Distribution of indications and procedures within the framework of centers participating in the WAA apheresis registry.

The WAA apheresis registry was established in 2003 and an increasing number of centers have since then included their experience and data of their procedures. The registry now contains data of more than 74,000 apheresis procedures in more than 10,000 patients. This report shows that the indications for apheresis procedures are changing towards more oncological diagnoses and stem cell collections from patients and donors and less therapeutic apheresis procedures. In centers that continue to register, the total extent of apheresis procedures and patients treated have expanded during the latest years.

[Systemic lupus erythematosus : Unusual cutaneous manifestations]. / Systemischer Lupus erythematodes : Ungewöhnliche Hautmanifestationen.

BACKGROUND: Various different mucocutaneous symptoms may affect up to 80 % of systemic lupus erythematosus (SLE) patients. OBJECTIVES: To investigate, various unspecific, but otherwise typical clinical symptoms of skin and mucous membranes that arise in SLE patients other than those defined as SLE criteria such as butterfly rash, chronic cutaneous lupus erythematosus, oral ulcers, and increased photosensitivity. MATERIALS AND METHODS: Extensive search of peer-reviewed scientific articles was performed, medical histories of several SLE patients seen in our department were analyzed, and the rare disease courses in three SLE patients are presented. RESULTS: Here we present a variety of unspecific but typical mucocutaneous manifestations in SLE patients: periungual erythema, periungual telangiectasia and periungual splinter hemorrhage, papules on the dorsum of the hands, scaling erythema, sometimes associated with necrosis, especially of the ears, along with complement deficiency, and the bizarre necroses of antiphospholipid syndrome. Furthermore, we show the typical clinico-histological features of neutrophilic urticarial dermatosis, as well as those of bullous SLE and finally a severe course of bacterial sepsis with Neisseria flavescens/macacae. CONCLUSIONS: Here we show several unspecific but rather typical mucocutaneous symptoms in lupus patients that are indicative of SLE and thus may lead to an early diagnosis. Also, life-threatening bacterial sepsis may occur with microorganisms that are commonly considered "apathogenic", such as Neisseria flavescens/macacae, which exclusively affect immunosuppressed patients.

Adverse events in apheresis: An update of the WAA registry data.

Apheresis with different procedures and devices are used for a variety of indications that may have different adverse events (AEs). The aim of this study was to clarify the extent and possible reasons of various side effects based on data from a multinational registry. The WAA-apheresis registry data focus on adverse events in a total of 50846 procedures in 7142 patients (42% women). AEs were graded as mild, moderate (need for medication), severe (interruption due to the AE) or death (due to AE). More AEs occurred during the first procedures versus subsequent (8.4 and 5.5%, respectively). AEs were mild in 2.4% (due to access 54%, device 7%, hypotension 15%, tingling 8%), moderate in 3% (tingling 58%, urticaria 15%, hypotension 10%, nausea 3%), and severe in 0.4% of procedures (syncope/hypotension 32%, urticaria 17%, chills/fever 8%, arrhythmia/asystole 4.5%, nausea/vomiting 4%). Hypotension was most common if albumin was used as the replacement fluid, and urticaria when plasma was used. Arrhythmia occurred to similar extents when using plasma or albumin as replacement. In 64% of procedures with bronchospasm, plasma was part of the replacement fluid used. Severe AEs are rare. Although most reactions are mild and moderate, several side effects may be critical for the patient. We present side effects in relation to the procedures and suggest that safety is increased by regular vital sign measurements, cardiac monitoring and by having emergency equipment nearby.

Immunoadsorption for systemic lupus erythematosus.

Immunoadsorption (IAS) with various methods is used as a rescue therapy in severely ill SLE patients who are refractory to conventional therapeutic procedures. The method aims at the rapid and extensive removal of pathogenic immunocomplexes (IC) and (auto-) antibodies (Abs). Long-term observational studies suggested efficacy and have not seen an increase in the risk of infections (as were seen in other extracorporeal procedures). Unfortunately, prospective, randomized controlled trials (RCT) are lacking. Recently, biologicals aiming at TNF-blockade or B-cell depletion have been used to treat severe SLE: They are easier to apply since they do not necessitate additional (expensive) hardware or specially trained staff. While there is emerging evidence for efficacy from uncontrolled observations, no RCT could so far demonstrate benefit in SLE. Under these circumstances, IAS still has a role in treating severe SLE, when other therapies are not effective enough or are contraindicated (as in pregnancy). These data are reviewed and illustrated in the case of a pregnant lupus patient with nephrotic syndrome.

