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Rheumatology 2001; 40: 513-521
© 2001 British Society for Rheumatology

Original Papers

Intravenous immunoglobulin application following immunoadsorption: benefit or risk in patients with autoimmune diseases?

S. Schmaldienst, M. Müllner1, A. Goldammer, S. Spitzauer2, S. Banyai, W. H. Hörl and K. Derfler

Department of Medicine III, Division of Nephrology and Dialysis,
1 Department of Emergency Medicine and
2 Department of Laboratory Medicine, University of Vienna, Vienna, Austria


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To evaluate infection rates, side-effects and autoantibody resynthesis after immunoadsorption with and without intravenous immunoglobulin substitution.

Methods. Thirty-five patients with autoimmune diseases who were on long-term immunoadsorption therapy participated in a prospective, randomized study.

Results and conclusions. Infections were rare but similar in frequency in patients receiving combined immunoadsorption and intravenous immunoglobulins (intervention group, n=17, 1.3 infections per patient-year) and in a control group (n=18, 0.9 infections per patient-year) treated by immunoadsorption alone. The reduction in IgG achieved with two immunoadsorptions within 3 days was 95.0±2.5%. The extent of removal of pathogenic autoantibodies was similar to the removal of IgG. Substitution of immunoglobulins was not associated with an increased circulating IgG level before the following immunoadsorption. Infusion of immunoglobulins at a dose of 0.14 g/kg (interquartile range 0.12–0.16) body weight in patients in whom circulating immunoglobulins had been depleted was associated with a high incidence of serious side-effects; these necessitated the termination of treatment in 24% of the patients. No evidence was found that immunoglobulin administration had any beneficial effect with respect to autoantibody resynthesis after immunoadsorption.

KEY WORDS: Immunoadsorption, Intravenous immunoglobulins, Autoimmune disease, Autoantibody resynthesis, Side-effects, Infection.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Immunoadsorption of circulating immunoglobulins is a novel extracorporeal treatment modality which has gained increasing clinical acceptance in the treatment of several autoimmune diseases, such as systemic lupus erythematosus, myasthenia gravis pseudoparalytica and Guillain–Barré syndrome [1–4]. Immunoadsorption (IgG apheresis) is commonly instituted in patients who have been treated hitherto by plasma exchange [5–7]. In contrast to plasma exchange, IgG apheresis allows nearly complete clearance of circulating immunoglobulins of all types and subtypes without the concomitant substitution of fresh frozen plasma or albumin solutions [8, 9]. In addition, the plasma volume processed is not restricted even when patients are maintained on daily immunoadsorption [10, 11]. For these reasons, immunoadsorption has high therapeutic efficacy even in the treatment of diseases in which plasma exchange had failed to achieve improvement in the clinical outcome [6, 10–12]. Immunoadsorption has been demonstrated to offer a treatment option in patients with spontaneous and acquired haemophilia A, patients with dilated cardiomyopathy and in highly sensitized (HLA antibodies) renal transplant recipients [11–15].

Almost complete depletion of IgG by repeated immunoadsorption might be associated with an increased risk of bacterial and viral infections, as in patients with hypo- or agammaglobulinaemia and in particular in patients receiving combined immunoadsorption and cytotoxic or immunosuppressive drug treatment. In patients with primary or secondary immunoglobulin deficiency, a beneficial effect with respect to the frequency and sever ity of infectious complications was found after substitution of intravenous immunoglobulins (IVIG) at a dose of 0.26–1.1 g/kg body weight (BW) [16–19]. Even in critically ill patients without primary hypogammaglobulinaemia, a reduced rate of infection was observed in the cohort treated prophylactically with IVIG compared with controls treated with placebo [20, 21].

IVIG has also been used for the treatment of patients with autoimmune and systemic inflammatory disorders. Despite a number of years of experience of this treatment, the mechanism of the immunomodulatory actions of IVIG is not fully understood [22]. However, IVIG is accepted as an effective and convenient alternative to plasmapheresis for the treatment of disorders that are mediated by circulating autoantibodies or immune complexes. Immunomodulatory effects have only been reported at a total dose greater than 1 g/kg BW [5, 22–41]. No beneficial effect was achieved with a combination of plasma exchange and IVIG compared with plasma exchange or IVIG alone in patients with Guillain–Barré syndrome [42].

