Safety and Tolerability of Plasma Exchange and Immunoadsorption in Neuroinflammatory Diseases.
ABSTRACT: Plasma exchange (PE) and immunoadsorption (IA) are frequently used for treatment of various autoimmune-mediated neurological diseases, including multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain-Barré syndrome (GBS). Although both methods are generally regarded as well-tolerated treatment options, evidence for safety and tolerability is low for most indications and largely relies on small case series. In this study, we retrospectively analysed adverse events (AEs) and laboratory changes in 284 patients with various neurological indications who received either PE (n = 65, 113 cycles) or IA (n = 219, 435 cycles) between 2013 and 2020 in our Neurology department. One standard treatment cycle for PE as well as IA consisted of five treatments on five consecutive days. During every treatment, the 2.0-2.5-fold individual plasma volume (PV) was treated in IA, while in PE, the 0.7-fold individual PV was replaced by human albumin solution. Overall, both methods showed an excellent safety profile; no deaths of life-threatening adverse events were recorded. Severe AEs (corresponding to grade 3 on the Common Terminology Criteria for Adverse Events grading scale v5.0) including three patients with sepsis, one pneumonia, and one pneumothorax were present in 5/435 IA cycles (1.1%); in the PE group, no severe AEs were recorded. Furthermore, although advantageous tolerability is generally considered the main advantage of IA over PE, we found that overall frequency of AEs (including grades 1 and 2) was higher in IA (67.1% of all cycles) compared to PE (35.4%; p < 0.001). The low incidence of AEs in PE might be caused by the lower PV exchanged during each treatment (0.7-fold) compared to previous studies which predominantly exchanged the 1.0-1.5-fold PV. In order to verify this hypothesis as well as confirming the efficacy of this lower-dosed scheme, prospective studies comparing different treatment regimens are needed.
Project description:Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens.We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline.Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2-4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD]?=?-0.76; -0.98 to -0.53, 95% CI, P?<?0.00001, and SMD?=?-0.36; -0.63 to -0.09 95% CI, P?=?0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ?5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR]?=?1.67; 1.09 to 2.56 95% CI, p?=?0.02), which was a result not seen within the 1 and 2-4 injection subgroups.Overall, 2-4 and ?5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2-4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.
Project description:Background:Plasma exchange (PE) constitutes the standard therapy for steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome. Immunoadsorption (IA) is an alternative method of apheresis which selectively removes immunoglobulines (Ig) while preserving other plasma proteins. Although IA is regarded as a well-tolerated, low-risk procedure, high-level evidence for its efficacy is lacking. Therefore, we sought to investigate whether IA is superior to PE in patients with acute relapse of multiple sclerosis or clinically isolated syndrome who had insufficiently responded to high-dose intravenous methylprednisolone (MP). Methods:Patients with acute relapse of multiple sclerosis or clinically isolated syndrome and without complete clinical remission of symptoms after at least one cycle of high-dose intravenous MP therapy were enrolled to our randomised, controlled, parallel-group, monocentric trial. Eligible patients were aged at least 12 years and had no clinical or laboratory signs of systemic infection. Eligible patients were randomly assigned (1:1) to receive either IA or PE. Patients in both groups received 5 treatments on 5 consecutive days. In the IA group, the 2.0-fold individual total plasma volume was processed on day 1, and the 2.5-fold on days 2-5. In the PE group, 2 liters of plasma (corresponding to the 0.69?±?0.12-fold individual total plasma volume) were removed each day and substituted by 5% human albumin solution. Patients were followed up directly after last apheresis as well as 2 and 4 weeks after last treatment. The primary endpoint was change of the Multiple Sclerosis Functional Composite (MSFC) after 4 weeks compared to baseline. Analyses of primary outcome and safety measures were done in all patients who received at least one treatment (intention-to-treat-population). The trial is registered with ClinicalTrials.gov, number NCT02671682. Findings:Between January 21, 2016, and October 26, 2018, 63 patients were screened for eligibility, and 61 patients were randomly assigned to receive IA (n?=?31) or PE (n?=?30). All randomised patients were included in the intention-to-treat-analysis. For the primary outcome, the median improvement of MSFC after 4 weeks compared to baseline was 0.385 (IQR 0.200-0.675; p?<?0.001) in the IA group and 0.265 (IQR 0.100-0.408; p?<?0.001) in the PE group. Improvement in the IA group was significantly larger (p?=?0.034) compared to PE. Response rates after 4 weeks were 86.7% in the IA group and 76.7% in the PE group. One deep venous thrombosis occurred in each group. Interpretation:Both IA and PE were safe in patients with steroid-refractory relapse and resulted in significant improvements of the primary outcome MSFC after 4 weeks compared to baseline. IA patients showed significantly larger improvements of MSFC compared to PE patients after 4 weeks. The results indicate a potential superiority of IA compared to PE in treatment of steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome, which has to be confirmed by future studies. Funding:Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.
