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1.
Alveolar Hemorrhage in ANCA-associated Vasculitis: Results of an International, Randomized, Controlled Trial (PEXIVAS)
Fussner, L. A., Flores-Suárez, L. F., Cartin-Ceba, R., Specks, U., Cox, P. G., Jayne, D. R. W., Merkel, P. A., Walsh M Md, PhD
American journal of respiratory and critical care medicine. 2024
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Editor's Choice
Abstract
RATIONALE Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The Plasma Exchange (PLEX) and Glucocorticoids (GC) in Severe AAV (PEXIVAS;NCT00987389) trial was the largest in AAV and first to enroll participants with DAH requiring mechanical ventilation. OBJECTIVES Evaluate characteristics, treatment effects, outcomes for patients with AAV with and without DAH. METHODS PEXIVAS randomized 704 participants to PLEX or no-PLEX and reduced or standard-dose GC. DAH status was defined at enrollment as no-DAH, non-severe, or severe (room air SpO(2)≤85% or use of mechanical ventilation). MEASUREMENTS AND MAIN RESULTS At enrollment, 191(27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n=513,72.9%). Among those with DAH, 8/95(8.4%) receiving PLEX died within one year vs. 15/96(15.6%) with no-PLEX (HR 0.52,CI 0.21-1.24), while 13/96(13.5%) receiving reduced-GC died vs. 10/95(10.5%) with standard-GC (HR 1.33,CI 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX vs. no-PLEX (medians 25,IQR 22-26 vs. 22-27), fewer with reduced-GC (23[20-25]) vs. standard-GC (26[25-28]). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191(12.0%) with DAH died within one year vs. 34/513(6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. CONCLUSION Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Clinical trial registration available at www. CLINICALTRIALS gov, ID: NCT00987389.
PICO Summary
Population
Patients with severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis including glomerulonephritis and/or diffuse alveolar hemorrhage (DAH), enrolled in the PEXIVAS trial (n= 704).
Intervention
Plasma exchange (PLEX) and standard glucocorticoid (GC) (n= 176). PLEX and reduced GC (n= 176).
Comparison
No PLEX and standard GC (n= 175). No PLEX and reduced GC (n= 177).
Outcome
At enrollment, 191 (27.1%) participants had DAH and were younger, more frequently relapsing, proteinase 3-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n= 513 (72.9%)). Among those with DAH, 8/95 (8.4%) receiving PLEX died within one year vs. 15/96 (15.6%) with no-PLEX (HR 0.52; CI [0.21, 1.24]), while 13/96 (13.5%) receiving reduced-GC died vs. 10/95 (10.5%) with standard-GC (HR 1.33; CI [0.57, 3.13]). When ventilated, ventilator-free days were similar with PLEX vs. no-PLEX (medians 25; IQR 22, 26 vs. 22, 27), fewer with reduced-GC (23 [20, 25]) vs. standard-GC (26 [25, 28]). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within one year vs. 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments.
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Randomized controlled trial of intravenous immunoglobulin for autoimmune postural orthostatic tachycardia syndrome (iSTAND)
Vernino, S., Hopkins, S., Bryarly, M., Hernandez, R. S., Salter, A.
Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 2024
Abstract
OBJECTIVE This study assesses response to intravenous immunoglobulin (IVIG) in presumed autoimmune postural orthostatic tachycardia syndrome (POTS). BACKGROUND POTS may be associated with autoimmune disorders, serum autoantibodies, or recent infection. Uncontrolled case studies suggest that IVIG is beneficial for treating autoimmune POTS. No previous randomized controlled trials have been conducted. METHODS This single-site randomized controlled trial compared IVIG with intravenous albumin infusions. Albumin comparator ensured blinding and control for effects of volume expansion. Eligible patients with POTS had COMPASS-31 total weighted score ≥ 40 and met predetermined criteria suggesting autoimmunity. Over 12 weeks, participants received eight infusions (0.4 gm/kg each). Four infusions were given weekly followed by four infusions every other week. Primary outcome measure was improvement in COMPASS-31 2 weeks after final infusion. RESULTS A total of 50 participants consented; 30 met inclusion criteria and received study drug (16 IVIG and 14 albumin; 29 female). Group baseline characteristics were well matched; 27 participants completed treatment protocol. Change in COMPASS-31 did not differ between groups (median change [IQR]; IVIG -5.5 [-23.3, 2.5] versus albumin: -10.6 [-14.1, -4.7]; p-value = 0.629). The IVIG group had a higher response rate (46.7% versus 38.5%), but this was not statistically significant. Adverse events were common but usually mild and did not differ between treatment groups. CONCLUSIONS This small randomized controlled trial of IVIG in POTS found no statistical difference in response compared with albumin infusion. Both groups showed improvement possibly related to volume expansion or other effects obscuring group differences. These findings inform development of future immunomodulatory clinical trials in POTS.