So far there has been no detailed report on the administration of IVIG after immunoadsorption. Such information might be of interest with respect to the additional immunosuppressive properties of combined treatment [43].

Immunoadsorption is commonly combined with polyclonal IVIG at the end of the last treatment of a course in order to restore the serum IgG level [1, 10–12, 15]. However, different amounts of IVIG have been used and there has been no prospective evaluation of the use of this type of combined treatment in order to reduce infectious complications and to delay antibody resynthesis. Beside the estimated beneficial effects of IVIG in immunoadsorption-treated patients, there may be serious side-effects due to IVIG, such as osmotic nephrosis, anaphylactic reactions, aseptic meningitis, nausea and/or hypotension [44–53]. Adverse reactions occurred in up to 8.7% of infusions and were more frequent at high infusion rates [45, 54]. Furthermore, even low-dose substitution of IVIG (0.15 g/kg BW) combined with immunoadsorption leads to a 50% increase in the cost of long-term immunoadsorption.

In this study, we investigated 35 patients on long-term immunoadsorption with respect to the rate of infection, the frequency of adverse reactions due to IVIG application and immunological effects associated with the combination of immunoadsorption with IVIG.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
Thirty-five patients who were being treated by immunoadsorption for immunological disorders were included in this prospective, randomized study. Demographic data are presented in Table 1Go. Patients already on long-term immunoadsorption (n=20) or who had been referred to the apheresis unit only recently (n=15) were included in the study protocol during a randomization period of 12 months. Patients with an expected short course of immunoadsorption (haemophiliacs and patients with Guillain–Barré syndrome [10, 11, 55]) were excluded, as were patients younger than 18 yr. The study period ended in October 1999 or when the patient was withdrawn from immunoadsorption.


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  		TABLE 1. Clinical characteristics of patients on long-term immunoadsorption treatment (IA) with (intervention group) or without (control group) immunoglobulin substitution after immunoadsorption

 
All subjects who were asked to participate in the study gave informed consent. The study protocol was reviewed and approved by the local ethics committee.

Sample size calculation and randomization
The primary end-point of this study was infection within the observation period, calculated as infection rate per patient-year. There are no data in the literature on how frequently infections are to be expected in patients receiving immunoadsorption treatment for autoimmune disease. We assumed that patients receiving immunoadsorption might have about two infections per year. Furthermore, we assumed that the administration of IVIG was a useful therapy if it reduced the risk of infection to one per year with a standard deviation of one infection per patient-year for each group. A power of 80% and a two-sided {alpha} level of 0.05 was assumed to be desirable; this required 16 patients per group.

All patients who consented to be included were assigned to the intervention group or the control group by drawing a sealed envelope containing the treatment allocation.

Intervention group
Seventeen patients were allocated to substitution of IVIG after every second immunoadsorption. Patients allocated to the intervention group who experienced severe adverse events as a result of IVIG administration, necessitating termination of IVIG (n=4), were evaluated only for the period during which immunoglobulins were administered.

Eight patients were already on routine immunoadsorption (55±32 treatments, mean±S.D.) before entry to the study.

Control group
Eighteen patients were allocated to long-term immunoadsorption treatment without subsequent IVIG. Twelve patients were already on long-term immunoadsorption (53±22 treatments). Routinely administered IVIG was terminated at entry to the study.

Immunoadsorption was performed periodically with two consecutive treatments within 3 days (=one cycle), and was followed by an interval without immunoadsorption (intervention group, 15.2±7.7 days; control group, 14.2±6.4 days; not significant). The number of treatments relative to the number of days did not differ significantly between groups.

More than 50% of the patients (20 of the 35 patients studied) received immunosuppressive therapy in addition to immunoadsorption (eight in the intervention group: one received cyclophosphamide and prednisone, three received azathioprine and steroids, one received mycophenolate mofetil and prednisone, and three received steroids alone; 12 in the control group: one received cyclophosphamide and prednisone, two received azathioprine and steroids, two received mycophenolate mofetil and prednisone, and seven received steroids alone). The daily dose of immunosuppressant administered orally was similar in the two groups.

