Immunoadsorption as maintenance therapy for refractory neuromyelitis optica spectrum disorder.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing autoimmune disease of the central nervous system, affecting mainly optic nerves and spinal cord. NMOSD pathophysiology is associated with anti-aquaporin-4 (AQP4) immunoglobulin G (IgG) autoantibodies. Rapid extracorporeal elimination of autoantibodies with apheresis techniques, such as immunoadsorption (IA), was proven to be an effective treatment of NMOSD attacks. Data on the long-term use of IA to prevent attacks or progression of NMOSD are lacking. Objectives: The aim of this study was to evaluate efficacy and safety of maintenance IA for preventing recurrence of NMOSD attacks in patients refractory to other immunotherapies. Design: Case study. Methods: Retrospective analysis of two female patients with severe NMOSD refractory to conventional immunotherapies was performed. Both patients had responded to tryptophan IA (Tr-IA) as attack therapy and subsequently were treated with biweekly maintenance Tr-IA. Results: Patient 1 (AQP4-IgG seropositive, age 42 years) had 1.38 attacks of optic neuritis per year within 10.1 years before commencing regular Tr-IA. With maintenance Tr-IA for 3.1 years, one mild attack occurred, which was responsive to steroid pulse therapy. Expanded Disability Status Scale (EDSS) was stable at 5.0. Visual function score of the last eye improved from 3 to 1. Patient 2 (AQP4-IgG seronegative, age 43 years) experienced 1.7 attacks per year, mainly acute myelitis and optic neuritis, during the period of 10.0 years before the start of Tr-IA. During regular Tr-IA treatment, no further NMOSD attack occurred. The patient was clinically stable without any additional immunosuppressive treatment for 5.3 years. EDSS improved from 6.0 to 5.0, and the ambulation score from 7 to 1. Tolerability of Tr-IA was good in both patients. No serious adverse events occurred during long-term clinical trajectories. Conclusion: Tr-IA was well tolerated as maintenance treatment and resulted in clinical stabilization of two patients with highly active NMOSD, who were refractory to standard drug therapy.

First-in-Man: Case Report of Selective C-Reactive Protein Apheresis in a Patient with SARS-CoV-2 Infection.

BACKGROUND C-reactive protein (CRP) plasma levels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel viral disease, are surprisingly high. Pulmonary inflammation with subsequent fibrosis in SARS-CoV-2 infection is strongly accelerated. Recently, we have developed CRP apheresis to selectively remove CRP from human plasma. CRP may contribute to organ failure and pulmonary fibrosis in SARS-CoV-2 infection by CRP-mediated complement and macrophage activation. CASE REPORT A 72-year-old male patient at high risk was referred with dyspnea and fever. Polymerase chain reaction analysis of throat smear revealed SARS-CoV-2 infection. CRP levels were ~200 mg/L. Two days after admission, CRP apheresis using the selective CRP adsorber (PentraSorb® CRP) was started. CRP apheresis was performed via peripheral venous access on days 2, 3, 4, and 5. Following a 2-day interruption, it was done via central venous access on days 7 and 8. Three days after admission the patient was transferred to the intensive care unit and intubated due to respiratory failure. Plasma CRP levels decreased by ~50% with peripheral (processed blood plasma ≤6000 mL) and by ~75% with central venous access (processed blood plasma ≤8000 mL), respectively. No apheresis-associated side effects were observed. After the 2-day interruption in apheresis, CRP levels rapidly re-increased (>400 mg/L) and the patient developed laboratory signs of multi-organ failure. When CRP apheresis was restarted, CRP levels and creatinine kinases (CK/CK-MB) declined again. Serum creatinine remained constant. Unfortunately, the patient died of respiratory failure on day 9 after admission. CONCLUSIONS This is the first report on CRP apheresis in a SARS-CoV-2 patient. SARS-CoV-2 may cause multi-organ failure in part by inducing an excessive CRP-mediated autoimmune response of the ancient innate immune system.

Lipoprotein apheresis in Germany - Still more commonly indicated than implemented. How can patients in need access therapy?

BACKGROUND: Although lipid-lowering drugs, especially statins, and recently also PCSK9 inhibitors can reduce LDL cholesterol (LDL-C) and decrease the risk for cardiovascular disease (CVD) including coronary artery disease (CAD) events most efficiently, only 5-10% of high-risk cardiovascular patients reach the target values recommended by international guidelines. In patients who cannot be treated adequately by drugs it is possible to reduce increased LDL-C and/or lipoprotein(a) (Lp(a)) values by the use of lipoprotein apheresis (LA) with the potential to decrease severe CVD events in the range of 70%->80%. Even in Germany, a country with well-established reimbursement guidelines for LA, knowledge about this life-saving therapy is unsatisfactory in medical disciplines treating patients with CVD. Starting in 1996 our aim was to offer LA treatment following current guidelines for all patients in the entire region of our clinic as standard of care. METHODS: Based on the experience of our large apheresis competence center overlooking now nearly 80,000 LA treatments in the last two decades, we depict the necessary structure for identification of patients, defining indication, referral, implementation and standardisation of therapy as well as for reimbursement. LA is unfamiliar for most patients and even for many practitioners and consultants. Therefore nephrologists performing more than 90% of LA in Germany have to form a network for referral and ongoing medical education, comprising all regional care-givers, general practitioners as well as the respective specialists and insurances or other cost bearing parties for offering a scientifically approved therapeutic regimen and comprehensive care. The German Lipid Association (Lipid-Liga) has implemented the certification of a lipidological competence center as an appropriate way to realize such a network structure. RESULTS: Working as a lipidological and apheresis competence center in a region of 400,000 to 500,000 inhabitants, today we treat 160 patients in the chronic LA program. In spite of the availability of PCSK9 inhibitors since 2015, LA has remained as an indispensable therapeutic option for targeted lipid lowering treatment. An analysis of nearly 37,000 LA treatments in our own center documented a >80% reduction of cardiovascular events in patients treated by regular LA when comparing with the situation before the start of the LA therapy. We have implemented the concept of an apheresis competence center characterised by ongoing medical education with a focus on lipidological and cardiovascular aspects, interdisciplinary networking and referral. CONCLUSIONS: Incidence and prevalence of LA patients in our region demonstrate that based on our ongoing patient-centered approach the access of patients in need to LA is substantially above the German average, thus contributing to an extraordinary reduction of cardiovascular events in the population we in particular feel responsible for.

Lipidological competence centres and networks: Future perspectives to improve healthcare of patients with disorders of lipid metabolism.

BACKGROUND: Numerous healthcare studies have shown that more than 90% of all patients with dyslipidaemia are not treated adequately. OBJECTIVES: The "Deutsche Gesellschaft zur Bekämpfung von Fettstoffwechselstörungen und ihren Folgeerkrankungen (DGFF)" [German Society of Lipidology], a non-profit professional membership organization, has already made a series of efforts to improve the care of patients suffering from dyslipidaemia. A recent outcome is the nationwide implementation and certification of Lipidological Competence Centres and Networks (LCCNs). METHODS AND RESULTS: By involving numerous external medical cooperation partners and combining the detailed work of different in-house medical specialists, the Medical Care Centre Kempten-Allgäu was able to improve both the diagnosis and treatment of patients exhibiting disorders of lipid metabolism (DLM). This local lipidological network is so successful, that it may serve as a nationwide standard model for outpatient lipidological care. Detailed organizational structures for improved lipidological care which are suitable to provide a template for future guidelines for the certification of LCCNs have been developed by the Medical Care Centre Kempten-Allgäu. Stringent requirements of implementation with respect to medical staff, content and structure, staff training, patient education and public relations as well as to documentation, quality assurance and quality improvement must be fulfilled both by the lipidological competence centre (LCC) and the cooperation partners within the lipidological network (LN). Finally, members of the health care system (e.g. health policy and health insurances) should be involved in this attempt and convinced of financial support. CONCLUSION: The implementation and certification of national LCCNs supported by DGFF could contribute to a comprehensive improvement in the care of patients with dyslipidaemia, resulting in prevention of cardiovascular diseases and reduction of cardiovascular sequelae.

Lipoprotein(a)-hyperlipoproteinemia as cause of chronic spinal cord ischemia resulting in progressive myelopathy - successful treatment with lipoprotein apheresis.

