INTRODUCTION/AIMS: Prospective, randomized, controlled trials of intravenous immunoglobulin (IVIG) maintenance therapy in myasthenia gravis (MG) are lacking. In this trial, we evaluated the safety and efficacy of caprylate/chromatography-purified IVIG; (IGIV-C) in patients with generalized MG undergoing standard care. METHODS: Sixty-two patients enrolled in this phase 2, multicenter, international, randomized trial (1:1 IGIV-C [2 g/kg loading dose; 1 g/kg every 3 weeks through week 21] or placebo). Efficacy was assessed by changes in Quantitative MG (QMG) score at week 24 versus baseline (primary endpoint) and percentage of patients with clinical improvement in QMG, MG Composite (MGC), and MG-Activities of Daily Living (MG-ADL) scores (secondary endpoints). Safety assessments reported all adverse events (AEs). RESULTS: The change in QMG at 24 weeks was -5.1 for IGIV-C and -3.1 for placebo (p = .187). Seventy percent of patients in the IGIV-C group had improvement in MG-ADL (≥2-point decrease) versus 40.6% in the placebo group (p = .025). Patients showing clinical improvement in QMG and MGC (≥3-point decrease) were 70.0% for IGIV-C versus 59.4% for placebo (p = .442) and 60.0% for IGIV-C versus 53.1% for placebo (p = .610). IGIV-C was well tolerated; serious AEs were similar between arms. Three of four MG exacerbations requiring hospitalizations occurred in the IGIV-C arm with one death. DISCUSSION: Several efficacy parameters showed numerical results greater than those seen in the placebo group. This was a small study and may have been underpowered to see significant differences. Additional studies may be warranted to fully determine the efficacy of IVIG maintenance therapy in MG.
- MeSH
- autoprotilátky krev MeSH
- činnosti denního života MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- imunologické faktory terapeutické užití škodlivé účinky aplikace a dávkování MeSH
- intravenózní imunoglobuliny * terapeutické užití škodlivé účinky aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- myasthenia gravis * farmakoterapie MeSH
- prospektivní studie MeSH
- receptory cholinergní * imunologie MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
In intravenous immunoglobulins (IVIG), and some other immunoglobulin products, protein particles have been implicated in adverse events. Role and mechanisms of immunoglobulin particles in vascular adverse effects of blood components and manufactured biologics have not been elucidated. We have developed a model of spherical silica microparticles (SiMPs) of distinct sizes 200-2000 nm coated with different IVIG- or albumin (HSA)-coronas and investigated their effects on cultured human umbilical vein endothelial cells (HUVEC). IVIG products (1-20 mg/mL), bare SiMPs or SiMPs with IVIG-corona, did not display significant toxicity to unstimulated HUVEC. In contrast, in TNFα-stimulated HUVEC, IVIG-SiMPs induced decrease of HUVEC viability compared to HSA-SiMPs, while no toxicity of soluble IVIG was observed. 200 nm IVIG-SiMPs after 24 h treatment further increased ICAM1 (intercellular adhesion molecule 1) and tissue factor surface expression, apoptosis, mammalian target of rapamacin (mTOR)-dependent activation of autophagy, and release of extracellular vesicles, positive for mitophagy markers. Toxic effects of IVIG-SiMPs were most prominent for 200 nm SiMPs and decreased with larger SiMP size. Using blocking antibodies, toxicity of IVIG-SiMPs was found dependent on FcγRII receptor expression on HUVEC, which increased after TNFα-stimulation. Similar results were observed with different IVIG products and research grade IgG preparations. In conclusion, submicron particles with immunoglobulin corona induced size-dependent toxicity in TNFα-stimulated HUVEC via FcγRII receptors, associated with apoptosis and mTOR-dependent activation of autophagy. Testing of IVIG toxicity in endothelial cells prestimulated with proinflammatory cytokines is relevant to clinical conditions. Our results warrant further studies on endothelial toxicity of sub-visible immunoglobulin particles.