Apheresis procedure
Blood was drawn via a 15-gauge needle from a peripheral vein at a flow rate of 50–80 ml/min. The blood was anticoagulated by continuous infusion of citrate [anticoagulant citrate dextrose, formula A (ACD-A); Baxter, Munich, Germany; the ratio of citrate to whole blood was kept at 1:22 (5.2%)] and sodium heparin (Heparin Immuno; Baxter-Immuno, Vienna, Austria) with an initial bolus of 4000 U and a continuous infusion rate of 1250 U/h. For plasma separation, the Cobe Spectra (Cobe Laboratories, Zovantem, Belgium) was used.

The separated plasma was transferred at a flow rate of 28–40 ml/min into an Adsorption–Desorption Automated System (ADA System; Medicap, Ulrichstein, Germany) containing two specific immunoadsorption columns. For antibody-based IgG immunoadsorption, each column contained 150 ml of Sepharose coupled to polyclonal sheep antibodies to human immunoglobulin (IgG, IgA, IgM) heavy and light chains (Ig-Therasorb; Plasmaselect, Teterow, Germany). Each column had an immunoglobulin-binding capacity of approximately 0.8–1.2 g per cycle. In a single treatment session, 14–18 cycles were performed and 6800±638 ml of plasma was processed over a period of 206.7±20.0 min. Columns were regenerated by elution of the adsorbed proteins with glycine buffer at pH 2.8, followed by a subsequent rinse with phosphate-buffered saline and 9 g/l isotonic sodium chloride solution. After passing through the columns, the plasma was mixed with the separated blood cells. Calcium gluconate was infused at a rate of 6 mmol/h to avoid citrate-induced hypocalcaemia [56]. The blood was then reinfused into the patient through another peripheral vein. Each patient was assigned two columns, which were reused and stored under sterile conditions.

IVIG preparations and mode of application
Three IVIG preparations (all 7S) were used [(i) Octagam; Octapharma, Vienna, Austria; (ii) Endobulin Pro-TIM; Baxter-Immuno, Vienna, Austria; (iii) Immunoglobulin i.v. Biochemie; Biochemie, Vienna, Austria]. Each batch of IVIG was made by cold ethanol fractionation (Cohn process) at a low pH. All preparations were virus-inactivated, stabilized with maltose and contained a similar amount of protein (50 mg/ml, mainly IgG) and a limited quantity of IgA plus IgM (<100 µg/ml).

Immunoglobulins (10–30 g per session, depending on the BW of the patients) were administered after every second immunoadsorption in the intervention group. The infusion rate was 25 ml/h (0.021 g/min) at the beginning and was increased, if the patient accepted this dose without side-effects, every 15 min by 25 ml/h to a maximum of 150 ml/h (0.125 g/min). All patients were premedicated with 0.5 mg dimetinden maleate before every IVIG administration. Patients who had at least one adverse reaction due to IVIG received 25–50 mg methylprednisolone immediately before the infusion. In addition, patients who had experienced a serious adverse event were switched to one of the other two IVIG preparations (n=5).

Blood samples and laboratory methods
Blood samples (serum) were drawn at the beginning and end of each single treatment.

IgG was measured with a nephelometric analyser (Nephelometer Behring; Behring, Marburg, Germany) for routine investigations and in the very low range by turbidometry using a Hitachi 911 analyser (Roche, Basel, Switzerland). Double-stranded DNA (ds DNA) antibodies, thyroid-stimulating hormone (TSH) receptor antibodies and acetylcholine receptor antibodies were determined by commercially available test systems (dsDNA antibodies: anti-ds DNS kit, Farr-assay, Amersham, UK; TSH receptor antibodies: TRAK-Assay, Brahms Diagnostica, Berlin, Germany; acetylcholine receptor antibodies: ARAb RRA, IBL, Hamburg, Germany). Measurements were made with a 1470 Wizzard analyser (Wallac, Turku, Finland).

Statistical analysis
Continuous data are presented as the median and interquartile range (IQR) unless stated otherwise. For frequencies, we calculated percentages. For the end-points of infection, side-effects and hospitalization and for the combined end-point of infection or side-effect or hospitalization, we calculated the incidence rate per patient-year. The Mann–Whitney U-test was used to compare groups of qualitative data, and groups of binary variables were compared by the use of Fisher's exact test. P<0.05 was considered statistically significant and P<0.2 to indicate a trend.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Baseline characteristics were comparable in the intervention group (n=17) and in the control group (n=18) (Table 1Go). During the study a total of 40.8 patient-years were evaluated. The observation period was shorter in the intervention group (P<0.04), whereas the number of treatments relative to the number of days under study was comparable in the two groups (Table 1Go). The difference in observation period was mainly due to serious side-effects of IVIG, enforcing termination of immunoglobulin substitution in four patients (24%) after a median observation time of 9.3 (7.0–10.5) months.

