Performance,clinical effectiveness,and safety of immunoadsorption in a wide range of indications

Immunoadsorption is well known to selectively remove immunoglobulins and immune complexes from plasma and is applied in a variety of autoimmune diseases and for desensitization before, or at acute rejection after organ transplantation. Performance, safety, and clinical effectiveness of immunoadsorption were the aim of this study. This prospective, noninterventional, multicentre cohort study included patients treated with immunoadsorption (Immunosorba or GLOBAFFIN adsorbers) for any indication. Clinical effectiveness was assessed after termination of the patient's individual treatment schedule. Eighty-one patients were included, 69 were treated with Immunosorba, 11 with GLOBAFFIN, one patient with both adsorbers. A majority of patients was treated for neurological indications, dilated cardiomyopathy, and before or after kidney or heart transplantation. Mean IgG reduction from pre- to post-treatment was 69.9% ± 11.5% for Immunosorba and 74.1% ± 5.0% for GLOBAFFIN, respectively. The overall IgG reduction over a complete treatment block was 68%–93% with Immunosorba and 62%–90% with GLOBAFFIN depending on the duration of the overall treatment. After termination of the immunoadsorption therapy, an improvement of clinical status was observed in 63.0%, stabilization of symptoms in 29.6%, and a deterioration in 4.9% of patients. Changes in fibrinogen, thrombocytes, and albumin were mostly classified as noncritical. Overall, the treatments were well tolerated. Immunoadsorption in routine clinical practice with both GLOBAFFIN and Immunosorba has been safely performed, was well tolerated by patients, and effective in lowering immunoglobulins with an improvement or maintenance of clinical status, thus represents an additional therapeutic option for therapy refractory immune disorders.     

Recambio plasmático en las enfermedades autoinmunes sistémicas

Therapeutic apheresis encompasses a large number of techniques whose main purpose is to process patients’ blood through an extracorporeal device. The aim is to remove antibodies and preformed immune complex to avoid tissue damage, eliminate inflammatory mediators – such as complement and cytokines, which could contribute to further damage – restore deficiencies, and stimulate lymphocyte clones to improve the response to immunosuppressive therapy.Among the different types of apheresis, the most commonly used for the treatment of autoimmune diseases are plasma exchange and immunoadsorption.To aid the correct use of these procedures, the American Society for Apheresis has established more than 65 indications classified into different categories according to the level of evidence. In this review, we analyze the distinct therapeutic indications for the treatment of different autoimmune diseases.This review indicates that plasma exchange is a safe and effective therapeutic option for treating the serious manifestations of systemic autoimmune diseases and is a valid option for those patients with diseases refractory to conventional treatments.     

LDL-Therasorb Immunoadsorption for the Treatment of Severe Hypercholesterolemia Refractory to Conventional Therapy

Abstract: The role of severe hypercholesterolemia (SH) as a major risk factor for coronary heart disease has been well established. Not all patients with SH can be treated sufficiently with diet and drugs. In such circumstances, extracorporeal removal of low-density lipoprotein (LDL) cholesterol is required in patients with existing atherosclerosis. The chronic regular application of extracorporeal cholesterol removal demands an efficient and selective method not influencing other plasma components. Several methods have been developed for the extracorporeal reduction of LDL cholesterol using different approaches to achieve selectivity. Today the most selective approach is the use of specific antibodies directed against apolipopro-tein B-100. For 17 years, this method has been used in the therapy of patients with SH. Numerous publications demonstrate the safety and efficacy of immunoadsorption (IA) with the LDL-Therasorb System. Within an IA treatment, LDL cholesterol is reduced by 60–70%. The system, however, allows for any desired reduction in the cholesterol levels because the double column system can be alternately loaded and regenerated to enable virtually unlimited treatment of plasma. The treatable plasma quantity is not limited by the nonspecific removal of other plasma components, e.g., coagulation factors, fibrinogen, plasminogen, or immunoglobulins. In long-term studies, the influence of LDL-Therasorb IA on coronary and peripheral atherosclerotic disease has been shown to have a favorable influence on the development of stenoses. In the majority of patients, a stop of progression and even a regression of stenoses could be demonstrated.     

