Result card

  • TEC1a: What are Intravenous Inmunoglobulins (IVIG)?
  • TEC1b: What are the potential comparators for IVIG use in Alzheimer’s disease and Mild Cognitive Impairment? Jump to
English
No adaptation help available for this domain

What are Intravenous Inmunoglobulins (IVIG)?

Authors: Jesús González-Enríquez, Nadine Berndt, Houria Mouas

Internal reviewers: Romana Tandara Haček, Mirjana Huic, Anna-Theresa Renner

Refer to domain search and domain methodology section.

1.            INTRODUCTION AND PRODUCT DESCRIPTION

Intravenous immunoglobulins (IVIG), human normal immunoglobulin for intravascular administration (ATC code J06BA02), is a medicinal product derived from human plasma of at least thousands of healthy voluntary donors, prepared industrially, containing polyclonal antibodies to produce passive immunity and other protective effects. Human normal immunoglobulin is a highly purified protein extracted from human plasma. It contains mainly immunoglobulin G (IgG), with a broad spectrum of antibodies against infectious agents. IVIG has been used as a medicine since the 1980s and has a wide range of activity against organisms that can cause infection. In 1982, IVIG use in the US was approximately 40,000 g, and in 2006 consumption was estimated to reach 36 million grams annually {Duff, 2006}{1}. IgG works by restoring abnormally low IgG levels to their normal range in the blood.

Human normal immunoglobulin contains mainly IgG with a broad spectrum of antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donors, usually thousands of blood donors. It has a distribution of IG subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range. The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.

Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments. The median IgG half-life after administration varies around 30 to 40 days approximately. This half-life may vary from patient to patient and clinical condition, in particular in primary immunodeficiency.

The rate of metabolism does not appear to increase with chronic administration. However, detailed pharmacokinetic studies are not available in patients with autoimmune diseases given repeated high dosages of IVIG.

Intravenous preparations of immune globulin (IVIG) first became available in the 1979 {The Consensus Working Group, 1997; Laupland KB, 2002}{2,3}, although these contained impurities that caused severe anaphylactoid reactions and protein aggregates that cause thromboembolies. Subsequent refinements allowed for safe administration of higher doses intravenously that more closely approximated physiologic levels.

Immune globulin may be administered by different routes: Intravenously (immune globulin, intravenous [human] "IVIG" or "IGIV"); subcutaneously (SCIG or IGSC) or intramuscularly (IGIM). Multiple products are available, which vary in concentration of IgG, additives and stabilizers, and IgA content. Most products are labeled for a specific route of administration. Subcutaneous and intramuscular products are generally more concentrated than intravenous preparations and should not be given intravenously.   

1.1 IVIG production and composition

Production of IVIG begins with pooled human plasma from several thousand screened volunteer donors. Cold alcohol fractionation is used to isolate the immunoglobulin-containing fraction. This is followed by further purification techniques, including additional precipitation steps to remove non-IgG proteins and ion exchange chromatography. Most IgG preparations also undergo several specific treatments to inactivate or removal potentially present blood-borne pathogens. These include low pH treatment, fatty acid treatment, solvent-detergent treatment, heat-treatment (pasteurization) and/or nanofiltration.

The World Health Organization has published minimum standards for manufacturing IVIG preparations {WHO 2008}{4}.

IVIG should be extracted from a pool of at least thousands of healthy screened donors.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

It should contain as little IgA as possible.

The IgG molecules should be modified biochemically as little as possible and possess opsonizing and complement-fixing activities.

It should be free from preservatives or stabilizers that might accumulate in vivo.

There are slight differences in the manufacturing procedures utilized by the different producers, and different stabilizers are used in the excipients. However, the final preparations are highly purified (>90 percent) polyvalent IgG. Products differ in storage requirements and shelf life. Stabilizers may include sugars, such as sucrose, glucose, or maltose. Some IVIG products contain amino acids such as glycine or proline. The sodium content of different products also varies.

The resulting products are generally believed to be equally effective for treatment of the autoimmune and immunodeficiency disorders. However, they differ from each other in ways that may be important in a particular patient.

Product presentation varies in concentration of human normal immunoglobulins. The product is packaged in different volume vials (glass) as solution for infusion. The content is high purity IgG. The distribution of IgG subclasses also is variable. The solution is clear or slightly opalescent and colourless or pale yellow.

1.2 Main therapeutic indications

(From Core Summary of Product Characteristics. Clinical Particulars)

Replacement therapy in adults, and children and adolescents (0-18 years) in:

- Primary immunodeficiency syndromes with impaired antibody production.

- Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

- Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.

- Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).

- Congenital AIDS with recurrent bacterial infections.

 

Immunomodulation in adults, and children and adolescents (0-18 years) in:

- Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

- Guillain Barré syndrome.