Infections and hospitalization
The primary outcome, the total incidence rate of infection, was low and comparable in the two groups [1.3 infections per patient-year (IQR 0–2.0) in the intervention group vs 0.9 (IQR 0–1.2) in the control group, P=0.27]. None of the infectious complications was lethal. The broad spectrum of infections is listed in Table 2Go. Antibiotic drugs were administered for nine infectious events (41%) recorded in the intervention group and for 10 infections (50%) recorded in the control group. There were three hospital admissions due to infections in the intervention group and one in the control group (P=0.23).


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  		TABLE 2. Infections observed during long-term immunoadsorption in patients with (intervention group) and without (control group) immunoglobulin substitution following immunoadsorption

 
When patients were evaluated for infectious complications according to additional steroid or cytotoxic drug treatment, no difference in infectious complications was detected. The median observation period was similar in patients with and without concomitant immunosuppression (403 days, IQR 348–558 vs 370 days, IQR 320–440; P=0.29). Twenty infections were recorded in the 20 patients who received additional immunosuppressive drug treatment, representing a median infection rate of 1.0 (IQR 0.3–1.7) per patient-year. In patients treated by immunoadsorption without additional immunosuppression (n=15), 15 infections were recorded (infection rate per patient-year 1.0, IQR 0–1.8; P=0.5).

Side-effects due to IVIG
A total of 337 IVIG treatments were performed in the intervention group. The mean dose at a single treatment was 0.14 g/kg (IQR 0.12–0.16) BW. The median of the highest accepted infusion rate was 120 ml/h (IQR 100–125) (0.1 g IVIG/min, IQR 0.08–0.1). Adverse events were observed in 12 out of 17 patients (71%). The side-effects recorded are listed in Table 3Go. Overall, 30 of 337 (9%) IVIG applications were associated with adverse events (in 21 cases a single complaint was recorded, in seven cases the patient reported two different complaints and in two cases three different complaints were reported). Because of the severity and the frequency of side-effects induced by each of the immunoglobulin preparations, IVIG had to be withdrawn in four patients (24%) and immunoadsorption was performed subsequently without additional IVIG. No side-effects due to immunoadsorption were recorded.


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  		TABLE 3. Side-effects due to IVIG administration in the intervention group

 
The cumulative frequency of any problem (infection, side-effect or hospital admission) was higher in the intervention group (2.6 per patient-year, IQR 1.8–3.7) than in the control group (0.9 per patient-year, IQR 0–1.2; P=0.004).

Immunological effects
Mean pretreatment values of IgG (before the first immunoadsorption of each cycle) were 680.7±208.6 (mean±S.D.) mg/dl in the intervention group and 665.3±229.0 mg/dl (not significant) in the control group. Comparable removal of circulating immunoglobulins was achieved in the intervention and control groups by processing similar plasma volumes. The mean reduction in IgG by a single treatment was 82.6±8.4% (Fig. 1Go). By combining two treatment sessions within 3 days (one cycle), immunoglobulin depletion of 95.0±2.5% (mean±S.D.) was achieved. After the initial immunoadsorption, the IgG level increased to 48.2± 6.2%, the IgA level to 54.2±1.2% and the IgM level to 63.6±4.1% of the pretreatment value. Additional immunosuppression did not result in reduced resynthesis of immunoglobulins [{Delta}increase in IgG between two cycles was 70.1±8.2 (mean±S.D.) in patients with additional immunosuppression and 73.5±10.4 in patients without concomitant immunosuppression (not significant)].



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  		FIG. 1. Immunoadsorption treatment in general is performed by a combination of two immunoadsorption sessions within 48 h (one cycle). Pre 1, immunoglobulin concentration immediately before the first immunoadsorption of a cycle; Post 1, immunoglobulin concentration immediately after the first immunoadsorption of a cycle; Pre 2, immunoglobulin concentration immediately before the second immunoadsorption of a cycle (increase in circulating immunoglobulins mainly due to redistribution from tissue stores); Post 2, immunoglobulin concentration at the end of the second immunoadsorption treatment (representing the complete removal of immunoglobulins by each cycle of immunoadsorption).

