Comparison of IVIg and TPE efficacy in the treatment of neurological disorders: a systematic literature review
Therapeutic Advances in Neurological Disorders. 2023;16:17562864231154306
BACKGROUND Intravenous immunoglobulin (IVIg) and therapeutic plasma exchange (TPE) are among the main immunotherapies for neurological disorders. Their benefit is greatest in immune-mediated conditions, but their distinct efficacy cannot be simply explained. OBJECTIVES This review aimed to systematically identify studies comparing the efficacy of TPE and IVIg treatments for selected autoimmune neurological disorders and identify optimal therapies for each condition. DATA SOURCES AND METHODS PubMed, MEDLINE and Embase databases were searched for original publications from 1990 to 2021. Additional publications were identified via expert recommendations. Conference abstracts older than 2017, review articles and articles without information on TPE and IVIg comparison in title and abstract were excluded. Risks of bias were descriptively addressed, without a meta-analysis. RESULTS Forty-four studies were included on Guillain-Barré syndrome (20 studies - 12 adult, 5 paediatric, 3 all ages), myasthenia gravis (11 studies -8 adult, 3 paediatric), chronic immune-mediated polyradiculoneuropathy (3 studies -1 adult, 2 paediatric), encephalitis (1 study in adults), neuromyelitis optica spectrum disorders (5 studies -2 adult, 3 all ages) and other conditions (4 studies - all ages). TPE and IVIg were mostly similarly efficacious, measured by clinical outcomes and disease severity scores. Some studies recommended IVIg as easy to administer. TPE procedures, however, have been simplified and the safety has been improved. TPE is currently recommended for management of neuromyelitis optica spectrum disorder relapses and some myasthenia gravis subtypes, in which rapid removal of autoantibodies is crucial. CONCLUSION Despite some limitations (e.g. the low evidence levels), this review provides an extensive 30-year-long overview of treatments for various conditions. Both IVIg and TPE are usually comparably efficacious options for autoimmune neurological disorders, with few exceptions. Treatment choices should be patient-tailored and based on available clinical resources. Better designed studies are needed to provide higher-level quality of evidence regarding clinical efficacy of TPE and IVIg treatments.
Standardized tapering off subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy
Journal of neuromuscular diseases. 2023
BACKGROUND Attempting discontinuation of treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is recommended. However, there is no evidence based regimen for tapering off subcutaneous immunoglobulin (SCIG). This trial investigated stepwise tapering off SCIG to detect remission and the lowest effective dosage. During tapering off, frequent vs less frequent clinical evaluation was compared. METHODS Patients with CIDP receiving a stable SCIG dosage followed a standardized tapering off regimen: 90%, 75%, 50%, 25% and 0% of the initial dose every 12th week, pending no deterioration occurred. In case of relapse during tapering off, the lowest effective dose was identified. Treatment with SCIG was registered for two years after participation. Disability score and grip strength were primary parameters. Participants were randomized to clinical evaluation every 6th week (frequent) or 12th week (less frequent). RESULTS Fifty-five patients were included of which thirty-five relapsed. Twenty patients (36%) were able to discontinue treatment without relapse. In relapsing patients, median dosage could be reduced by 10% (range, 0-75). After two years, 18 of 20 patients were still in remission without treatment. Frequent clinical evaluation did not detect deterioration more frequently than less frequent evaluation; RR 0.5 (95% CI, 0.2-1.2) (p = 0.17). CONCLUSION In stable CIDP patients, SCIG could be completely tapered off in 36% of the patients and only in 10% of these patients relapse occurred during the following two years. More frequent evaluation was not superior to detect deterioration.
