scholarly journals Update on Intravenous Immunoglobulin in Neurology: Modulating Neuro-autoimmunity, Evolving Factors on Efficacy and Dosing and Challenges on Stopping Chronic IVIg Therapy

2021 ◽  
Author(s):  
Marinos C. Dalakas
Keyword(s):  
Intravenous Immunoglobulin ◽  
Autoimmune Encephalitis ◽  
Ivig Therapy ◽  
Antigenic Peptides ◽  
Factors Affecting ◽  
Autoimmune Epilepsy ◽  
Healthy Donors ◽  
Chronic Therapy ◽  
Individualized Dosing ◽  
Genes Encoding

AbstractIn the last 25 years, intravenous immunoglobulin (IVIg) has had a major impact in the successful treatment of previously untreatable or poorly controlled autoimmune neurological disorders. Derived from thousands of healthy donors, IVIg contains IgG1 isotypes of idiotypic antibodies that have the potential to bind pathogenic autoantibodies or cross-react with various antigenic peptides, including proteins conserved among the “common cold”-pre-pandemic coronaviruses; as a result, after IVIg infusions, some of the patients’ sera may transiently become positive for various neuronal antibodies, even for anti-SARS-CoV-2, necessitating caution in separating antibodies derived from the infused IVIg or acquired humoral immunity. IVIg exerts multiple effects on the immunoregulatory network by variably affecting autoantibodies, complement activation, FcRn saturation, FcγRIIb receptors, cytokines, and inflammatory mediators. Based on randomized controlled trials, IVIg is approved for the treatment of GBS, CIDP, MMN and dermatomyositis; has been effective in, myasthenia gravis exacerbations, and stiff-person syndrome; and exhibits convincing efficacy in autoimmune epilepsy, neuromyelitis, and autoimmune encephalitis. Recent evidence suggests that polymorphisms in the genes encoding FcRn and FcγRIIB may influence the catabolism of infused IgG or its anti-inflammatory effects, impacting on individualized dosing or efficacy. For chronic maintenance therapy, IVIg and subcutaneous IgG are effective in controlled studies only in CIDP and MMN preventing relapses and axonal loss up to 48 weeks; in practice, however, IVIg is continuously used for years in all the aforementioned neurological conditions, like is a “forever necessary therapy” for maintaining stability, generating challenges on when and how to stop it. Because about 35-40% of patients on chronic therapy do not exhibit objective neurological signs of worsening after stopping IVIg but express subjective symptoms of fatigue, pains, spasms, or a feeling of generalized weakness, a conditioning effect combined with fear that discontinuing chronic therapy may destabilize a multi-year stability status is likely. The dilemmas of continuing chronic therapy, the importance of adjusting dosing and scheduling or periodically stopping IVIg to objectively assess necessity, and concerns in accurately interpreting IVIg-dependency are discussed. Finally, the merit of subcutaneous IgG, the ineffectiveness of IVIg in IgG4-neurological autoimmunities, and genetic factors affecting IVIg dosing and efficacy are addressed.

scholarly journals Anti-SARS-CoV-2 Antibodies Within IVIg Preparations: Cross-Reactivities With Seasonal Coronaviruses, Natural Autoimmunity, and Therapeutic Implications

2021 ◽  
Vol 12 ◽  
Author(s):  
Marinos C. Dalakas ◽  
Kleopatra Bitzogli ◽  
Harry Alexopoulos
Keyword(s):  
Ivig Therapy ◽  
Treated Group ◽  
Cross Reactivity ◽  
Controlled Study ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Dose ◽  
Antigenic Peptides ◽  
Protein Fragments ◽  
Therapeutic Implications ◽  
Healthy Donors

