Original Title: Usage optimal des immunoglobulines en rhumatologie. Rapport en soutien au guide d’usage optimal

Authors' objectives: Nonspecific 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 several medical disciplines, including rheumatology. 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 rheumatological 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 rheumatology in the form of an optimal use guide. On completion of this project, INESSS had developed clinical recommendations for the optimal use of intravenous Igs (IVIg) in rheumatology, specifically, for the treatment of the 34 indications under consideration.

Authors' results and conclusions: The results of primary studies and systematic reviews of primary studies permit the conclusion, with a level of evidence considered moderate to low, that IVIg therapy is efficacious in three indications: systemic lupus erythematosus, diffuse or localized systemic sclerosis, and Kawasaki disease. All the clinical practice guidelines selected recommend the use of IVIg to treat these conditions. The results of the systematic reviews indicate, with a level of evidence considered low, that IVIg is efficacious in five indications. The CPG recommendations and the clinicians perspective concur and permit recommending IVIg as a treatment option for four indications: cutaneous lupus, Sjörgren’s syndrome, eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis. For one indication, antiphospholipid syndrome, the clinicians consulted suggested that the use of IVIg not be recommended. The results of the systematic reviews indicate, with a level of evidence considered low, that IVIg did not show significant benefit over other treatment options for four indications: rheumatoid arthritis, juvenile idiopathic arthritis, dermatomyositis and Susac syndrome. According to the clinicians consulted, IVIg can be considered a treatment option for children with a severe and systemic form of juvenile idiopathic arthritis and for patients with dermatomyositis in cases where first-line therapies fail or to reduce high chronic corticosteroid doses. They do not recommend the use of IVIg to treat rheumatoid arthritis. The data are insufficient for recommending or not recommending IVIg to treat Susac syndrome. Lastly, the results of the systematic reviews indicate that, in 12 of the 34 rheumatological indications of interest, the level of evidence is insufficient to draw any conclusions regarding the efficacy of IVIg. This can be explained mainly by the fact that most of these indications are very rare and that is difficult to recruit a sufficient number of participants with them for a randomized clinical trial, or, as the case may be, by the contradictory results from small studies. However, for eight indications, the analysis of all the available data permits a differentiated reading. • In one indication, microscopic polyangiitis, the assessment of the scientific data, the best clinical practice recommendations and the clinicians perspective indicates that the use of IVIg as a treatment option confers a beneficial clinical effect. • In two indications, necrotizing myositis and polymyositis, the best clinical practice recommendations and the clinicians perspective indicates that the use of IVIg as a treatment option to be considered. • In four indications, IgA vasculitis, leukocytoclastic vasculitis, lymphocytic vasculitis and inclusion body myositis, only the clinicians perspective leads to the conclusion that the use of IVIg is not recommended for the treatment of these rheumatological conditions. • For one indication, polyarteritis nodosa, there is insufficient evidence to recommend or not recommend IVIg. However, the committee’s members indicated that IVIg may be considered for the treatment of the juvenile form of polyarteritis nodosa, when the form of the disease is severe or in the event of failure, contraindication or intolerance to the other therapeutic options. The scientific safety data indicate that most of the transfusion reactions that occur after IVIg administration are not serious. However, different serious reactions, which are usually rare, have been reported in the scientific literature or to Québec’s hemovigilance system. Two of these, thromboembolic reaction and hemolytic reaction, have been the subject of studies and communications on the part of Health Canada and the FDA in recent years. Lastly, the results of the systematic reviews do not permit any conclusions regarding the efficacy of SCIg as a treatment for rheumatological conditions. Conclusions Evidence on the efficacy of IVIg was available for only a minority of the indications. Based on the scientific data reviewed, most of the indications (31 out of 34), were associated with a level of evidence considered low or insufficient. This can be explained mainly by the fact that these indications are rare and that it is therefore difficult to recruit a sufficient number of participants for a randomized clinical trial. Thus, the CPG recommendations and the opinions of the advisory committee’s experts carried more weight than for the other indications when developing the clinical recommendations. Given that the available data exclusively concern IVIg and that there is insufficient evidence regarding the efficacy of SCIg for the treatment of rheumatological conditions, INESSS has developed a specific optimal use guide on IVIg.

Authors' methods: For the purpose of the MSSS’s request, INESSS used a collaborative approach called "knowledge mobilization". This approach consists in analyzing and assessing scientific and contextual data and the clinicians perspective. Scientific data To assess the efficacy and safety of Igs in children and adults in each of the 34 rheumatological indications selected, 30 systematic reviews were conducted in several bibliographic databases from the date of their creations to July 2020 to identify all the primary studies and systematic reviews, with or without a meta-analysis, published on the subject. In addition, four literature updates were carried out for the period from January 2017 to July 2020, based on the methodology used during the development of the state the knowledge on use of immunoglobulins in neurology published in May 2017 by INESSS [INESSS, 2017a]. 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 accident and incident published by the Institut national de santé publique du Québec (INSPQ) were also consulted to complete the research regarding safety. To document the conditions of use of Igs, a systematic literature review was conducted to identify guidance documents, clinical practice guidelines (CPGs) and any other items containing clinical recommendations published between January 2010 and July 2020 for 30 of the indications of interest. An update of the recommendations for treating the four indications involving different types of myositis was also carried out for the period from January 2017 to July 2020, based the methodology used during the development of the state of knowledge on the use of immunoglobulins in neurology [INESSS, 2017a]. The grey literature and the official product monographs for Health Canada-approved Igs were consulted to complete the search on the conditions of use of Igs. Items were selected according to predefined inclusion and exclusion criteria. The 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 the 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 and insufficient). Lastly, to determine the main characteristics of the 34 rheumatological indications of interest, we explored the scientific literature, the clinical practice guidelines and the website Orphanet. Contextual data and clinicians perspective The number of patients treated and the quantity (expressed in grams) of Igs administered in Québec in 2018 and 2019 were documented from a report on the use of IVIg prepared by the INSPQ using information extracted from the TraceLine™ system database. Health Canada’s website was consulted to determine the approval status of intravenous Igs (IVIg) and subcutaneous Igs (SCIg). The recommendations were developed in collaboration with the advisory committee. In general, the information on the contextual data and the perspective of the clinicians consulted was presented in narrative form and summarized in tables. Process for developing recommendations The analysis and synthesis of the scientific and contextual data and the clinicians perspective enabled us to structure the arguments leading to the development of the recommendations. Only those recommendations for which there was consensus among the experts were selected. The 34 rheumatological indications were classified into four use categories: IVIg recommended, IVIg are possible treatment option, IVIg 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-rhumatologie.html

Year Published: 2021

URL for published report: https://www.inesss.qc.ca/fileadmin/doc/INESSS/Rapports/Medicaments/INESSS_Ig_rhumatologie_GN.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

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: L'Institut national d'excellence en sante et en services sociaux (INESSS)