Case report: Acute necrotizing encephalopathy: a report of a favorable outcome and systematic meta-analysis of outcomes with different immunosuppressive therapies
Frontiers in neurology. 2023;14:1239746
Acute Necrotizing Encephalopathy (ANE) is a condition characterized by symmetric, bilateral lesions affecting the thalamus and potentially other areas of the brain following an acute febrile illness. It manifests clinically as abrupt development of encephalopathy, or alteration in mental status that often includes development of seizures and progression to coma. Treatment strategies combine immunosuppressive therapies and supportive care with varying levels of recovery, however there are no universally accepted, data-driven, treatment algorithms for ANE. We first report a case of a previously healthy 10-year-old female with acute onset diplopia, visual hallucinations, lethargy, and seizures in the setting of subacute non-specific viral symptoms and found to have bilateral thalamic and brainstem lesions on MRI consistent with ANE. She was treated with a combination of immunomodulatory therapies and ultimately had a good outcome. Next, we present a meta-analysis of 10 articles with a total of 158 patients meeting clinical and radiographic criteria for ANE. Each article reported immunosuppressive treatments received, and associated morbidity or mortality outcome for each individual patient. Through our analysis, we confirm the effectiveness of high-dose, intravenous, methylprednisolone (HD-IV-MP) therapy implemented early in the disease course (initiation within 24 h of neurologic symptom onset). There was no significant difference between patients treated with and without intravenous immunoglobulin (IVIG). There was no benefit of combining IVIG with early HD-IV-MP. There is weak evidence suggesting a benefit of IL-6 inhibitor tocilizumab, especially when used in combination with early HD-IV-MP, though this analysis was limited by sample size. Finally, plasma exchange (PLEX) improved survival. We hope this meta-analysis will be useful for clinicians making treatment decisions for patients with this potentially devastating condition.
Chronic inflammatory demyelinating polyradiculoneuropathy in patients with diabetes mellitus - treatment with intravenous immunoglobulins: A systematic review
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;164:114974
BACKGROUND Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare disease, but it is one of the most common inflammatory neuropathies in the population. It is particularly common among patients with diabetes mellitus. This raises many problems, both with the differential diagnosis of diabetic and inflammatory neuropathy, as well as the choice of treatment. Intravenous immunoglobulin (IVIG) is one of the therapeutic options. There is evidence for the effectiveness of IVIG in treating about two-thirds of patients. However, no review has been published to date systematising studies evaluating the response to IVIG treatment in patients with CIDP and coexisting diabetes. METHODS The present study is based on the PRISMA statement and is registered at PROSPERO (CRD42022356180). The study included searches of the databases of MEDLINE, ERIC, CINAHL Complete, Academic Search Ultimate and Health Source: Nursing/Academic Edition, finally including seven original papers evaluating a total of 534 patients in the review. The main inclusion criteria were the presence of a group of patients with CIDP and comorbid diabetes in the study. RESULTS The systematic review showed a lower efficacy of IVIG treatment among patients with coexisting diabetes compared with idiopathic CIDP (61 % vs 71 %). In addition, the presence of conduction blocks on neurography and shorter disease duration proved to be significant factors improving response to treatment. CONCLUSIONS Current scientific data do not allow for strong recommendations on the choice of treatment for CIDP. A randomised, multicentre study evaluating the efficacy of different therapeutic approaches to this disease entity needs to be planned.
Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: the ADVANCE-CIDP 1 randomized controlled trial
Journal of the peripheral nervous system : JPNS. 2023
BACKGROUND AND AIMS ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n=62) or placebo (n=70). CIDP relapse was reduced with fSCIG 10% versus placebo (n=6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n=22 [31.4%; 21.8%, 43.0%), respectively; absolute difference: -21.8% [-34.5%, -7.9%], P=.0045). Relapse probability was higher with placebo versus fSCIG 10% over time (P=.002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment. This article is protected by copyright. All rights reserved.
