The world apheresis association registry, 2023 update.

The WAA apheresis registry contains data on more than 140,000 apheresis procedures conducted in 12 different countries. The aim is to give an update of indications, type and number of procedures and adverse events (AEs). MATERIAL AND METHODS: The WAA-registry is used for registration of apheresis procedures and is free of charge. The responsible person for a center can apply at the site www.waa-registry.org RESULTS: Data includes reported AEs from 2012 and various procedures and diagnoses during the years 2018-2022; the latter in total from 27 centers registered a total of 9500 patients (41% women) that began therapeutic apheresis (TA) during the period. A total of 58,355 apheresis procedures were performed. The mean age was 50 years (range 0-94). The most common apheresis procedure was stem cell collection for which multiple myeloma was the most frequent diagnosis (51%). Donor cell collection was done in 14% and plasma exchange (PEX) in 28% of patients; In relation to all performed procedures PEX, using a centrifuge (35%) and LDL-apheresis (20%) were the most common. The main indication for PEX was TTP (17%). Peripheral veins were used in 56% as the vascular access. The preferred anticoagulant was ACD. AEs occurred in 2.7% of all procedures and were mostly mild (1%) and moderate 1.5% (needed supportive medication) and, only rarely, severe (0.15%). CONCLUSION: The data showed a wide range of indications and variability in apheresis procedures with low AE frequency.

Using the World Apheresis Association Registry Helps to Improve the Treatment Quality of Therapeutic Apheresis.

Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. CONCLUSION: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects.

Antigen-Specific Immunoadsorption With the Glycosorb® ABO Immunoadsorption System as a Novel Treatment Modality in Pure Red Cell Aplasia Following Major and Bidirectional ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation.

Pure red cell aplasia (PRCA) after ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT) is caused by persisting host-derived isohemagglutinins directed against donor red blood cell (RBC) antigens. ABO antigen-specific immunoadsorption (ABO-IA) with Glycosorb®, commonly used for desensitization therapy in ABO-incompatible living donor renal transplantation, specifically eliminates circulating isohemagglutinins and might represent a novel treatment option for post-HSCT PRCA. In this prospective observational (n = 3) and retrospective (n = 3) analysis of six adult HSCT-recipients with PRCA, ABO-IA was initiated at 159 (range: 104-186) days following HSCT. The median treatment frequency was 4.5 (range: 3.9-5.5) sessions/week. ABO-IA-treatment led to a continuous decrease in isohemagglutinin titers. Reticulocytes increased to ≥30 G/L after 17.5 (range: 4-37) immunoadsorption sessions over 28.5 (range: 6-49) days and continued to rise after that. By the end of the 3-month follow-up period after discontinuation of ABO-IA, all patients showed a sustained remission of PRCA and were independent of erythropoietin-stimulating agents and transfusions. No case of infection or graft-versus-host disease was observed. After a median follow-up of 22.03 (range: 6.08-149.00) months after ABO-IA-treatment, all patients were alive and showed a stable RBC engraftment of the donor blood group. Our data provide the first evidence for ABO-IA as an effective treatment for post-HSCT PRCA.

One year follow-up of patients with reduced left ventricular ejection fraction (LVEF) on lipoprotein apheresis.

BACKGROUND: Left ventricular ejection fraction (LVEF) is a valuable measure to assess left ventricular systolic function. Lipid lowering therapy by statins has been shown to have an impact on LVEF already after a 6 months treatment. Higher doses of statins have been claimed to be more effective as compared to a conventional one and even a difference between lipophilic and hydrophilic compounds has been reported. The effect of regular lipoprotein-apheresis (LP-apheresis) on LVEF was previously poorly examined. Patients involved in a regular LP-apheresis program are supposed to undergo a number of follow-up investigations among them myocardial scintigraphy and LVEF, measured by radionuclide ventriculography. METHODS: We examined 18 patients before initiation and after one year of ongoing LP-apheresis. 13 patients (11 males, 2 females, mean age 58.3 ±â€¯5.3 years, groups A) were since more than a year on stable, unchanged statin treatment (atorvastatin 40 mg, simvastatin 40 mg, rosuvastatin 20 mg±ezetimibe), the other 5 patients (3 males, 2 females, mean age 57.1 ±â€¯4.6 years, group B) were intolerant to statins being on micronized fenofibrate±resorption inhibitors (cholestyramine). All patients had a Lp(a) < 30 mg/dl. As part of the usual follow-up monitoring, LVEF was determined by means of radionuclide ventriculography after application of 550 MBq 99m Tc-pertechnetate. RESULTS: The follow-up LVEF was checked at a mean of 48.7 weeks in group A and 51.2 weeks in group B. Except in 1 patient (LVEF 46.8% before vs. 45.2% after LP-apheresis initiation) in group A we noted a significant increase in LVEF in 12 patients of group A (92%) and in all patients of group B. Mean LVEF increased significantly in both groups (A: 42.7±8.1 → 46.5±7.5% (p < 0.001) and B: 41.9±8.4 → 46.5±6.3 %; p < 0.001). The relative rise was nearly identical (group A 9.6%, in group B 9.7%). CONCLUSIONS: Our findings indicate that regular long-term LP-apheresis treatment apparently increases LVEF, independently on current statin treatment. This implies a role of lowering of atherogenic lipoproteins as underlying mechanism. A prospective study should clarify the relative extent of LVEF improvement induced by LP-apheresis.