Neurologic diseases of the central nervous system with pathophysiologically relevant autoantibodies – Perspectives for immunoadsorption

Immediate antibody elimination, pulsed induction of antibody redistribution, and immunomodulation are major forces of efficacy of therapeutic apheresis (i.e. plasma exchange [PE] or immunoadsorption [IA]) for autoimmune neurologic disorders. Therapeutic apheresis can offer rapid response for severe acute neurologic symptoms, and stable rehabilitation in long-term clinical courses being refractory to drug based strategies or complicated by drug side effects. PE or IA in these situations must be considered as part of multimodal or escalating immune treatment strategies in combination or in competition with intravenously administered immunoglobulins (ivIg), corticosteroids, the full spectrum of immunosuppressive drugs, and bioengineered antibodies. Selective IA is increasingly replacing PE due to its superior safety profile and increasing knowledge on pathogenic relevance of autoantibodies. Recent experiences in autoimmune diseases of the central nervous system, e.g. multiple sclerosis, neuromyelitis optica, and autoimmune encephalitis confirmed this concept.     

Non-specific immunoadsorption in patients with dilated cardiomyopathy: mechanisms and clinical effects

An association between viral myocarditis and DCM has been hypothesized for a subset of patients with DCM. In addition to abnormalities of the cellular immune system, disturbances of humoral immunity have been described in DCM patients. A number of antibodies against various cardiac cell proteins have been identified in DCM. The functional role of cardiac autoantibodies in DCM is under debate. Circulating antibodies are extractable by immunoadsorption (IA). IA has been successfully used for treatment of a number of autoimmune diseases. IA may also represent a therapeutic option for a subset of patients with DCM. Recent open controlled pilot studies showed that removal of circulating antibodies by IA induces improvement of cardiac function in DCM. IA, furthermore, decreases myocardial inflammation. In vitro data indicate that removal of negative inotropic antibodies may represent the essential mechanism of IA in DCM. These antibodies belong to immunoglobulin G subclass 3 and may play an important role in cardiac dysfunction of DCM patients. A larger, randomized, prospective, multi-centre study will be necessary to confirm therapeutic efficacy of IA therapy in DCM.     

Removal Characteristics of Immunoadsorption with the Tryptophan‐Immobilized Column Using Conventional and Selective Plasma Separators in the Treatment of Myasthenia Gravis

Autoimmune neurological diseases are often treated by immunoadsorption using a conventional plasma separator and tryptophan‐immobilized column (IA). However, there is only one case report on treatment with immunoadsorption using a selective plasma separator and tryptophan‐immobilized column (SeIA) in clinical practice. This study aimed to investigate the removal characteristics of antibodies against acetylcholine receptors (AChRAb), immunoglobulin G, fibrinogen, and factor XIII (FXIII) in IA and SeIA in four patients with myasthenia gravis. A total of 19 sessions of immunoadsorption were performed (five sessions of IA and 14 sessions of SeIA) when the processed plasma volume was 2 L. The corresponding reductions were 52.5% ± 6.2% for AChRAb, 58.8% ± 4.2% for fibrinogen, and 36.9% ± 5.5% for FXIII after one session of IA. The corresponding reductions were 45.2% ± 9.9% for AChRAb, 3.5% ± 6.9% for fibrinogen, and ?4.6% ± 11.1% for FXIII after one session of SeIA. The removal rates for AChRAb, fibrinogen, and FXIII in IA were significantly higher than those in SeIA. IA could effectively remove AChRAb, and SeIA could retain fibrinogen and FXIII. IA can be combined with SeIA, resulting in both IgG autoantibodies removal by IA and retention of coagulation factors by SeIA.     

Immunoadsorption in Systemic Connective Tissue Diseases and Primary Vasculitis

Abstract: Immunoadsorption offers some advantages over plasmapheresis; until recently the primary advantage has been avoidance of substitution fluids. In collagen vascular disorders, immunoadsorption is performed for the same indications as plasma exchange; most often adsorbers with binding capacities for IgG and circulating immune complexes are used. Tested ligands are protein A, anti-IgG antibodies, Clq, phenylalanine, and tryptophan. Human IgG was utilized to adsorb rheumatoid factor and dextran sulfate, DNA, or specific anti-idiotypes for anti-DNA antibodies in systemic lupus erythematous (SLE). Most applications have used immunoadsorbent columns in pre-transplantation treatment of patients with high panel reactivity and in patients with idiopathic thrombocytopenic purpura (ITP). For these indications, as for systemic connective tissue diseases, randomized trials have yet to be conducted. SLE controlled trials have been completed for IMPH-350 and Ig-Therasorb. Results indicated excellent biocompatibility and good clinical responses. Using protein A in primary systemic vasculitis, histologically proven inactivation of renal involvement was demonstrated, but the patients were also treated with immunosuppressive drugs. Randomized controlled trials are mandatory to provide continued support to the therapeutical opportunities offered only by immunoadsorption.—     

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.     

