What is the burden of immunoglobulin replacement therapy in adult patients with primary immunodeficiencies? A systematic review

© 2018 Jones, Vogt, Chambers, Clowes and Shrimpton. Background: Primary immunodeficiency disorders (PIDs) are a group of heterogeneous rare disorders, whereby the immune system is missing or not functioning adequately. For patients requiring treatment, the most common option is immunoglobulin replacement therapy (Ig). Treatment of PIDs is simultaneously associated with both improvements in health-related quality of life (HRQoL) and increased treatment burden. Objectives: This review sought to review studies investigating the burden of Ig treatment, synthesize evidence in relation to administration routes (subcutaneous or intravenous) and instruments used, as well as make recommendations for clinical and research applications in this area for patients aged 16 years and older. Methods: We searched Medline, EMBASE, and The Cochrane Library. Sifting of titles was performed by two reviewers, and the assessment of full-text articles by three. From a database which contained 3,770 unique results, 67 full texts were reviewed. Eventually, 17 studies were found to meet the inclusion criteria, and included in this review. Due to data heterogeneity, a narrative, descriptive synthesis of the evidence was undertaken. Results: Most studies were carried out in the USA/North America, used a prospective observational design and involved patients with common variable immune deficiency. Four studies measured the burden of receiving IVIg therapy and 13 measured SCIg therapy. A wide range of measures, primarily designed to measure aspects of treatment satisfaction (e.g., life quality index or a slightly modified version) and HRQoL (e.g., The Short Form-36) had been used. Conclusion: Lack of a parallel control group in most studies meant that changes in outcomes could be due to factors other than changes in the treatment regimen. However, overall, PID patients appeared to report little Ig treatment burden and were satisfied with either modality. However, patient preference appeared to be the delivery of the Ig treatment in the patient's home and SCIg was preferred after switching from IVIg therapy. Individual differences appeared to affect treatment preference and therefore understanding the decision support needs of PID patients facing IG treatment choices would be valuable. Using a questionnaire specifically designed to measure the burden of Ig treatment from the patient's perspective is recommended in future research

Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency

Background: Subcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (WIG) therapy.Methods: We evaluated the efficacy and safety of the SCIG Vivaglobin (R) (formerly known as Beriglobin (R) SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with WIG (including 11 children <14 years) using the Short Form 36 (SF-36) for patients >= 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children <14 years of age. Treatment preferences were assessed in adults.Results: The mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p<0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by >= 5 points were observed in 5 of 8 SF-36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p <= 0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over WIG therapy (92%) and home therapy over therapy at the clinic/physician (83%).Conclusion: This study confirms that therapy with Vivaglobin (R) at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency

Predictive markers for humoral influenza vaccine response in patients with common variable immunodeficiency (CVID)

BACKGROUND: A subgroup of patients with common variable immunodeficiencies (CVID) responds to vaccination. The aim of the study was to try to identify predictive markers for those who developed a humoral immune response after influenza vaccination. METHODS: 48 patients with CVID (29 females, 19 males, mean age 59.4 years) were vaccinated with the A(H1N1) influenza vaccine Pandemrix® and boosted after one month. Blood samples were collected prior to each vaccination and two months later. Patients with a 4-fold titer increase of the hemagglutinin inhibition test (≥ 1:40) were considered responders and compared to non-responders for clinical, immunological and genetic markers. RESULTS: Eight (16.7%) patients responded to the vaccination. A significantly higher proportion of the responders, who showed a Euroclass SmB-Trnorm21norm profile (p=0.03) with a post-germinal center B cell pattern (p=0.04) in blood, suffered from enteropathies (p=0.04) as compared to non-responders. Bronchiectasis on the other hand, was exclusively found among non-responders (n=7), as was autoimmune cytopenia (n=5). Non-responders with a Euroclass SmB-21lowTrnorm profile (p=0.02), had a significantly higher prevalence of progressive antibody deficiency (p=0.048) and, at diagnosis, a higher mean serum IgM level (p=0.03), a lower mean serum IgG1 level (p=0.007), an expansion of absolute counts of cytotoxic CD8+ T-cells (p=0.033) and an increased proportion of memory CD8+ T-cells (p=0.044) in blood. CVID associated HLA markers were not detected in non-responders (p=0.03). CONCLUSION: About one-fifth of the CVID patients achieved protective antibody levels after A(H1N1) vaccination and selected clinical and immunological markers were identified that may predict a positive outcome of influenza vaccination

