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Background. Rituximab (RTX) is a chimeric monoclonal antibody that binds the CD20 molecule on the surface of B cells and leads to B cell depletion. RTX is recommended by the European League Against Rheumatism (EULAR) as off-label in patients affected by idiopathic inflammatory myopathies (IIM). The real-world experience has shown that hypogammaglobulinemia occurring early after anti-CD20 treatment can be multifactorial (active disease, effect of other drugs) and usually transient, with a minimal increase in the risk of infections. The present study aimed to analyse the differences in the rate of RTX-associated hypogammaglobulinemia in a cohort of IIM patients in clinical practice, as well as the onset of major infections and its correlation with hypogammaglobulinemia. Methods. Patients followed at Rheumatology Unit of Siena University Hospital from January 2020 to September 2021 were retrospectively enrolled. Inclusion criteria were as follows: fulfilment of disease-specific classification criteria 2017 EULAR criteria and /or Peter and Bohan criteria for dermatomyositis (DM) and polymyositis (PM), positivity of anti-synthetase antibody and typical clinical features for anti-synthetase syndrome (ASS) and the measurement of serum Ig levels at the time of RTX administration (maximum 2 weeks before) (T0) and 6 (T1) to 12 (T2) months later, consistently with previous studies. Ig serum levels, measured by standard nephelometry (normal ranges: IgG 700-1600 mg/dL, IgM 40-240 mg/dL, IgA 70-400 mg/dL) were assessed as part of routine clinical care. Hypogammaglobulinemia was defined as moderate (serum IgG <600 mg/dL) and severe (IgG <400 mg/dL), as previously reported. Results. Seven patients (mean+/-SD, 57.3+/-19.7 years;7 female) were enrolled. Three of them had diagnosis of DM, three ASS and one PM. Two patients showed MDA5-positivity, two JO1-positivity, one TIF1-gamma-positivity, one PL7-positivity and the other one PM/Scl-positivity. All patients had at least two organs involved, and 4 out of 7 (57%) suffered from interstitial lung disease. Before starting RTX treatment, three and four patients underwent at least one and two synthetic immunosuppressants. All patients underwent low dosage of corticosteroids, and four patients underwent concomitant synthetic immunosuppressants (2 hydroxychloroquine and 2 MTX). IgG concentrations were statically lower at T2 compared to those at baseline (p=0.0391). None of them showed severe hypogammaglobulinemia. Similarly, IgM concentration significantly decreased at T2 compared to those at baseline (p=0.0078). Two patients showed major infections and two patients had paucisymptomatic COVID-19 (one of them had twice). Corticosteroids dosages were inversely correlated with IgG T2 concentrations (p=0.040, r=-0.919). Conclusion. Hypogammaglobulinemia following RTX is uncommon in IIM and is more likely in patients with high glucocorticoids, immunosuppressants and CYC exposure. IgG monitoring at least 6 months after RTX treatment may be useful in stratifying patients to identify those who require closer monitoring. These results shine a spotlight for increased awareness of the role of immunoglobulin measurement before maintenance doses of RTX.