Introduction: Cross-reactivity to SARS-CoV-2 antigenic peptides has been detected on T-cells from pre-pandemic donors due to recognition of conserved protein fragments within members of the coronavirus's family. Further, preexisting antibodies recognizing SARS-CoV-2 with conserved epitopes in the spike region have been now seen in uninfected individuals. High-dose Intravenous Immunoglobulin (IVIg), derived from thousands of healthy donors, contains natural IgG antibodies against various antigens which can be detected both within the IVIg preparations and in the serum of IVIg-receiving patients. Whether IVIg preparations from pre-pandemic donors also contain antibodies against pre-pandemic coronaviruses or autoreactive antibodies that cross-react with SARS-CoV-2 antigenic epitopes, is unknown.Methods: 13 samples from 5 commercial IVIg preparations from pre-pandemic donors (HyQvia (Baxalta Innovations GmbH); Privigen (CSL Behring); Intratect (Biotest AG); IgVena (Kedrion S.p.A); and Flebogamma (Grifols S.A.) were blindly screened using a semi-quantitative FDA-approved and validated enzyme-linked immunosorbent assay (ELISA) (Euroimmun, Lubeck, Germany).Results: Nine of thirteen preparations (69.2%), all from two different manufactures, were antibody-positive based on the defined cut-off positivity (index of sample OD to calibrator OD > 1.1). From one manufacturer, 7/7 lots (100%) and from another 2/3 lots (67%), tested positive for cross-reacting antibodies. 7/9 of the positive preparations (77%) had titers as seen in asymptomatically infected individuals or recent COVID19-recovered patients, while 2/9 (23%) had higher titers, comparable to those seen in patients with active symptomatic COVID-19 infection (index > 2.2).Conclusion: Pre-pandemic IVIg donors have either natural autoantibodies or pre-pandemic cross-reactive antibodies against antigenic protein fragments conserved among the “common cold” - related coronaviruses. The findings are important in: (a) assessing true anti-SARS-CoV-2-IgG seroprevalence avoiding false positivity in IVIg-receiving patients; (b) exploring potential protective benefits in patients with immune-mediated conditions and immunodeficiencies receiving acute or chronic maintenance IVIg therapy, and (c) validating data from a recent controlled study that showed significantly lower in-hospital mortality in the IVIg- treated group.

scholarly journals Refractory Toxic Shock-Like Syndrome fromStreptococcus dysgalactiaessp.equisimilisand Intravenous Immunoglobulin as Salvage Therapy: A Case Series

2016 ◽  
Vol 2016 ◽  
pp. 1-3
Author(s):  
Marjan Islam ◽  
Dennis Karter ◽  
Jerry Altshuler ◽  
Diana Altshuler ◽  
David Schwartz ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Intravenous Immunoglobulin ◽  
Salvage Therapy ◽  
Adjunctive Therapy ◽  
Case Series ◽  
Ivig Therapy ◽  
Mortality Rates ◽  
Invasive Disease ◽  
Streptococcus Dysgalactiae ◽  
Toxic Shock

Infections fromStreptococcus dysgalactiaessp.equisimilis(SDSE) can cause a wide variety of infections, ranging from mild cellulitis to invasive disease, such as endocarditis and streptococcal toxic shock-like syndrome (TSLS). Despite prompt and appropriate antibiotics, mortality rates associated with shock have remained exceedingly high, prompting the need for adjunctive therapy. IVIG has been proposed as a possible adjunct, given its ability to neutralize a wide variety of superantigens and modulate a dysregulated inflammatory response. We present the first reported cases of successful IVIG therapy for reversing shock in the treatment of SDSE TSLS.

scholarly journals VNTR2/VNTR3 genotype in the FCGRT gene is associated with reduced effectiveness of intravenous immunoglobulin in patients with myasthenia gravis

2021 ◽  
Vol 14 ◽  
pp. 175628642098674
Author(s):  
Shengyao Su ◽  
Qing Liu ◽  
Xueping Zhang ◽  
Xinmei Wen ◽  
Lin Lei ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Intravenous Immunoglobulin ◽  
Medical Records ◽  
Daily Living ◽  
Response Rate ◽  
Predictive Marker ◽  
Ivig Therapy ◽  
Variable Number ◽  
Ivig Treatment ◽  
Therapeutic Outcomes

