Matthew Helbert MBChB PhD FRCP FRCPath
Manchester Royal Infirmary,
Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
To reduce the risk of infection in patients with primary immunodeficiencies, replacement therapy with immunoglobulin is required. Subcutaneous administration of IgG is gaining acceptance among patients and clinicians.
Purified immunoglobulin (Ig) was initially produced as a byproduct when plasma was fractionated to produce albumin for severely injured US soldiers during World War 2. A clinical use for Ig was identified when antibody deficiency was first described in the early 1950s. Antibody deficiency syndromes predispose patients to a life-long risk of severe infections. The very first route for Ig administration was subcutaneous, although intramuscular Ig was widely adopted to enable increased dosing. As it became clear that antibody-deficient patients need several hundred grams of Ig replacement per year to remain free of infection, the intravenous (IV) route was explored and then widely adopted.
IVIg is effective at preventing infections in antibody-deficient patients, but requires prolonged infusions every three-to-four weeks. Some patients can be trained to administer these at home, but many are required to attend hospitals for treatment. To overcome this, some immunology teams evaluated smaller doses of Ig given subcutaneously (Sc). ScIg appears to be non-inferior to IVIg at preventing infections, although there is a paucity of head-to-head data. ScIg also appears be better tolerated than IVIg, possibly because of differences in catabolism and pharmacokinetics.
IgG catabolism takes place in diverse tissues throughout the body. One of the main factors affecting the rate of catabolism is a specialised Ig receptor, the neontal Fc receptor (FcRN).(1) Despite its name, FcRN is expressed throughout life, binds IgG and protects it from catabolism. This is a saturable mechanism, so that, when serum IgG is high, catabolism increases.
A dose of IVIg achieves Cmax and 100% bioavailability immediately after completion of the infusion. High peak IgG levels are thus achieved with a relatively short half-life of 34–37 days.(2) IVIg replacement is typically given every three weeks, so, by the time the next infusion is given, up to 50% of the infused Ig may have been catabolised and the trough IgG level may be 50% lower than the peak (Figure 1).
ScIg is generally given weekly at smaller doses. ScIg has a much lower bioavailability of approximately 60%, as much of a dose is degraded by tissues at the injection site and as the immunoglobulin diffuses to lymphatics. The immunoglobulin passes to the thoracic duct and finally the Cmax is achieved about 60 hours after the infusion. The peak of IgG level following ScIg is relatively low and thus the half life is over 40 days.
The same total dose of ScIg subcutaneously will achieve 10–20% higher trough IgG levels, compared with IVIg. Another way of looking at this is based on trough IgG levels; doses may be reduced by approximately 30% in patients switching from IVIg to ScIg.(3) The European Medicines Agency requires non-inferiority of trough- or steady-state levels when considering evidence on Ig products. By contrast, the US Food and Drug Administration requires area under the curve data. However, because of lower bioavailability, larger doses of ScIg are required to achieve the same area under the curve as IVIg. In the US, patients switching from IVIg to ScIg may have their doses increased by 137%. Meta-analysis suggests that the higher doses are associated with fewer infections.(4)
Impact of Ig in infections
The impact of IgG levels on infections have been ascertained through meta-analysis of trial and observational data on IVIg5 and ScIg.(6) These data suggest that the incidence of infection decreases as the IgG trough (with IVIg) or steady-state level (for ScIg) increases, without any clear plateau effect. Thus, the optimal dose or blood level for immunoglobulin replacement has not been determined.
These differences in pharmacokinetics are thought to be responsible for the improved health-related quality of life scores reported for ScIg. Patients receiving ScIg do not have dips in wellbeing that are associated with low trough levels in the days leading up to IVIg infusions. Similarly, ScIg recipients do not have the acute side-effects caused by rapidly increasing IgG levels, enabling ScIg patients to be treated safely at home. In one study, 92% of patients who had experienced both routes preferred ScIg.(7) Of course, this choice could also be affected by the shorter durations or the increased ability to proceed to home therapy. ScIg has been adopted widely in Northern Europe for treating antibody‑deficient patients, although IVIg is still used more frequently in North America.
New products and indications
Conventional 16% ScIg only delivers a relatively small dose of IgG, which is the reason why weekly infusions are required. Dosing can be increased by using a higher (20%) concentration of immunoglobulin. For example, Hizentra is the first 20% product and has been shown to meet both European and US licensing criteria. In clinical trials, it is non-inferior to other ScIg or IVIg products in adults and children.
Sc recombinant hyaluronidase
Another new approach is pre-treating with subcutaneous recombinant hyaluronidase, which temporarily breaks down the intercellular matrix, creating more ‘space’ for Ig. Anecdotal evidence from antibody-deficient patients suggests that this approach may enable higher doses of IgG to be tolerated.(8) It is claimed that the bioavailability of this preparation is greater than conventional ScIg, implying that clinical trials will be required to re-evaluate its efficacy and toxicity.