Efficacy and Safety of a New 20% Immunoglobulin Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary Immunodeficiency

Subcutaneous human IgG (SCIG) therapy in primary immunodeficiency (PID) offers sustained IgG levels throughout the dosing cycle and fewer adverse events (AEs) compared to intravenous immunoglobulin (IVIG). A phase I study showed good local tolerability of IgPro20, a new 20% liquid SCIG stabilized with L-proline. A prospective, open-label, multicenter, single-arm, phase III study evaluated the efficacy and safety of IgPro20 in patients with PID over 15 months. Forty-nine patients (5–72 years) previously treated with IVIG received weekly subcutaneous infusions of IgPro20. The mean serum IgG level was 12.5 g/L. No serious bacterial infections were reported. There were 96 nonserious infections (rate 2.76/patient per year). The rate of days missed from work/school was 2.06/patient per year, and the rate of hospitalization was 0.2/patient per year. Ninety-nine percent of AEs were mild or moderate. No serious, IgPro20-related AEs were reported. IgPro20 effectively protected patients with PID against infections and maintained serum IgG levels without causing unexpected AEs

Efficacy and Safety of Hizentra®, a New 20% Immunoglobulin Preparation for Subcutaneous Administration, in Pediatric Patients with Primary Immunodeficiency

Subcutaneous IgG treatment for primary immunodeficiencies (PI) is particularly well suited for children because it does not require venous access and is mostly free of systemic adverse events (AEs). In a prospective, open-label, multicenter, single-arm, Phase III study, 18 children and five adolescents with PI were switched from previous intravenous (IVIG) or subcutaneous (SCIG) IgG treatment to receive dose-equivalent, weekly subcutaneous infusions of Hizentra® for 40 weeks. Mean IgG trough levels were maintained in patients previously on SCIG, or increased in those previously on IVIG, regardless of age. No serious bacterial infections were reported during the efficacy period of the study. The rates of non-serious infections were 4.77 (children) and 5.18 (adolescents) infections per patient per year. Related AEs were observed in seven children (38.9%) and two adolescents (40%). Three serious AEs and two AEs leading to discontinuation (all unrelated) were reported in children. Hizentra® is an effective and well-tolerated treatment for pediatric patients

Primary immune deficiencies - principles of care

Primary immune deficiencies (PIDs) are a growing group of over 230 different disorders caused by ineffective, absent or an increasing number of gain of function mutations in immune components, mainly cells and proteins. Once recognized, these rare disorders are treatable and in some cases curable. Otherwise untreated PIDs are often chronic, serious, or even fatal. The diagnosis of PIDs can be difficult due to lack of awareness or facilities for diagnosis, and management of PIDs is complex. This document was prepared by a worldwide multi-disciplinary team of specialists; it aims to set out comprehensive principles of care for PIDs. These include the role of specialized centers, the importance of registries, the need for multinational research, the role of patient organizations, management and treatment options, the requirement for sustained access to all treatments including immunoglobulin therapies and hematopoietic stem cell transplantation, important considerations for developing countries and suggestions for implementation. A range of healthcare policies and services have to be put into place by government agencies and healthcare providers, to ensure that PID patients worldwide have access to appropriate and sustainable medical and support services

Current treatment options with immunoglobulin G for the individualization of care in patients with primary immunodeficiency disease

Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin (Ig)G to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualized to provide optimal medical and quality‐of‐life outcomes in infants, children, adults and elderly people. Frequency, dose, route of administration, home or infusion‐centre administration, and the use of self‐ or health‐professional‐administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patient's treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self‐infusion regimens, however, require independence and self‐reliance, good compliance on the part of the patient/parent and the confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self‐administer or a lack of self‐reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health‐related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed