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Clinical and Experimental Immunology
I M M U N O G LO BU L I N I N C L I N I C A L P R AC T I C E
doi:10.1111/cei.12515
7th International Immunoglobulin Conference: Immunoglobulin in Clinical Practice
R. S. Shapiro* and M. Borte† *Midwest Immunology Clinic, Plymouth, MA, USA, and †St Georg Hospital, Leipzig, Germany
Correspondence: M. Borte. E-mail: [email protected]
Summary Immunoglobulin (Ig) replacement therapy has been the mainstay of primary immunodeficiencies (PID) treatment for more than 30 years and has substantially changed the lives of patients. This review focuses on aspects of Ig use in clinical practice in addition to discussing prioritizing future Ig use. Despite Ig therapy, PID patients continue to be predisposed to recurrent, subclinical respiratory tract infections, which may lead to chronic lung disease. Research has shown that one of the underlying reasons for this deterioration in lung function is the differential distribution and concentration of Ig isotypes in the airway lumen. Further to this, the relationship between Ig dose and infection outcome is explored, expanding on end-of-cycle loss of efficacy (wear-off) particularly with intravenous immunoglobulin (IVIg), how this can confound the determination of optimal IgG dose and how our aim of treatment should be to improve clinical outcome. This review goes on to discuss the safety of Ig replacement therapy, which is generally well tolerated by most patients, compares the rates of systemic adverse reactions between IVIg and SCIg and highlights the advantages of SCIg administration in this respect, including the use of pre-infused subcutaneous recombinant human hyaluronidase to aid subcutaneous infusion volumes. The growing demand for Ig replacement therapy is challenging physicians; here we show the development of prioritization algorithms to assist in identifying those who will benefit most from this clinically valuable therapy. Keywords: facilitated infusion, intravenous immunoglobulin, prioritization, subclinical infection, subcutaneous immunoglobulin
Introduction The treatment of deficiencies in antibody production with immunoglobulin (Ig) has been the standard of care globally for over 30 years. In this session, chaired by Drs Shapiro and Borte, selected aspects of the use of Ig in clinical practice will be discussed. As summarized by Dr Jolles, despite the relationship between IgG dose and IgG trough level, and the known inverse relationship between trough serum Ig level and infection outcome, patients with primary immunodeficiency (PID) who appear to be adequately replaced with Ig continue to be susceptible to recurrent, clinical and subclinical respiratory tract infections. Data from studies in patients with common variable immunodeficiency (CVID) indicate that chronic lung disease is a major cause of morbidity and mortality [1]. Additionally, analysis of large cohorts of PID patients has shown that the IgG trough
levels required to prevent breakthrough bacterial infections varies between patients identifying the need for individualized dosing strategies. Dr Baumann describes a metaanalysis of the incidence of airway infection in patients with CVID and X-linked agammaglobulinaemia (XLA). Chronic sinusitis and bronchiectasis are a significant problem in these patient groups, and it is suggested that the cause may be differences in the concentration and distribution of Ig isotypes in the airway lumen, leading to the concept of systemic and local application of different isotypes. Thus, an understanding of the aetiology of progressive structural lung disease, as well as the relationship between Ig dose and infection outcome, may help to individualize Ig treatment in PID patients. Dr Misbah reports on the end-of-cycle loss of efficacy (wear-off), particularly with intravenous immunoglobulin (IVIg), which can confound the determination of optimal
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 65–66
65
R. S. Shapiro & M. Borte
IgG dose. With regard to dosing strategies, attainment of a target trough serum IgG level [2] and individualization of doses and target serum IgG levels [3] have both been evaluated. Dr Misbah additionally explores the alternative administration method of subcutaneous immunoglobulin (SCIg) as a means of reducing end-of cycle loss of efficacy. Adverse effects of Ig therapy, focusing on thromboembolism and haemolysis, and the risk factors associated with them, are discussed by Dr Bonilla. Overall, Ig replacement therapy is generally well tolerated by most patients and any reported systemic adverse events are mostly mild and reversible or treatable. Rapid absorption of Ig from infusion sites into the circulation and three-dimensional mobility of Ig in the subcutaneous (s.c.) space is impeded by hyaluronan, a constituent of the extracellular matrix. Consequently, SCIg infusion volumes are lower than with IVIg and require an increased number of s.c. infusion sites to accommodate the required dose. Dr Wassermann summarizes trial data showing that pre-infusion of s.c. recombinant human hyaluronidase allows SCIg delivery into a single site in an infusion time comparable to IVIg. Finally, with the growing number of indications for Ig, the demand for this clinically valuable resource has increased, leaving health-care professionals with the dilemma of how to identify patients who will benefit most from therapy. Dr Orange has modelled the demand for Ig therapy and describes a theoretical model based on decision analysis aimed at prioritizing evidence-based indications for IVIg [4]. In the same session, Dr Orange calls upon the multi-speciality audience to provide an additional level of consensus with the invitation to rate six Ig indications.