Immunoadsorption in SLE: three different high affinity columns are adequately effective in removing autoantibodies and controlling disease activity.

INTRODUCTION: Pathogenic autoantibodies (Abs) are a hallmark of SLE and their rapid removal is beneficial in active SLE. Immunoadsorption (IAS) is effective in removing serum levels of all classes of immunoglobulin (Ig), immune complexes (IC) and anti-dsDNA Abs and appears superior to plasmapheresis with respect to side effects. IAS can be performed with different columns, which use different ligands to bind their target. In particular, high affinity columns are in the focus of interest. Their ligands are either sheep IgG directed against human Ig (Ig-column, Ig-Therasorb®), or staphylococcal Protein A (ProtA-column, Immunosorba®), or the synthetic peptide Gam146 (GAM-column, Globaffin®). In our experience Ig-columns have been effective in treating active renal SLE. However, no analysis has so far been published on which column type should be preferred in treating SLE patients. PATIENTS AND METHODS: Among our SLE patients maintained on prolonged IAS therapy, we identified those with stable renal SLE and low to moderate disease activity who were successfully treated by using Ig-columns. Six of these patients were switched to ProtA-columns, keeping the rest of the protocol and the medication constant. In addition, two patients were switched from Ig- to GAM-columns. RESULTS: All types of columns significantly lowered the serum levels of IgG, IgM, and anti-dsDNA Abs. Disease activity was constantly low before and after the switch, as were parameters of renal function. In addition, patients with highly active disease were effectively treated when ProtA- (n=6) or GAM-columns (n=1) were used as first-line extracorporeal treatment. CONCLUSION: Our data demonstrate that all columns are adequately effective in controlling key parameters of SLE. Thus, it is not the type of the ligand, but only the outcome, i.e. the successful removal of Ig, IC, and (auto-) Abs that is required for controlling SLE activity.

Immunoadsorption in severe C4d-positive acute kidney allograft rejection: a randomized controlled trial.

Antibody-mediated rejection (AMR) frequently causes refractory graft dysfunction. This randomized controlled trial was designed to evaluate whether immunoadsorption (IA) is effective in the treatment of severe C4d-positive AMR. Ten out of 756 kidney allograft recipients were included. Patients were randomly assigned to IA with protein A (N = 5) or no such treatment (N = 5) with the option of IA rescue after 3 weeks. Enrolled recipients were subjected to tacrolimus conversion and, if indicated, 'anti-cellular' treatment. All IA-treated patients responded to treatment. One death unrelated to IA occurred after successful reversal of rejection. Four control subjects remained dialysis-dependent. With the exception of one patient who developed graft necrosis, non-responders were subjected to rescue IA, however, without success. Because of a high graft loss rate in the control group the study was terminated after a first interim analysis. Even though limited by small patient numbers, this trial suggests efficiency of IA in reversing severe AMR.

IgG immunoadsorption reduces systemic lupus erythematosus activity and proteinuria: a long term observational study.

OBJECTIVE: To analyse the effects of rigorous immunoglobulin removal by immunoadsorption (IAS) on proteinuria (primary outcome variable), disease activity (SIS, SLEDAI, ECLAM), and autoantibodies to double stranded DNA (anti-dsDNA) in active systemic lupus erythematosus (SLE). METHODS: 16 patients with severe SLE and renal disease, in whom cyclophosphamide was contraindicated or failed to halt disease progression, were treated with IAS for 3 months. Patients achieving at least 20% improvement in two or more of the outcome measures were considered responders and offered a 9 months' extension period. RESULTS: Within 3 months, 14 patients responded and 11 opted for an extension. Proteinuria decreased from 6.7 (4.6) g/day (mean (SD)) at baseline to 4.3 (3.5) g/day at 3 months and 2.9 (2.4) g/day at 12 months (p<0.001). From baseline to 3 and 12 months, disease activity improved independently of scoring by SIS (15 (5) to 5 (2) and to 5 (2), p<0.0001), SLEDAI (21 (7) to 5 (4) and to 5 (4), p<0.0001), or ECLAM (7 (2) to 2 (1) and to 3 (1), p<0.0001). Anti-dsDNA fell from 391 (647) IU/ml to 146 (218) and to 53 (50) IU/ml at 3 and 12 months, respectively. Steroids could be tapered from 117 (159) mg/day at baseline to 29 (17) mg/day at 3 months and 9 (2) mg/day at 12 months. IAS was not associated with an excess of infections. However, one patient died of septicaemia after 1 month of treatment. CONCLUSION: In this negatively selected cohort of patients with SLE, IAS was associated with a significant response shown by reduced proteinuria, improved global disease activity, decreased anti-dsDNA, and lower glucocorticoid dosages, suggesting therapeutic benefit.