Therapeutic Apheresis for Renal Disorders

Many primary renal diseases are associated with either antibody deposition within the glomerulus or an antibody associated autoimmunity, as may be seen with certain vasculitidies. Other immunoglobulins may be nephrotoxic or glomerulopathic; such may be the case with myeloma related light chains or cryoglobulins. Given the rapid removal of immunoglobulins by therapeutic plasma exchange, this modality has been considered an appealing management option in the treatment of these autoimmune related renal diseases. Although not classically considered as autoimmune diseases, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are related syndromes which often involve the kidneys. In many cases therapeutic plasma exchange has been found to be a useful treatment modality for these microangiopathic hemolytic anemias. This paper will provide a concise review of the renal indications for therapeutic plasma exchange.     

Immunoadsorption in steroid-refractory multiple sclerosis: Clinical experience in 60 patients

BackgroundMultiple sclerosis (MS) is the most common autoimmune inflammatory demyelinating disease of the central nervous system with a frequently relapsing or progressive course. For steroid-resistant relapse, plasma exchange (PE) has been established as guidelines-recommended treatment option. While PE is a non-selective extracorporeal blood purification process with elimination of plasma and subsequent substitution, immunoadsorption (IA) is a selective technique for the removal of autoantibodies and immune complexes with less adverse effects. So far there are only few reports on the treatment of MS by IA. The aim of this retrospective study was to assess the efficacy and safety of IA as an escalation therapy in MS patients.Patients and methodsA total of 60 patients with steroid-refractory MS relapse were treated by IA and analyzed retrospectively. Patients received six standardized IA sessions using a non-regenerable tryptophan immunoadsorber, at average 58 days after first indications of relapse. The treated plasma volume was two liters per IA session. Outcome was measured as improvement in relapse symptoms. From the pilot phase of the study comprising the first fourteen patients, detailed neurological examinations before and after IA such as Expanded Disability Status Scale (EDSS), Functional System Score (FS) and visual acuity are reported. Of the following 46 patients, only qualitative data regarding the therapeutic success, and in addition clinical data on tolerability, are presently available.ResultsIn 53 of 60 patients clinically relevant improvement of the main symptom of MS relapse was noted after IA, there was no change in six patients, deterioration in one. This corresponds to a response rate of 88%. Symptomatic improvement was first registered on average after the third IA. 87.5% of patients could be treated through a peripheral venous access. Only 12.5% needed a central venous catheter. In four of 396 single treatments (1%) significant complications occurred, mild side effects or discomfort were registered 16 times (4%). If peripheral venous access was chosen, missed puncture or puncture hematoma occurred in 22 cases (5.5%).ConclusionImmunoadsorption for the treatment of steroid-refractory MS relapse is safe and effective. The response rate was 88% and non-inferior to previous results with plasma exchange. Due to good tolerability, the treatment with immunoadsorption, which is usually possible through a peripheral venous access, can be performed on an outpatient basis.     

Immunoadsorption in Guillain‐Barré Syndrome and Myasthenia Gravis

Elimination of circulating antibodies by hemapheresis is an empirical treatment concept in various neuroimmunological diseases. Plasma exchange (PE) has been shown to be superior to symptomatic treatment in Guillain‐Barré syndrome (GBS) in two large multicenter studies. It is also effective in myasthenia gravis (MG), although no comparative studies have been performed. Immunoadsorption (IA) using polyvinyl alcohol gel columns to which phenylalanin (IM‐PH) or tryptophan (IM‐TR) are covalently bound is an alternative to PE, and seems to have equal efficacy and comparable side effects. This method also obviates the need for replacement of plasma with human albumin or plasma. We compared the treatment results of 11 patients with GBS treated by PE to those of 13 patients treated by IA using an IM‐TR column. Here, we found no statistically significant differences with regard to efficacy and clinical or procedural complications. From these data we conclude that immunoadsorption can be used as an equal alternative to PE. A large multicenter study comparing PE, intravenous immunoglobulins (IVIG), and the combination of both in the treatment of GBS revealed no significant difference between the 3 treatment groups. In MG, only 2 small studies have been performed using IA, and no studies comparing PE or other treatments to IA have been conducted. Both investigations of IA therapy demonstrated a marked reduction in the acetylcholine receptor (AchR) antibodies and a sustained improvement of the clinical signs. These results therefore show that IA is an effective treatment for myasthenia gravis.     