- MeSH
- apoptóza účinky léků MeSH
- autofagie * účinky léků MeSH
- endoteliální buňky pupečníkové žíly (lidské) * účinky léků metabolismus MeSH
- intravenózní imunoglobuliny * MeSH
- lidé MeSH
- mezibuněčná adhezivní molekula-1 metabolismus MeSH
- oxid křemičitý chemie toxicita MeSH
- proteinová korona metabolismus MeSH
- receptory IgG * metabolismus MeSH
- TNF-alfa * metabolismus MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- velikost částic MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disorder characterised by weakness and sensory loss. We assessed the neonatal Fc receptor inhibitor rozanolixizumab for CIDP management. METHODS: CIDP01 (NCT03861481) was a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a study. Adults with definite or probable CIDP receiving subcutaneous or intravenous immunoglobulin maintenance therapy were randomised 1:1 to 12 once-weekly subcutaneous infusions of rozanolixizumab 10 mg/kg or placebo, stratified according to previous immunoglobulin administration route. Investigators administering treatment and assessing efficacy, and patients, were blinded. The primary outcome was a change from baseline (CFB) to day 85 in inflammatory Rasch-built Overall Disability Scale (iRODS) score. Eligible patients who completed CIDP01 entered the open-label extension CIDP04 (NCT04051944). RESULTS: In CIDP01, between 26 March 2019 and 31 March 2021, 34 patients were randomised to rozanolixizumab or placebo (17 (50%) each). No significant difference in CFB to day 85 in iRODS centile score was observed between rozanolixizumab (least squares mean 2.0 (SE 3.2)) and placebo (3.4 (2.6); difference -1.5 (90% CI -7.5 to 4.5)). Overall, 14 (82%) patients receiving rozanolixizumab and 13 (76%) receiving placebo experienced a treatment-emergent adverse event during the treatment period. Across CIDP01 and CIDP04, rozanolixizumab was well tolerated over up to 614 days; no clinically meaningful efficacy results were seen. No deaths occurred. CONCLUSIONS: Rozanolixizumab did not show efficacy in patients with CIDP in this study, although this could be due to a relatively high placebo stability rate. Rozanolixizumab was well tolerated over medium-to-long-term weekly use, with an acceptable safety profile.
- MeSH
- chronická zánětlivá demyelinizační polyneuropatie * farmakoterapie MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * terapeutické užití škodlivé účinky aplikace a dávkování MeSH
- intravenózní imunoglobuliny terapeutické užití škodlivé účinky MeSH
- jednoduchá slepá metoda MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an inflammatory disease affecting the peripheral nerves and the most frequent autoimmune polyneuropathy. Given the lack of established biomarkers or risk factors for the development of CIDP and patients' treatment response, this research effort seeks to identify potential clinical factors that may influence disease progression and overall treatment efficacy. METHODS: In this multicenter, retrospective analysis, we have screened 197 CIDP patients who presented to the University Hospitals in Düsseldorf, Berlin, Cologne, Essen, Magdeburg and Munich between 2018 and 2022. We utilized the respective hospital information system and examined baseline data with clinical examination, medical letters, laboratory results, antibody status, nerve conduction studies, imaging and biopsy findings. Aside from clinical baseline data, we analyzed treatment outcomes using the Standard of Care (SOC) definition, as well as a comparison of an early (within the first 12 months after manifestation) versus late (more than 12 months after manifestation) onset of therapy. RESULTS: In terms of treatment, most patients received intravenous immunoglobulin (56%) or prednisolone (39%) as their first therapy. Patients who started their initial treatment later experienced a worsening disease course, as reflected by a significant deterioration in their Inflammatory Neuropathy Cause and Treatment (INCAT) leg disability score. SOC-refractory patients had worse clinical outcomes than SOC-responders. Associated factors for SOC-refractory status included the presence of fatigue as a symptom and alcohol dependence. CONCLUSION: Timely diagnosis, prompt initiation of treatment and careful monitoring of treatment response are essential for the prevention of long-term disability in CIDP and suggest a "hit hard and early" treatment paradigm.
- MeSH
- chronická zánětlivá demyelinizační polyneuropatie * diagnóza terapie farmakoterapie MeSH
- dospělí MeSH
- intravenózní imunoglobuliny terapeutické užití aplikace a dávkování MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- prednisolon terapeutické užití aplikace a dávkování MeSH
- progrese nemoci MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Termín „monoklonální gamapatie klinického významu“ (Monoclonal Gammopathy of Clinical Significance – MGCS) je zastřešující termín pro velké spektrum poruch s poškozením orgánů monoklonálními imunoglobuliny (M-Ig) či volnými lehkými řetězci (free light chain – FLC), produkovanými typicky nemaligním klonem lymfatických či plazmatických buněk. Etiopatogeneze poškození organismu je velmi pestrá, patří sem depozice M-Ig či FLC, poškození biologickou aktivitou M-Ig, asociace tvorby M-Ig s nadměrnou produkcí angiogenních a proinflamatorních cytokinů a někdy zůstává etiopatogeneze neobjasněná. Vymizení poruchy po potlačení tvorby M-Ig či FLC potvrzuje souvislost poškození s gamapatií. Některé formy MGCS poškozují dominantně jeden orgán, periferní nervy, kůži, ledviny či oči, zatímco jiné mají systémové projevy. Vyšetření M-Ig a FLC u jednotlivých poruch spolu s tkáňovými biopsiemi vedou ke stanovení diagnózy. Léčba je podobná léčbě mnohočetného myelomu či Waldenströmovy makroglobulinemie, ale na rozdíl od těchto chorob není parciální remise dostačující, cílem je dosažení kompletní remise (CR) s totálním vymizením M-Ig a FLC. Jen CR je předpokladem signifikantního zlepšení a obnovení funkce orgánů a tkání. K léčbě se používá tzv. „clone-directed therapy“, vysoce účinná antiplazmocytární či antilymfocytární léčba obsahující monoklonální protilátky (anti-CD20 nebo anti-CD38), tedy kombinace s vysokou pravděpodobností dosažení úplného vymizení M-Ig a FLC. Další léčebnou možností jsou imunomodulační dávky intravenózních imunoglobulinů (2 g/kg) podávané v 28denních intervalech. Tato terapie brzdí progresi, neodstraňuje příčinu, proto musí být podávána dlouhodobě jako udržovací léčba.