Prolonged red cell aplasia after major ABO-incompatible allogeneic hematopoietic stem cell transplantation: removal of persisting isohemagglutinins with Ig-Therasorb immunoadsorption.

Delayed donor red cell engraftment and prolonged red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT). There is an intense debate about the impact on outcome, severity of hemolysis, association with graft-versus-host disease and survival after blood group-incompatible stem cell transplantation. Therefore, therapeutic strategies should be considered to avoid these possible complications. We present five patients, who received allogeneic HSCT from human leukocyte antigen-identical donors for hematological malignancies, which were treated with Ig-Therasorb immunoadsorption (five treatments/week) to remove persisting incompatible isohemagglutinins. After a median of 17 treatments (range 9-25), all the patients became transfusion independent with the presentation of donor's blood group. No side effects occurred during treatment. Ig-Therasorb immunoadsorption seems to be a promising therapeutic method for rapid, efficient and safe elimination for persisting isohemagglutinins for patients with PRCA after allogeneic hematological stem cell transplantation.

Autologous blood stem cell transplantation in refractory systemic lupus erythematosus with severe pulmonary impairment: a case report.

For patients with severe forms of autoimmunity, including systemic lupus erythematosus (SLE), purging autoreactive T cells from the immune repertoire by transplanting autologous hematopoietic stem cells (ASCT) is a therapeutic option. We describe an 18-year-old woman with SLE who had been treated with corticosteroids, azathioprine, cyclophosphamide (CYC), and immunopheresis for 4 years, during which time mechanical ventilation for lupus pneumonitis had been repeatedly required. After the patient was conditioned by administration of CYC and antithymocyte globulin, a total of 8.87 x 10(6) purified CD34+ cells per kg of body weight was infused. Hematopoietic regeneration was observed within 9 days. Twenty-one months after ASCT, the patient continues to be in complete clinical remission, with no signs of SLE-related disease activity and without any immunosuppressive medications. Her pulmonary function has returned to normal. Although a longer followup is required for assessment of the durability of response, the patient's course indicates that ASCT may be a way to reinduce tolerance in patients with SLE.

Influence of lipoprotein(a) on restenosis after femoropopliteal percutaneous transluminal angioplasty in Type 2 diabetic patients.

OBJECTIVE: The influence of vascular morphology and metabolic parameters including lipoprotein(a) (Lp(a)) on restenosis after peripheral angioplasty has been compared in Type 2 diabetes (DM) vs. non-diabetic patients (ND). RESEARCH DESIGN AND METHODS: The clinical course and risk profile of 132 (54 DM vs. 78 ND) patients with peripheral arterial occlusive disease (PAD) were observed prospectively following femoropopliteal angioplasty (PTA). Clinical examination, oscillometry, ankle brachial blood pressure index (ABI) and the toe systolic blood pressure index (TSPI) were used during follow-up. Duplex sonography and reangiography were also used to verify suspected restenosis or reocclusion. RESULTS: At the time of intervention patients with DM had a lower median Lp(a) of 9 vs. 15 mg/dl (P < 0.01) in patients without diabetes. Recurrence within 1 year after PTA occurred in 25 diabetic (= 46%, Lp(a) 12 mg/dl) and 30 non-diabetic (= 38%, Lp(a) 48 mg/dl) patients. DM patients with 1 year's patency had a median Lp(a) of 7 vs. 11 mg/dl in non-diabetic patients (P < 0.05). However, 12 months after angioplasty Lp(a) correlated negatively with the ABI (r = -0.44, P < 0.01) in diabetic and in non-diabetic patients (r = -0.20, P < 0.05). The probability of recurrence after PTA continuously increased with higher levels of Lp(a) in each subgroup of patients. CONCLUSIONS: Our data indicate that Lp(a) is generally lower in those with peripheral arterial occlusive disease and Type 2 diabetes than in non-diabetic individuals. The increased risk for restenosis with rising levels of Lp(a) is set at a lower Lp(a) in diabetes and may be more harmful for diabetic patients.

Immunoadsorption therapy (therasorb) in patients with severe lupus erythematosus.