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Clinical Information Patient Initials or Identifier Number: BP4****/22 Relevant Clinical History and Physical Exam: A 55 Y / Female C/C : Pain, numbness, cold sensation & weakness of left upper limb for 2 hours. Risk Factor : Hypertension, diabetes mellitus O/E : Pale, cold and absent of radial, ulnar, brachial pulse of left upper limb. Muscle power 3/5 left side. So2 86%, BP undetectable. Right upper limb were normal. BP 160/90 mm of hg, pules : 112 b/min, RR : 26/min. Body Temperature 37.5 C [Formula presented] [Formula presented] Relevant Test Results Prior to Catheterization: CBC : WBC 7450, HB % 10.8 g/dl, ESR 20mm in 1st hour, Platelets : 262000, SARS Cov2 Antigen : Negative PT 14.3 sec, INR : 1.07 APTT : 32.4 sec. blood group: O positive Serum Creatinine : 1.1 mg/dl Plasma glucose 9.7 mmmol/l HIV Ab : Negative HBs Ag : Negative Anti-HCV : Negative Urine R/E : Normal lipid profile : Cholesterol 280mg/dl Vascular duplex ultrasound of left upper limb : A dilated echogenic thrombus had blocked the left subclaviav artery lumen. Relevant Catheterization Findings: Conventional angiography with the lowest amount of contrast agent through the right femoral artery, revealed that left subclavian artery thrombosis with total occlusion distal to Left internal mammary artery. [Formula presented] [Formula presented] [Formula presented] Interventional Management Procedural Step: A5Fr MPA catheter with side holes was negotiated through a right femoral sheath and was placed in the left subclavian artery. Initially thrombus aspiration was done with Eliminate aspiration catheter (TERUMO) with no success. Then suction was done with the MPA catheter itself with partial removal of thrombus. Then a 5Fr Pigtail catheter was placed inside the thrombus and kept in situ. For residual thrombus 250,000u of Inj. Streptokinase as a thrombolytic drug was given through the Pigtail catheter as bolus over 30 min. The maintenance dose 100,000 u per hour was given over 24 hours through the Pigtail catheter via infusion pump. After 24 hours of thrombolytic therapy, her pain was reduced, the left hand became slightly warm, and distal pulses were feebly palpable. Moreover, the skin colour returned to near normal with improvement of pallor. Bleeding was well controlled at the catheter site. Doppler sounds revealed partial improvement of arterial flow. After evaluation of partial improvement, a low dose 1000 iu per hour of heparin (UFH)was infused intravenously for 24 hours. After 48 hours, repeat angiography via the inserted catheter at the site did not reveal any atherosclerotic plaque and confirm the thrombosis-dissolution. The latter practice demonstrated a good blood flowto the left upper distal limb leaving a little thrombus in the superficial palmer arch. [Formula presented] [Formula presented] [Formula presented] Conclusion(s): Catheter-based thrombus aspiration and thrombolytic therapy is primarily reserved for patients with acute viable limb ischemia. As observed in the presented case, thrombus aspiration and thrombolytic therapy is recommended to be considered as an alternative therapeutic method for patients with arterial thrombosis due to the rapid response, shorter treatment time and lower cost, compared to common and sometimes unsuccessful therapies.Copyright © 2023
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Introduction and Objective: Intravesical Bacillus Calmette-Guerin (iBCG) therapy for urinary bladder cancer (UBC) is associated with poor compliance due to various psycho-social issues unique to its treatment. The objective of this study was to identify and analyse the patient's perception and the factors that affected its adherence. Method(s): This mixed-method study was conducted on UBC patients who received/received iBCG. Following purposive sampling, patients who received at least one induction and one maintenance dose were assigned to a compliant group, and who did not were assigned to the non-compliant group. The patient's quality of life was assessed using the World Health Organization Quality of Life Instrument (WHOQOL-BREF). Semi-structured, in-depth interviews (IDI) of 35-40 minutes were conducted. The transcribed verbatim was analysed by deductive coding and content analysis. The appropriate codes, domains and themes were identified and analysed. Result(s): Demographic and socio-economic characteristics were comparable in both groups. The mean treatment expenditure was higher in the non-compliant group (1.87+/-0.75 vs 3.87+/-1.31;p=0.04). The quality of life measured was similar in both groups. IDI analysis noted that the primary reasons for non-compliance were frequent hospital commute, COVID travel restrictions, lack of knowledge, loss of daily wage, paucity at various levels in government hospitals and expensive corporate healthcare. Treatment-related severe frequency and dysuria also significantly contributed to non-compliance. Conclusion(s): Compliance can be achieved if the patients cope with the initial phase of treatment with positivity and optimism. Good symptomatic relief with proper knowledge and guidance could address the non-compliance.
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Perinatal arterial ischemic stroke (PAIS) is a rare cause of neonatal seizures, with an incidence of 1 in 2500 to 4000 live births, globally. This is a case of a neonate with PAIS due to transpla-cental passage of COVID-19 IgG antibodies from the mother. A term, male neonate, born to a primigravida with an unevent-ful antenatal history was presented on the second day of life with multiple episodes of focal clonic seizures involving the right upper and lower limbs. Magnetic resonance imaging revealed an acute infarct in the left frontal lobe, extending into the parietal region, anterior limb, and genu of internal capsule suggestive of arterial ischemic stroke. The known causes of PAIS were evaluated and ruled out. The result of reverse transcription polymerase chain reaction analysis for SARS-CoV-2 antigen was negative for both the mother and the neonate. COVID-19 IgG antibodies in the mother and neonate were elevated. Seizures were controlled with antiepileptics. The neonate had no further seizure episodes and was discharged on oral levetiracetam. The infant was developmentally and neurologically normal at 3 months of age. PAIS is a rare cause of neonatal seizures, and maternal COVID-19 infection may be associated with neonatal stroke.Copyright © 2022, Himalaya Wellness Company. All rights reserved.
