Original Title: Usage optimal des immunoglobulines en immunologie clinique

Authors' objectives: Non-specific human immunoglobulins (Igs) are stable products derived from human plasma. Their cost is high, their supply variable, and their use in Québec has been steadily increasing for many years, particularly in immunological indications. Additionally, there is concern on the part of Québec’s Comité consultatif national de médecine transfusionnelle (CCNMT), which has called attention to the lack of recommendations regarding the use of Igs in most immunological indications. At the CCNMT’s suggestion, the Ministère de la Santé et des Services sociaux (MSSS) therefore asked the Institut national d'excellence en santé et en services sociaux (INESSS) to develop clinical recommendations regarding the use of Igs in clinical immunology in the form of an optimal use guide (OUG). On completion of this project, INESSS had developed clinical recommendations for the optimal use of intravenous Igs (IVIgs) or subcutaneous Igs (SCIgs) in clinical immunology to treat primary and secondary immune deficiencies.

Authors' results and conclusions: RESULTS: The literature review yielded evidence on the efficacy of Igs in treating immunodeficiencies for only a minority of the indications. This can be explained mainly by the fact that most immunodeficiencies are rare, with the result that it can be difficult to put together randomized controlled trials (RCTs) on them with a sufficient number of patients. Moreover, for certain indications (e.g., agammaglobulinemias, severe combined immunodeficiencies, combined immunodeficiencies, and common variable immunodeficiency), it is unethical to conduct an RCT with placebo or another therapeutic option as a comparator, because the use of Igs is recognized as the standard and essential treatment. Thus, it is difficult to obtain high-level evidence studies on the efficacy and safety of Igs in this context. Consequently, the results of primary studies with a control group and systematic reviews of primary studies permit the conclusion, with a level of evidence considerated low to moderate, that Igs are efficacious as first-line treatment for the following 3 indications : agammaglobulinemias, common variable immunodeficiency and hyper-IgM syndromes. Moreover, the results of primary studies with a control group and systematic reviews of primary studies permit recommend Igs as a treatment option for the following 8 indications: transient hypogammaglobulinemia of infancy, IgG2 subclass deficiency (associated or not with IgA deficiency), hypogammaglobulinemia following treatment with B-cell-targeted therapies, including rituximab, or with immunosuppressants, including high-dose corticosteroids, hypogammaglobulinemia associated with chylothorax, or nephrotic syndrome or severe burn, and for treating an infection in preterm newborns with an immature immune system. In addition, the CPG recommendations and the experiential data concur and permit recommending the use of Igs for these 11 indications. Igs are approved by Health Canada for primary and secondary immunodeficiencies. The results of primary studies and systematic reviews of primary studies indicate, with a level of evidence considered moderate to high, that there is no significant difference proving that the efficacy of IVIgs is superior to that of a treatment whose efficacy is recognized in preterm newborns in the context of infection prevention. Based on the experiential data, and given the absence of recommendations in the CPGs, IVIgs are not recommended for infection prevention in preterm newborns. CONCLUSION: Evidence based solely on control group studies on the efficacy of IVIgs was available for a minority of the indications. This can be explained mainly by the fact that most immune deficiencies are rare, with the result that it can be difficult to put together randomized controlled trials (RCTs) on them with a sufficient number of patients. Moreover, for certain indications (e.g., agammaglobulinemias, severe combined immunodeficiencies, combined immunodeficiencies and common variable immunodeficiency), it is unethical to conduct an RCT with placebo or another therapeutic option as a comparator, because the use of Igs is recognized as the standard, essential treatment. Therefore, it is difficult to obtain high-level evidence studies on the efficacy and safety of Igs in this context. Thus, the best clinical practice recommendations and the opinions of the advisory committee's experts, in accordance with international recommendations and the recommendations of learned societies, carried significant weight when developing the clinical recommendations for most immunological indications.

Authors' methods: For the purposes of the MSSS's request, INESSS adopted a collaborative approach called "knowledge mobilization”. This approach consists in analyzing and triangulating scientific and contextual data and experiential knowledge. (Scientific data) To assess the efficacy and safety of Igs in children and adults in each of the immune deficits of interest, we conducted systematic reviews in several bibliographic databases from the date of their creation to June 2019 to identify all the primary studies and systematic reviews, with or without meta-analysis, published on the subject. The official product monographs for Health Canada-approved Igs, Health Canada and U.S. Food and Drug Administration (FDA) advisories, and a report on transfusion accidents and incidents published by the Institut national de santé publique du Québec (INSPQ) were consulted to complete the research regarding safety. To document the conditions of use of Igs, we conducted a systematic literature review to identify guidance documents, clinical practice guidelines (CPGs) and any other items containing clinical recommendations published between January 2009 and June 2019. The grey literature and the official product monographs for Health Canada-approved Igs were consulted to complete the research on the conditions of use of Igs. Items were selected according to predefined exclusion and inclusion criteria, and their quality of these items was assessed using the appropriate tools. These steps were carried out independently by two reviewers. The data were then extracted by one reviewer and validated by another. The results were presented in tables and summarized in the form of an analytical narrative synthesis. The main efficacy results reported in the selected studies were expressed as brief statement of scientific evidence, and an overall level of scientific evidence was assigned to each statement of evidence according to a four-level scale (high, moderate, low, insufficient). Lastly, to determine the main characteristics of the indications for the primary and secondary immunodeficiencies of interest, we explored the scientific literature, the CPGs and the website Orphanet. (Contextual data and experiential knowledge) The number of patients treated and the quantity (expressed in grams) of Igs administered in Québec in 2016 and 2017 were documented from a report on the use of IVIgs prepared by the INSPQ using information extracted from the TraceLineTM system database. Health Canada’s website was consulted to determine the approval status of intravenous immunoglobulins (IVIgs) and subcutaneous immunoglobulins (SCIgs). The recommendations were developed in collaboration with the advisory committee. In general, the information on the contextual and experiential data was presented in narrative form and summarized in tables. (Process for developing recommendations) Triangulating the scientific and contextual data and experiential knowledge enabled us to structure the arguments leading to the development of recommendations. Only those for which there was a consensus among the experts were selected. The indications concerning primary and secondary immunodeficiencies were classified into 4 use categories: IVIgs or SCIgs recommended, IVIgs or SCIgs are possible treatment option, IVIgs or SCIgs not recommended, and insufficient data.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/usage-optimal-des-immunoglobulines-en-immunologie-clinique.html

Year Published: 2020

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/usage-optimal-des-immunoglobulines-en-immunologie-clinique.html

English language abstract: There is no English language summary available

Publication Type: Other

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: INESSS