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Safety and tolerability of intravenous immunoglobulin in patients with active dermatomyositis: results from the randomised, placebo-controlled ProDERM study
Aggarwal, R., Schessl, J., Charles-Schoeman, C., Bata-Csörgő, Z., Dimachkie, M. M., Griger, Z., Moiseev, S., Oddis, C. V., Schiopu, E., Vencovský, J., et al
Arthritis research & therapy. 2024;26(1):27
Abstract
BACKGROUND Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study. METHODS ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0-16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16-40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented. RESULTS The 95 patients enrolled were randomised to receive IVIg (N = 47) or placebo (N = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4-15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred. CONCLUSIONS Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors. TRIAL REGISTRATION ProDERM study (NCT02728752).
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Risk factors for coronary artery abnormalities and resistance to immunoglobulin plus ciclosporin A therapy in severe Kawasaki disease: subanalysis of the KAICA trial, randomized trial for cicrosporin A as the first-line treatment
Murayama, Y., Hamada, H., Shiko, Y., Onouchi, Y., Kakimoto, N., Ozawa, Y., Hanaoka, H., Hata, A., Suzuki, H.
Frontiers in pediatrics. 2023;11:1321533
Abstract
BACKGROUND To investigate risk factors for coronary arterial abnormalities (CAAs) and resistance to treatment in patients with Kawasaki disease (KD) receiving intravenous immunoglobulin (IVIG) plus ciclosporin A (CsA) as the first-line treatment, we performed a subanalysis of baseline data of participants in the KAICA trial, a phase 3, randomized study (JMA-ILA00174). METHODS All data of the patients enrolled in the KAICA trial, who had a Gunma score ≥5 at diagnosis and had been randomly assigned to either IVIG (2 g/kg/24 h) plus CsA (5 mg/kg/day for 5 days) (n = 86) or IVIG alone (n = 87), were subjected to this study. CAA was defined by a Z score ≥2.5 observed within 4 weeks after treatment initiation. Baseline data including genotypes of KD susceptibility genes were compared between subgroups of patients for CAA or treatment response for each treatment group. Backword-forward stepwise logistic regression analyses were performed. RESULTS Pre-Z-max, defined as the maximum among Z scores on four coronary artery branches before treatment, was higher in patients with CAA in both treatment groups and was associated with CAA in IVIG plus CsA treatment group [odds ratio (OR) = 17.0]. High serum total bilirubin level was relevant to treatment resistance only in the IVIG plus CsA group (OR = 2.34). CONCLUSIONS Coronary artery enlargement before treatment is a major determinant of CAA even in KD patients treated with initial IVIG treatment intensified by addition of CsA. Baseline serum total bilirubin level was a risk factor associated with resistance to IVIG plus CsA.
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Fostamatinib for warm antibody autoimmune hemolytic anemia: Phase 3, randomized, double-blind, placebo-controlled, global study (FORWARD)
Kuter, D. J., Piatek, C., Röth, A., Siddiqui, A., Numerof, R. P., Dummer, W.
American journal of hematology. 2023
Abstract
Warm antibody autoimmune hemolytic anemia (wAIHA) is characterized by hemolysis and symptomatic anemia with no approved treatment options. Fostamatinib is an oral spleen tyrosine kinase inhibitor approved in the US and Europe for treatment of adults with chronic immune thrombocytopenia. In this phase 3 study, patients with an insufficient response to ≥1 prior wAIHA treatment were randomized to fostamatinib or placebo. The primary endpoint was the proportion of patients to achieve a durable hemoglobin (Hgb) response (Hgb ≥10 g/dL and increase from baseline of ≥2 g/dL on 3 consecutive visits) during the 24-week treatment period. Ninety patients were randomized, 45 to each arm. Of the fostamatinib-treated patients, 35.6% achieved a durable Hgb response versus 26.7% on placebo (p = .398). A post hoc analysis revealed a large placebo response in Eastern European patients. Significantly more patients on fostamatinib from North America, Australia and Western Europe exhibited a durable Hgb response compared to placebo (36% vs. 10.7%, p = .030). After censoring for Hgb values impacted by steroid rescue received during screening and excluding 2 placebo patients found to likely not have wAIHA, a reanalysis demonstrated a difference in durable Hgb response between fostamatinib and placebo (15/45 [33.3%] vs. 6/43 [14.0%], p = .0395). At least 1 AE was reported in 42 (93.3%) and 40 (88.9%) patients receiving fostamatinib and placebo, respectively. The most common AEs in the fostamatinib group were diarrhea (26.7%), hypertension (24.4%), and fatigue (15.6%). In this study, fostamatinib demonstrated a clinically meaningful benefit for patients in Western regions, and no new safety signals were identified.
