Original Title: Avis et guide usage optimal: immunoglobulines en neurologie

Authors' objectives: Non specific human immunoglobulins (Igs) are stable products derived from human plasma. They are expensive, their supply varies, and their use in Québec has been steadily increasing for many years, mostly for neurological indications. In addition to these issues was the concern of Québec’s Comité consultatif national de médecine transfusionnelle (CCNMT) that there was a lack of recommendations concerning the use of Igs in the treatment of most neurological indications. As part of the Clinical Relevance Project, the ministère de la Santé et des Services sociaux (MSSS), at the CCNMT’s suggestion, asked the Institut national d’excellence en santé et en services sociaux (INESSS) to develop clinical recommendations regarding the use of Igs in neurology in the form of an optimal usage guide (OUG). Provided at the end of this report are clinical recommendations for the optimal use of intravenous immunoglobulins (IVIgs) in 25 neurological indications, implementation recommendations, and recommendations for evaluating and monitoring them.

Authors' results and conclusions: RESULTS: (SYSTEMATIC REVIEWS OF EFFICACY, SAFETY AND CONDITIONS OF USE) In the systematic literature reviews performed in this project, the efficacy, safety and conditions of use of Igs were examined for 25 neurological indications. However, for two of these indications, multiple sclerosis and myasthenia gravis, the studies selected distinguished different clinical situations or forms of the disease. Consequently, the results concern a total of 28 indications. IVIgs were found to be efficacious in randomized clinical trials (RCTs) or meta-analyses of RCTs, based on an overall level of evidence considered: • High for two indications (chronic inflammatory demyelinating polyneuropathy [CIDP] and Guillain-Barré syndrome); • Moderate for one indication (multifocal motor neuropathy); • Low for six indications (dermatomyositis, myasthenia gravis [exacerbation, crisis], polymyositis, remitting multiple sclerosis, stiff person syndrome, and Lambert-Eaton myasthenic syndrome). As well, the results of RCTs or meta-analyses of RCTs did not show IVIgs to be more efficacious than placebo or no intervention, based on an overall level of evidence considered moderate or low, for four indications (adrenoleukodystrophy, Alzheimer’s disease, inclusion body myositis, and progressive-secondary multiple sclerosis). Although it cannot be formally concluded that IVIgs are ineffective, it can be assumed that their efficacy is inadequate in these situations. The scientific data were considered insufficient for 14 indications: diabetic amyotrophy, acute disseminated encephalomyelitis (ADEM), autoimmune encephalitis, Rasmussen’s encephalitis, the chronic form of myasthenia gravis, neuromyelitis optica, paraneoplastic neuropathy, IgM paraproteinemic neuropathy, intensive care polyneuropathy, primary-progressive multiple sclerosis, lateral amyotrophic sclerosis, opsomyoclonus syndrome, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), and autism spectrum disorder. Indeed, for these indications, the data are based mainly on case series or case studies, or on RCTs whose results do not permit a conclusion. The results of some of the studies identified do suggest, however, that in four of these indications (ADEM, Rasmussen’s encephalitis, neuromyelitis optica and opsomyoclonus syndrome), certain patients may experience a clinical response. On the other hand, the results suggest that IVIgs are ineffective in two indications (intensive care polyneuropathy and amyotrophic lateral sclerosis). Most transfusion reactions that occur after the administration of IVIgs are usually nonserious. Serious transfusion reactions are rare but have nonetheless been reported, such as thromboembolic reactions, hemolytic reactions, and transfusion-associated circulatory overload (TACO). There is little scientific data available on the use of SCIgs in neurology. The results of systematic literature reviews [INESSS, 2017] permit the conclusion, with a level of evidence considered low, that SCIgs are efficacious in two indications, CIDP and multifocal motor neuropathy, in patients previously treated with and who responded to IVIgs. The transfusion reactions to SCIgs reported in studies were mainly local and transient (redness, swelling, pain and tenderness at the injection site, skin induration). No serious reactions were observed. Three CPGs of good methodological quality were selected for documenting the conditions of use. They are from Canada, Australia and the United Kingdom and concern IVIgs. Their conclusions regarding the indications for which the administration of IVIgs is or is not recommended converge for most of the indications, although the details for administering them are often different. For initial therapy, the data from the CPGs are in agreement for recommending a total dose of 2 g/kg administered over 2 to 5 days. However, for maintenance therapy, the data are more divergent, both with respect to the doses to be administered and the frequency of the treatments, but all three CPGs recommend aiming for the minimum effective dose and trying to reduce the doses by increasing the interval between treatments or administering lower doses. (CONTEXTUAL AND EXPERIENTIAL DATA) Six meetings were held with the expert members of the advisory committee between December 2015 and November 2016. All the information gathered during these meetings was compiled and cross-referenced with other data sources to arrive at the clinical recommendations. The medico-administrative data show that, compared to SCIgs, the use of IVIgs in neurology accounts for more than 99% of the total amount of Igs administered and that the four indications which account for the greatest use of IVIgs are CIDP, myasthenia gravis, dermatomyositis and Guillain-Barré syndrome. CONCLUSION: Efficacy evidence for IVIgs was available for a minority of the indications. Based on the scientific data reviewed, most of the indications (17 out of 28) were associated with a level of evidence considered low or insufficient. All this can be explained mainly by the fact that these indications are rare and that it is therefore difficult to put together RCTs with a sufficient number of patients. Therefore, for these 17 indications, CPG recommendations and the opinion of the advisory committee’s experts carried more weight than for the other indications when developing the clinical recommendations. Given that the available data concern IVIgs almost exclusively and that the current use of SCIgs in Québec is marginal, INESSS developed an OUG specifically for IVIgs. Mention is nonetheless made of SCIgs.

