Immunoglobulin Dosage and Switch from Intravenous to Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Hypogammaglobulinemia: Decreasing Dosage Does Not Alter Serum IgG Levels
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- Thépot, S., Malphettes, M., Gardeur, A. et al. J Clin Immunol (2010) 30: 602. doi:10.1007/s10875-010-9417-2
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The impact of reducing immunoglobulin dosage while switching from intravenous to subcutaneous replacement therapy was evaluated.
Sixty-five patients with primary hypogammaglobulinemia on stable intravenous replacement therapy were included in a monocentric longitudinal trial. IgG trough levels were measured at baseline and during 1 year following the switch to the subcutaneous route.
Mean IgG trough level after 12 months of subcutaneous therapy was increased by 5.4% (8.37–8.82 g/l, p = 0.3), while immunoglobulin dosage had been reduced by 28.3% (151–108 mg/kg/week, p < 0.0001). For the patients with the lowest serum IgG level upon intravenous infusions, serum IgG level rose by 37% (5.33–7.33 g/l, p = 0.003), while mean immunoglobulin dosage was reduced by 36% (170–109 mg/kg/week, p = 0.04).
The present study shows that sustained serum IgG levels can be achieved after switching towards subcutaneous replacement despite using reduced immunoglobulin doses.
KeywordsSubcutaneous immunoglobulin replacementtherapyprimary immune deficiency
Patients with primary hypogammaglobulinemia, such as common variable immunodeficiency (CVID), X-linked agammaglobulinemia (XLA), or symptomatic selective IgG-subclass deficiency, are prone to recurrent or severe bacterial infections [1–4]. To prevent or alleviate infections, replacement therapy with IgG is needed, usually on a life-long basis [5–8]. Replacement immunoglobulin (Ig) can be given either as intravenous (IV) or subcutaneous (SC) infusions . Subcutaneous immunoglobulin (SCIg) therapy has shown many advantages compared with the IV administration. It is safe when used in patients with previous adverse effects to IV administration. The infusion technique is easy to learn and there is no need for venous access [10–12]. No difference in efficacy and safety has been reported between both administration routes when similar doses are applied when switching from the IV to the SC route . However, there are still open issues on the optimal doses to deliver through the SC route.
We studied the use of reduced cumulative SC doses compared to standard IV doses. To that purpose, we took advantage of a switch period from IVIg to SCIg in patients included in the French DEFI national study. The primary endpoint was the resulting IgG serum trough levels after 12 months of SCIg.
This study was designed as a longitudinal trial using each participant as his/her own control by comparing baseline IgG trough levels with the data collected during the 12-month study. The patients were followed in a single center (Hôpital Saint-Louis, Paris) and were included in the French DEFI national study on adults with primary hypogammaglobulinemia. The study has been approved by the local ethics committee, and all patients gave written informed consent.
Patients diagnosed with primary hypogammaglobulinemia and on stable IVIg replacement therapy for at least 1 year were eligible for the study. At enrollment, a retrospective analysis of IVIg replacement therapy within the last 12 months was performed.
Patients were proposed to switch towards home SCIg replacement therapy and were offered an educational program for self-administration. Subcutaneous IgG replacement therapy started 2 or 3 weeks after the last IV infusion and was repeated on a weekly basis. The first three or four SC infusions were performed under the supervision of training nurses. The following infusions were performed at home and the patients were followed at the outpatient clinic every 3 months for 1 year.
Three different types of concentrated (16–16.5%) immunoglobulin preparations were used according to the availability of the products (Subcuvia®, Gammanorm®, Vivaglobin®). Two small portable pumps were used simultaneously for once-per-week self-infusions, so that 20 ml could be administered at each infusion site. Infusions were delivered either in the abdominal wall or in the thighs. Infusion rate ranged between 10 and 15 ml/h.
Serum IgG levels
Serum IgG level was determined prior to the first SC infusion and thus reflected the serum IgG level in the second half of a dosing interval between two IV infusions. Thereafter, serial IgG dosages were performed after 3, 6, 9, and 12 months of SCIg replacement therapy.
Statistical comparisons were based on paired t test, and Wilcoxon matched-pairs or signed-rank test when appropriate. The Spearman rank correlation coefficient was used to estimate the correlation between IgG at day 0 and month 12. All p values were calculated by two-sided tests. Analyses were conducted using Stata, version 11.0 (StatCorp Inc., College Station, TX, USA).
From April 2005 until July 2008, 83 patients with primary hypogammaglobulinemia were eligible for the study. Ten patients were not offered to enter the trial. The reasons for not offering a switch towards home self-administrated SCIg therapy were the following: language problems, age, low IQ, and logistic problems. Further eight patients were not interested in switching towards home SCIg substitution therapy.
Therefore, a total of 65 patients aged 15 to 73 (mean = 43.8) entered the study. The mean weight was 64.3 kg (range = 40–103).
Diagnoses were as follows: 53 CVID (81.5%), four subclass deficiencies, three Good syndromes, three X-linked agammaglobulinemia, one hyper-IgM type I, and one X-linked lymphoproliferative syndrome.
Previous IVIg Replacement Therapy
All patients were receiving IV immunoglobulin therapy for more than 1 year at the time of inclusion. Thirty-six patients had received IVIg every 4 weeks, 20 every 3 weeks, and 4 every 2 weeks. The mean dosage for IVIg infusions was 32 g (range = 20–50) or 507 mg/kg (range = 308–1,000). The mean weekly dosage (total dose over the previous 12 months/52) was 9.4 g (range = 5–25) or 151 mg/kg (range = 77–454).