 
The kinetics of the pathogenic autoantibodies was studied in patients suffering from Graves disease (TSH receptor antibody; n=15), myasthenia gravis (acetylcholine receptor antibody; n=11) or systemic lupus erythematosus (dsDNA antibody; n=7). Reductions in pathogenic antibodies found after immunoadsorption are shown in Table 4Go. No significant difference in antibody resynthesis between two treatment cycles was observed when the intervention group was compared with the control group (Table 4Go). Autoantibody concentrations after resynthesis did not exceed initial pre-apheresis concentrations in either group. The increase in autoantibody concentration ({Delta}increase, the difference between the concentration at the end of one cycle and the pretreatment value of the following cycle) was different for the different autoantibodies (Table 4Go).


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  		TABLE 4. Kinetics of pathogenic antibodies

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In this first long-term investigation of immunoadsorption, no beneficial effect of additional IVIG administration at a low dose with respect to infection rate and immunomodulatory properties could be proven.

The serum IgG level was reduced by >95% by two consecutive immunoadsorptions (Fig. 1Go). Thus, these patients seemed to be at an increased risk of bacterial and viral infections in particular without substitution of IVIG. Our long-term results clearly demonstrate that the overall incidence of infection was low in patients whether or not they were treated by substitution of immunoglobulins following immunoadsorption. Even in patients who received additional steroid or cytotoxic drug treatment, low-dose substitution with IVIG was unable to further reduce the low rate of infectious complications.

Removal of circulating antibodies by immunoadsorption was not followed by an increase in the level of antibody resynthesis. In addition, the increase in pathogenic antibodies following immunoadsorption was unaffected by whether or not IVIG were administered. After the almost complete removal of circulating immunoglobulins by immunoadsorption, infusion of any of the three immunoglobulin preparations was associated with a comparable high frequency of moderate or severe adverse events. Although the preparation of immunoglobulins was changed, severe side-effects enforced termination of IVIG in 24% of the patients.

In subjects suffering from agammaglobulinaemia or hypogammaglobulinaemia and in critically ill patients after surgery or with burn injuries, a beneficial effect of prophylactic IVIG substitution could be demonstrated [16, 20, 57]. Hereditary hypogammaglobulinaemic states are characterized by a persistent deficiency of circulating IgG due to inadequate production of immunoglobulins, while patients in whom immunoglobulins have been depleted by immunoadsorption are suggested to have a physiological resynthesis rate of approximately 32 mg/kg BW per day [16, 18, 19]. Patients in intensive care units have IgG levels at the lower limit of the normal range, but despite this they are at increased risk of infection due to intravenous lines or post-surgical wounds [20, 21]. In an attempt to prevent complications arising through the use of central lines in combination with low immunoglobulin levels due to long-term immunoadsorption, a peripheral venovenous vascular access was used for the extracorporeal therapy in 34 of 35 patients. Overall, there were just a few severe bacterial infections in our patients. Endocarditis was observed in a woman treated via a central venous line for more than 6 months and osteomyelitis was a post-surgical complication after hip arthroplasty.

As the removal of pathogenic antibodies is suggested to be associated with decreased disease activity, the extent of resynthesis is of great interest in patients on long-term immunoadsorption [8, 10, 12, 13]. Thus, additional immunosuppression or immunomodulatory treatment with IVIG was suspected to be essential to avoid excessive antibody resynthesis [10–12, 55, 58, 59]. Our long-term observations clearly demonstrate that the increase in pathogenic antibodies between two treatment cycles did not exceed the pretreatment value of the previous immunoadsorption (Table 4Go). This observation was not influenced by additional immunosuppressive and/or immunomodulatory therapy (IVIG). Surprisingly, the extent of removal of TSH receptor antibodies was lower than that of dsDNA antibodies and acetylcholine receptor antibodies. The apparent lower extent of elimination of TSH receptor antibodies was due largely to methodical limitations in the precise determination of values lower than 9 U/l (interassay coefficient of variation 20%), as achieved in patients after two consecutive immunoadsorptions, in particular in patients with already low pretreatment concentrations.