Lipoprotein apheresis in Austria - Reduction of cardiovascular events by regular lipoprotein apheresis treatment.

BACKGROUND: In Austria, about 12 patients per 1 million inhabitants are treated currently with lipoprotein (LP-) apheresis. In 2016 it has been suggested, that about 5000 patients were treated worldwide with LP-apheresis, more than half of them in Germany. Regular LP-apheresis aims to decrease apolipoprotein B-rich lipoproteins and to reduce cardiovascular events. In this analysis we present the current situation of LP-apheresis in Austria and we evaluated the cardiovascular event rate 2 years before versus 2 years after starting LP-apheresis. METHODS: A retrospective analysis of 30 patients (19 men and 11 women) was performed at Athos Institute, Vienna, Austria. The study period included two years prior versus two years after the beginning of LP-apheresis. Cardiovascular events and interventions were defined as regarding the coronary (MACE) or the non-coronary (peripheral, cerebral or renal) vascular system. RESULTS: The first cardiovascular event before treatment initiation occurred at a mean age of 48.4 years (range 34-73), treatment was started at a mean age of 55.6 years (range 34-73). The mean rate of incidence of cardiovascular events per patient per 2 years before beginning of LP-apheresis (y-2 and y-1) versus 2 years during treatment (y+1 and y+2) was reduced by 77.78% (1.50 versus 0.33 events/patient/2 years, p = 0.003). CONCLUSIONS: The significant reduction in MACE and vascular disease during regular LP-apheresis at weekly intervals is consistent with data from the literature. Difficulties arise in comparing such studies due to different definition of events or interventions and different study durations. However, LP-apheresis is an efficient treatment option and causes significantly prolonged event-free survival for patients at risk.

Pleiotropic effects of regular lipoprotein-apheresis.

BACKGROUND: Lipoprotein(LP)-apheresis is the treatment of choice in patients suffering from severe familial hypercholesterolemia. A wide range of mechanisms has been claimed to be responsible for the known clinical benefit. METHODS: Patients suffering from heterozygous familial hypercholesterolemia undergoing LP-apheresis either with direct adsorption of lipoproteins (DALI) or dextran sulfate (DS) were examined. A total volume of 10 l blood was exchanged. Non-lipid effects, mainly concerning endothelial function (circulating endothelial cells, circulating endothelial progenitor cells, flow-mediated vasodilation, microalbuminuria) as well as left ventricular ejection fraction and homocysteine were assessed. RESULTS: A single LP-apheresis session improves paradox contractile response in statin intolerant patients, but not in those on regular statin therapy. In contrast, over a 6-months follow-up after treatment initiation, all the examined parameters (circulating endothelial cells, circulating endothelial progenitor cells, flow mediated vasodilatation, homocysteine, microalbuminuria and left ventricular ejection fraction) improved. When available, a comparison between DS vs. DALI was performed. In none of the subgroups a significant difference was noted. DISCUSSION: These findings indicate that beyond the well known lipid/lipoprotein lowering action the broad spectrum of functional tests examined reflecting mainly endothelial function is significantly improved by LP-apheresis treatment on the long-term and seems to be a key underlying reason for the clinical improvement seen in these patients.

Immunoadsorption in Autoimmune Diseases Affecting the Kidney.