- Kawasaki disease.

- Product specific auto-immune indications (e.g. multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), myasthenia gravis exacerbations) and other product specific indications – see Guideline on the Clinical Investigation of Human Normal Immunoglobulin for Intravenous Administration (IVIg) EMA/CHMP/BPWP/94033/2007 rev. 2.

There has been a rapid expansion in the use of intravenous immunoglobulin (IVIG) for an ever growing number of conditions and often used more extensively than the authorized indications (“off-label use”). IVIG use has had a major impact in neurology, haematology, immunology, rheumatology and dermatology. (See B002)

1.3 Dosing

The dose and dose regimen is dependent on the indication. (See TEC-1 Figure 1)TEC-1 Figure 1

 

Replacement therapy in primary immunodeficiency syndromes:

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/l. The recommended starting dose is 0.4-0.8 g/kg given once, followed by at least 0.2 g/kg given every three to four weeks. Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels.

Subcutaneous preparations are widely used in immunodeficiency because the gradual and steady introduction of immune globulin into the patient's circulation appears to have advantages. In addition, subcutaneous immune globulin (SCIG) is frequently self-administered at home, which could be more convenient for some patients.

 

Infusion rates for intravenous immunoglobulin:

Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Initial intravenous infusion rates are low, and if well tolerated, the rate of administration may be increased, as specified in the products’ Summary of Product Characteristics (SPC). For certain products, the SPC indicates that if the higher rate is tolerated, the rate may be further increased in primary immunodeficiency (PID) patients to the maximum infusion rate. Higher infusion rates may lead to improved convenience for patients and may reduce nursing time and the need for hospital resources. Patients at high risk for tromboembolic events should not receive rapid infusion of IVIG. Infusion rates for each of the licensed immunoglobulins are provided in the table below. Immunoglobulin should be administered according to the manufacturers’ recommendations. The table below gives the infusion rates, and the infusion time at maximum infusion rate of 1 g/kg dose in a 70 kg person {Department of Health, 2011}{5}.(See TEC-1 Figure 2). TEC-1 Figure 2

Patients with particular clinical conditions are at risk for certain adverse events. Adverse events can be reduced by downgrading the dose, the rate and the volume of the infusion. IVIG is well tolerated by the majority of patients, but it is important to note that, just as each patient may require a different immunoglobulin product, each may also require an individualized infusion regimen in order to achieve the desired therapeutic response. Once a successful regimen has been developed, it should be carefully followed with every infusion. This includes not only the rate of the infusion and necessary premedications, but the specific product, as well.

1.4 Adverse effects

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

It is strongly recommended that every time that IVIG preparation is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Serious reactions are uncommon. Adverse reactions occur more often when a patient is either receiving IVIG for the first time, or switching from one preparation to another or when there has been a long interval since the previous infusion.

It is important to maintain patients consistently on one IVIG product to reduce the risk of adverse events.

Certain patient groups are at higher risk for serious complications, such as those receiving high dose IVIG, patients with dehydration, the elderly, and those with preexisting renal or cardiovascular disorders, previous IVIG treatment complications, history of migraine, diabetes, concomitant use of nephrotoxic drugs, sepsis and fluid volume depletion.

Many reactions are dose rate-related. Common adverse reactions include fever, chills, malaise, headache, dizziness, nausea vomiting, allergic reactions, arthralgia, influenza-like illness, chest discomfort, chest tightness, chest pain, asthenia, malaise, peripheral oedema, infusion site pain, infusion site swelling, infusion site reaction, rigors, pruritus, rash, urticaria, back pain, myalgia, muscle spasms, muscular weakness. These reactions usually respond to temporary discontinuation of the infusion. If reactions are anticipated, a patient can be premedicated with antihistamines and intravenous hydrocortisone.

Patients with active infections may experience fever, rigors, and "flu-like" symptoms during infusion of IVIG, which is believed to result from lysis of bacteria and release of cytokines. When possible, infections should be treated with antibiotics before administration of IVIG.

Hematologic and thrombotic complications include hemolysis, anaemia, lymphadenopathy, neutropenia, and thrombotic and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis {Micromedex Drugdex Database, 2014; Loeffler DA, 2013}{6,7}.

2.            IVIG IN NEUROLOGICAL DISEASES

Intravenous immunoglobulin (IVIG) has been successfully used to treat a number of immune-mediated diseases of the central and peripheral nervous system.

Although underlying mechanisms of action of IVIG have not been fully explained, it is known that IVIG can interfere with the immune system at several levels. The effect of IVIG in one of particular diseases may not be attributed to only one of its mechanisms of action, because the pathophysiology of these diseases is complex.

The efficacy of IVIG has been proven in Guillain-Barre´ syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended asa second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing–remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (level A), stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point) {EFNS, 2008}{8}.