Pretreatment (first immunoadsorption of a cycle) IgG levels were comparable in patients receiving and not receiving IVIG administration. IVIG therapy is often associated with a significant increase in circulating IgG levels [16, 17]. The failure to increase IgG levels in the intervention group further may be explained by diminished IgG production following IVIG, even at a low dose. This hypothesis could be confirmed by the fact that the half-life of the immunoglobulin preparations (21–23 days) exceeds the duration of the treatment interval (15.2±7.7 days in the intervention group and 14.2±6.4 days in the control group; mean±S.D.; not significant). Thus, if a normal level of immunoglobulin synthesis is postulated, there should be an additive effect regarding serum immunoglobulin levels. Thus, it must be assumed that IVIG has an immunomodulatory effect even at the dose of 0.15 g/kg BW.

Immunoadsorption treatments were scheduled as cycles each consisting of two immunoadsorption procedures within 3 days in all patients included in this study. An increase in IgG after the first immunoadsorption session to 48.2±6.2% of the initial IgG level was observed; this represents the redistribution of IgG from tissue to the circulation. When immunoadsorption was performed on two consecutive days by treating comparable plasma volumes, an increase in IgG level of about 59±20% of the initial value due to re-equilibration was reported [13]. Thus, an extended period within two immunoadsorption treatments seems not to be associated with greater redistribution of IgG from tissue stores.

Despite the very low dose of IVIG used in our protocol, we observed a high frequency of adverse events. The mechanisms responsible for the occurrence of severe, sometimes life-threatening reactions enforcing termination of routine IVIG (which occurred in 24% of all patients in the intervention group) are not completely understood. However, in patients in whom all types of circulating immunoglobulins were almost completely depleted, the rate of serious adverse events exceeded the frequency reported for IVIG in primary and secondary hypogammaglobulinaemic states [16, 18–23]. Severe anaphylactic reactions may occur in patients who have a large deficiency of IgA. This serious side-effect has been thought to be associated with IgE or IgG antibodies against IgA, which react with the IgA in the IVIG preparation [60, 61]. Patients who are on immunoadsorption are nearly completely depleted of IgG and IgA (Fig. 1Go). The high incidence of serious reactions associated with IVIG following immunoadsorption might be due to the infusion of low concentrations of IgA (<100 µg/ml), which are detectable in all commercially available IVIG preparations. In our immunoadsorption patients, the presence of antibodies against IgA was uncertain (they were not measured), as IgA values were within the normal range before immunoadsorption therapy.

All patients were premedicated with 0.5 mg of dimetinden maleate before every administration of IVIG. If there were any side-effects after IVIG treatment, 25–50 mg of methylprednisolone was administered before the next treatment. But no improvement in tolerability was achieved in any of the patients in whom serious side-effects occurred. In general, serious side-effects were not observed during the initial IVIG substitutions but did occur in later courses, enforcing the termination of IVIG treatment in 24% of patients after a median period of 9.3 (7.0–10.5) months.

In conclusion, this study demonstrates that there is no evidence of any beneficial effect of IVIG substitution at a low dose after immunoadsorption. In contrast to primary and secondary hypogammaglobulinaemic states, the low rate of viral and bacterial infections in these patients, in whom circulating immunoglobulins were almost completely depleted by immunoadsorption, did not depend on IVIG therapy. Thus, our results clearly demonstrate that in patients without impaired B-cell function the rate of infection is not correlated with the circulating IgG level. Furthermore, the increase in pathogenic antibodies after immunoadsorption was similar in patients receiving low-dose IVIG substitution and in controls, and did not exceed the concentration found before the first immunoadsorption of the preceding cycle. Immunoadsorption treatment in combination with the administration of IVIG at a dose of 0.15 g/kg BW was associated with a higher cost—about 8400 euros per year (50% of the cost of immunoadsorption per year)—compared with the control group. However, it cannot be excluded that the combination of immunoadsorption and high-dose IVIG treatment (>1 g/kg BW) might offer advantages in serious autoimmune diseases.


   Notes
 
Correspondence to: S. Schmaldienst, Department of Medicine III, Division of Nephrology and Dialysis, University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria. Back


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 5 May 2000; Accepted 27 November 2000


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