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Acknowledgements M. B. is grateful for the continuous support of Dr Maria Fasshauer (Germany) in conducting immunoglobulin studies. The authors would like to thank Meridian HealthComms Ltd for providing medical writing services.
Disclosures R. S. has received support as a consultant, principle investigator and speaker for Baxter, CSL Behring, Shire, BPL and Kedrion. M. B. has received support for consulting and conferences from Baxter, CSL Behring, Octapharma, Grifols and Biotest and research grants from Octapharma and CSL Behring.
References 1 Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119:1650–7. 2 Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol 2010; 137:21–30. 3 Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol 2010; 125:1354– 60 e4. 4 Orange JS, Ochs HD, Cunningham-Rundles C. Prioritization of evidence-based indications for intravenous immunoglobulin. J Clin Immunol 2013; 33:1033–6.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 65–66
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Clinical and Experimental Immunology
I M M U N O G LO BU L I N I N C L I N I C A L P R AC T I C E
doi:10.1111/cei.12515
7th International Immunoglobulin Conference: Immunoglobulin in Clinical Practice
R. S. Shapiro* and M. Borte† *Midwest Immunology Clinic, Plymouth, MA, USA, and †St Georg Hospital, Leipzig, Germany
Correspondence: M. Borte. E-mail: [email protected]
Summary Immunoglobulin (Ig) replacement therapy has been the mainstay of primary immunodeficiencies (PID) treatment for more than 30 years and has substantially changed the lives of patients. This review focuses on aspects of Ig use in clinical practice in addition to discussing prioritizing future Ig use. Despite Ig therapy, PID patients continue to be predisposed to recurrent, subclinical respiratory tract infections, which may lead to chronic lung disease. Research has shown that one of the underlying reasons for this deterioration in lung function is the differential distribution and concentration of Ig isotypes in the airway lumen. Further to this, the relationship between Ig dose and infection outcome is explored, expanding on end-of-cycle loss of efficacy (wear-off) particularly with intravenous immunoglobulin (IVIg), how this can confound the determination of optimal IgG dose and how our aim of treatment should be to improve clinical outcome. This review goes on to discuss the safety of Ig replacement therapy, which is generally well tolerated by most patients, compares the rates of systemic adverse reactions between IVIg and SCIg and highlights the advantages of SCIg administration in this respect, including the use of pre-infused subcutaneous recombinant human hyaluronidase to aid subcutaneous infusion volumes. The growing demand for Ig replacement therapy is challenging physicians; here we show the development of prioritization algorithms to assist in identifying those who will benefit most from this clinically valuable therapy. Keywords: facilitated infusion, intravenous immunoglobulin, prioritization, subclinical infection, subcutaneous immunoglobulin
Introduction The treatment of deficiencies in antibody production with immunoglobulin (Ig) has been the standard of care globally for over 30 years. In this session, chaired by Drs Shapiro and Borte, selected aspects of the use of Ig in clinical practice will be discussed. As summarized by Dr Jolles, despite the relationship between IgG dose and IgG trough level, and the known inverse relationship between trough serum Ig level and infection outcome, patients with primary immunodeficiency (PID) who appear to be adequately replaced with Ig continue to be susceptible to recurrent, clinical and subclinical respiratory tract infections. Data from studies in patients with common variable immunodeficiency (CVID) indicate that chronic lung disease is a major cause of morbidity and mortality [1]. Additionally, analysis of large cohorts of PID patients has shown that the IgG trough