2.2          IVIG AND ALZHEIMER’S DISEASE

IVIG products are thought to contain the full range of antibodies present in the human repertoire. IVIG’s mechanisms of action in different disorders are generally poorly understood. It contains several antibodies that have the potential to reduce AD-type pathology, but whether these antibodies can actually do so is unclear {Loeffler DA, 2013}{7}.

IVIG products contain antibodies to Aβ oligomers and fibrils and perhaps also to monomeric Aβ. These drugs differ in their levels of anti-Aβ antibodies. IVIG has been shown in vitro to disaggregate preformed Aβ fibrils, promote Aβ phagocytic removal, protect against Aβ neurotoxicity, and prevent formation of Aβ soluble oligomers {Dodel R, 2010} {9}.

IVIG’s antibodies recognize multiple sites on conformational Aβ epitopes, and its main binding to Aβ is reportedly to Aβ25-40. This differs from the monoclonal anti-Aβ antibodies that have been used in clinical trials, Bapineuzumab and Solanezumab, which recognize only one epitope in linear Aβ and bind to Aβ1-5 and Aβ13-28, respectively. A recent review {Moreth J, 2013}{10} suggested that using the IVIG polyclonal antibody approach in an effort to deplete the spectrum of aggregated Aβ species might be more promising than using monoclonal antibodies targeting a single Aβ species.

Other proposed mechanisms of action are anti-inflammatory effects, possible anti-tau effects, alteration of Aβ passage in and out of the brain and other non-antibody-mediated effects.

IVIG contains other non-antibody proteins in addition to sLRP, which could influence its actions in AD in ways that are not clear. Interferon-γ, an inflammatory cytokine that also has some anti-inflammatory actions, is present in IVIG. Soluble human leukocyte antigen (HLA) class I and II molecules are present in some IVIG products, as are their “physiological ligands,” CD4 and CD8. Soluble CD4 in IVIG might interfere with HLA class II molecules on antigen-presenting cells, competing with HLA-class II-restricted T cells and possibly causing immunosuppression. Transforming growth factor (TGF)-β1 and TGF-β2 are also present in IVIG. TGF-β1 is increased in AD brain, where it is associated with plaques, but it also may promote Aβ clearance, so its significance in AD is unclear.

Intravenous immunoglobulin (IVIG) products are being investigated as potential agents for treatment or prevention of Alzheimer´s Disease (AD). Polyclonal naturally occurring autoantibodies against amyloid β are found in serum of healthy persons and are reduced in AD patients. The IVIG product Octagam (Octapharma) was shown by Dodel et al. in 2002 to contain antibodies against amyloid β (Aβ), suggesting that IVIG might be useful for treatment of AD. These antibodies might interfere with metabolism of Aβ and be reduced in patient with AD {Dodel R, 2002}{11}. This provided the rationale for IVIG pilot studies in AD patients. Three small clinical trials have tested the efficacy of intravenous immunoglobulin for mild-to-moderate Alzheimer’s disease. In an initial uncontrolled trial, five patients received 1-2 g/kg intravenous immunoglobulin every 4 weeks for 6 months. The concentration of total Aβ decreased in CSF and increased in blood compared with baseline. The patients had no cognitive deterioration {Dodel R, 2004}{12}. These results were independently reproduced in an uncontrolled trial {Relkin NR, 2009}{13} with eight patients (given 0.4–2. 0 g/kg per month for 6 months). Finally, a placebo-controlled (saline) multiple dose study {Weksler M, 2010}{14} of 24 patients (given 0.2 g/kg or 0.4 g/kg once every 2 weeks or 0.4 g/kg or 0.8 g/kg per month for 6 months) has been done. Patients who were treated with intravenous immunoglobulin 0.4 g/kg every 2 weeks had the best outcome, with no decline in cognitive and functional measures. The results of these studies were encouraging leading to phase II AD trials with these products {Dodel R, 2013}{15}. Additional phase III AD trial with another IVIG product is in progress. Now it is unclear whether any IVIG products will offer a breakthrough for treatment of AD. Differences have been reported between IVIG products for the concentrations of some of their antibodies and their biological activities. These may be due to differences in manufacturing practices and/or the antigenic exposure of the plasma donors. With regard to AD, differences between IVIG preparations have been found for anti-Aβ and anti-tau antibodies. Determination of whether IVIG products differ in their ability to slow AD’s progression will require comparative studies, as have been done for other diseases (Kawasaki disease and primary immune deficiency){Loeffler DA, 2013}{7}.