Project description:Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv).In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n?=?374), SP plus artesunate (AS) (4 mg/kg, 3 d, n?=?374), or placebo (n?=?373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10-43, p ? 0.001) in children receiving SP-AQ and 12% (95% CI, -11 to 30, p?=?0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9-54, p?=?0.012) and Pv incidence was 23% (95% CI, 0-41, p?=?0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE?=?31%, 95% CI, 4-51, p?=?0.027), not against Pv episodes (PE?=?6%, 95% CI, -24 to 26, p?=?0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p > 0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%-2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention.IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.
Project description:To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n = 176]) and safety (hepatic [n = 238], visual [n = 199], and psychiatric [n = 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [C(min)]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and C(min)) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on ClinicalTrials.gov (NCT00531479).
Project description:Intro: Lymphatic filariasis (LF) is a neglected tropical disease caused by the nematode parasite Wuchereria bancrofti. The primary tool used by the Global Program to Eliminate LF is mass drug administration (MDA), and some 500 million people take the medications each year. Mild to moderate adverse events (AEs) are common after LF treatment, and these pose a challenge for the LF elimination program. To better understand the pathogenesis of AEs, we studied patients from a LF treatment trial in Côte d’Ivoire. Method: Total RNA was extracted from peripheral blood leukocytes collected before and 24h after treatment (when AEs peak). Global RNA sequencing was performed for 9 individuals with systemic moderate AEs and for 9 matched controls without AEs. Differential gene expression analysis (DESeq) identified transcriptional signatures (TS) associated with post-treatment AEs. Results: Out of the 36 sequenced samples, the 9 post-treatment samples from subjects with AEs had a distinct TS (P=0.006 by clustering analysis); 744 genes were significantly upregulated in this group (post vs pre-treatment, paired). These genes were enriched for many biological pathways that included pro-inflammatory pathways such as TLR and NF-kappa B signaling. Genes upregulated in AEs were also significantly enriched for having STAT1/2/3 transcription factor binding sites indicating the importance for interferons in the AEs pathogenesis. Overall design: A total of 38 samples were sequenced (pre and post-treatment samples from 19 individuals. Ten of the individuals had adverse events (Aes) (9 with moderate Aes and 1 with mild Aes), and 9 individuals had no Aes. 16 samples were sequenced on HiSeq2000, and 22 samples were sequenced on HiSeq4000 (Illumina TruSeq Stranded Total RNA)
Project description:This report describes outpatient (OP) administration of clofarabine in older patients (≥60 years) with untreated acute myelogenous leukemia (AML). Overall, 112 patients underwent clofarabine induction. Clofarabine was administered to 35 OPs for a total of 72 OP cycles, with 81% of these cycles representing consolidation treatment. Median length of hospital stay was 0-6 days and 5-25 days across OP and inpatient (IP) cycles, respectively. The most common adverse events (AEs) were nausea, vomiting, diarrhea, febrile neutropenia, edema, hypokalemia and pneumonia. The overall frequency of treatment-emergent grade ≥3 AEs and serious AEs was generally not different with IP or OP administration of clofarabine. No deaths were reported within 30 days following OP or IP consolidation cycles. In the appropriately selected older patient, OP administration of clofarabine consolidation appears feasible, is as well tolerated as IP administration and has potential to contribute to the quality of life in elderly patients with AML.
Project description:<h4>Introduction</h4>The Kellgren-Lawrence (K-L) grade is the most commonly used measure of radiographic disease severity in knee osteoarthritis (OA). Studies suggest that intra-articular hyaluronic acid (IA-HA) should only be considered in cases of early stage knee OA. The purpose of this review was to determine if trials administering IA-HA in early-moderate knee OA patients demonstrated greater pain relief than studies that also included patients with end-stage disease.<h4>Methods</h4>We conducted a systematic search of the literature to identify randomized controlled trials (RCT) comparing IA-HA with saline injections and that diagnosed disease severity using the K-L grade criteria. The primary outcome was mean change in pain from baseline at 4-13 weeks and 22-27 weeks. Safety was evaluated on the total number of participants experiencing a treatment-related adverse event (AE).<h4>Results</h4>Twenty RCTs were included. In the early-moderate OA subgroup, the mean change in pain scores was statistically significant favoring IA-HA from baseline to 4-13 weeks [SMD?=?- 0.30, 95% CI - 0.44 to - 0.15, p?<?0.0001] and within 22-27 weeks [SMD?=?- 0.27, 95% CI - 0.39 to - 0.16, p?<?0.00001]. No significant differences were observed in the late OA subgroup. IA-HA was associated with a significantly greater risk of treatment-related AEs relative to saline in the late OA subgroup [RR?=?1.76, 95% CI 1.16-2.67, p?=?0.008].<h4>Conclusion</h4>IA-HA provides significant pain relief compared to saline for patients with early-moderate knee OA, compared to cohorts including patients with end-stage OA (KL grade 4), with no increase in the risk of treatment-related AEs, up to 6 months. Patients with end-stage disease had lower levels of pain relief and may be diluting study results if included in the treatment cohort.<h4>Funding</h4>Ferring Pharmaceuticals.