Authors' methods: For the purpose of the MSSS’s request, INESSS used a collaborative approach, knowledge mobilization. It is based on the triangulation of three types of data: scientific, contextual and experiential. (SCIENTIFIC DATA) To evaluate the efficacy and safety of Igs in children and adults with one of the 25 neurological indications selected, a search was performed for Cochrane systematic reviews, and an update of these reviews was carried out. When no Cochrane systematic review was available, ad hoc systematic reviews were undertaken of studies published after the Canadian clinical practice guidelines (CPGs) [Feasby et al., 2007]. The official product monographs for Health Canada-approved Igs, Health Canada and Food and Drug Administration (FDA) advisories, and the transfusion accident and incident report published by the Institut national de santé publique du Québec (INSPQ) were consulted to complete the search regarding safety. To document the conditions of use of Igs, we searched the grey literature for the relevant CPGs and consulted the official product monographs for Health Canada-approved Igs. The literature search was conducted in several databases for the period from January 2005 to January 2017. Publications were selected according to predefined exclusion and inclusion criteria. The quality of the publications selected was assessed with the appropriate tools. These steps were performed 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. To determine the main features of the 25 indications selected, we explored the scientific literature, the CPGs, the Orphanet website and the website of the Regroupement québécois des maladies orphelines (RQMO). (CONTEXTUAL AND EXPERIENTIAL DATA) The number of patients treated and the number of grams of Igs administered for the year 2014-2015 in Québec were documented from a report on the use of IVIgs in neurology prepared by the INSPQ from data mined from the Trace Line database (unpublished data). Information on the organizational and administrative aspects of using Igs in Québec was obtained from MSSS, INSPQ and Héma-Québec documents and was supplemented by consultations with different stakeholders. Health Canada’s website was consulted to check the approval status of IVIgs and subcutaneous immunoglobulins (SCIgs). The recommendations were developed in collaboration with three working groups: the advisory committee, the follow-up committee and the governance committee. The members of INESSS’s advisory committee on the standardization of practices regarding beta-lactam allergies were consulted for the purpose of harmonizing the terminology and developing the recommendation concerning a history of allergic reactions to IVIgs. A pediatric rheumatologist was consulted as well. In general, the information on the contextual and experiential data was presented in narrative form and summarized in tables. (PROCESS FOR EVALUATING SCIENTIFIC EVIDENCE) The main efficacy results reported in the studies selected are presented as brief statements of the 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). (PROCESS FOR DEVELOPING RECOMMENDATIONS) Triangulating the scientific, contextual and experiential data enabled us to structure the argument leading to the development of recommendations. Only those for which there was a consensus among the experts were selected. The 25 indications of interest were placed in four usage categories: • IVIgs that are recommended: indications for which efficacy has been demonstrated with a high, moderate or low level of evidence and for which the data triangulation led to recommending their use on a first-line basis. • IVIgs that are possible treatment options: indications for which, in terms of efficacy, there is a low or insufficient level of evidence and for which the data triangulation permitted considering their use as a second-line treatment option (failure of or intolerance or contraindications to their use on a first-line basis), or in special situations. • IVIgs that are not recommended: indications for which the scientific and experiential data suggest a lack of efficacy or even a possible deleterious effect, or for which the pathophysiological justification is insufficient. • Insufficient data: indications for which the data triangulation did not permit any conclusions to be drawn regarding the efficacy or ineffectiveness of IVIgs.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/guide-dusage-optimal-des-immunoglobulines-en-neurologie.html

Year Published: 2017

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/guide-dusage-optimal-des-immunoglobulines-en-neurologie.html

Requestor: Minister of Health

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 santé et en services sociaux (INESSS), gouvernement du Québec