Background: Intravenous immunoglobulin (IVIG) has been commonly used to treat myasthenia gravis exacerbation, but is still ineffective in nearly 30% of patients. A variable number of tandem repeat (VNTR) polymorphism in the FCGRT gene has been found to reduce the efficiency of IgG biologics. However, whether the polymorphism influences the efficacy of IVIG in generalized myasthenia gravis (MG) patients with exacerbations remains unknown. Methods: The distribution of VNTR genotypes was analyzed in 334 patients with MG. Varied VNTR alleles were determined by capillary electrophoresis and confirmed by Sanger sequencing. Information of endogenous IgG levels were collected in patients without previous immunotherapy ( n = 26). Medical records of patients who received IVIG therapy were retrospectively analyzed for therapeutic outcomes of IVIG treatment ( n = 61). Patients whose Activities of Daily Living scores decreased by 2 or more points on day 14 were considered responders to the treatment. Results: The VNTR3/3 and VNTR2/3 genotypes were detected in 96.7% (323/334) and 3.4% (11/334) patients, respectively. Patients with VNTR2/3 heterozygosity had lower endogenous IgG levels than those with VNTR3/3 homozygosity (9.81 ± 2.61 g/L versus 12.41 ± 2.45g/L, p = 0.016). The response rate of IVIG therapy was 78.7% (48/61). All responders and nine non-responders were VNTR3/3 homozygotes, whereas all the patients with VNTR2/3 genotypes were non-responders ( n = 4). In patients who took IVIG treatments, endogenous IgG levels were significantly lower in non-responders compared with responders (12.93 ± 2.24 g/L versus 8.85 ± 2.69 g/L, p = 0.006), especially in VNTR2/3 heterozygotes (7.86 ± 1.78 g/L, p = 0.001). Conclusion: The VNTR2/3 genotype could influence endogenous IgG levels and serve as a predictive marker for poor responses to IVIG in MG patients.

ACUTE CORONARY SYNDROME FOLLOWING INTRAVENOUS IMMUNOGLOBULIN THERAPY : A HIDDEN RISK

2021 ◽  
pp. 78-79
Author(s):  
Karthikkeyan Rajachandran ◽  
Giphy Susan Varghese
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Intravenous Immunoglobulin ◽  
Ivig Therapy ◽  
Immunoglobulin Therapy ◽  
Left Ventricular ◽  
Intravenous Immunoglobulin Therapy ◽  
Severe Left Ventricular Dysfunction ◽  
St Segment Elevation ◽  
Coronary Syndrome

Intravenous immunoglobulin (IVIG) is one of the main line modalities of therapy for chronic inammatory demyelinating polyneuropathy (CIDP). We hereby, report an incidence of acute myocardial infarction probably induced by IVIG during the treatment of CIDP. A 76 year old female with no history suggestive of cardiovascular disease, developed an acute Non ST Segment Elevation Myocardial Infarction (NSTEMI) and severe left ventricular dysfunction after receiving three doses of IVIG. Since hypercoagulability is a concern with IVIG therapy, it was discontinued. Hence, we highlight the importance of cardiac evaluation before initiation and during the course of IVIG therapy in elderly patients as well as in patients with known risk factors for cardiovascular disease and thrombotic events.

scholarly journals Genetic or Autoimmune: POLG-Related Epilepsy Initially Treated as an Autoimmune Encephalitis, a Case Report

2020 ◽  
Vol 11 (1) ◽  
pp. 80-83
Author(s):  
Suma Shah ◽  
Abigail Berezoski ◽  
Shareena Rahman ◽  
Christopher Eckstein ◽  
Matthew Luedke
Keyword(s):  
Valproic Acid ◽  
Liver Transplantation ◽  
Autoimmune Encephalitis ◽  
Healthy Person ◽  
Autoimmune Epilepsy ◽  
Number Of Patients ◽  
Autoimmune Processes ◽  
Refractory Seizures ◽  
New Onset