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Efficacy of intravenous immunoglobulins (IVIg) in improving skin symptoms in patients with dermatomyositis: a post-hoc analysis of the ProDERM study
Werth, V. P., Aggarwal, R., Charles-Schoeman, C., Schessl, J., Levine, T., Kopasz, N., Worm, M., Bata-Csörgő, Z.
EClinicalMedicine. 2023;64:102234
Abstract
BACKGROUND Dermatomyositis (DM) is a rare autoimmune disease characterized by skin involvement, with or without proximal muscle weakness. Recently, following the ProDERM study, intravenous immunoglobulin (IVIg) was approved for treatment of DM. Until ProDERM evidence from large, placebo-controlled studies supporting its use for dermatological symptoms, was lacking. Here we present efficacy data from ProDERM of IVIg versus placebo for treatment of the cutaneous aspect of DM. METHODS ProDERM was a double-blind, randomized, multicenter, Phase 3 study. In the First Period (Weeks 0-16), adults with active DM received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label Extension Period (Weeks 16-40), all patients received IVIg for 6 additional cycles. Cutaneous disease was assessed using measures including modified cutaneous DM disease area and severity index activity (CDASI-A) and damage (CDASI-D) scores, and myositis disease activity assessment tool (MDAAT) including visual analogue scale (VAS). This trial is registered with ClinicalTrials.gov, NCT02728752. FINDINGS The study took place from February 2017 to November 2019. 95 patients received IVIg (N = 47) or placebo (N = 48) in the First Period. Together, 664 IVIg infusion cycles were administered (median dose, 2.0 g/kg). At Week 16, mean CDASI-A change from baseline was -9.36 (95% CI: -12.52, -6.19) in the IVIg group versus -1.16 (-3.32, 0.99) in placebo group (p < 0.0001). At the end of the Extension Period, mean changes from baseline were -10.44 (95% CI: -13.94, -6.94) and -10.03 (-13.12, -6.94), respectively. Similar changes were seen for CDASI-D and VAS of MDAAT. These observations were seen regardless of baseline disease severity. INTERPRETATION ProDERM is the first large prospective, randomized trial to demonstrate the efficacy of IVIg to improve the cutaneous manifestations of DM. IVIg treatment significantly improved dermatological symptoms in patients with DM, regardless of disease severity before treatment, suggesting that IVIg is effective for even the most severe cutaneous DM. FUNDING This study was sponsored by Octapharma Pharmazeutika Produktionsges m.b.H.
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The effects of glucocorticoid plus intravenous immunoglobulin (IVIG) vs IVIG alone on platelet activation in children with Kawasaki disease
Wang, Q. Q., Zheng, L. Y., Zhao, S.
The Turkish journal of pediatrics. 2023;65(4):640-649
Abstract
BACKGROUND Even though intravenous immunoglobulin (IVIG) is a current treatment for Kawasaki disease (KD), 10-20% of patients require additional therapy. This study seeks to investigate the therapeutic effects of glucocorticoids plus IVIG on KD and to ascertain the subsequent effect on platelet activation during the acute phase. METHODS A total of 32 children with KD were randomly classified into two groups: the experimental group (16 cases) and the control group (16 cases). The control group was exposed to IVIG (2 g/kg), whereas children in the experimental group were treated with IVIG (2 g/kg) + glucocorticoid. Peripheral venous blood samples were obtained from all participants before treatment as well as three days post-treatment to test platelet activation levels with procaspase activating compound-1 (PAC-1) antibody, Toll-like receptor 4 (TLR4), interleukin-6 (IL- 6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and C-reactive protein (CRP). Fever duration posttreatment was documented for both groups. Additionally, the coronary arteries in both groups were evaluated during three months of treatment. RESULTS After treatment, the experimental group had remarkably lower levels of TNF-α, CRP, PCT, IL-6, PAC- 1, and TLR4 relative to the control group. The fever persistence rate was considerably elevated in the control group compared to the experimental group (log-rank, P=0.024). In addition, the z-score of coronary artery size dropped after IVIG + glucocorticoids treatment compared to the control group, although this difference was not significant. CONCLUSIONS The IVIG + glucocorticoids can quickly mitigate the inflammatory response and platelet activation. Moreover, it can also improve clinical symptoms in children with KD.
