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.

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.

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.

Assessment of Immediate Allergic Reactions After Immunization With the Pfizer BNT162b2 Vaccine Using Intradermal Skin Testing With the COVID-19 Vaccines.

BACKGROUND: Allergic reactions to the coronavirus disease 2019 (COVID-19) vaccines have raised concerns, particularly as repeated doses are required. Skin tests with the vaccines excipient were found to be of low value, whereas the utility of skin tests with the whole vaccine is yet to be determined. OBJECTIVE: To evaluate a panel of skin tests and the outcomes of subsequent doses of immunization among subjects who suffered an immediate allergic reaction to the BioNTech (BNT162b2) COVID-19 vaccine. METHODS: Between March and December 2021, patients who experienced symptoms consistent with immediate allergic reactions to the BNT162b2 vaccine and were referred to the Sheba Medical Center underwent skin testing with polyethylene glyol (PEG)-containing medicines, Pfizer-BNT162b2, and Oxford-AstraZeneca vaccine (AZD1222). Further immunization was performed accordingly and under medical observation. RESULTS: A total of 51 patients underwent skin testing for suspected allergy to the COVID vaccines, of which 38 of 51 (74.5%) were nonreactive, 7 of 51(13.7%) had no skin sensitization but suffered a clinical reaction during skin testing (mainly cough), and 6 of 51 (11.7%) exhibited immediate skin sensitization. Both skin sensitization and cough during testing were related to a higher use of adrenaline following immunization (P = .08 and P = .024, respectively). Further immunization with the BNT162b2 vaccine was recommended unless sensitization or severe reaction to previous immunization was evident. The latter were referred to be tested/receive the alternative AZD1222 vaccine. Ten patients underwent skin testing with AZD1222: 2 of 10 (20%) demonstrated skin sensitization to both vaccines; thus, 8 of 10 were immunized with the AZD1222, of which 2 of 8 (25%) had allergic reactions. CONCLUSIONS: Immediate allergic reactions to COVID-19 vaccines are rare but can be severe and reoccur. Intradermal testing with the whole vaccine may discriminate sensitized subjects, detect cross-sensitization between vaccines, and enable estimation of patients at higher risk.

Long Term Follow up of Patients With Primary Obstetric Antiphospholipid Syndrome.

Introduction: Primary obstetric antiphospholipid syndrome (OAPS) is defined by specific morbidities and/or losses of pregnancy in the presence of persistent antiphospholipid antibodies (aPL). This variant of APS is usually treated during pregnancy and the post-partum period. Data on occurrence of thrombotic event during long term follow-up of OAPS patients is limited. Methods: A multi-centre retrospectively cohort of female patients with primary APS (pAPS) was assembled during 2004-2019. Patients were grouped according to disease presentation as pure OAPS or thrombotic APS (tAPS) for those presenting with thrombosis. Clinical and serological data were compared between groups. Results: Of 219 pAPS female patients 67 (30.6%) were diagnosed with OAPS and 152 (69.4%) with tAPS. During >10 years of follow-up 24/67 (35.8%) OAPS and 71/152 (50%) tAPS suffered a new thrombotic event (p = 0.06), while obstetric morbidity was more likely in the OAPS group (31.3 vs. 10.5%, p < 0.001) respectively. Among patients with OAPS at presentation heart valve disease and the presence of ANA were related to thrombosis following diagnosis (25 vs. 4.7%, p = 0.02; and 45.8 vs. 20.8%, p = 0.04 respectively). Conclusion: Thrombotic event following diagnosis were common among female patients with pAPS regardless of disease presentation. Heart valve disease and ANA positivity may be risk factors for thrombosis during follow-up of patients presenting with pure OAPS.

Prevalence of Allergic Reactions After Pfizer-BioNTech COVID-19 Vaccination Among Adults With High Allergy Risk.