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Objective Encouraged by reports of favorable outcomes following the use of corticosteroids in patients with moderate-to-severe coronavirus 2019 (COVID-19) pneumonia, we aimed to present our experience with early short-term corticosteroid use at our center in pediatric patients with COVID-19 pneumonia. Methods One hundred and twenty-nine pediatric patients were included in the study. Patients were divided into four groups according to the type and dose of corticosteroids given: Group 1 (those receiving dexamethasone 0.15 mg/kg/d);Group 2 (those receiving methylprednisolone 1 mg/kg/d);Group 3 (those receiving methylprednisolone 2 mg/kg/d);and Group 4 (those receiving pulse methylprednisolone 10-30 mg/kg/d). Results Of 129 patients, 19 (14.7%) patients were assigned to Group 1, 30 (23.3%) patients to Group 2, 30 (23.3%) patients to Group 3, and 50 (38.8%) patients to Group 4. Thirty-two (24.8%) patients were followed in the pediatric intensive care unit (PICU), of whom 13 (10%) required mechanical ventilation, and 7 (%5.4) died. In Group 4, the hospitalization length was significantly longer than in other groups (p < 0.001, p < 0.001). No significant difference was found among the groups in terms of mortality (p = 0.15). The most common comorbidity was obesity (33%). A significant association was found between the presence of comorbidity and mortality (p < 0.001). All patients who died had an underlying disease. Cerebral palsy was the most common underlying disease among the patients who died. Worsening of lymphopenia was significant in patients with severe COVID-19 pneumonia at the time of transfer to the PICU (p = 0.011). Conclusion Although children usually have a milder course of COVID-19 than adults, underlying diseases and obesity increase the severity of disease manifestations also in children. Further studies are needed to define the exact role of corticosteroids in COVID-19 patients. © 2022. Thieme. All rights reserved.
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Case report - Introduction: This case highlights the dilemma of keeping rheumatoid arthritis disease under control in active cancer cases and establishing a consistent multidisciplinary dialogue during a pandemic and staffing crises. During chemotherapy and active cancer treatment, disease-modifying therapies (conventional and biologic) are often stopped. In some cases, the potential benefits versus risks of restarting usual therapies have to be balanced against risks of suppressing disease activity with highdose steroids. Risks of infection (common and atypical) need to be considered. Case report - Case description: A is a 67-year-old female nonsmoker diagnosed with seropositive rheumatoid arthritis (RF, anti - CCP positive) in 2008. Other conditions include type 2 diabetes, atrial fibrillation (on warfarin), hypothyroidism and obstructive sleep apnoea. Due to active disease, despite triple therapy (methotrexate, sulphasalazine and hydroxychloroquine), anti-TNF therapy (etanercept) commenced in 2009 with primary non-response. However, she responded well to B-cell therapy (rituximab) in conjunction with oral methotrexate (25mg weekly) receiving annual infusions from 2010 to 2016. In 2017, an elective sleeve gastrectomy procedure for high BMI was abandoned after peritoneal deposits of concern were noted. Histology and CT imaging were consistent with a primary peritoneal malignancy (Stage 3c low-grade serous adenocarcinoma). Treatment involved debulking surgery (total abdominal hysterectomy, bilateral salpinoophorectomy, omentectomy) and tamoxifen. Treatment for rheumatoid arthritis stalled during this period but as frequent steroids were required for active joint inflammation, in agreement with the oncologists, she had a rituximab cycle in 2018. Unfortunately, in 2019 she had signs of cancer progression (elevated tumour markers, CT imaging) and has subsequently started carboplatin chemotherapy. She has been unable to continue methotrexate or rituximab pending completion of the chemotherapy cycles (ongoing). However, her arthritis is now uncontrolled without increased steroids. Due to recurrent flares, her maintenance dose has been increased from 5mg to 7.5-10mg prednisolone daily until we can establish if it is safe and appropriate to recommence her usual arthritis regime. Even without disease-modifying therapy like methotrexate and rituximab, risk of infection (including atypical ones) is still significant with the combination of chemotherapy and steroids. Risk of progressive joint damage and adverse quality of life with active arthritis also needs to be considered. Staffing crises, exacerbated by COVID pandemic issues, have added to complexity of decision making and coordination of regular multidisciplinary discussions regarding treatment. Case report - Discussion: Cancer is a known association in rheumatoid arthritis patients with a twofold higher risk of lymphoma compared to the general population. Whether condition or treatment affects risk remains unclear as immune dysregulation is relevant in both autoimmunity and cancer. Paraneoplastic, recent onset arthritis, chemotherapy- or immunotherapy-induced arthralgia/arthritis are also well