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Efficacy of intralesional injections of platelet-rich plasma in patients with oral lichen planus: A pilot randomized clinical trial
Hijazi A, Ahmed W, Gaafar S
Clinical and experimental dental research. 2022
Abstract
OBJECTIVE To evaluate the clinical efficacy of intralesional platelet-rich plasma (PRP) injections compared to intralesional triamcinolone acetonide (TA) injections in the treatment of erosive oral lichen planus (EOLP). MATERIAL AND METHODS Twenty patients with EOLP were assigned randomly to either PRP or TA group. Patients received weekly intralesional injections for 4 weeks, and then followed up for 3 months on regular visits every 2 weeks. Pain scores using numerical pain score and clinical score were recorded by a blinded assessor each visit for all patients and remission score at the end of the trial was recorded. RESULTS Both groups showed significant improvement in the clinical parameters (pain and clinical score) "p = .001." Regarding remission of the lesions, 80% of patients in the PRP group showed complete remission compared to 70% in the TA group. However, there is no statistical significance when comparing the two groups in pain score, clinical score, or remission. CONCLUSIONS PRP injections could be considered as an effective alternative single treatment modality for EOLP. The protocol for this study registered in Clinicaltrials.gov registry under the identifier number: NCT03293368.
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Subcutaneous Gammanorm® by pump or rapid push infusion: Impact of the device on quality of life in adult patients with primary immunodeficiencies
Warnatz, K., Jolles, S., Agostini, C., Vianello, F., Borte, M., Bethune, C., Grigoriadou, S., Richter, A., Jain, R., Lowe, D. M., et al
Clinical Immunology (Orlando, Fla.). 2022;236:108938
Abstract
Many patients with immunodeficiencies require lifelong immunoglobulin replacement therapy (IgRT). In a multicenter, randomized, open-label, crossover, non-inferiority 3-month-trial, we compared the impact of the subcutaneous immunoglobulin Gammanorm® administered via pump or syringe (rapid push). Primary endpoint was the life quality index (LQI), secondary endpoints were QoL (SF36v2), satisfaction (TSQM-11), disease and treatment burden (PRISM), incidence of infections and adverse events (AE), treatment costs, and IgG levels. 28/30 patients completed the study. Most of the endpoints were comparable. Drug administrations with rapid push were more frequent, but reduced total time expenditure and some costs. Of the TSQM-11/LQI/SF36 components only "treatment interference with daily activities" was superior with pump and two QoL domains with rapid push. Both delivery devices showed favorable safety. Rapid push was preferred by 34.5% of patients. It proved to be an efficacious and cost-effective alternative to pumps adding to patient choice and increasing flexibility during long-term IgRT.
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A Randomized, Double-Blind, Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis
Bril V, Szczudlik A, Vaitkus A, Rozsa C, Kostera-Pruszczyk A, Hon P, Bednarik J, Tyblova M, Köhler W, Toomsoo T, et al
Neurology. 2022
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Editor's Choice
Abstract
BACKGROUND AND OBJECTIVES Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CS) and intravenous immunoglobulin (IVIG). This study was conducted to determine if immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent MG patients. METHODS In this randomized, double-blind, placebo-controlled trial, CS-dependent MG patients (MGFA class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/day) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every three weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (QMG score ≥ 4 points from baseline). CS doses were increased (based on current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy endpoint (at week 39) was a ≥ 50% reduction in CS dose. Secondary and safety endpoints were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at: ://clinicaltrials.gov/ct2/show/NCT02473965. RESULTS The primary endpoint (≥ 50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary endpoints. Safety data indicated that IGIV-C was well-tolerated. DISCUSSION In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥ 50% reduction in corticosteroid dose compared to placebo.
PICO Summary
Population
Corticosteroids-dependent myasthenia gravis patients (n= 60).
Intervention
Immune globulin injection, 10% caprylate/chromatography purified IGIV-C (n= 30).
Comparison
Placebo (n= 30).
Outcome
The primary endpoint (≥ 50% reduction in corticosteroids dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary endpoints. Safety data indicated that IGIV-C was well-tolerated.