Autoantibodies play an important role in the pathophysiology of renal involvement in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), systemic vasculitis, and anti-glomerular basement membrane disease (or Goodpasture syndrome). Direct removal of autoantibodies therefore has been tried in various ways, first by plasma exchange. Today, immunoadsorption is the extracorporeal method that most effectively removes (pathogenic) immune complexes and antibodies. Although past data have shown efficacy and biocompatibility of immunoadsorption in (renal) SLE, it is still an experimental and expensive procedure, and evidence from randomized controlled trials is needed. Nevertheless, immunoadsorption is being used as a rescue therapy in life-threatening situations of SLE patients because of its fast mode of action and its acceptable safety profile. In granulomatosis with polyangiitis (GPA) (or Wegener's granulomatosis), microscopic polyangiitis (MPA), and anti-glomerular basement membrane disease, the current standard is plasma exchange. Immunoadsorption, which probably would reduce the autoantibody burden more effectively, might be an even better more effective option, but sufficient evidence is lacking.

Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy.

BACKGROUND: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE. OBJECTIVE: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes. METHODS: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014. RESULTS: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids. CONCLUSIONS: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

Effect of combined treatment with immunoadsorption and membrane filtration on plasma coagulation--Results of a randomized controlled crossover study.

The combined use of immunoadsorption (IA) and membrane filtration (MF) may markedly enhance removal of IgM and complement component C1q, supporting its use as an element of recipient desensitization in antibody-incompatible transplantation. However, coagulation factor removal may contribute to altered hemostasis, posing a risk of bleeding in the perioperative setting. This secondary endpoint analysis of standard coagulation assays and rotational thromboelastometry (ROTEM®) was performed in the context of a randomized controlled crossover study designed to assess the effect of combined IA (GAM-146-peptide) and MF on levels of ABO antigen-specific IgM. Fourteen patients with autoimmune disorders were randomized to a single treatment with IA+MF followed by IA alone, or vice versa. MF was found to markedly enhance fibrinogen depletion (57% vs. 28% median decrease after IA alone, P < 0.001), whereby four patients showed post-treatment fibrinogen concentrations below 100 mg dL(-1). In support of a critical contribution of fibrinogen depletion to impaired coagulation, extrinsically activated ROTEM(®) analysis revealed a marked reduction in fibrinogen-dependent clot formation upon IA+MF (59% median decrease in FIBTEM mean clot firmness (MCF) as compared to 24% after IA alone, P < 0.001). Moreover, the addition of MF led to a substantial prolongation of activated partial thromboplastin time, possibly due to depletion of macromolecular coagulation factors contributing to intrinsically activated coagulation. Our study demonstrates substantial effects of combined IA+MF on clot formation, which may be mainly attributable to fibrinogen depletion. We suggest that the use of combined apheresis in the setting of transplant surgery may necessitate a careful monitoring of coagulation.

Lipoprotein-apheresis: Austrian consensus on indication and performance of treatment.

The prevalence of familial disorders of lipid metabolism in Europe is higher than believed so far. In severely affected patients in whom conventional combined lipid lowering agents are insufficient to achieve target values, patients being intolerant to all the available members of the statin family as well as in patients with elevated lipoprotein(a) (100 mg/dl) and progression of atherosclerotic vascular disease, despite even normal low-density lipoproteins (LDL)-cholesterol values, lipoprotein-apheresis treatment is indicated. The Austrian Apheresis Consensus compares the inclusion criteria for patients to be treated in Austria with those from Italy, Germany, Spain, Japan, UK and the United States. The cut off level of 100 mg/dl for lipoprotein(a) is higher in Austria as compared to the aforementioned countries (50 or 60 mg/dl, respectively). The available clinical data reveal that regular weekly lipoprotein apheresis not only results in a significant lowering of the respective atherogenic lipid and lipoprotein parameters, but also in a significant decrease in clinical events and interventions. The underlying mechanisms such as non-lipid effects, side effects as well as the different available treatment principles are compared. For patients meeting the inclusion criteria, lipoprotein apheresis is a safe and effective therapy significantly reducing vascular events.

Fibrinogen reduction and bleeding complications in plasma exchange, immunoadsorption and a combination of the two.

BACKGROUND: Immunoadsorption (IAS) and therapeutic plasma exchange (TPE) are considered safe although fibrinogen is removed. To date no comparison of fibrinogen reduction and associated risk of bleeding in apheresis exists. METHODS: Retrospective analysis of TPE, three IAS adsorbers, and combined TPE/IAS regarding fibrinogen reduction and bleeding incidence in 67 patients (1,032 treatments). RESULTS: TPE and TPE/IAS reduced fibrinogen by 64 ± 11% and 58 ± 9%, leading to concentrations <100 mg/dl in 20 and 17% of treatments, respectively. IAS decreased fibrinogen less than TPE (26 ± 6%, p < 0.0001), resulting in fibrinogen concentrations <100 mg/dl in 1% of treatments. The processed volume correlated with reduction in TPE (r = 0.64, p < 0.01), but not in IAS. Bleeding occurred in 1.3% (IAS), 2.3% (TPE) and 3.1% (TPE/IAS) of treatments. CONCLUSION: Hypofibrinogenemia occurs in 20% of patients after TPE and TPE/IAS, but rarely after IAS. IAS removes fibrinogen independently of volume processed. Overall, bleeding is rare in apheresis.

