and hypersensitivity reactions. Despite this, reactions generally do not commonly recur, cause sequelae, or contraindicate revaccination. In this Clinical Management Review, we provide an updated perspective of COVID-19 vaccine reactions, their spectrum and epidemiology, and recommended approaches to evaluation and management.

Heart Valve Surgery in Antiphospholipid Syndrome Patients-Morbidity and Mortality.

OBJECTIVES: To assess valve surgery outcomes in antiphospholipid syndrome (APS). METHODS: A retrospective study assessing complications and mortality rate and possible factors associated with adverse outcomes of APS patients undergoing valve surgery in two tertiary medical centers. RESULTS: Twenty-six APS patients (median age at surgery 47.5 years) who underwent valve surgery were detected, of whom 11 (42.3%) had secondary APS. The mitral valve was most commonly involved (n = 15, 57.7%). A valve replacement was performed in 24 operations (92.3%), 16 of which (66.7%) were mechanical valves. Fourteen (53.8%) patients sustained severe complications, and four of them died. The presence of mitral regurgitation (MR) was associated with severe complications and mortality (odds ratio (95% confidence interval) 12.5 (1.85-84.442), p = 0.008, for complications. All deceased patients had MR (p = 0.033). The presence of Libman-Sacks endocarditis (LSE) (7.333 (1.272-42.294), p = 0.045), low C3 (6.667 (1.047-42.431), p = 0.05) and higher perioperative prednisone doses (15 ± 21.89 vs. 1.36 ± 3.23 mg/day, p = 0.046) were also associated with complications. A lower glomerular filtration rate (GFR) was associated with mortality (30.75 ± 19.47 vs. 70.68 ± 34.44 mL/min, p = 0.038). CONCLUSIONS: Significant morbidity and mortality were observed among APS patients undergoing valve surgery. MR was associated with mortality and complications. LSE, low complement and higher doses of corticosteroids were associated with complications, while a low GFR was associated with mortality.

A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations.

Objective: We aimed to characterize the course of COVID-19 in autoimmune inflammatory rheumatic disease (AIIRD) patients in Israel, taking into consideration several remarkable aspects, including the outcomes of the different outbreaks, the effect of vaccination campaigns, and AIIRD activity post-recovery. Methods: We established a national registry of AIIRD patients diagnosed with COVID-19, including demographic data, AIIRD diagnosis, duration and systemic involvement, comorbidities, date of COVID-19 diagnosis, clinical course, and dates of vaccinations. COVID-19 was diagnosed by a positive SARS-CoV-2 polymerase chain reaction. Results: Israel experienced 4 outbreaks of COVID-19 until 30.11.2021. The first three outbreaks (1.3.2020 - 30.4.2021) comprised 298 AIIRD patients. 64.9% had a mild disease and 24.2% had a severe course; 161 (53.3%) patients were hospitalized, 27 (8.9%) died. The 4th outbreak (delta variant), starting 6 months after the beginning of the vaccination campaign comprised 110 patients. Despite similar demographic and clinical characteristics, a smaller proportion of AIIRD patients had negative outcomes as compared to the first 3 outbreaks, with regards to severity (16 patients,14.5%), hospitalization (29 patients, 26.4%) and death (7 patients, 6.4%). COVID-19 did not seem to influence the AIIRD activity 1-3 months post-recovery. Conclusions: COVID-19 is more severe and has an increased mortality in active AIIRD patients with systemic involvement, older age and comorbidities. Vaccination with 3 doses of the mRNA vaccine against SARS-CoV-2 protected from severe COVID-19, hospitalization and death during the 4th outbreak. The pattern of spread of COVID-19 in AIIRD patients was similar to the general population.

The third dose of BNT162b2 COVID-19 vaccine is efficacious and safe for systemic lupus erythematosus patients receiving belimumab.

INTRODUCTION: Over 95% of healthy subjects develop anti-COVID IgG antibodies after receiving two doses of BNT162b2 COVID-19 vaccine. In comparison, 20%-30% of SLE patients do not seroconvert following 1-2 doses of COVID vaccines, potentially due to immunosuppression. The aim of this study was to assess immunogenicity and safety of BNT vaccine in SLE patients treated with Belimumab and especially the yield of a booster third dose in this population. METHODS: SLE patients treated with Belimumab in the Sheba Medical Center, Israel, were included in this study. All were recommended to receive the BNT vaccine according to national guidelines; and were advised to perform serologic tests after receiving second and third doses. Clinical data included demographics, SLE treatments, adverse effects to vaccines and SLEDAI scores performed 2 weeks before vaccinations and 6-12 weeks after receiving the second or third dose of the vaccine. RESULTS: Our cohort included 17 patients, 14 (82.35%) females, median age 50 ± 14.2 years, and disease duration 12 ± 10.57 years. Belimumab therapy was given for a mean of 6 ± 2.5 years. Of them, 15/17 patients received 3-doses of BNT vaccine. Serologic assessment was performed for 10 patients, 7/10(70%) became seropositive following the second dose, while 2/3 patients seroconverted only after the third dose. Vaccinations were well tolerated with minimal adverse events and no disease flares. SLEDAI scores before and after vaccinations were 4 ± 3.8 and 4 ± 2.7 (p = 0.69), respectively. CONCLUSIONS: Immunization with the BNT vaccine is efficacious and safe for SLE patients treated with Belimumab. Following the third dose of vaccine, immunogenicity among SLE patients mounted to 90%, thereby approximating the general healthy population. No SLE disease flares and/or significant adverse events were noted in our cohort. Assessment of seroconversion and consideration of subsequent boosters of COVID-vaccine should be considered in this group of patients.

Late Hypersensitivity Reactions to the BNT162b2 SARS-CoV-2 Vaccine Are Linked to Delayed Skin Sensitization and Prior Exposure to Hyaluronic Acid.

Background: Late hypersensitivity reactions (HSRs) to the BNT162b2-vaccine have raised concerns regarding its safety, particularly as further immunizations are required. The yield of skin testing with the BNT162b2v is unclear, as well as the risk factors and outcomes of re-immunization after late HSRs. Objective: We studied a series of patients with late HSRs to BNT162b2v. Methods: Patients referred to the Sheba medical center from December 2020 to May 2021 with late HSRs to the first dose of BNT162b2 were included. HSRs were defined as late if they appeared or lasted >24 h after inoculation. We compared late HSRs to immediate HSRs that appeared within minutes−2 h after vaccination. Intradermal testing with PEG-containing medication and BNT162b2v was performed. Results: A total of 17 patients that presented with late HSRs (study group) were compared to 34 patients with immediate HSRs (control group). Delayed sensitivity to intradermal testing of the BNT162b2v was observed in 9/17 (53%) of the study group compared to 4/34 (12%) in the control group (p = 0.01). Former exposure to a dermal filler with hyaluronic acid was documented among 7/17 (41%) vs. 2/34 (6%) in the study and control groups, respectively, (p = 0.0038). All patients who presented with late HSRs were advised to receive subsequent doses of the BNT162b2v vaccine with or without concomitant medication, and all were re-immunized successfully. Conclusions: Late HSRs to BNT162b2v were linked with positive responses to intradermal testing with the vaccine and prior exposure to derma fillers with hyaluronic acid. This may elude to an immune mechanism triggered by former exposures. Although further studies are needed, late HSRs to the BNT162b2-vaccine did not prevent patients from receiving subsequent doses of the vaccines.