levels required to prevent breakthrough bacterial infections varies between patients identifying the need for individualized dosing strategies. Dr Baumann describes a metaanalysis of the incidence of airway infection in patients with CVID and X-linked agammaglobulinaemia (XLA). Chronic sinusitis and bronchiectasis are a significant problem in these patient groups, and it is suggested that the cause may be differences in the concentration and distribution of Ig isotypes in the airway lumen, leading to the concept of systemic and local application of different isotypes. Thus, an understanding of the aetiology of progressive structural lung disease, as well as the relationship between Ig dose and infection outcome, may help to individualize Ig treatment in PID patients. Dr Misbah reports on the end-of-cycle loss of efficacy (wear-off), particularly with intravenous immunoglobulin (IVIg), which can confound the determination of optimal
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 65–66
65
R. S. Shapiro & M. Borte
IgG dose. With regard to dosing strategies, attainment of a target trough serum IgG level [2] and individualization of doses and target serum IgG levels [3] have both been evaluated. Dr Misbah additionally explores the alternative administration method of subcutaneous immunoglobulin (SCIg) as a means of reducing end-of cycle loss of efficacy. Adverse effects of Ig therapy, focusing on thromboembolism and haemolysis, and the risk factors associated with them, are discussed by Dr Bonilla. Overall, Ig replacement therapy is generally well tolerated by most patients and any reported systemic adverse events are mostly mild and reversible or treatable. Rapid absorption of Ig from infusion sites into the circulation and three-dimensional mobility of Ig in the subcutaneous (s.c.) space is impeded by hyaluronan, a constituent of the extracellular matrix. Consequently, SCIg infusion volumes are lower than with IVIg and require an increased number of s.c. infusion sites to accommodate the required dose. Dr Wassermann summarizes trial data showing that pre-infusion of s.c. recombinant human hyaluronidase allows SCIg delivery into a single site in an infusion time comparable to IVIg. Finally, with the growing number of indications for Ig, the demand for this clinically valuable resource has increased, leaving health-care professionals with the dilemma of how to identify patients who will benefit most from therapy. Dr Orange has modelled the demand for Ig therapy and describes a theoretical model based on decision analysis aimed at prioritizing evidence-based indications for IVIg [4]. In the same session, Dr Orange calls upon the multi-speciality audience to provide an additional level of consensus with the invitation to rate six Ig indications.
66
Acknowledgements M. B. is grateful for the continuous support of Dr Maria Fasshauer (Germany) in conducting immunoglobulin studies. The authors would like to thank Meridian HealthComms Ltd for providing medical writing services.
Disclosures R. S. has received support as a consultant, principle investigator and speaker for Baxter, CSL Behring, Shire, BPL and Kedrion. M. B. has received support for consulting and conferences from Baxter, CSL Behring, Octapharma, Grifols and Biotest and research grants from Octapharma and CSL Behring.
References 1 Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119:1650–7. 2 Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol 2010; 137:21–30. 3 Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol 2010; 125:1354– 60 e4. 4 Orange JS, Ochs HD, Cunningham-Rundles C. Prioritization of evidence-based indications for intravenous immunoglobulin. J Clin Immunol 2013; 33:1033–6.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 65–66
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