Hospital neurologists participate at the forefront of managing fulminant acute and subacute onset epilepsy, frequently attributed to autoimmune encephalitis (AE). As the recognition of antibody-mediated AE grows, there is a growing number of patients who are treated as antibody-negative AE. While antibody-negative autoimmune processes should be considered in the setting of acute and subacute onset of fulminant epilepsy, other causes must be considered before subjecting patients to long-term immunomodulatory treatments and other potential therapeutic toxicities. We present the case of a previously healthy young man who presented with new-onset refractory seizures treated with escalating doses of anti-epileptic drugs as well as immunosuppression for presumed autoimmune epilepsy. He developed valproic acid induced hepatotoxicity requiring liver transplantation and was later found to have a POLG mutation. We discuss the presentation of POLG mutations as well as the diagnosis of seronegative autoimmune encephalitis. We highlight the need for a broad differential when evaluating new onset refractory seizures in an otherwise healthy person.

scholarly journals RARE-36. BORTEZOMIB WOKE UP A PATIENT WITH ANTI-NMDA RECEPTOR ENCEPHALITIS REFRACTORY TO STANDARD THERAPY AND LONG TERM FOLLOW-UP

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi229-vi229
Author(s):  
Kong Xiao-Tang ◽  
Leonid Groysman ◽  
Cyrus Dastur ◽  
Beverly Fu ◽  
Daniela Bota
Keyword(s):  
Nmda Receptor ◽  
Standard Therapy ◽  
Autoimmune Encephalitis ◽  
Ivig Therapy ◽  
Term Care ◽  
Good Communication ◽  
Nmda Receptor Encephalitis ◽  
Long Term Follow Up ◽  
One Year

Abstract OBJECTIVE To report a case with refractory NMDA encephalitis in comatose for 18 months, who was treated successfully with bortezomib. BACKGROUND Anti-NMDA encephalitis is a rare autoimmune encephalitis. Standard therapy include corticosteroid, IVIG or plasma exchange, cyclophosphamide, rituximab, and tumor removal. Refractory cases are very severe and often stay in ICU on ventilation for several months to years. Bortezomib for the treatment of refractory anti-NMDA receptor encephalitis was reported. We have applied the treatment to our refractory case and successfully woke up the patient. And we have followed up the patient for 3 years. METHODS Case report. RESULTS A 40 yo male was diagnosed as anti-NMDA encephalitis. Standard therapy was applied. After stabilization, the patient was eventually discharged to ICU at a long term care subacute hospital. The patient was brought back for more Rituxan or steroid or IVIG therapy. The condition had not improved at all. Eighteen months in comatose, the patient had worsening NMDA titer in CSF to 1:640. Decision was made to start bortezumib as reported with modification: 1.3 mg/m2 bortezomib were administered on days 1, 8, 11 and 14 and allowed two weeks off therapy. After first cycle, the patent started to talk first word “hurt.” After 6 cycles, the patient sat up and started riding bicycles for physical therapy. The NMDA titer in CSF was reduced to 1:40 at the end of 6 cycles. One year later, the patent stood up and ambulated with a walker. One and half year later, the patient walks without assistance and his speech and cognition have significantly improved with good communication with family members and staff. CONCLUSIONS Proteasome inhibitor bortezomib might be considered to be the third line therapy as early as possible if the first line and second line are ineffective to treat anti-NMDA receptor encephalitis.