Important
Completely
González-Enríquez J et al. Result Card TEC1a In: González-Enríquez J et al. Description and technical characteristics of technology In: Jefferson T, Cerbo M, Vicari N [eds.]. Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali ; 2015. [cited 31 October 2020]. Available from: http://corehta.info/ViewCover.aspx?id=267

What are the potential comparators for IVIG use in Alzheimer’s disease and Mild Cognitive Impairment?

Authors: Jesús González-Enríquez, Nadine Berndt, Houria Mouas

Internal reviewers: Romana Tandara Haček, Mirjana Huic, Anna-Theresa Renner

Refer to domain search and domain methodology section.

1.         The Interventions on Alzheimer´s Disease

At present there is no cure for AD. The current mainstays of drug treatment are pharmaceuticals intended to address the cognitive symptoms of AD, in combination with supportive medical and behavioral intervention {Upadhyaya P, 2010} {16}.

HTA and coverage bodies value trials of a new therapy given in combination with already-employed therapies that target different physiological processes than the new drug. Disease-modifying therapies should be assessed in combination with symptomatic therapies such as cholinesterase inhibitors or NMDA receptor antagonists. Add-on studies are one strategy to accomplish this assessment. Other strategies include limited placebo period studies, randomized withdrawal, factorial designs, and three-arm trials. The specific goals of the trial should determine the relative timing of the combination of drugs, but will typically involve adding the investigational drug to a stable dose of a commonly prescribed drug with regulatory approval {Green Park Collaborative (GPC), 2013}{17}.

Symptomatic treatment of dementia with cholinesterase-inhibitors is considered as standard of care, particularly in mild to moderate Alzheimer’s disease. Therefore in the future new treatments for dementia may be evaluated more and more by using add-on-designs, particularly in long term studies the “pure” use of placebo control for demonstration of efficacy may be difficult to justify.

Two major classes of drugs are currently available to treat the symptoms of AD:

Marketed Drugs

Acetylcholinesterase inhibitors (AChEIs): These include donepezil, rivastigmine, and galantamine. An older AChEI, tacrine, is rarely used due to concerns about liver toxicity. AChEIs boost the amount of acetylcholine, an important neurotransmitter in the areas of the brain that control learning and memory. These drugs have been approved for use in patients with mild-to-moderate AD on the basis of short-term (i.e., 6 months or less) improvements in memory and cognition in clinical trials. There are no data suggesting that use of AChEIs modifies or delays disease progression.

N-methyl-D-aspartate (NMDA) receptor antagonists: A single NMDA receptor antagonist, memantine, is currently approved for the treatment of symptoms of moderate-to-severe AD. Memantine binds to NMDA receptors that are associated with excessive stimulation and eventual death of neurons. Findings from clinical trials suggest small positive effects of memantine on cognition, activities of daily living, and behavior. Memantine is not thought to affect disease trajectory or progression.

 

Disease-Modifying Therapy

In addition to the symptomatic treatments currently marketed, a host of potentially disease-modifying therapies have been studied, and numerous others are in development. These include treatments that modulate inflammation and oxidative damage, as well as treatments that interfere with Aβ deposition such as anti-amyloid aggregation agents, drugs to reduce Aβ production, drugs to promote Aβ clearance as active vaccination or passive immunization with monoclonal anti-amyloid antibodies, and other potential therapeutic approaches { Moreth J, 2013; Salomone S, 2011; Nygaard HB, 2013}{10,18,19}.

Non drugs interventions

There is much interest in the use of cognitive therapies in AD. Preliminary studies seem to suggest a beneficial effect of cognitive stimulation, also known as Reality Orientation. Although promising, cognitive stimulation and exercise have limited evidence to support their use in persons with mild to moderate dementia or mild cognitive impairment.

Treatment of behavioural and psychological symptoms. 

Management of BPSD begins with careful search for trigger and/or exacerbating factors including environmental cues, physical problems (infections, constipation), medication and depression or psychosis. As studies of BPSD indicate a high placebo response, safe non-pharmacological management (education, exercise, aromatherapy, sensory  stimulation, personalized music) should be tried wherever possible in the first instance as symptoms may naturally resolve within a short time {Hort J, 2010; NICE, 2014; Lin JS, 2013}{20,21,22}.

 

2. The Interventions on Mild Cognitive Impairment

At present time there is no effective drug to treat or delay the progression from mild cognitive impairment (MCI) to dementia. There are no evidence-based interventions for MCI. Cognitive enhancers are agents that are often used to treat dementia, but did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. {Tricco AC, 2013; Russ TC,  2012; Birks J, 2006; Cooper C 2013 }{23,24,25,26}.

Important
Partially
González-Enríquez J et al. Result Card TEC1b In: González-Enríquez J et al. Description and technical characteristics of technology In: Jefferson T, Cerbo M, Vicari N [eds.]. Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali ; 2015. [cited 31 October 2020]. Available from: http://corehta.info/ViewCover.aspx?id=267

References