Treatment of Autoimmune Disease: Synergy Between Plasma Exchange and Intravenous Immunoglobulins

Abstract: Therapeutic plasma exchange (PE) has been used for three decades in the treatment of autoimmune disease. Its mechanism of action hinges on a profound modulation of the immune system which is only partially understood. Removal of circulating immune complexes, immunoglobulins, and complement components play a role. Moreover, the substitution of plasma components like anti‐idiotypic antibodies and immunoglobulins targeted against a host of antigens may add to its beneficial effects. Recently, intravenous administration of immunoglobulins was found to mimic the effects of PE in certain diseases. In fact, downregulation of Fc receptors, modulation of the complement activation, and anti‐idiotypic downregulation of primary autoantibodies are mechanisms held to be responsible for its immunosuppressive effects.This article summarizes the effects of both treatment modalities, discusses their pros and cons, and makes differential therapeutic suggestions for the clinician of which to use in various autoimmune diseases.     

The Six Year Experience of Plasmapheresis in Patients with Myasthenia Gravis

Abstract: Plasmapheresis (PP) effectively removes autoantibodies in various autoimmune diseases. The use of PP in the treatment of myasthenia gravis (MG) has been widely accepted since the 1970s. The treatment protocol, however, has not been standardized. For the last 6 years, we collected a total of 94 MG patients, 38 males and 56 females aged 14–80 years, who received 175 courses of PP treatment for a total of 823 sessions. The methods we used were double filtration plasmapheresis (DF), immunoadsorption plasmapheresis (IA), and plasma exchange (PE). There were 167 courses of DF, 6 courses of IA, and 2 courses of PE. Each course of treatment consists of 4 to 5 sessions of apheresis. The processed volume of plasma is 1 calculated plasma volume. All patients tolerated PP well although 2.3% of them experienced hypotension. Our experiences are summarized as follows. Both DF and IA effectively ameliorate symptoms and signs of MG. IA removes acetylcholine receptor antibody more effectively than DF does, but clinical effects between these 2 methods are similar. A daily schedule seems more effective than an alternate daily schedule. The optimal number of PP sessions for each course is 4. The factors correlating with better clinical response are high MG score, nonthymoma patients, younger age at onset, and higher removal rate for immunoglobulin G.     

Plasmapherese und Immunadsorption auf der Intensivstation

Over the last 40 years plasmapheresis technology and its indications for use have been continually evolving. With the growing incidence for autoimmune diseases, unsatisfactory therapeutic options, side-effects of drug therapy, economic relevance and apheresis, clinicians have been tending more towards selective plasmapheresis techniques through the use of immunoadsorption columns. Immunoadsorption is used to target specific disease-producing pathogens for removal during extracorporeal therapy. Evidence is accumulating for the use of plasmapheresis and immunoadsorption in several immune-mediated conditions in critically ill patients. The outlook for some emergencies continues to be desolate, however, and various therapies are used based on evidence from case reports and small case series even if randomized, controlled studies are still lacking for many diseases. The new therapies are relatively safe but careful monitoring is needed, because there is a potential for serious adverse events.     

Removal Kinetics of Antibodies Against Glutamic Acid Decarboxylase by Various Plasmapheresis Modalities in the Treatment of Neurological Disorders

Plasmapheresis is one of the acute treatment modalities for neurological disorders associated with antibodies against glutamic acid decarboxylase (anti‐GAD). However, there is little information about the removal kinetics of anti‐GAD by various plasmapheresis modalities. Here, we investigated the removal rate of anti‐GAD and fibrinogen (Fib) by immunoadsorption (IA), plasma exchange using a conventional plasma separator (OP‐PE), and plasma exchange using a high cut‐off selective membrane plasma separator (EC‐PE) in two cases of anti‐GAD‐associated neurological diseases. In case 1, IA and OP‐PE were used, and the percent reductions were as follows: anti‐GAD: 38.2% and 69.1% and Fib: 67.7% and 68.2%, respectively. In case 2, OP‐PE and EC‐PE were used, and the percent reductions were as follows: anti‐GAD: 65.8% and 48.5% and Fib: 68.5% and 19.8%, respectively. OP‐PE could remove anti‐GAD more efficiently than IA. Further, EC‐PE could maintain coagulation factors such as Fib better than IA and OP‐PE. It is important to select the appropriate plasmapheresis modality on the basis of the removal kinetics.     