Long-term outcome of anti-glomerular basement membrane antibody disease treated with immunoadsorption.

BACKGROUND: Anti-glomerular basement membrane (GBM) antibody disease may lead to acute crescentic glomerulonephritis with poor renal prognosis. Current therapy favours plasma exchange (PE) for removal of pathogenic antibodies. Immunoadsorption (IAS) is superior to PE regarding efficiency of antibody-removal and safety. Apart from anecdotal data, there is no systemic analysis of the long-term effects of IAS on anti-GBM-disease and antibody kinetics. OBJECTIVE: To examine the long-term effect of high-frequency IAS combined with standard immunosuppression on patient and renal survival in patients with anti-GBM-disease and to quantify antibody removal and kinetics through IAS. DESIGN: Retrospective review of patients treated with IAS for anti-GBM-antibody disease confirmed by biopsy and/or anti-GBM-antibodies. SETTING: University Hospital of Vienna, Austria. PARTICIPANTS: 10 patients with anti-GBM-disease treated with IAS. MEASUREMENTS: Patient and renal survival, renal histology, anti-GBM-antibodies. RESULTS: Anti-GBM-antibodies were reduced by the first 9 IAS treatments (mean number of 23) to negative levels in all patients. Renal survival was 40% at diagnosis, 70% after the end of IAS, 63% after one year and 50% at the end of observation (mean 84 months, range 9 to 186). Dialysis dependency was successfully reversed in three of six patients. Patient survival was 90% at the end of observation. CONCLUSION: IAS efficiently eliminates anti-GBM-antibodies suggesting non-inferiority to PE with regard to renal and patient survival. Hence IAS should be considered as a valuable treatment option for anti-GBM-disease, especially in patients presenting with a high percentage of crescents and dialysis dependency due to an unusual high proportion of responders.

ABO antibody and complement depletion by immunoadsorption combined with membrane filtration--a randomized, controlled, cross-over trial.

BACKGROUND: Potent antibody depletion techniques have paved the way to successful ABO-incompatible transplantation. Considering its efficiency regarding IgG removal, the use of non-antigen-specific semi-selective immunoadsorption (IA) has been advocated. One attractive strategy to overcome the caveat of incomplete IgM depletion and to interfere with complement activation could be the adjunctive use of membrane filtration (MF) to enhance the removal of macromolecules. METHODS: To investigate the depletion efficiency of semi-selective IA plus MF, we conducted a randomized, controlled, cross-over trial including patients on regular IA treatment for indications outside recipient desensitization. According to the results of sample size calculation, 14 subjects were enrolled. Two treatment sequences, a single session of IA plus MF followed by IA alone after ≥7 days (and vice versa), were analysed. RESULTS: IA plus MF markedly enhanced the median per cent reduction of ABO-specific IgM determined by flow cytometry (primary end point; 59 versus 23%, P < 0.001) and haemagglutination (2 versus 1 titre steps, P < 0.001), respectively. Combined treatment also substantially lowered C1q concentrations (86 versus 58% reduction, P < 0.001) and the functionality of classical complement as reflected by impaired in vitro C3 activation capability. IgG was strongly reduced without any additional effect of MF. CONCLUSIONS: We demonstrate that the innovative strategy of combining MF with semi-selective IA may substantially increase IgM elimination and affect classical complement activation. Our findings suggest that this new treatment concept could be an efficient strategy for recipient desensitization in ABO- and HLA-incompatible transplantation.

Apolipoprotein B100 is a suppressor of Staphylococcus aureus-induced innate immune responses in humans and mice.

Plasma lipoproteins such as LDL (low-density lipoprotein) are important therapeutic targets as they play a crucial role in macrophage biology and metabolic disorders. The impact of lipoprotein profiles on host defense pathways against Gram-positive bacteria is poorly understood. In this report, we discovered that human serum lipoproteins bind to lipoteichoic acid (LTA) from Staphylococcus aureus and thereby alter the immune response to these bacteria. Size-exclusion chromatography and solid-phase-binding analysis of serum revealed the direct interaction of LTA with apolipoproteins (Apo) B100, ApoA1, and ApoA2. Only ApoB100 and the corresponding LDL exerted biological effects as this binding significantly inhibited LTA-induced cytokine releases from human and murine immune cells. Serum from hypercholesterolemic mice or humans significantly diminished cytokine induction in response to S. aureus or its LTA. Sera taken from the patients with familial hypercholesterolemia before and after ApoB100-directed immuno-apheresis confirmed that ApoB100 inhibited LTA-induced inflammation in humans. In addition, mice in which LDL secretion was pharmacologically inhibited, displayed significantly increased serum cytokine levels upon infection with S. aureus in vivo. The present study identifies ApoB100 as an important suppressor of innate immune activation in response to S. aureus and its LTA.

