Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy

Abstract

The importance of serum immunoglobulin (Ig)G concentration in IgG replacement therapy for primary immunodeficiency diseases is established in certain settings. Generally, IgG is infused via the intravenous (IVIG) or subcutaneous (SCIG) route. For IVIG infusion, published data demonstrate that higher IgG doses and trough levels provide patients with improved protection from infection. The same conclusions are not yet accepted for SCIG; data from two recent Phase III studies and a recent post-hoc analysis, however, suggest the same correlation between higher SCIG dose and serum IgG concentration and decreased incidence of infection seen with IVIG. Other measures of clinical efficacy have not been considered similarly. Thus, combined analyses of these and other published SCIG studies were performed; a full comparison of the 13 studies was, however, limited by non-standardized definitions and reporting. Despite these limitations, our analyses indicate that certain clinical outcomes improve at higher SCIG doses and associated higher serum IgG concentrations, and suggest that there might be opportunity to improve patient outcomes via SCIG dose adjustment.

Fig. 1

Suggested dose-related response in two recent clinical studies. The higher immunoglobulin (Ig)G dose in the Hizentra® US study [19] resulted in an increased serum IgG concentration and reduced days on antibiotics, days in hospital, days off work/school and non-serious infections. The x-axis shows the log ratio between efficacy indicators in the US and European trials [25].

Fig. 2

Subcutaneous immunoglobulin (SCIG) dose and serum IgG concentration. Higher SCIG doses were correlated significantly with higher serum IgG concentrations (r = 0·746, P = 0·013). Mean, median and mean of median data provided in [7,13,17,20,24,25] were analysed. The outlier [24] might occur because no washout period was incorporated between intravenous immunoglobulin (IVIG) and SCIG therapy and the serum IgG concentration range for months 0–6 was provided. Black circles are prospective clinical trials, and the grey circle is the only retrospective study: Maroto et al. [20]. The solid trendline represents the weighted regression excluding Maroto et al.; the dashed trendline includes data from Maroto et al. Circles are sized proportionally to the number of patients in the study, with text overlay indicating the study: Chapel 2000 (Ch), Fasth 2007 (Fa), Gardulf 1991 (Ga91), Gardulf 2006 (Ga06), Hagan 2010 (Ha), Jolles 2011 (Jo), Maroto 2008 (Ma), Ochs 2006 (Oc), Thepot 2010 (Th) and Wasserman 2011 (Wa11).

Fig. 3

Rate of infection and steady-state immunoglobulin (Ig)G level. A higher serum IgG concentration results in a lower rate of non-serious infection. The correlation is significant (P = 0·030) when only clinical trial data are included. Significance is lost when the retrospective study by Maroto et al. is included (P = 0·178). Black circles are clinical trials and the grey circle is the retrospective study. The solid trendline represents the weighted regression excluding Maroto et al.; the dashed trendline includes data from Maroto et al. Circles are sized proportionally to the number of patients in the study, with text overlay indicating the study: Berger 2009 (Be), Chapel 2000 (Ch), Desai 2009 (De), Fasth 2007 (Fa), Gardulf 2006 (Ga06), Hagan 2010 (Ha), Jolles 2011 (Jo), Maroto 2008 (Ma), Ochs 2006 (Oc), Wasserman 2010 (Wa10) and Wasserman 2011 (Wa11).

Fig. 4

Subcutaneous immunoglobulin (SCIG) dose and rate of infection. The SCIG dose did not correlate with the rate of infection. However, data from the larger clinical trials (black circles) suggest that under these conditions SCIG dose might be linked to infection rate. Black circles are clinical trials and the red circle the retrospective study. The solid trendline represents the weighted regression excluding Maroto et al.; the dashed trendline includes data from Maroto et al. Circles are sized proportionally to the number of patients in the study, with text overlay indicating the study: Chapel 2000 (Ch), Fasth 2007 (Fa), Gardulf 2006 (Ga06), Hagan 2010 (Ha), Jolles 2011 (Jo), Maroto 2008 (Ma), Ochs 2006 (Oc) and Wasserman 2011 (Wa11).