documented. This case had a seropositive rheumatoid arthritis phenotype quite a few years prior to cancer diagnosis. Primary peritoneal cancer is uncommon, often presenting as in this case as an incidental finding. It is usually treated like ovarian cancer Whilst methotrexate has been implicated in lung cancer, melanoma and non-Hodgkin lymphoma, overall safety data suggest any risk is quite low (e.g., EBV-associated lymphoproliferative disorders usually resolve with drug discontinuation). It is also a known chemotherapeutic agent. Anti-TNF treatment algorithms generally exclude patients with recent cancer. Rituximab, originally developed as a cancer drug, is not thought to affect risk of cancer development or progression. Treatment with disease-modifying therapy (conventional and biologics) is often withheld in patients with active malignancy undergoing chemotherapy due to a theo etical risk of potentiated immunosuppression and toxicity, particularly cytopaenias. However, maintaining arthritis control with glucocorticoids also has short- and long-term risks. Combining chemotherapy agents like carboplatin with methotrexate has been used for urothelial carcinoma and can be well tolerated with close monitoring of haematological parameters. Thus, it could be argued this patient is at risk of infections whichever treatment approach is taken and regaining control of arthritis with recommencement of methotrexate and rituximab is much better for her quality of life. Regular multidisciplinary discussions are important to outline risks versus benefits of combined treatment. This may be difficult in practice during staffing crises. Covid risk in patients receiving rituximab and/or chemotherapy, timing and response to COVID vaccination are also important considerations. Case report - Key learning points: . Primary peritoneal cancer is uncommon and can present as an incidental finding . Whilst treatment for progressive cancer is important, withholding rheumatoid arthritis treatment can have a significant adverse impact on quality of life . Morbidity and mortality risks of stopping treatment versus combined treatment (cancer therapy and disease-modifying therapy) ideally needs to be fully discussed and agreed with the patient and all care providers - lack of "named" providers, restructuring, redeployment, multi-specialty care and a global pandemic can make coordination of this difficult.
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Background. Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods. Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results. The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion. The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days.
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Introduction: Siponimod is approved in Australia for adults with secondary progressive multiple sclerosis (SPMS). Prescreen requirements for siponimod include a CYP2C9 genotype test to determine maintenance dosing. An integrated digital platform, 'MSGo', was developed by Novartis and RxMx to support Healthcare Professionals and their multiple sclerosis patients. Objective(s): Data derived exclusively from MSGo was utilised to explore the onboarding experience of siponimod patients in Australia. Aim(s): To provide real world evidence on siponimod for SPMS patients in Australia. Method(s): The study enrolled >350 adults with SPMS registered in MSGo for siponimod in Australia. Primary endpoint is the average time for onboarding with key secondary endpoints addressing adherence and variables that influence onboarding and adherence. Result(s): Final data extraction on April 20th, 2022 included 368 patients (median age of 59y).CYP2C9 genotype testing took a median of 19 days (95%CI 17-21) from registration and maintenance doses of 2mg (n=166) or 1mg (n=27) were initiated as per label recommendations;1mg was initiated for two rare allele genotypes (*1*5 and*1*11) in the absence of label recommendations. Mixture-cure modelling estimated that 58% of patients will ever initiate siponimod, with a median time to initiation of 56d (95%CI 47-59) from registration. Among those who initiated siponimod the most common reported reason for delayed initiation was 'waiting for vaccination'. Self-reporting of daily treatment, captured under the treatment reminder function in MSGo, had a drop-off of ~25% after the first week of initiation;a continued decline in reporting over time limited assessment of adherence. Continued self-reporting of daily dosing trended lower with older patients with only 28% of those >70y continuing to self-report at day 90 compared to 47-69% with the younger age groups. The study uncovered the important role of care partners, with Cox regression analyses demonstrating that SPMS patients who nominated a care partner were more likely to initiate (HR:2.1, 95%CI 1.5-3.0) and to continue self-reporting their daily medication (HR:2.2, 95%CI 1.3-3.7). A total of 90 patients discontinued the study;48 prior to and 42 after siponimod exposure. Conclusion(s): This study provides insights into siponimod onboarding for adults living with SPMS in Australia and demonstrates the impact of MSGo and care partner support during a period challenged by the COVID-19 pandemic.