Safety and Tolerability of Intravenous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy: Results of the ProCID Study
Drug safety. 2023
BACKGROUND AND AIMS The ProCID study evaluated the efficacy and safety of three doses of a 10% liquid intravenous immunoglobulin (IVIg) preparation (panzyga(®)) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This report describes the safety findings. METHODS Patients were randomised to receive a 2.0 g/kg induction dose followed by maintenance doses of either 0.5, 1.0 or 2.0 g/kg IVIg every 3 weeks over 24 weeks. RESULTS All 142 enrolled patients were included in the safety analyses. In total, 286 treatment-emergent adverse events (TEAEs) were reported in 89 patients, of which 173 (60.5%) were considered treatment-related. Most TEAEs were of mild severity. Eleven serious TEAEs were reported in 6 patients. Two serious TEAEs in one patient (headache and vomiting) were considered related to treatment, which resolved without study discontinuation. No treatment-related thrombotic events, haemolytic transfusion reactions or deaths occurred. One patient discontinued the study due to a TEAE (allergic dermatitis) probably related to IVIg. Headache was the only dose-dependent TEAE, with incidences ranging from 2.9 to 23.7%, the incidence of all other TEAEs was similar across treatment groups. Most TEAEs were associated with the induction dose infusion, and the rate of TEAEs decreased thereafter. The median (IQR) daily IVIg dose was 78 (64-90) g, and 94.4% of patients tolerated the maximal infusion rate of 0.12 ml/kg/min without pre-medication. INTERPRETATION Infusions of 10% IVIg at doses up to 2.0 g/kg with high infusion rates were safe and well tolerated in patients with CIDP. CLINICAL TRIAL NUMBERS EudraCT 2015-005443-14, NCT02638207.
Adverse Reactions Associated with Intravenous Immunoglobulin Administration in the Treatment of Neurological Disorders: A Systematic Review
International Archives of Allergy and Immunology. 2023;:1-16
Intravenous immunoglobulin (IVIg), which is used to treat multiple neurological conditions, may be associated with serious adverse reactions. The individual neurological disease characteristics associated with adverse reactions, along with strategies to prevent and treat adverse reactions, are uncertain. A systematic review was conducted of the databases PubMed, Embase, and Cochrane Library to summarise studies that report adverse reactions of IVIg therapy in patients with neurological disease. There were 65 studies included in the review. The reported rates of adverse reactions vary widely, but the best evidence suggests rates between 25 and 34% per patient. Common adverse reactions include headache and laboratory abnormalities. Less common but serious adverse reactions included thromboembolic complications and anaphylaxis. Overall, there is a lack of high-quality comparative data to definitively determine if any specific neurological indications are associated with a higher risk of adverse reactions. However, individual neurological disease characteristics possibly associated with an increased likelihood of adverse reactions include limited mobility (as in certain neuromuscular conditions), paraproteinaemia (as in certain peripheral neuropathies), and cardiomyopathy (as in certain myopathies). There is limited evidence to support the effectiveness of prevention and treatment strategies, which may include modification to dose, reduced infusion rate, and premedication. Further studies regarding methods to prevent and treat IVIg-ARs in neurology patients are required.
Effectiveness and tolerability of different therapies in preventive treatment of MOG-IgG-associated disorder: A network meta-analysis
Frontiers in immunology. 2022;13:953993
BACKGROUND Immunotherapy has been shown to reduce relapses in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder (MOG-AD); however, the superiority of specific treatments remains unclear. AIM: To identify the efficacy and tolerability of different treatments for MOG-AD. METHODS Systematic search in Pubmed, Embase, Web of Science, and Cochrane Library databases from inception to March 1, 2021, were performed. Published articles including patients with MOG-AD and reporting the efficacy or tolerability of two or more types of treatment in preventing relapses were included. Reported outcomes including incidence of relapse, annualized relapse rate (ARR), and side effects were extracted. Network meta-analysis with a random-effect model within a Bayesian framework was conducted. Between group comparisons were estimated using Odds ratio (OR) or mean difference (MD) with 95% credible intervals (CrI). RESULTS Twelve studies that compared the efficacy of 10 different treatments in preventing MOG-AD relapse, including 735 patients, were analyzed. In terms of incidence of relapse, intravenous immunoglobulins (IVIG), oral corticosteroids (OC), mycophenolate mofetil (MMF), azathioprine (AZA), and rituximab (RTX) were all significantly more effective than no treatment (ORs ranged from 0.075 to 0.34). On the contrary, disease-modifying therapy (DMT) (OR=1.3, 95% CrI: 0.31 to 5.0) and tacrolimus (TAC) (OR=5.9, 95% CrI: 0.19 to 310) would increase the incidence of relapse. Compared with DMT, IVIG significantly reduced the ARR (MD=-0.85, 95% CrI: -1.7 to -0.098). AZA, MMF, OC and RTX showed a trend to decrease ARR, but those results did not reach significant differences. The combined results for relapse rate and adverse events, as well as ARR and adverse events showed that IVIG and OC were the most effective and tolerable therapies. CONCLUSIONS Whilst DMT should be avoided, IVIG and OC may be suited as first-line therapies for patients with MOG-AD. RTX, MMF, and AZA present suitable alternatives.
