Effective dosing strategies for therapeutic immunoglobulin: managing wear-off effects in antibody replacement to immunomodulation.

Abstract

Determining optimal dosing strategies for therapeutic immunoglobulin (Ig) to minimize ‘wear-off’ effects (defined here as end-of-cycle loss of efficacy, although wear-off may also refer to secondary end-points such as fatigue) is particularly challenging in the face of limited data. Loss of efficacy of Ig therapy is linked to waning bioavailability and may be explained on the basis of Ig pharmacokinetics and catabolism. It is predominantly a problem with intravenous immunoglobulin (IVIg) as replacement therapy or as an immunomodulator. However, there are no systematic data on the scale of the problem. When Ig is used as antibody replacement therapy, the frequency of infections and trough/steady state IgG levels could be considered as surrogate markers for wear-off effects. A clear inverse relationship between trough/steady state IgG levels and pneumonia has been shown in studies of patients with primary immunodeficiency disease (PID) treated with either intravenous or subcutaneous Ig 1,2. A 27% decrease in the incidence of pneumonia for every 100 mg/dl increase in IgG trough level was reported by a meta-analysis of 17 clinical studies of patients on IVIg replacement therapy 1. Although no given IgG trough level is necessarily adequate for all patients, maintaining higher IgG levels may be beneficial 2. However, even with the use of recommended doses and achievement of Ig trough levels within the reference range, overall lung function has been shown to decline. In addition, despite adequate Ig replacement, silent and asymptomatic progression of pulmonary changes has been shown to occur in patients with primary hypogammaglobulinaemia 3. A prospective study of patients with common variable immunodeficiency disorders (CVIDs) or X-linked agammaglobulinaemia (XLA), carried out over a period of 22 years in our department, showed that a wide range of trough Ig levels was required to keep patients infection-free 4. Therefore, the goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level 4. Data from a national online registry of PID in the United Kingdom (UKPID Registry) has shown that the annual incidence of new infections is approximately one patient per year 5. In patients with PID receiving IVIg the frequency of infection varies by week, with the highest frequency of infections at the end of 3- or 4-week dosing cycles, which may be indicative of a ‘wear-off’ effect 6. Whether this effect is clinically significant is debatable. Although trough Ig levels have been shown to be a reasonable marker of infection protection, trying to capture wear-off effects is challenging; there is no direct relationship between dose of Ig and infection protection once a certain critical trough IgG level has been reached. The use of trough serum IgG within the reference range as a therapeutic target has been complemented by studies supporting the concept of individualized dosing as providing optimal protection against infections 7. As these principles are increasingly translated into clinical practice and patients receive better protection, it is probable that the scale of significant wear-off effects in patients receiving Ig for antibody replacement is likely to be limited. In contrast, the serendipitous discovery of the use of Ig as an immunomodulator has meant that initial dosing strategies for the treatment of autoimmune disease were set empirically at 2 g/kg. In patients receiving IVIg for autoimmune neuropathies, end-of-cycle wear-off effects in the form of worsening weakness, paresthaesia and fatigue are well recognized clinically. In individual patients, serial measurement of muscle strength has enabled neurological ‘wear-off’ effects to be quantified. The strength of ankle dorsiflexion in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) improved following the administration IVIg reaching a peak around day 10 and then declined to pretreatment level 8. A similar fluctuation in muscle strength has been shown in a patient with multifocal motor neuropathy (MMN) during monthly IVIg 9. This clear cyclical wear-off effect can be avoided following transition to a weekly regimen of subcutaneous immunoglobulin (SCIg) administration without deterioration and with a sustained overall improvement in health-related quality of life 10. Similarly, a retrospective chart review of a cohort of patients (n = 43) with autoimmune neuropathy (MMN, n = 26; CIDP, n = 8; other, n = 9) has shown that definite wear-off effects were observed more commonly in patients receiving IVIg compared with SCIg therapy (11 versus 3; unpublished data, Table 1). Clinically stable patients treated with IVIg have low intra- and interpatient variability in IgG levels, which may indicate that constant levels are required for this stability 11. Does this imply that patients with fluctuating IgG levels have suboptimally controlled disease? Data from a randomized controlled trial suggest that patients with CIDP have stable disease on monthly doses of 1 g/kg 12. However, observational studies document a wide range of doses and treatment intervals, including 0·19–1·15 g/kg every 2–17 weeks 13 and 0·8–1·8 g/kg every 1–13 weeks 14, suggesting substantial disease heterogeneity and variation in the extent of wear-off effects. Table 1 Extent of wear-off effects in an Oxford cohort of autoimmune neuropathy patients receiving immunoglobulin (Ig) therapy In the absence of systematic data on the magnitude of ‘wear-off’ effects, Ig dosing is still tinged with empiricism. Where Ig is used as replacement therapy, the increasing acceptance of individualized dosing regimens may make accurate quantification of ‘wear-off’ effects challenging. In contrast, the emerging evidence attesting to SCIg being as equally efficacious maintenance therapy as IVIg in autoimmune neuropathies has led to its increasing adoption as an effective method of minimizing wear-off effects in this group. Data from prospective comparative trials of IVIg versus SCIg will be required to confirm this clinical impression.