Subcutaneous Immunoglobulin for Primary and Secondary Immunodeficiencies: an Evidence-Based Review
Substitution with immunoglobulin can be administered intravenously (IV) or subcutaneously (SC) to patients with immunodeficiency, but it is not clear which route is to be preferred.
The aim of this study was to compare IV and SC administration of immunoglobulin regarding efficacy, safety, health-related quality of life and health economics in patients with primary or secondary immunodeficiency.
PubMed and other databases were searched. Reference lists of retrieved articles were scanned and major immunoglobulin producers were contacted for additional articles. Randomized and non-randomized clinical studies that compared SC with IV immunoglobulin substitution in patients with immunodeficiency were included. The validity of the findings in the included studies was evaluated and summarized in accordance with the GRADE approach.
Twenty-five studies were included; two randomized and 17 non-randomized studies of patients with primary immunodeficiency, one non-randomized study of patients with secondary immunodeficiency and five studies of health economics. The quality of evidence as assessed by the GRADE score was found to be moderate or low for all outcomes. Both IV and SC administration of immunoglobulin was found to be highly effective in preventing serious bacterial infections. IgG trough levels were higher with SC immunoglobulin substitution. Both therapy forms were concluded to be safe, as no serious adverse event was reported. Minor adverse events, consisting of local symptoms that were usually mild, were more frequent with SC immunoglobulin substitution. Health-related quality of life improved when patients switched from hospital-based IV immunoglobulin substitution to SC immunoglobulin substitution at home. The studies that evaluated health economics all found that SC administration was considerably more cost effective in comparison with IV immunoglobulin substitution. The main difference was that the number of lost work or school days was lower in patients with SC administration.
Both SC and IV immunoglobulin substitution offer protection from serious bacterial infections and have good safety. On the basis of available studies it is not possible to rate one of the two substitution modes as superior to the other, at least not regarding efficacy and safety. Improvement of health-related quality of life with SC immunoglobulin substitution largely seems to be related to home therapy. Studies including patients with secondary immunodeficiency were few, as were randomized studies of patients with primary immunodeficiency.
- 5.Eijkhout HW, van der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia: a randomized, double-blind, multicenter crossover trial. Ann Intern Med. 2001;135:165–74.PubMedCrossRefGoogle Scholar
- 10.Guidelines for diagnosis and treatment of primary immunodeficiency [in Swedish)], 3rd ed. 2011. http://www.slipi.nu/klinik/Broschyr_Riktlinjer_V3_2011.pdf.
- 11.Guidelines for diagnosis and treatment of primary immunodeficiency [in Danish], 2nd ed. 2013. ISBN 978-87-92568-01-4 http://www.immundefekt-diagnostik.dk.
- 13.Food and Drug Administration. Guidance for industry safety, efficacy, and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency. 2008. http://www.fda.gov/cber/guidelines.htm.
- 17.Busse J, Hoffman F, Schlieben S, et al. Subcutaneous immunoglobulin substitution in primary B-cell defects. Review of the literature and experiences with 17 patients over a period of 6 years [in German]. Tagliche Praxis. 2005;46:185–92.Google Scholar
- 22.Helbert M, Farragher A. Subcutaneous immunoglobulin for patients with antibody deficiency. Br J Hosp Med (Lond). 2007;68:206–10.Google Scholar
- 41.Kobrinsky L. Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases. Biologics. 2012;6:277–87.Google Scholar
- 43.Schünemann H, Brożek J, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendation. Version 3.2 (updated March 2009). The GRADE Working Group, 2009. Available from http://www.cc-ims.net/gradepro.
- 44.Checklist from SBU regarding randomized controlled trials http://www.sahlgrenska.se/upload/SU/HTA-centrum/Hj%c3%a4lpmedel%20under%20projektet/B02_Granskningsmall%20f%c3%b6r%20randomiserad%20kontrollerad%20pr%c3%b6vning.doc. [Accessed 2012 Jan 03].
- 45.Checklist from SBU regarding cohort studies. Version 2010:1. http://www.sahlgrenska.se/upload/SU/HTA-centrum/Hj%c3%a4lpmedel%20under%20projektet/1/B03_Granskningsmall%20f%c3%b6r%20kohortstudier%20med%20kontrollgrupp%20modifierad%20OS%20IT.doc. [Accessed 2012 Jan 03].
- 46.Checklist from SBU regarding economic studies. Version 2012:1 http://www.sbu.se/upload/ebm/metodbok/Mall_modell_halsoekonomi.pdf. [Accessed 2012 Jan 03].
- 60.Maroto Hernando M, Soler Palacín P, Martin Nalda N, et al. Subcutaneous gammaglobulin in common variable immunodeficiency: first experience in Spain [in Spanish]. An Pediatr 2009;70:111–9.Google Scholar
- 73.Gennery AR, Slatter MA, Grandin L, on behalf of members of European Group for Blood and Marrow Transplantation and European Society for Immunodeficiency, et al. Long term survival and transplantation of haematopoietic stem cells for primary immunodeficiencies: report of the European experience 1968–2005. J Allergy Clin Immunol. 2010;126:602–10.PubMedCrossRefGoogle Scholar
- 77.FDA Safety Communication: New boxed warning for thrombosis related to human immune globulin products. 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm355986.htm.
- 78.European Medicines Agency. Hizentra. Product information. EMEA/H/C/002127-II/0020/G. 2013 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002127/human_med_001440.jsp&mid=WC0b01ac058001d124.