Anti-A/B antibody depletion by semiselective versus ABO blood group-specific immunoadsorption.

BACKGROUND: Recipient desensitization using blood group (BG)-specific immunoadsorption (ABO-IA) has proven to enable successful kidney transplantation across major ABO barriers. In this context, the efficiency of non-antigen-specific (semiselective) IA adsorbers has not yet been established. The objective of our study was to quantify anti-A/B antibody depletion by protein A-, peptide ligand- and anti-human immunoglobulin-based semiselective IA in comparison to ABO-IA. METHODS: Eight ABO-IA-treated transplant candidates and 39 patients subjected to semiselective IA for a variety of different indications outside the context of ABO-incompatible transplantation were included. Antibody patterns (IgG, IgG1-4 subclasses, IgM, C4d-fixing reactivities) were analysed applying conventional agglutination testing and flow cytometry. RESULTS: As assessed by sensitive flow cytometric antibody detection, ABO-IA-based desensitization led to a profound even though often incomplete reduction of anti-A/B reactivities. Persistent complement- or non-complement-fixing reactivities, however, were not associated with transplant rejection or capillary C4d deposition. Single sessions of semiselective IA turned out to be more effective than ABO-IA in decreasing levels of anti-A/B IgG [median reduction to 28 versus 59% (ABO-IA) of baseline values, P < 0.001). In contrast, BG-specific IgM (74 versus 30%, P < 0.001) and IgG3 (72 versus 42%, P < 0.05) were reduced to a lesser extent, without differences between tested adsorber types. Analysis of four consecutive IA sessions revealed that inferior efficiency could not be overcome by serial treatment. CONCLUSION: Our observation of limited adsorption capacities regarding distinct BG-specific Ig (sub)classes suggests caution in applying semiselective IA techniques in ABO-incompatible kidney transplantation.

Lupus nephritis: prolonged immunoadsorption (IAS) reduces proteinuria and stabilizes global disease activity.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by pathogenic autoantibodies, which can be removed by extracorporeal procedures. While previous studies have shown short-term efficacy of immunoadsorption (IAS) in SLE, no information on long-term benefit and safety is available. METHODS: IAS was offered to patients with highly active renal disease when conventional therapy had failed. Eleven patients entered the prolonged IAS programme and were followed for up to 10 years (mean 6.4 ± 3.5). Efficacy of IAS was determined by reduction in proteinuria (primary outcome), global disease activity [SLE Disease Activity Index (SLEDAI)] and anti-double-stranded DNA (anti-dsDNA) levels (secondary outcomes). Full/partial remission was defined as ≤ 0.5/≤ 1.0 g/day for proteinuria, ≤ 5/≤ 8 for SLEDAI and ≤ 25/≤ 50 IU/mL for anti-dsDNA levels. We further assessed flares, infections, malignancies and procedure-related adverse events. RESULTS: Short-term IAS (≤ 1 year) resulted in a significant reduction of proteinuria (9.2 ± 3.7 to 2.3 ± 2.4, P = 0.0001), disease activity (SLEDAI 19 ± 8 to 4 ± 2, P = 0.0004) and dsDNA levels (168 ± 205 to 45 ± 34, P = 0.001). In patients without remission after 1 year (n = 5), prolonged IAS decreased proteinuria from 4.3 ± 2.4 to 0.5 ± 0.4 g/day, P = 0.02. At the end of observation, complete remission in proteinuria was achieved in seven patients (64%) and partial remission in two (18%) additional patients. One patient flared and was discontinued; in all other patients, disease activity and anti-dsDNA stabilized at remission levels. Flares (0.28 ± 0.30) and infections (0.66 ± 0.70 per patient/year) were relatively uncommon; no malignancies, anaphylactic or orthostatic adverse events were observed. CONCLUSION: IAS is effective in short-term use but prolonged IAS can provide additional therapeutic benefit while showing an acceptable safety profile. The vast majority of initially therapy-refractory patients met the remission criteria at the end of observation.