Intravenous Immunoglobulin (IVIG) Therapy of Neonatal Alloimmune Granulocytopaenia

1991 ◽  
Vol 80 (8-9) ◽  
pp. 885-886
Author(s):  
Anna-Liisa Järvenpää ◽  
Jukka Rajantie
Keyword(s):  
Intravenous Immunoglobulin ◽  
Ivig Therapy

Inhibition of Cell Adhesion by Antibodies to Arg-Gly-Asp (RGD) in Normal Immunoglobulin for Therapeutic Use (Intravenous Immunoglobulin, IVIg)

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3624-3631 ◽  
Author(s):  
Tchavdar L. Vassilev ◽  
Michel D. Kazatchkine ◽  
Jean-Paul Duong Van Huyen ◽  
Medina Mekrache ◽  
Emmanuelle Bonnin ◽  
...  
Keyword(s):  
Intravenous Immunoglobulin ◽  
Attachment Site ◽  
Ivig Therapy ◽  
Adenosine Diphosphate ◽  
Matrix Proteins ◽  
Enzyme Linked Immunosorbent Assay ◽  
Rgd Sequence ◽  
Β3 Integrin ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Intravenous immunoglobulin (IVIg) therapy is associated with a broad range of immunomodulatory activities. Several of the postulated mechanisms of IVIg action relate to the presence of antibodies to molecules relevant for regulation of the immune response. This article reports that IVIg contains antibodies to the Arg-Gly-Asp (RGD) sequence, and the attachment site of a number of adhesive extracellular matrix proteins, including ligands for β1, β3, and β5 integrins. Anti-RGD antibodies were identified in IVIg by enzyme-linked immunosorbent assay and by using the BIAcore (BIAcore, Uppsala, Sweden) technology. The affinity of anti-RGD antibodies to a synthetic RGD-containing peptide and to fibronectin (Fn) was found to be in the micromolar range. F(ab′)2 fragments specific for RGD were purified from IVIg by affinity chromatography. Anti-RGD F(ab′)2 antibodies inhibited adenosine diphosphate induced IIb/β3 integrin-mediated platelet aggregation and the adhesion of activated 4β1 integrin-expressing B cells to Fn. Adhesion of unstimulated platelets to fibrinogen (Fg) involving both the γ-chain dodecapeptide sequence and the RGD sequence was inhibited by anti-RGD antibodies. In addition, adhesion of thrombin-stimulated platelets to von Willebrand factor or Fg was completely inhibited by affinity-purified anti-RGD antibodies. Our results suggest that the presence of natural IgG antibodies to the RGD motif may contribute to the immunomodulatory and anti-inflammatory effects of therapeutic preparations of normal IgG.

scholarly journals High-dose intravenous immunoglobulin therapy induces and maintains complete remission for polyarteritis nodosa

2014 ◽  
Vol 1 (1) ◽  
pp. 13
Author(s):  
Kazu Ode ◽  
Yoshinori Taniguchi ◽  
Yoshitaka Kumon ◽  
Yoshio Terada
Keyword(s):  
Complete Remission ◽  
Intravenous Immunoglobulin ◽  
Polyarteritis Nodosa ◽  
Alternative Therapy ◽  
Ivig Therapy ◽  
Immunoglobulin Therapy ◽  
High Dose ◽  
Intravenous Immunoglobulin Therapy ◽  
First Line Therapy ◽  
High Dose Ivig

We report a case of successful high-dose intravenous immunoglobulin (IVIG) use in a patient with refractory polyarteritis nodosa (PAN). Treatments with prednisolone (PSL) and various types of immunosuppressants including methotrexate (MTX) and intravenous cyclophosphamide (IVCY) were unsuccessful, and then, high-dose IVIG therapy was added. High-dose IVIG therapy improved all symptoms including high fever, arthralgia, mononeuritis multiplex and indurated erythema due to PAN. Moreover, serum inflammatory markers were also normalized. High-dose IVIG is maintaining complete remission for PAN without flare-up for additional 4 years. Therefore, high-dose IVIG therapy might be considered as a first-line therapy in patients with PAN or alternative therapy in refractory PAN.

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