Therapeutic removal of immune complexes and antibodies by plasmapheresis has been used in patients with systemic lupus erythematosus (SLE) since 1974. Modern methods of selective adsorption of immunoglobulins from the patient plasma (immunoadsorption, IAS) have been developed; they deserve to be investigated as a tool in the management of difficult cases of SLE. We report our experience in an uncontrolled series of five consecutive SLE patients, in whom cytotoxic immunosuppression was contraindicated or not sufficient to control the disease. Ig-Therasorb columns containing polyclonal sheep antihuman immunoglobulin antibodies were used for IAS for periods of 4 to 54 weeks. In order to prevent rebound autoantibody production, low doses of normal human immunoglobulin were substituted. Improvement in clinical and laboratory signs of disease activity was observed in all patients. In two patients the effect of cyclophosphamide therapy for lupus pneumonitis and lupus-associated thrombopenic purpura was consolidated. In three patients suffering from pancytopenia or lupus vasculitis, the use of cytotoxic substances could be avoided for more than a year. IAS seems to be a safe replacement of conventional plasmapheresis in difficult cases of severe lupus complications. Although controlled studies are lacking, this method may occupy a few important niches as an adjunct in managing immune complex mediated diseases.

Atorvastatin improves blood rheology in patients with familial hypercholesterolemia (FH) on long-term LDL apheresis treatment.

To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia (FH) on regular LDL apheresis, we prospectively studied the rheological variables fibrinogen, plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit and platelet aggregation in 12 patients (two homozygous, ten heterozygous) before and during treatment with atorvastatin. Baseline values of red cell aggregation and whole blood viscosity were increased in FH patients on regular LDL apheresis compared with healthy controls (P<0.05), whereas fibrinogen, plasma viscosity and hematocrit were similar in the two groups. Treatment with atorvastatin reduced red cell aggregation (P<0.01), whole blood viscosity (P<0.01), plasma viscosity (P<0.01) and platelet aggregation (P<0.05), but caused a slight increase in plasma fibrinogen (by 5%; P<0.01). Our findings suggest that atorvastatin improves blood rheology in patients with FH on regular LDL-apheresis. This improvement in blood flow properties may contribute to the well-known beneficial effects of atorvastatin on cardiovascular risk in patients with severe hyperlipidemia and atherosclerotic vascular disease.

Quantification of coronary artery calcification in patients with FH using EBCT.

BACKGROUND: Calcification of the coronary vessel wall is regarded as a marker of advanced coronary atherosclerosis. METHODS: To test whether patients with heterozygous familial hypercholesterolemia (FH) exhibit excessive calcification of the coronary vessel wall, we quantified coronary artery calcium in LDL-apheresis treated FH-patients with known severe coronary artery disease (CAD) (n = 10), in patients with moderate hypercholesterolemia and known severe CAD (n = 10), and in asymptomatic controls (n = 10) using electronic beam CT. The total coronary calcium score (Agatston-Score), the number of calcified lesions and the calcified plaque volume were evaluated for this study. RESULTS: CAD-patients with FH, although on average 10 years younger, had a significantly higher total coronary calcium score (702/2018/2890), number of lesions (34/43/49) and calcified plaque volume (700/1818/2313) compared to patients with CAD only (480/641/1362, 10/16.5/22, 480/588/1209, respectively) and controls (10/47/137, 2/4/10, 15/50/144, respectively). Furthermore, we observed a significant correlation (r = 0.93; P < 0.01) between LDL-cholesterol levels (pretreatment levels of the CAD-FH group) and the total coronary calcium score in all three groups. Our results demonstrate that coronary artery calcification is more extensive in CAD-patients with FH than in CAD-patients with moderate hypercholesterolemia. In addition, we provide evidence that the amount of calcium in the coronary vessel wall in FH patients result from a long lasting history of elevated LDL-Cholesterol levels. CONCLUSION: These findings emphasize the significance of LDL-cholesterol as a risk factor for atherosclerosis and underline the importance of early diagnosis of CAD and early cholesterol lowering therapy in FH patients.

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

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.

Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb).