Project description:BACKGROUND:Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid-related adverse events (AEs) is unproven. OBJECTIVES:To utilize data collected in a French investigator-initiated, phase III, open-label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV. METHODS:This was an independently conducted post hoc analysis of the moderate-to-severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg-1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg-1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ? 2 months, and 24-month efficacy and safety results were also reported. RESULTS:At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ? 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab-plus-prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS-related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone. CONCLUSIONS:In patients with moderate-to-severe PV, rituximab plus short-term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life-threatening CS-related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus. Corticosteroids, a standard first-line treatment for PV, have significant side-effects. Although their effects are unproven, adjuvant corticosteroid-sparing agents are routinely used to minimize steroid exposure and corticosteroid-related side-effects. There is evidence that the anti-CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator-initiated trial. Rituximab plus prednisone had a steroid-sparing effect and more patients achieved complete remission off prednisone. Fewer patients experienced grade 3 or grade 4 steroid-related adverse events than those on prednisone alone. This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate-to-severe PV.
Project description:Background:The development of minimally invasive surgical approaches has revolutionized surgical care and greatly improved surgical outcomes. This study aimed to evaluate the clinical effectiveness of a powered vascular stapler (PVS) during video-assisted thoracoscopic surgery (VATS) lobectomy. Methods:This prospective, multi-center, post-market clinical study in China enrolled 50 patients with either a suspected or formal diagnosis of clinical stage IA to IIB non-small cell lung cancer (NSCLC) scheduled for VATS lobectomy. The clinical effectiveness of the PVS for successful pulmonary artery (PA)/pulmonary vein (PV) transection was evaluated. In addition, the surgeon's stress, device usability, and surgeon satisfaction were measured using multiple questionnaires. Results:A total of 167 PAs/PVs were transected with 3 (1.8%) requiring intra-operative intervention. Fourteen of the 50 patients (28.0%) experienced at least one adverse event (AE), among whom 5 (10.0%) suffered from serious AEs. There were no postoperative hemorrhagic complications related to transection of the PA/PV with PVS. Surgeon satisfaction was surveyed by questionnaire after each of the 50 procedures resulting in a 96% reported satisfaction with device usability, specifically related to a low stress load and an increase in work efficiency. Conclusions:For VATS lobectomy, the PVS demonstrated a positive surgical effectiveness and value in cognitive and physical distress reduction. Complications following VATS lobectomy to treat NSCLC were generally low and as expected. Intraoperative complications were few and there were no postoperative complications related to the transection of the PA and PV during VATS lobectomy. Favorable results were reported on the surgeon satisfaction questionnaire regarding usability and surgeon stress.
Project description:BACKGROUND:Histone deacetylase inhibitor romidepsin has demonstrated durable clinical responses and tolerability in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma (PTCL, CTCL). Selection of novel drug therapies for patients with relapsed/refractory aggressive lymphoma requires not only considerations regarding efficacy but also careful evaluation of toxicities as well as overall clinical benefit. The purpose of this analysis was to examine common adverse events (AEs) reported in pivotal trials of romidepsin in relapsed/refractory PTCL or CTCL and to more clearly define the overall AE profile in these populations. METHODS:Patients with relapsed/refractory PTCL or CTCL were treated with romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles for up to 6 cycles; patients with at least stable disease could extend therapy until progressive disease or another withdrawal criterion was met. All enrolled patients who received???1 dose of romidepsin were included in the AE analyses. RESULTS:Overall, safety profiles of common AEs were similar, although patients with relapsed/refractory PTCL had more frequent hematologic toxicities and grade???3 infections. In both patient populations, the greatest incidence of grade???3 AEs and the majority of discontinuations due to AEs occurred during cycles 1-2. Early discontinuations were primarily related to infection, thrombocytopenia, or electrocardiogram abnormalities, confirming the need to closely monitor patients with poor bone marrow reserve or other comorbidities. Despite this, 28% of patients with relapsed/refractory PTCL and 36% of patients with relapsed/refractory CTCL continued on romidepsin treatment for???6 cycles. CONCLUSIONS:This study demonstrates that patients with relapsed/refractory PTCL or CTCL have similar AE profiles with romidepsin treatment, although patients with PTCL experienced more frequent and more severe hematologic toxicities and more frequent grade???3 infections. The greatest incidence of grade???3 AEs and the majority of discontinuations due to AEs occurred during treatment cycles 1-2. Extended dosing of romidepsin can be tolerated in responding patients. TRIAL REGISTRATION:NCT00426764,NCT00106431.