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Purpose : Autosomal recessive CEP290-LCA (LCA10) is a severe inherited retinal disease resulting in early vision loss and currently has no treatment. Sepofarsen is an RNA antisense oligonucleotide targeting the most common c.2991+1655A>G disease-causing variant in the CEP290 gene. Long-term safety and efficacy of sepofarsen in the first eye treated (FE) and safety and efficacy in the second eye treated (SE) in this extension trial (Insight;NCT03913130) were evaluated. Methods : Subjects who completed the Ph1b/2 sepofarsen trial could enroll in the extension trial for continued dosing in the FE and initiation in the SE with the 160/80μg loading/maintenance dose. Frequency and severity of adverse events, and change in best-corrected visual acuity (BCVA) and full-field stimulus testing (FST) threshold were assessed. Baseline was defined as the value measured within the same month of-or last measurement prior to-the first dosing for each eye. Due to covid-19, some participants have missed scheduled injections. As such data up to-or available measurement prior to-6 months after the last dosing have been included in the analysis for each eye. Results : At data cut-off in mid-October 2021, 9 subjects (of 11 from the Ph1b/2 trial) aged 15-45 years were followed up to 46 months, 5 of them received at least one intravitreal injection of sepofarsen in the SE. Three subjects developed cataracts in the FE and 2 in the SE, of which 2 recovered following cataract surgery. Time to onset since initial dose was 13 months or later. Between 35-46 months after the 1 injection, long term BCVA improvement was reported in 4/6 FE ranging from-0.20 to-0.54 logMAR and 5/5 FE improved in either blue FST, red FST or both ranging from-0.21 to-2.06 log cd/m2. The SE showed a similar trend as the FE in BCVA (3/5 SE showed a change ranging from-0.06 to-2.50 logMAR) and in blue and red FST (4/4 SE showed improvement ranging from-0.27 to-4.57 log cd/m2). st Conclusions : The longer-term sepofarsen safety profile is consistent with that observed in the Ph1b/2. Meaningful BCVA and FST improvements observed in the Ph1b/2 continued up to 46 months. The responses in the SE were similar to the responses seen in the FE in both visual acuity and retinal sensitivity improvements. A Phase 2/3 (ILLUMINATE;NCT03913143), multiple dose, double-masked, randomized, sham-controlled trial is ongoing.
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Background: Per label, mogamulizumab (Moga) is administered on days 1, 8, 15, and 22 of the first 28-day cycle (loading) and on days 1 and 15 of each subsequent cycle (maintenance) for adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after ≥1 prior systemic therapy. During the COVID-19 pandemic, professional organizations suggested dosing intervals for systemic cancer therapies be extended to limit in-person visits. This study examined the real-world use of Moga before and during the COVID-19 pandemic in the United States. Methods: Using the Symphony Health Solutions database, adults with ≥1 diagnosis (dx) of MF or SS (ICD-10 CM: C84.0x or C84.1x) and ≥1 Moga claim during 10/1/2018-5/6/2021 were identified. Within the MF (no SS dx) and SS (any SS dx) cohorts, patients were divided into 2 subgroups based on their Moga initiation date: 10/1/2018-3/31/2020 (pre COVID-19) and 4/1/2020-5/6/2021 (COVID-19). Patient characteristics and dosing intervals between Moga doses 1-4 (loading) and between subsequent doses (maintenance) were examined. Results: Overall, 154 MF and 204 SS patients initiated Moga during the study period (mean age: 66.8 and 69.2 years;male: 64% and 55%, respectively). In the MF cohort, 98 and 56 patients were in the “pre COVID-19” and “COVID-19” subgroups. The mean dosing interval was shorter among patients in the “COVID-19” subgroup for both the loading (9.1 vs. 13.2 days) and maintenance doses (15.2 vs. 16.1 days) (Table). In the SS cohort, 121 and 83 patients were in the “pre COVID-19” and “COVID-19” subgroups. Mean loading (9.0 vs. 11.1 days) and maintenance (15.0 vs. 16.8 days) dosing intervals were shorter for patients included in the “COVID-19” subgroup. Conclusions: Among MF and SS patients, dosing intervals for Moga in loading and maintenance were not extended during the 1st year of the COVID-19 compared to pre COVID-19. There was a trend towards closer concordance with the label during COVID-19.