Importance: Allergic reactions among some individuals who received the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine discourage patients with allergic conditions from receiving this vaccine and physicians from recommending the vaccine. Objective: To describe the assessment and immunization of highly allergic individuals with the BNT162b2 vaccine. Design, Setting, and Participants: In a prospective cohort study from December 27, 2020, to February 22, 2021, 8102 patients with allergies who applied to the COVID 19 vaccine referral center at the Sheba Medical Center underwent risk assessment using an algorithm that included a detailed questionnaire. High-risk patients (n = 429) were considered "highly allergic" and were immunized under medical supervision. Exposures: Pfizer-BioNTech (BNT162b2) COVID-19 vaccine. Main Outcomes and Measures: Allergic and anaphylactic reactions after the first and second doses of BNT162b2 vaccine among highly allergic patients. Results: Of the 429 individuals who applied to the COVID-19 referral center and were defined as highly allergic, 304 (70.9%) were women and the mean (SD) age was 52 (16) years. This highly allergic group was referred to receive immunization under medical supervision. After the first dose of the BNT162b2 vaccine, 420 patients (97.9%) had no immediate allergic event, 6 (1.4%) developed minor allergic responses, and 3 (0.7%) had anaphylactic reactions. During the study period, 218 highly allergic patients (50.8%) received the second BNT162b2 vaccine dose, of which 214 (98.2%) had no allergic reactions and 4 patients (1.8%) had minor allergic reactions. Other immediate and late reactions were comparable with those seen in the general population, except for delayed itch and skin eruption, which were more common among allergic patients. Conclusions and Relevance: The rate of allergic reactions to BNT162b2 vaccine, is higher among patients with allergies, particularly among a subgroup with a history of high-risk allergies. This study suggests that most patients with a history of allergic diseases and, particularly, highly allergic patients can be safely immunized by using an algorithm that can be implemented in different medical facilities and includes a referral center, a risk assessment questionnaire, and a setting for immunization under medical supervision of highly allergic patients. Further studies are required to define more specific risk factors for allergic reactions to the BNT162b2 vaccine.

A New Method for Percutaneous Drug Delivery by Thermo-Mechanical Fractional Injury.

BACKGROUND AND OBJECTIVES: Percutaneous drug delivery (PDD) is a means of increasing the uptake of topically applied agents into the skin. Successful delivery of a photosensitizer into the skin is an important factor for effective photodynamic therapy. To evaluate the efficacy of pretreatment by thermomechanical fractional injury (TMFI) (Tixel®, Novoxel®, Israel) at low-energy settings in increasing the permeability of the skin to a known hydrophilic-photosensitizer medication, 5-amino-levulinic-acid hydrochloride (ALA) in compounded 20% ALA gel. To compare the effect of TMFI on ALA permeation into the skin in compounded gel to three commercial photosensitizing medications in different vehicles: ALA microemulsion gel, methyl-amino-levulinic-acid hydrochloride (MAL) cream, and ALA hydroalcoholic solution. STUDY DESIGN/MATERIALS AND METHODS: Five healthy subjects were treated in two separate experiments and on a total of 136 test sites, with four topical photosensitizer preparations as follows: compounded 20% ALA gel prepared in a good manufacturing practice (GMP)-certified pharmacy (Super-Pharm Professional, Israel), 10% ALA microemulsion gel (Ameluz®, Biofrontera Bioscience GmbH, Leverkusen, Germany), 16.8% MAL cream (Metvix®, Galderma, Lausanne, Switzerland), and 20% ALA hydroalcoholic solution (Levulan Kerastick®, DUSA Pharmaceuticals, Inc., Wilmington, MA, USA). The dermal sites were pretreated by Tixel® (Novoxel® Ltd., Israel) prior to topical drug application. One site was untreated to serve as control. Protoporphyrin IX (PpIX) fluorescence intensity readouts were taken immediately and 1, 2, 3, 4, and 5 hours posttreatment. RESULTS: The highest average PpIX fluorescence intensity measurements were obtained for the compounded 20% ALA gel following pre-treatment by TMFI at 6 milliseconds pulse duration. After 2 and 3 hours, TMFI-treated sites exhibited an increased hourly rate in readouts of FluoDerm units, which were 156-176% higher than the control rates (P ≤ 0.004). TMFI pre-treatment did not enhance the percutaneous permeation of either ALA or MAL following the microemulsion gel, hydroalcoholic solution, and cream applications. CONCLUSIONS: Pretreatment with low-energy TMFI at a pulse duration of 6 milliseconds increased the percutaneous permeation of ALA linearly over the first 5 hours from application when the compounded 20% ALA gel was used. Formulation characteristics have substantial influence on the ability of TMFI pretreatment to significantly increase the percutaneous permeation of ALA and MAL. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Control of the micromovements of a composite-material nail design: A finite element analysis.

