Original Title: Efficacité et innocuité des immunoglobulines en rhumatologie. Rapport de revues systématiques

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. 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 medical disciplines, including rheumatology. 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 for the use of Igs in rheumatology, in the form of an optimal usage guide. For the purposes of the MSSS's request, INESSS adopted a collaborative approach called "knowledge mobilization", which is based on the assessment of three types of data: scientific, contextual and the clinician perspective. The present report, which stems from that request, is aimed at providing scientific data on the efficacy, safety and conditions of use of Igs in each of the 34 rheumatological indications of interest

Authors' results and conclusions: Efficacy and safety of IVIg The systematic literature reviews and literature updates performed to evaluate the efficacy and safety of intravenous immunoglobulins (IVIg) concerned 34 rheumatological indications. A beneficial effect of IVIg was observed in primary studies or systematic reviews of primary studies, based on an overall level of evidence considered: • Moderate to low for three indications: systemic lupus erythematosus, diffuse or localized systemic sclerosis, and Kawasaki disease; • Low for five indications: cutaneous lupus, Sjögren's syndrome, antiphospholipid syndrome, eosinophilic granulomatosis with polyangiitis, and granulomatosis with polyangiitis. For four indications, rheumatoid arthritis, juvenile idiopathic arthritis, dermatomyositis and Susac syndrome, the results of primary studies or systematic reviews of primary studies indicate, based on an overall level of evidence considered low, that IVIg did not show significant benefit over other treatment options. The scientific data on the following 12 indications were considered insufficient: microscopic polyangiitis, polyarteritis nodosa, Cogan's syndrome, hypocomplementemic urticarial vasculitis syndrome, IgA vasculitis, leukocytoclastic vasculitis, lymphocytic vasculitis, primary central nervous system vasculitis, and levamisole vasculopathy, and, with respect to the literature update, inclusion body myositis, necrotizing myositis, and polymyositis. The adverse effects can be divided into the following two types, depending on their severity: • The non-serious adverse effects, which are the most common ones, include post-IVIg headache, febrile non-hemolytic reaction, chills, urticaria, asthenia, nausea, vomiting, flu-like symptoms, atypical pain, and transfusion-related hypertension or hypotension. • The serious adverse effects, which are usually rare, include immediate anaphylactic-type reaction, thromboembolic reaction, immediate or delayed hemolytic reaction, aseptic meningitis, transfusion-related acute lung injury, transfusion-associated circulatory overload, and acute renal failure. Conditions of use To document the conditions of Igs use, 23 clinical practice guidelines (CPGs) considered to be of sufficient methodological quality were selected, although several of the indications of interest were dealt with in only three national general CPGs (Canada, the United Kingdom and Australia). In general, the conclusions of the different guidelines are similar regarding the indications for which the use of IVIg is recommended or considered. With respect to the IVIg dosage, the GPC data agree on the recommendation of a total dose of 1 to 2 g/kg administered in a single dose or divided over 2 to 5 days, which can be repeated every 4 weeks for chronic rheumatological conditions. Conclusion The available evidence on the efficacy of IVIg were associated with a moderate to low level of evidence for only three indications: systemic lupus erythematosus, diffuse or localized systemic sclerosis, and Kawasaki disease. Based on the scientific data reviewed, most of the indications, that is, 31 out of a total 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 put together a randomized clinical trial with a sufficient number of participants. The administration of IVIg may be associated with non-serious adverse effects. However, serious adverse effects, which are rare, have been reported. No evidence regarding the use of subcutaneous immunoglobulin (SCIg) in rheumatology was found.

Authors' methods: Systematic literature reviews To assess the efficacy and safety of Igs in children and adults, we conducted systematic reviews in several bibliographic databases for 30 of the rheumatological indications of interest, and a literature update was carried out for 4 indications for which the scientific evidence was previously examined in 2017, when the project on the optimal use of immunoglobulins in neurology was published [INESSS, 2017b]. Each database was searched from the date of their inception to July 2020 to identify all the primary studies and systematic reviews, with or without a meta-analysis, published on the subject. As for the four indications concerning the myositis, a literature update was 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, 2017b].The official product monographs for Health Canada-approved Igs, advisories from Health Canada and the U.S. Food and Drug Administration, and a transfusion accident and incident report published by the Institut national de santé publique du Québec (INSPQ) were also consulted to complete the research concerning safety. To document the conditions of Ig use, we conducted a systematic literature review to identify guidance documents, clinical practice guidelines (CPGs) and other items containing clinical recommendations published between January 2010 and July 2020 for 30 of the indications of interest. As well, an update of myositis treatment recommendations was also carried out for the period from January 2017 to July 2020, based on the methodology used during the development of the state of knowledge on the use of immunglobulins in neurology [INESSS, 2017b]. The grey literature was consulted to complete the search on the conditions of use of Igs. Items were selected according to predefined inclusion and exclusion 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 the other. The results were presented in tables and summarized in the form of an analytical narrative synthesis. Process for assessing the quality of the scientific evidence The main efficacy results reported in the selected studies are presented as brief statements of scientific evidence. An overall level of scientific evidence was assigned to each statement of evidence using a four-level scale (high, moderate, low and insufficient).

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_EC.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)