SCIg Replacement Therapy
All patients started with SCIg on a weekly basis. Fifty-four patients started with a standard dose of 6.4–6.6 g (40 ml) per week. Five patients were assigned to a 9.6 g (60 ml) per week dosage because of higher needs (above 10 g/week) through the IV route and one received 50 ml per week. The mean weekly dose for SCIg infusions was 6.7 g (range = 6.4–9.6) or 108 mg/kg (range = 62–174).
Serum IgG Trough Levels
No severe adverse reaction was observed in patients receiving SCIg during the 1-year follow-up. However, three patients preferred to switch back to the IV route because of fever, myalgia, and arthralgia in the days following the infusion. In order to evaluate the occurrence of major clinical events during the study, we focused on the hospitalization rates (HR) during two 12-month periods: before (upon IVIg) and after (upon SCIg) the switch. Forty-three hospitalizations (>24 h) have been recorded in 24 patients (HR = 0.84/pt. year) during the 12-month IVIg period, and 56 hospitalizations (>24 h) have been recorded in 15 patients (HR = 1.19/pt. year) during the 12-month SCIg period.
SCIg replacement as life-long therapy is being applied increasingly in patients with primary antibody deficiencies. However, only a few published pharmacokinetic studies are available for this route of administration [14–16]. One of those pharmacological studies had been carried out to determine the SCIg dosage required to achieve a comparable area under the curve of serum IgG level over time with both routes. The conclusion was that SCIg dose should be increased by 37% of the IVIg dose, this resulting in a mean SCIg dose of 158 mg/kg/week. The prospective study conducted thereafter with these newly determined doses showed that serum IgG level rose from 7.86 g/l at baseline to 10.4 g/l during SCIg treatment, representing an increase of IgG trough level by 39% . However, this increased SCIg dose did not appear to confer any additional clinical benefits when compared to a concomitant study where SCIg dose was kept identical to the previous IVIg dose. The latter study conducted in Europe and Brazil demonstrated that administering a SCIg dose equal to the previous IVIg dose (approximately 100 mg/kg/week) resulted in an IgG trough level of 9.2 g/l providing adequate protection to the patients . Overall, both SCIg doses were found to produce almost identical rates of overall infections and serious infections.
The currently recommended weekly dose of SCIg is 100–200 mg/kg/week. Doses may be adjusted over time to achieve the desired clinical response and serum IgG trough levels. However, for patients already upon IVIg replacement, the monthly IV dose is typically split into smaller doses for weekly infusions [13, 17].
Longer half-lives have been reported for SCIg in part due to longer Tmax and slower catabolic rates resulting from more stable serum levels since half-life varies with serum IgG concentrations [15, 18, 19]. Several studies have demonstrated that subcutaneous regimens result in higher IGG trough levels than those achieved on IV route, even when dosages are kept identical [20, 21].
We thus estimated that it was possible to consider Ig dose reduction while switching from IV to SC route. In our center, Ig dosage given intravenously had been adjusted individually in order to achieve both clinical (decreased infections) and biological (serum IgG above 7 g/l) targets. In order to optimize convenience, we proposed a standard SCIg dose of 6.4–6.6 g/week (40 ml) to most of the patients, even though it resulted in reducing IG dosage for some of them. IVIg dosage differs strikingly among centers and countries, which represents an issue regarding the comparison of subsequent SCIg dose [13, 16, 17]. It was therefore important to study the impact of SCIg dose reduction on IgG trough level in a crossover study, using the patients as their own controls. This is the first demonstration that significant reduction in SCIg doses provides suitable serum IgG levels.
Beyond achievement of a stable serum IgG level over time, we showed that IgG level upon SCIg was even above that reached in the middle of a dosing interval between two IV infusions. More interestingly, we also found that SCIg allowed achievement of adequate serum IgG levels in a subset of patients “refractory” to IVIg replacement. Those patients were unable to achieve sufficient IgG level while receiving high doses of IVIg, and this was overcome in most of them even with reduced SCIg doses. One can speculate on a more favorable pharmacokinetic profile of infused Ig using the SC route in patients with high Ig catabolism upon the IV route.
Overall infection rates could not be assessed, as a prospective and exhaustive collection of infectious events had not been performed during the IVIg period. We therefore evaluated the occurrence of major clinical events through the hospitalization rates and retrospective analysis of patient charts. Although the number of hospitalizations was slightly higher during the SCIg period, the number of patients requiring hospitalization was lower (15 during the SC period vs 24 during the IV period). Four patients had seven or more hospitalizations: one in the IV period (immune thrombocytopenia) and three during the SC period (granulomatous disease, IL2 therapy for severe CD4 lymphopenia, chronic enteropathy). Excluding these four patients, the hospitalization rates were very similar in both periods: 0.56/pt. year in the IV period and 0.42/pt. year in the SC period.
The perception of discomfort by the patient is a major factor for patient compliance. Discomfort should result from both the length of the perfusion as well as the number of infusion sites. In that attempt, a recent study investigated 200 mg/kg SCIg administered every other week . The bi-weekly schedule was well tolerated and resulted in high and stable serum IGG levels, offering interesting perspectives. Reduction in cumulative SCIg dose as demonstrated in our study represents an effective alternative mean to achieve better comfort.
In conclusion, the present study shows that SCIg replacement using reduced Ig doses is safe and effective, at least on the basis of achieved IgG trough levels. High serum IgG trough levels were easily maintained after the switch from IVIg to SCIg therapy, especially in patients with the lowest IgG trough level upon IVIg. Although no cost study has been performed, it can be assumed that this reduction in immunoglobulin dosage might result in important saves, as the immunoglobulin preparation constitutes most of the treatment cost.
We are grateful to the nurses from the Department of Immunology who were very enthusiastic to develop an educational program for home self-administration and to supervise the training of the patients. Most importantly, we thank the patients without whom there could be no study.