Pharmacological treatment in adult patients with CRPS-I: A systematic review and meta-analysis of randomised controlled trials
Rheumatology (Oxford, England). 2022
OBJECTIVE Several pharmacological treatments have been proposed for the treatment of Complex regional pain syndrome type-I (CRPS-I) in adults, but data regarding the efficacy of various agents for this disease is scarce. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to analyse pharmacological approaches in adults with CRPS-I. METHODS We systematically searched PubMed, Scopus, and Web of Science databases from the inception date to 30, June 2021 for identifying placebo-controlled or active-controlled RCTs using bisphosphonates, ketamine, corticosteroids, anti-epileptics, NSAIDs/COXIBs, opiates, antidepressants, scavengers/magnesium sulphate or intravenous immunoglobulins for the treatment of CRPS-I. The primary outcomes included changes in the visual analogue scale (VAS) or numeric rating scale (NRS) for pain before and after treatment. RESULTS We included 20 placebo-controlled or active-controlled RCTs (for a total of 818 CRPS-I adults) that used bisphosphonates (n = 7), ketamine (n = 2), corticosteroids (n = 2), anti-epileptics (n = 1), NSAIDs/COXIBs (n = 2), scavengers/magnesium (n = 5), or intravenous immunoglobulins (n = 1) to treat CRPS-I during a median follow-up of 26 weeks. The treatment with bisphosphonates showed a significant reduction of the values of the VAS/NRS pain scale compared with placebo or reference therapy (random effects weighted mean difference [WMD]: -23.8, 95%CI-28.0 to -19.6; I2=36.4%). Treatment with ketamine also documented a reduction in the values of the VAS/NRS pain scale (random effects WMD: -8.27,95%CI -12.9 to -3.70; I2=0%). Treatment with other agents did not improve the values of the VAS/NRS pain scale. CONCLUSION This systematic review and meta-analysis supports the recommendation of parenteral bisphosphonates as the first-line agent in the treatment of CRPS-I. REGISTRATION NUMBER Open Science Framework registries; osf.io/et9gu.
Assessing deterioration using impairment and functional outcome measures in chronic inflammatory demyelinating polyneuropathy: a post-hoc analysis of the IOC trial
Journal of the peripheral nervous system : JPNS. 2022
BACKGROUND AND AIMS It is unclear whether frequently used cut-off values for outcome measures defining minimal clinically important differences (MCIDs) can accurately identify meaningful deterioration in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS We used data from the IOC trial, in which sixty clinically stable CIDP patients were randomized to IVIg withdrawal or continuation. We calculated change scores of the Inflammatory Rasch-Built Overall Disability Scale (I-RODS), grip strength, and MRC sum score (MRC-SS) and classified visits based on a treatment anchor (i.e. decision to restart/increase treatment after reaching a predefined early endpoint of deterioration). The variability of scores in patients without deterioration was calculated using the limits of agreement. We defined optimized MCIDs for deterioration and specific combinations of MCIDs from different outcome measures, and subsequently calculated the accuracies of the (combined) MCIDs. RESULTS Substantial variability was found in scores of the I-RODS, grip strength and MRC-SS in patients without deterioration over time, and most MCIDs were within the limits of the variability observed in patients without deterioration. Some MCID cut-offs were insensitive but highly specific for detecting deterioration, e.g. the MCID-SE of -1.96 of the I-RODS and -2 point on the MRC-SS. Others were sensitive, but less specific, e.g. -4 centiles of the I-RODS. Some combined MCIDs resulted in high specificities and moderate sensitivities. INTERPRETATION Our results suggest that clinically important deterioration cannot be distinguished from variability over time with currently used MCIDs on the individual level. Combinations of MCIDs might improve the accuracy of determining deterioration, but this needs validation.