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Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell therapy (HSCT) with incidence rates ranging from 10-35%. The predominant mechanism leading to TA-TMA is endothelial cell damage leading to complement dysregulation and microvascular hemolysis. Complement dysregulation is particularly important in the pathophysiology of TA-TMA as initial trials have shown response to complement blockade using eculizumab, a humanized monoclonal antibody targeting the terminal complement pathway. Ravulizumab is a longer acting monoclonal antibody with the same target as eculizumab that is increasingly used for treatment of atypical hemolytic uremic syndrome. Herein, we describe the case of an African American female with relapsed/refractory infantile B-cell acute lymphoblastic leukemia (B-ALL) who underwent 10/10 HLA-matched sibling donor allogeneic transplant (conditioning: busulfan/fludarabine/thiotepa;GVHD prophylaxis: tacrolimus/methotrexate) who developed TA-TMA marked by pericardial effusion, elevated LDH, proteinuria, hypertension, thrombocytopenia, anemia, and evidence of microangiopathy. Upon diagnosis, as ravulizumab was on formulary and readily available unlike eculizumab, she was treated with ravulizumab instead of eculizumab. Objectives: To describe the therapeutic response to ravulizumab in one patient diagnosed with TA-TMA. Design/Method: A retrospective chart review was performed regarding this patient's ravulizumab treatment course, and direct discussions were had with the patient's care team. Results: Ravulizumab (loading dose of 600 mg followed 2 weeks later by maintenance dosing of 600 mg every 4 weeks) was administered. Pre-treatment CH50 was >75 U/mL (range: 30-75 U/mL) with sC5b9 and C3 complement levels at the upper limit of normal at 220 ng/mL (range: ≤244 ng/mL) and 143 mg/dL (range: 72-164 mg/dL), respectively. Clinical normalization of the patient's TA-TMA was achieved two weeks after loading dose administration with normalization of LDH and blood pressure values, improved proteinuria, decreased transfusion requirements, absence of schistocytes on peripheral smear, and complete resolution of pericardial effusion. A total of 5 maintenance doses of ravulizumab were administered approximately every 4 weeks with CH50 ranging <3-33 U/mL during this time period. Five maintenance doses were administered as the optimal duration was unknown and the patient's TA-TMA treatment course was complicated by COVID-19 infection, for which there was concern could lead to TA-TMA reactivation (which did not occur). The ravulizumab was well tolerated throughout with amoxicillin used for meningococcal prophylaxis. Conclusion: While studies evaluating ravulizumab for treatment of TA-TMA are ongoing, ravulizumab successfully led to complement blockade and clinical improvement in this patient with TA-TMA.