Monoclonal gammopathy of clinical significance (MGCS) is an umbrella term to describe a broad spectrum of disorders with remarkable organ dysfunctions related to the underlying non-malignant B or plasma cell clone. Although the clone itself is typically very small, it is associated with diverse clinical manifestations through different mechanisms, such as monoclonal protein deposition, the biological activity of the monoclonal immunoglobulin, or angiogenic/inflammatory cytokine hyper-secretion, or the ethiopathogensis is still unknown. Some predominantly involve a single organ, commonly peripheral nerves, kidney, skin and eye, while others are systemic diseases with syndromic presentations. Recognizing the clinical features with appropriate workups, analysis of monoclonal immunoglobulin in serum and urine and free light chain analysis in serum with particular tissue biopsies, are the key to making a timely diagnosis, especially when the kidney or skin is affected. Treatment strategy is similar to multiple myeloma or Waldenström macroglobulinemia, complete remission of gammopathy is prerequisite of significant improvement of clinical symptoms and reversal of organ dysfunctions. Therapy is based on clone-directed therapy, application of high effective antiplasmocytic or antilymphocytic therapy with monoclonal antibody (anti-CD20 or anti-CD38) with high probability of total disappearing of monoclonal immunoglobulin. Other therapeutic possibility is immunomodulation with high-dose intravenous immunoglobulin 2g/kg administered in 28days interval as maintenance therapy.
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).
- MeSH
- dermatomyozitida * farmakoterapie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- intravenózní imunoglobuliny škodlivé účinky MeSH
- intravenózní infuze MeSH
- lidé MeSH
- myozitida * chemicky indukované MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- MeSH
- COVID-19 * diagnóza patofyziologie terapie MeSH
- heparin aplikace a dávkování terapeutické užití MeSH
- intravenózní imunoglobuliny aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- methylprednisolon aplikace a dávkování terapeutické užití MeSH
- syndrom systémové zánětlivé reakce * etiologie farmakoterapie patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
INTRODUCTION: Human immunoglobulin (IG) administered intravenously (IVIG) or subcutaneously (SCIG) is used to prevent infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. AREAS COVERED: This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. EXPERT OPINION: Individualized treatment for PIDD in children is necessary given the different factors that affect administration of SCIG. Variables such as the dose, dosing interval, administration sites, and ancillary equipment can be adjusted to impact the long-term satisfaction with SCIG administration in pediatric patients. The successful work that has been conducted by both professional and patient organizations to increase awareness of PIDD, especially in pediatric patients, is substantial and ongoing. The importance of early diagnosis and treatment in the pediatric patient population cannot be overstated. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.
- MeSH
- dítě MeSH
- imunoglobulin G MeSH
- intravenózní imunoglobuliny terapeutické užití MeSH
- lidé MeSH
- nežádoucí účinky léčiv * farmakoterapie MeSH
- subkutánní infuze metody MeSH
- syndromy imunologické nedostatečnosti * farmakoterapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- antifosfolipidové protilátky farmakologie MeSH
- antifosfolipidový syndrom * patologie MeSH
- antikoagulancia farmakologie terapeutické užití MeSH
- antimalarika farmakologie terapeutické užití MeSH
- chorea * diagnóza farmakoterapie patologie MeSH
- diagnostické zobrazování metody MeSH
- diferenciální diagnóza MeSH
- glukokortikoidy farmakologie terapeutické užití MeSH
- inhibitory agregace trombocytů farmakologie terapeutické užití MeSH
- intravenózní imunoglobuliny terapeutické užití MeSH
- lidé MeSH
- plazmaferéza metody MeSH
- rizikové faktory MeSH
- systémový lupus erythematodes diagnóza farmakoterapie patologie MeSH
- Check Tag
- lidé MeSH