Coagulation inhibitors may occur as alloantibodies in patients with congenital factor deficiencies or as autoantibodies in patients with a previously normal coagulation. We treated 10 patients with factor VIII inhibitors (three haemophiliacs and seven patients with acquired factor VIII inhibitors) and one patient with a factor V inhibitor using extracorporeal immunoadsorption to immobilized antibodies against human immunoglobulins (Ig-Therasorb). The initial inhibitor titre was between 18 BU/ml and 540 BU/ml. Nine patients had signs of bleeding. Eighty-nine immunoadsorption sessions were performed in the 11 patients (8.1 +/- 5.1 per patient), each processing 6980 +/- 880 ml of plasma in 3.8 +/- 0.5 h. The mean reduction of the inhibitor titre was 71.9 +/- 19.4% per session. Serum IgG, IgA and IgM levels decreased by 68.7 +/- 10.1%, 55.7 +/- 12.7% and 48.6 +/- 11.1% respectively. In two haemophiliac patients, an initial titre reduction prior to an immune tolerance protocol was performed. Another haemophiliac patient was treated because of acute cerebral bleeding. In six out of eight patients with acquired inhibitors, a durable elimination was achieved within a median of 18 d. Treatment was safe and well-tolerated and seems to be a promising method in the treatment of patients with coagulation inhibitors, especially when a fast inhibitor titre reduction is necessary.

Local anticoagulation of the extracorporeal circuit with heparin and subsequent neutralization with protamine during immunoadsorption.

A regimen of local anticoagulation of an immunoadsorption device was studied. The extracorporeal circuit was anticoagulated with citrate (5.5%) and a continuous infusion of heparin (2,000 U/h or 1,500 U/h), which was neutralized by a continuous infusion of protamine chloride (75% of the heparin dose) before reinfusion in 23 patients treated with low-density lipoprotein or immunoglobulin apheresis. Sufficient anticoagulation of the extracorporeal circuit was obtained (activated partial thromboplastin time [APTT] > 180 seconds; thrombin time [TT] > 120 seconds; anti-Xa activity, 1.05 +/- 0.21 U/mL) during the entire treatment of 190 minutes, whereas coagulation parameters in the patients' blood stayed within the normal range. In a control group without heparin neutralization, full systemic anticoagulation of the patients occurred (APTT, 157.8 +/- 30.6 seconds; TT, 119.8 +/- 0.4 seconds; anti-Xa activity, 0.88 +/- 0.21 U/mL). No side effects or clotting of the system were observed. Our data show that this regimen of local anticoagulation is a safe protocol for extracorporeal circulation without exposing the patients to anticoagulants.

Prospective randomised cross-over comparison of three LDL-apheresis systems in statin pretreated patients with familial hypercholesterolaemia.

Various LDL-apheresis systems have gained wider clinical acceptance in recent years to treat patients with severe familial hypercholesterolaemia, in particular in patients with coronary artery disease. For each single device data on efficacy have been provided, but up to now no comparative analysis including the novel direct adsorption of lipoproteins from whole blood has been reported. This prospectively designed cross-over comparison of three commercially available LDL-apheresis systems (immunoadsorption, IMAL; dextran sulphate adsorption, DSA; direct adsorption of lipoproteins, DALI) was performed in eight patients with homozygous (n = 3) and heterozygous (n = 5) familial hypercholesterolaemia. Removal of atherogenic lipoproteins was highly effective in all systems, for LDL-cholesterol in particular: DSA: - 84.3 +/- 6.2%; IMAL: -82.1 +/- 8.3%; DALI: -76.6 +/- 7.2% (P < 0.05 as compared DALI versus IMAL and DSA). A reduction in Lp(a) of about 63% was achieved by each device. Loss in HDL-cholesterol was highest with IMAL (-21.3 +/- 4.9%, P < 0.05) as compared to the other two treatment modalities. DSA decreased HDL-cholesterol by - 10.4 +/- 6.1% and the DALI system by -12.7 +/- 5.0%. Remarkable differences were found for the removal of fibrinogen (DSA: -29.8 +/- 14.7%, (P < 0.05 versus DALI/IMAL); IMAL: -21.4 +/- 10.1% (P < 0.05 versus DALI); DALI: -14.8 +/- 8.0%). The shortest duration for treatment was achieved by the DALI system (135 +/- 20 min, P < 0.05 versus IMAL (195 +/- 20 min) and DSA (187 +/- 29 min)). No side effects were recorded in the total of 96 treatments performed during the study. Long-term observations have yet to prove whether these differences in efficacy may be of clinical relevance.

Immunoadsorption in Goodpasture's syndrome.

Patients with Goodpasture's syndrome presenting with dialysis-dependent end-stage renal failure at diagnosis almost never regain independent renal function. We report a patient with a 100% crescentic lesion in whom reversal of dialysis dependence was achieved by immunoadsorption together with immunosuppression. In a second patient, early initiation of immunoadsorption was able to completely restore normal renal function as early as 1 month after the start of treatment. These data give evidence of the use of immunoadsorption as a hopeful alternative to conventional plasma exchange in patients with Goodpasture's syndrome showing advanced renal failure.