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Amplification and/or overexpression of HER2 in breast cancer (BCa) patients is associated with aggressive disease and poor prognosis. Herceptin® (trastuzumab), a monoclonal antibody targeting HER2, has an established role in the treatment of HER2 positive BCa. Addition of trastuzumab to anthracycline-and taxane-based neoadjuvant treatment in women with HER2-positive BCa has resulted in improvements in pathological complete response (pCR, a strong predictor for long-term clinical outcome), event-free survival (EFS) and overall survival (OS). This study is designed to compare efficacy (pCR) and safety between the originator Herceptin and the proposed trastuzumab biosimilar EG12014. The study is conducted during the COVID-19 pandemic (last patient in: March 2020, last patient last visit: planned Jan 2022) in Belarus, Chile, Colombia, Georgia, India, Russia, South Africa, South Korea, Taiwan, and the Ukraine. Methods: Neoadjuvant phase: 807 patients were randomized (1:1) into 2 arms receiving epirubicin (90 mg/m 2) and cyclophosphamide (600 mg/m2) every 3 weeks for 4 cycles, followed by EG12014 (arm 1) or Herceptin (arm 2) (both at loading dose: 8 mg/kg and maintenance dose: 6 mg/kg) and paclitaxel (175 mg/m2) every 3 weeks Sfor 4 cycles. Subsequently, the patients underwent surgery, and primary endpoint (pCR [ypT0/is ypN0]) was assessed. Adjuvant phase: After surgery, the patients received EG12014 or Herceptin (both at loading dose: 8 mg/kg and maintenance dose: 6 mg/kg) to complete 12 months of overall trastuzumab treatment. COVID-19 infections in the study population were not expected to affect primary endpoint analysis;thus, no sensitivity analysis was performed regarding COVID-19 status (symptomatic/asymptomatic). Differences between the 2 arms regarding delays in study treatments and procedures due to COVID-19 were assessed. Results (at interim data base lock, blinded as study is ongoing): Study population: the mean age was 50 years, the majority were white Europeans with tumor stage II, estrogen receptor positive and progesterone receptor negative. The median time from date of first diagnosis was 0.5 months. Primary endpoint pCR (ypT0/is ypN0) was reached with relative risk ratio (RR) for the full analysis set: 0.992 (90% CI 0.880 to 1.118) between the 2 treatment arms. Secondary pCR endpoints (defined as ypT0 ypN0 and ypT0/is) were also reached, with RR between the treatment arms: 0.917 and 0.992, respectively. Objective clinical response prior to surgery was similar for the 2 treatment arms: 83.8% and 83.6%, respectively. EFS, OS, safety endpoints (e.g., adverse events [most frequently reported: alopecia], serious adverse events, and deaths), and toxicity assessments, supported similarity between EG12014 and Herceptin. Sixty-two patients (7.7%) were infected with COVID-19;the infections were equally distributed between the 2 treatment arms. COVID-19 did not cause any discontinuations or deaths in the study. Among all reported COVID-19 events, 13 (21%) were asymptomatic, 11 (18%) were graded as 3 (severe), and 1 (1.6%) was graded as grade 4 (life threatening). Conclusion: EG12014 has shown equivalent efficacy to Herceptin in regard to clinical response (pCR) and has also demonstrated a similar safety profile. The impact of the COVID-19 pandemic has been comparable between the two treatment arms. The influence of the pandemic on this clinical study has been relatively low considering timing and the participating countries.
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Background. Antimicrobial resistance is a major public health threat internationally but, particularly in Colombia. High and increasing rates of carbapenemases are challenging. Implementing antimicrobial stewardship programs (AMSs) in a large, academic, public network hospitals in Bogotá, Colombia.will help curb inappropriate antibiotic use. Methods. AMS was established in April 2020 consisting of an administrative champion, Infectious Diseases staff, nurse, General Physician, microbiologist, and pharmacists. Antimicrobial stewardship program interventions included postprescriptive audit and establishment of institutional guidelines. The AMS tracked appropriate drug selection including loading dose, maintenance dose, frequency, route, duration of therapy, de-escalation, and compliance with AMS recommendations. Defined daily dose (DDD) of drugs and health economics evaluations of antimicrobials (April-December 2020). Recommendations are placed in the electronic medical record as a progress note. Results. From April to December 2020, 1013 patients were evaluated by means of a prospective methodology. Unnecessary 689 days of hospitalization and 4420 days of antibiotic therapy were avoided. Among the top antibiotics discontinued were piperacillin tazobactam for the months of July, August, November and December, while for September and October was meropenem. The intensive care unit was the most frequently intervened service (52%), followed by hospitalization (43%) and the emergency department (5%).Over the course of the year, there was significant adherence to the program, with 100% in July, followed by 93.3% in April, 87% in December, 86.6% in May and June, 83% in November, 80% in September, 73.3% in August and 57% in October. The AMS program was able to save $47.409US in antibiotics and $55.529US in hospitalization, and 11% decrease in nephrotoxicity events (14 renal failures were avoided), which also saved additionally $ 23.503 US for a total of an estimated cost saving for the network public hospitals of $ 126.441 US by 2020. Conclusion. Implementation of a multidisciplinary antibiotic stewardship program in this academic, large, academic, public network hospitals in Bogotá, Colombia demonstrated feasibility and economic benefits even in a Covid19 pandemic situation.