The role of plasma exchange in the management of autoimmune disorders

Therapeutic plasma exchange (TPE) has been mainly used in the treatment of autoimmune diseases. The main mechanisms of action of TPE include the removal of circulating autoantibodies, immune complexes, complement components, cytokines and adhesion molecules, along with sensitization of antibody-producing cells to immunosuppressant agents. TPE is useful in autoimmune haematological, renal, rheumatic and neurological diseases, and is recommended for acute disorders, together with relapsed or worsened chronic diseases that are often unresponsive to conventional treatments. The American Society for Apheresis and the British Society of Haematology have published guidelines on the clinical use of apheresis procedures, indicating the different levels of efficacy of TPE. Based on the evidence from current literature and our personal experience, this review discusses the indications and the suggested regimens for TPE in autoimmune haematological and non-haematological disorders.     

Leukocytapheresis Therapy by Extracorporeal Circulation Using A Leukocyte Removal Filter

Abstract: Leukocytapheresis therapy has been used to try to treat such intractable diseases as autoimmune and neurologic diseases, achieving good results. However, a number of problems have been identified in leukocyte removal by thoracic duct drainage or continuous centrifugal separation; namely the high risk, expensive cost, and complicated operation. Asahi Medical Co. has developed an innovative solution for such conventional problems. Its new leukocyte removal filter (Cellsorba) is capable of removing white blood cells by perfusion of whole blood by means of simple extracorporeal circulation. Leukocytapheresis therapy using the Cellsorba column is being confirmed as extremely effective for many inflammatory diseases, as well as in autoimmune and neurologic diseases. This paper outlines information about the Cellsorba column and introduces several reports on therapeutic results.     

Removal Dynamics of Autoantibodies,Immunoglobulins, and Coagulation Factors by Selective Plasma Exchange on Three Consecutive Days

Selective plasma exchange has been shown to be effective in various diseases, but no studies have assessed the benefits of daily treatment. We aimed to investigate the removal dynamics of immunoglobulins, fibrinogen, and factor XIII on three consecutive days in three patients. For mean processed plasma volumes of 1.06 × plasma volume, reductions of 79.6%, 49.3%, and 8.6% were seen for immunoglobulins G, A, and M, respectively. The reductions for fibrinogen and factor XIII were 18.4% and 13.0%, respectively. Removal dynamics were similar for immunoglobulin G-related autoantibodies and immunoglobulin G when using daily selective plasma exchange. Moreover, daily use effectively removed the immunoglobulin G while retaining the coagulation factors. When disease-specific autoantibodies are limited to immunoglobulin G, daily selective plasma exchange may be a useful and safe method of intensive induction treatment for plasmapheresis. However, further study is required in larger cohorts to confirm these findings.     

Immunoadsorption in Dilated Cardiomyopathy

Abstract: The prognosis for patients suffering from advanced stages of dilated cardiomyopathy (DCM) is poor. Recent studies have shown that immunoadsorption (IA) may represent an effective alternative therapeutic approach for other kinds of autoimmune diseases with circulating autoantibodies. The objective of this pilot study was to ascertain the short‐term hemodynamic effects of IA in patients with idiopathic DCM and circulating autoantibodies. Our study included 9 patients with circulating β₁‐adrenoreceptor antibodies who suffered from idiopathic DCM as well as severe heart failure (left ventricular ejection fraction <30%). Immunoadsorption was performed on 5 consecutive days using an adsorber against immunoglobulins (Ig Therasorb, Baxter, Unterschleissheim, Germany). Substitution of 0.5 g/kg of polyclonal immunoglobulin took place after the final IA session. During IA, the cardiac index and stroke volume index increased from 2.0 ± 0.42 to 2.9 ± 0.79 L/min^?1/ m^?2, p < 0.01, and from 24.0 ± 7.4 to 35.9 ± 10.3 ml/m², p < 0.05, respectively. In addition to drug therapy, IA may represent a promising alternative therapeutic possibility for hemodynamic stabilization of patients with severe idiopathic DCM.