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  • ETH2: What are the known and estimated benefits and harms for patients when implementing or not implementing IGG?
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What are the known and estimated benefits and harms for patients when implementing or not implementing IGG?

Authors: Plamen Dimitrov, Anelia Koteva

Internal reviewers: Pseudo99 Pseudo99

Although there is no available medication for the treatment of Alzheimer’s disease that may stop or reverse the course of the pathology, the process related to the development and testing of new innovative drugs still continues. Research efforts are primarily devoted to the elucidation of the pathogenetic mechanisms of Alzheimer’s disease and the establishment of a comprehensive theoretical foundation on which modern disease-modifying therapy should be based on, as contrasted to current symptomatic treatment. In this sense, future hopes are associated with immunotherapy, which is believed to limit the development and deposition of abnormal amyloid protein in the brain.

 

The experimental technology, i.e. intravenous immunoglobulin infusions by maintaining optimal level of antibodies in the patient’s organism constitutes a form of passive immunotherapy with a potential for reduction of beta-amyloid plaques, where the technology is expected to help completely heal or significantly improve the cognitive status of the treated subjects with all subsequent benefits, i.e. improved social interaction and quality of life.

 

A pilot study examining the efficacy and safety of the treatment of Alzheimer’s disease with immunoglobulins, conducted by Dodel et al.[1] on five patients, who have been treated for over six months with the blood product, reported stabilization of cognitive function as measured by the neuropsychological test “Mini-Mental State Examination” together with reduction in beta-amyloid deposits in the cerebral spinal fluid compared to baseline.

 

Promising results were also reported by Relkin et al.[2] on a sample of eight patients. The authors found improved cognition and seized cognitive decline in the majority of patients based on MMSE scale following a six-month IVIG administration, suggesting that the method could delay, withhold or even reverse the course of the pathology.

 

In mid-2013 were announced the results from the phase III of a large-scale randomized double-blind placebo-controlled clinical trial[3] that enrolled 390 patients with mild to moderate Alzheimer’s disease, who have been treated by intravenous immunoglobulins for 18 months. The study, popularly known as “GAP” (“Gammaglobulin Alzheimer’s Partnership”), like in previous clinical trials, traces the biomarkers’ dynamics and the change in the cognitive status of involved individuals. The results to date are contradictory.

 

Although the above-mentioned data generally demonstrate relatively good tolerability of the blood product, specialized medical literature seems to argue that the potential of the new therapeutic alternative should not be generalized. Despite the somewhat reduced risks associated with passive immunotherapy vs. active one, hazards do exist, being still unknown and unpredictable. The following side effects or complications that may occur during treatment with both active and passive immunotherapy have been reported[4]: autoimmune diseases, brain inflammation (meningoencephalitis), microhemorhages, increased amyloid angiopathy, residual neurofibrillary tangles, brain volume reductions and problems with blood-brain barrier passage of antibodies, posing a threat to patients’ health and worsening their quality of life. Therefore, in view of these considerations very cautious administration of IVIG products is required only after thorough testing on nonmurine animal species (primates) and further validation.

 

Given that IVIG treatment is still at an experimental stage, it may need additional confirmation based on quite more studies with expanding the number of both the people involved and the time period, with the authors warning that the new approach should not be taken for a universal treatment strategy on the principle “One size fits all.” and therefore not to be viewed as a first-choice therapeutic alternative.

 

With a view to the above considerations, involved medical personnel needs to be responsible for balancing benefits and risks. In bioethics literature, this is known as a “risk-benefit analysis” where the researcher must weigh and balance the possible benefits and damages occurring in the course of research. One of the main tasks of the medical staff is to ensure that the principle of nonmaleficence has been observed or refrain from causing harm to the subjects in the study by assuring that potential benefits exceed unknown risks. Other negative consequences, such as in the case of patients with compromised decision-making capacity must also be envisaged, for example a decisionally impaired person, who has significantly recovered due to the treatment, might realize his/her deteriorating physical and mental state and as a result become distressed, feel anxiety, hopelessness and despair, thus causing increased suicidal risk among these patients. Physicians should be prepared for timely response to prevent this side effect.

 

[1] Dodel, R.C., Y.Du, C. Depboylu, H. Hampel, L. Frölich, A. Haag, U. Hemmeter, S. Paulsen, S.J. Teipel, S. Brettschneider, A. Spottke, C.  Nölker, H.J. Möller, X. Wei, M. Farlow, N. Sommer and W.H. Oertel “Intravenous Immunoglobulins Containing Antibodies against β-amyloid for the Treatment of Alzheimer’s Disease” (Short Report), “Journal of Neurology, Neurosurgery and Psychiatry” 2004; 75: 1472-1474, available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1738770/pdf/v075p01472.pdf .

[2] Relkin, N.R., P. Szabo, B. Adamiak, T. Burgut, C. Monthe, R.W. Lent, S. Younkin, L. Younkin, R. Schiff and M.E. Weksler, “18-Month Study of Intravenous Immunoglobulin for Treatment of Mild Alzheimer Disease”, “Neurobiology of Aging”, volume 30, issue 11, November 2009, pp. 1728-1736, available at:  http://www.ncbi.nlm.nih.gov/pubmed/18294736 .

[3]Updated Results from Phase 3 Trial of IVIG for Alzheimer’s Disease(Featured Research), Weill Cornell Medical College, July 2013, available at: http://www.sciencedaily.com/releases/2013/07/130716092743.htm .

[4] Foster, J.K., G. Verdile, K.A. Bates and R.N. Martins, “Immunization in Alzheimer’s Disease: Naïve Hope or Realistic Clinical Potential?”, “Molecular Psychiatry” (2009) 14, 239-251, available at:  http://www.nature.com/mp/journal/v14/n3/full/mp2008115a.html .

Dimitrov P, Koteva A Result Card ETH2 In: Dimitrov P, Koteva A Ethical analysis 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 30 October 2020]. Available from: http://corehta.info/ViewCover.aspx?id=267