BACKGROUND: Intramedullary nail fixation is the most accepted modality for stabilizing long bone midshaft fractures. The commercially used nails are fabricated from Stainless Steel or Titanium. Composite-materials (CM) mainly carbon-fiber reinforced polymers (CFRP) have been gaining more interest and popularity due to their properties, such as modulus of elasticity close to that of bone, increased fatigue strength, and radio-opacity to irradiation that permits a better visualization of the healing process. The use of CFRP instead of metals allows better control of different directional movements along a fracture site. The purpose of this analysis was to design a CM intramedullary nail to enable micromovements as depicted on a finite element analysis method. METHODS: We designed a three-dimentional femoral nail model. Three CFRP with different laminates arrangements, were included in the analysis. The finite element analysis involved applying vertical and horizontal loads on each of the designed and tested nails. RESULTS: The nails permitted a transverse micromovement of 0.75mm for the 45° lay-up and 1.5mm for the 90° lay-up for the CM, 1.38mm for the Titanium and 0.74mm for the Stainless Steel nails. The recorded axial movements were 0.53mm for the 45° lay-up, 0.87mm for the 90° lay-up, 0.46mm for the unsymmetrical lay-up CM, 0.046 for the Titanium and 0.02 for the Stainless Steel nails. Overall, the simulations showed that nail transverse micromovements can be reduced by using 45° carbon fiber orientations. Similar results were observed with each metal nails. INTERPRETATION: We found that nail micromovements can be controlled by changing the directional stiffness using different lay-up orientations. These results can be useful for predicting nail micromovements under specified loading conditions which are crucial for stimulating callus formation in the early stages of healing.

Mitochondrial induction as a potential radio-sensitizer in lung cancer cells - a short report.

INTRODUCTION: Lung cancer is the leading cause of cancer death. Radiation therapy plays a key role in its treatment. Ionizing radiation induces cell death through chromosomal aberrations, which trigger mitotic catastrophe and apoptosis. However, many lung cancer patients show resistance to radiation. Dichloroacetate (DCA) is a small molecule that can promote mitochondrial activation by increasing the influx of pyruvate. Here, we tested whether DCA may increase the sensitivity of non-small cell lung cancer (NSCLC) cells to radiation through this mechanism. METHODS: Two representative NSCLC cell lines (A549 and H1299) were tested for their sensitivity to radiation with and without pre-exposure to DCA. The treatment efficacy was evaluated using a clonogenic survival assay. An extracellular flux analyzer was used to assess the effect of DCA on cellular oxygen consumption as a surrogate marker for mitochondrial activity. RESULTS: We found that DCA increases the oxygen consumption rate in both A549 and H1299 cells by 60% (p = 0.0037) and 20% (p = 0.0039), respectively. Pre-exposure to DCA one hour before radiation increased the cytotoxic death rate 4-fold in A549 cells (55 to 13%, p = 0.004) and 2-fold in H1299 cells (35 to 17%, p = 0.28) respectively, compared to radiation alone. CONCLUSION: Mitochondrial induction by DCA may serve as a radio-sensitizer in non-small cell lung cancer.

Braided cerclage wires: a biomechanical study.

BACKGROUND: One of the drawbacks that makes many surgeons reluctant to use cerclage wires is the risk of periosteal vascular compromise. A new, easily applied braided wire configuration has been developed to improve mechanical wire gripping and to decrease the contact area between the hardware and the bony surface. MATERIALS AND METHODS: Braided wires with two diameters (1 mm and 1.5 mm) were compared to single strand and double-strand wire configurations. The biomechanical properties, peak and elongation loads,and wire pressure imprint points of this new configuration were evaluated in the current study. RESULTS: The braided wire was found to have the same peak load as the double-strand wire (P = 0.315) and more than twice the peak load than the single-strand wire (P = 0.0001), but a much shorter elongation peak than the other two. The imprint test showed that the braided wire has an interrupted dotted pattern compared to the continuous circular one that characterises the single-strand and double strand wires, indicating less potential damage to the bone. CONCLUSIONS: The braided cerclage wire may decrease the extent of insult to the bone by decreasing the contact area between the hardware and the bony surface and by enhancing stability by reducing the elongation peak, affording increased fracture fixation stability.

Synthesis and characterization of polymeric implant for kyphoplasty.

Copolymers of methyl methacrylate (MMA) and lauryl methacrylate (LMA) were prepared to obtain injectable ductile materials to be used in restoring vertebra height in kyphoplasty. Copolymers with M(w) in the range of 130,000 and polydispersity of 1.8 were obtained. Several aspects of the effect of adding LMA monomers were examined including intrinsic viscosity, thermal properties, mechanical properties, and the ability to be injected under high pressure. By increasing the amount of LMA, the ductility of the polymer was increased, accompanied by a decrease in Young's modulus and strength. The copolymer with monomers ratio (MMA:LMA) 1:1 v/v possessed the most suitable mechanical properties and injectability, which may have potential clinical use in orthopedics.