IVIg has been thoroughly investigated over the past 30 years in patients with antibody deficiency, yielding considerable efficacy and pharmacokinetic data. Some of these antibody-deficient patients develop autoimmune problems, for example thrombocytopenia. Ig was serendipitously found to have benefits in these autoimmune conditions. Randomised controlled trials have subsequently confirmed that IVIg is effective in a variety of autoimmune problems, and subsequent work showed that these immunomodulatory effects are optimised with high-dose IVIg. In the past ten years, the use of immunomodulatory Ig has become established for a variety of autoimmune diseases and this use is beginning to outstrip the use of Ig in antibody deficiency.
Immunomodulatory effects may be mediated through several different mechanisms. For example, there is evidence that high-dose IVIg occupies the protective FcRN, exposing any pathogenic auto-antibodies to catabolic processes. Alternatively, high-dose IVIg could bind to an inhibitory receptor – FcγRIIB – which downregulates the inflammatory response. Other potential modes of action include the effects of IgG dimmers or even excipients. Regardless of which of these is operating in any given autoimmune disease, an important requirement is high-dose IVIg.
The use of high-dose IVIg in many disorders, such as immune thrombocytopenia or Gullain-Barre syndrome, is generally for short periods of time. In other conditions, particularly the autoimmune neuropathies, treatment might continue for years at a time. Apart from the health economic implications, the long-term requirement for a person to visit hospital for infusions is undesirable. Neurologists have begun to evaluate ScIg as an alternative to IVIg in this setting.
For example, multifocal motor neuropathy is a chronic disabling neuropathy for which Ig is recommended. In one small crossover study (n=9), patients were treated with IVIg given every 18–56 days to weekly ScIg. The total dose per day was the same and similar IgG levels were obtained (although it is not clear if these are trough, peak or steady-state). The efficacy of the two treatments was very similar.(9)
Health economics have been applied to both ScIg and IVIg in the setting of antibody deficiency. Such studies are difficult to carry out because doses of Ig are usually customised and outcomes may be long term and diffuse (such as opportunity gains of days at work). Both ScIg and IVIG cost the same on a per gram basis. In the UK, there are savings on value-added tax for patients on home therapy. Pumps and disposables are more expensive for patients on ScIg at home, largely because they will be infusing weekly. Disposables cost less for IVIg, as it is usually given every three weeks. The largest single variable cost may be the cost of admission to a day unit. Generally ScIg patients are more able to transit to home therapy. Taking these factors into account, one model has established that home IVIg is most cost effective, followed by home Scig, with hospital-based IVIg being the most expensive.(10)
The demand for different Ig products is growing. However, the cost of fractionating Ig has increased, as the other major plasma components, such as albumin and factor VIII, have fallen into disuse because of lack of evidence, or have been replaced by a recombinant protein. Furthermore, the real or theoretical risks of blood-borne infections have affected supply from time to time. For example, because of the theoretical risk of transmission of the prions that cause vCJD and BSE, UK plasma is no longer fractionated.
In the UK, a national demand management scheme has been set up by the Department of Health.(11) This ensures that patients with good evidence for Ig treatment are prioritised for treatment.
In the future, Ig replacement for antibody deficiency will not be superseded by recombinant proteins. This is because polyclonal antibodies, with specificity against many thousands of pathogens, is required. Once the mode of action of immunomodulatory Ig is established, it is hoped that FcR ligands will be developed, relieving the pressure on Ig supplies.
- Subcutaneous immunoglobulin (ScIg) is widely used in antibody deficiency.
- Newer ScIg products are being developed to enable high-dose delivery (for example, Hizentra).
- The pharmacokinetics of intravenous Ig and ScIg are not the same.
- The pharmacokinetics of ScIg might explain why it has fewer side-effects.
- Because the pharmacokinetics are different, assumptions about similar efficacies of ScIg and IVIg cannot be made.
- Kuo TT et al. Neonatal Fc receptor: from immunity to therapeutics. J Clin Immunol 2010;30:777–89.
- Berger M. Choices in IgG replacement therapy for primary immune deficiency diseases: subcutaneous IgG vs. intravenous IgG and selecting an optimal dose. Curr Opin Allergy Clin Immunol 2011;11:532–8.
- Thépot S et al. Immunoglobulin dosage and switch from intravenous to subcutaneous immunoglobulin replacement therapy in patients with primary hypogammaglobulinemia: decreasing dosage does not alter serum IgG levels? J Clin Immunol 2010;30:602–6.
- Orange JS et al. Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy 1. Clin Exp Immunol 2012;169(2):172–81.
- Orange JS et al. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol 2010;137:21–30.
- Berger M. Incidence of Infection is inversely related to steady-state (trough) serum IgG level in studies of subcutaneous IgG in PIDD. J Clin Immunol 2011;31(5):924–6.
- Gardulf A et al. Lifelong treatment with gam-maglobulin for primary antibody deficiencies: the patients’ experiences of subcutaneous self-infusions and home therapy. J Adv Nurs 1995;21:917–27.
- Knight E et al. Self-administered hyaluronidase facilitated subcutaneous immunoglobulin home therapy in a patient with primary immunodeficiency. J Clin Pathol 2010;63:846–7.
- Harbo T et al. Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single-blinded cross-over trial. Eur J Neurol 2009;16:631–8.
- Hogy B, Keinecke HO, Borte M. Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance. Eur J Health Econ 2005;6:24–9.
- Department of Health. Clinical guidelines for immunoglobulin use (second edition). www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_085235 (accessed 30 August 2012).