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INTRODUCTION: Continuous renal replacement therapy (CRRT) augments a patient's volume of distribution and clearance leading to frequent subtherapeutic levels with intermittently dosed vancomycin. Continuous infusion (CI) vancomycin may offer an advantage in CRRT. Limited studies exist comparing intermittent infusion (II) and CI vancomycin. The purpose of this study was to determine if CI vancomycin in patients receiving CRRT results in more frequent therapeutic concentrations compared to II vancomycin. METHODS: This was a single-center, retrospective chart review of critically ill adult patients receiving CI or II vancomycin while on CRRT between January 1, 2017 and March 31, 2021. The primary outcome was frequency of therapeutic vancomycin concentration (15-25 mcg/mL) at 24 ± 6 hours. Secondary outcomes included percentage of patients therapeutic at first concentration, percentage of patients with subtherapeutic and supratherapeutic concentrations, and intensive care unit (ICU) and hospital mortality. RESULTS: A total of 268 patients were screened and 59 patients met inclusion criteria. Seventeen patients received CI vancomycin and 42 patients received II vancomycin. Baseline characteristics were similar with the exception of more COVID-19 patients, more frequent vasopressor therapy, a higher mean SOFA score, and higher BUN at CRRT initiation in the CI group. The total median loading dose was 1000 mg (IQR 1000-1750 mg) in the CI group and 2000 mg (IQR 1500-2000 mg) in the II group (p=0.003). The daily maintenance dose was 1250 mg (IQR 1250-1500 mg) in CI group and 1000 mg (IQR 1000-1000 mg) in the II group (p< 0.0001). Therapeutic concentration at 24 ± 6 hours was achieved in 52.9% of CI patients compared to 47.6% of II patients (p=0.78). Subtherapeutic concentrations occurred less frequently in the CI group (11.8% vs 42.9%, p=0.03) whereas supratherapeutic concentrations occurred more frequently in the CI group (35.3% vs 2.4%, p=0.0016). ICU and hospital mortality were higher in the CI group (88.2% vs 52.4%, p=0.02). CONCLUSION: CI vancomycin was associated with less subtherapeutic concentrations as compared to II vancomycin in patients receiving CRRT. However, there was no difference in frequency of therapeutic concentrations at 24 hours and CI was associated with more frequent supratherapeutic concentrations.
ABSTRACT
INTRODUCTION: Benzodiazepine (BZD)-based regimens are first-line therapy for alcohol withdrawal syndrome (AWS). Phenobarbital (PHB) is an alternative treatment but with limited guidance for use. We evaluated the efficacy and safety of PHB compared to BZD for AWS. METHODS: This was a single-center retrospective cohort study. Adult patients were included if they received BZD symptom-triggered protocol or PHB monotherapy for management of AWS and excluded if they received both therapies, were COVID positive, or died within 48 hours of hospital admission. Data collection started on December 31, 2020 and data were collected in reverse chronological order until target sample size was attained. Primary endpoint evaluated was development of AWS-related complications. Secondary endpoints included need for adjunct therapy, duration of mechanical ventilation, hospital and ICU length of stay (LOS), and hospital mortality. Safety endpoints included incidence of hypotension, bradycardia, and significant respiratory depression. RESULTS: 100 patients out of 164 screened patients were included, with 50 patients in PHB and 50 patients in BZD cohorts. Baseline characteristics were similar, except more patients in PHB cohort had history of alcohol dependence (82% vs. 56%, p< 0.001). Majority of BZD patients were in medical ICU while PHB patients were in surgical ICU. Baseline median MINDS scores were similar [PHB, 10 (5-16) vs. BZD, 11 (5-15), p=0.99]. Median (IQR) phenobarbital loading dose given was 14.8 (12.8-15.9) mg/kg followed by maintenance dose 356 (259-389) mg with a duration of 5 (3-5) days. Total lorazepam-equivalent dose given was 19.3 (5.0-44.0) mg with a duration of 4 (3-5) days. There was no significant difference in the primary endpoint [4 (8%) vs. 4(8%), p=1.00]. MINDS score post therapy initiation was significantly higher in BZD cohort [5 (1-14) vs. 15 (8-19), p< 0.001]. Patients who received PHB therapy had significantly shorter ICU LOS in days [3 (1-7) vs. 5 (2-6), p< 0.001] but no difference in hospital LOS [PHB, 8 (5-13) vs. BZD, 7 (5-12), p=0.37]. There were no significant differences in other secondary and safety endpoints. CONCLUSION: In this study there was no difference in efficacy or safety of PHB in management of AWS compared to BZD. Larger studies to confirm PHB as first-line AWS therapy are warranted.