High concentrations of lipoprotein(a) (Lp(a)) represent an important independent and causal risk factor associated with adverse outcome in atherosclerotic cardiovascular disease (CVD). Effective Lp(a) lowering drug treatment is not available. Lipoprotein apheresis (LA) has been proven to prevent cardiovascular events in patients with Lp(a)-hyperlipoproteinemia (Lp(a)-HLP) and progressive CVD. Here we present the course of a male patient with established peripheral arterial occlusive disease (PAOD) at the early age of 41 and coronary artery disease (CAD), who during follow-up developed over 2 years a progressive syndrome of cerebellar and spinal cord deficits against the background of multifactorial cardiovascular risk including positive family history of CVD. Spastic tetraplegia and dependency on wheel chair and nursing care represented the nadir of neurological deficits. All conventional risk factors including LDL-cholesterol had already been treated and after exclusion of other causes, genetically determined Lp(a)-HLP was considered as the major underlying etiologic factor of ischemic vascular disease in this patient including spinal cord ischemia with vascular myelopathy. Treatment with an intensive regimen of chronic LA over 4.5 years now was successful to stabilize PAOD and CAD and led to very impressive neurologic and overall physical rehabilitation and improvement of quality of life.Measurement of Lp(a) concentration must be recommended to assess individual cardiovascular risk. Extracorporeal clearance of Lp(a) by LA should be considered as treatment option for select patients with progressive Lp(a)-associated ischemic syndromes.

Efficacy, safety, and tolerability of long-term lipoprotein apheresis in patients with LDL- or Lp(a) hyperlipoproteinemia: Findings gathered from more than 36,000 treatments at one center in Germany.

LDL cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are main risk factors for cardiovascular disease (CVD). Efficacy, safety, and tolerability of lipoprotein apheresis (LA) were investigated in 36,745 LA treatments of 118 patients with CVD in a retrospective, monocentric study. Indications were severe hypercholesterolemia (n = 83) or isolated Lp(a) hyperlipoproteinemia (n = 35). Average age of patients at start of LA treatment was 58.1 years for males and 62.5 years for females. Medium interval between the first cardiovascular event and LA treatment was 6.4 ± 5.6 years and the average LA treatment period was 6.8 ± 4.9 years. On average treatments were performed once a week, via peripheral venous access in 79.3% of non-hemodialysis patients. In patients with hypercholesterolemia initial pre-LA LDL-C was lowered from 176.4 ± 67.0 mg/dL by 66.7 ± 10.8% per session, achieving a long-term interval mean value of 119.8 ± 34.7 mg/dL, i.e. reduction by 32.1 ± 19.6% (p < 0.0001). In patients with isolated elevated Lp(a) initial pre-LA Lp(a) was lowered from 127.2 ± 67.3 mg/dL by 66.8 ± 5.8% per session, achieving a long-term interval mean value of 60.0 ± 19.5 mg/dL, i.e. reduction by 52.8 ± 23.0% (p < 0.0001). After start of LA the average annual rate of major adverse coronary events (MACE) of all patients declined by 79.7% (p < 0.0001). Subgroup analysis showed decline by 73.7% (p < 0.0001) in patients with severe hypercholesterolemia, and by 90.4% (p < 0.0001) in patients with isolated elevated Lp(a). Adverse events (AE) occurred in 1.1% of treatments. LA treatment of patients with high risk for CVD due to LDL and/or Lp(a) hyperlipoproteinemia was effective, safe, and well tolerated. The number of cardiovascular events, at least during a six-year period, declined by 80%.

Clinical benefit of long-term lipoprotein apheresis in patients with severe hypercholesterolemia or Lp(a)-hyperlipoproteinemia with progressive cardiovascular disease.

Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are established causal risk factors for cardiovascular disease (CVD). Efficacy, safety, and tolerability of lipoprotein apheresis (LA) were investigated in 118 patients with CVD covering a period with 36,745 LA treatments in a retrospective, monocentric study. Indications for LA were severe hypercholesterolemia (n = 83) or isolated Lp(a) hyperlipoproteinemia (Lp(a)-HLP) (n = 35). In patients with hypercholesterolemia, initial pre-LA LDL-C was 176.4 ± 67.0 mg/dL. In patients with isolated Lp(a)-HLP, initial pre-LA Lp(a) was 127.2 ± 67.3 mg/dL. Mean reduction rates of LA were 67 % for both LDL-C and Lp(a). During chronic LA, the average annual rate of major adverse cardiac events of all patients declined by 79.7 % (p < 0.0001). Subgroup analysis showed decline by 73.7 % (p < 0.0001) in patients with severe hypercholesterolemia, and by 90.4 % (p < 0.0001) in patients with isolated Lp(a)-HLP. Adverse events occurred in 1.1 % of treatments. LA treatment of patients with a high risk for CVD due to hypercholesterolemia and/or Lp(a)-HLP demonstrated clinical benefit and was safe and well tolerated.

Lipoprotein apheresis standard for apheresis competence centers--an updated synthesis and amendment to pre-existing standards.

With several techniques of selective apheresis treatment, some of which have been established for over 30 years, severe and pharmacologically unmanageable dyslipidemia can be treated successfully. The long-term lowering of LDL cholesterol and lipoprotein(a) by 60-80 percent, together with pleiotropic effects, allow for significant risk reduction in otherwise progressive chronic atherosclerotic disease, i.e. chronic coronary artery disease in most apheresis patients, and improvement of quality of life. For various reasons, worldwide only an estimated 2500 patients, among them 1400 to 1500 in Germany, are regularly treated by apheresis. This relatively small number of apheresis patients in Germany is being cared for in more than 200 centers, by more than 750 physicians approved for extracorporeal treatment, resulting in unraveling of expertise and diversity of treatment strategies instead of the needed concentration. Here we present a comprehensive standard for competence centers in apheresis treatment, which is an updated synthesis and amendment to previously published standards, based on the experience from more than 30,000 apheresis treatments in our own center. The presented standard provides a guideline for apheresis treatments, comprising all procedures, indications, detailing the application procedure, as well as suggestions for supportive care in extracorporeal therapy. In the absence of large studies of sufficient quality, this standard represents our "good clinical practice" and refers the "best available evidence", providing the indispensable basis for working in an apheresis center. The apheresis standard also aims to contribute to quality assurance, another intention is to increase the acceptance of this valuable treatment, with a view to admitting more patients in need to apheresis programs, on the basis of reliable cost reimbursement.

Immunoadsorption in steroid-refractory multiple sclerosis: clinical experience in 60 patients.

BACKGROUND: Multiple 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 METHODS: A 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. RESULTS: In 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%). CONCLUSION: Immunoadsorption 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.

Characteristics of carotid atherosclerotic plaques of chronic lipid apheresis patients as assessed by in vivo high-resolution CMR--a comparative analysis.

BACKGROUND: Components of carotid atherosclerotic plaques can reliably be identified and quantified using high resolution in vivo 3-Tesla CMR. It is suspected that lipid apheresis therapy in addition to lowering serum lipid levels also has an influence on development and progression of atherosclerotic plaques. The purpose of this study was to evaluate the influence of chronic lipid apheresis (LA) on the composition of atherosclerotic carotid plaques. METHODS: 32 arteries of 16 patients during chronic LA-therapy with carotid plaques and stenosis of 1-80% were matched according to degree of stenosis with 32 patients, who had recently suffered an ischemic stroke. Of these patients only the asymptomatic carotid artery was analyzed. All patients underwent black-blood 3 T CMR of the carotids using parallel imaging and dedicated surface coils. Cardiovascular risk factors were recorded. Morphology and composition of carotid plaques were evaluated. For statistical evaluation Fisher's Exact and unpaired t-test were used. A p-value <0.05 was considered statistically significant. RESULTS: Patients in the LA-group were younger (63.5 vs. 73.9. years, p<0.05), had a higher prevalence of hypercholesterolemia and of established coronary heart disease in patients and in first-degree relatives (p<0.05, respectively). LA-patients had smaller maximum wall areas (49.7 vs. 59.6mm2, p<0.05), showed lower prevalence of lipid cores (28.1% vs. 56.3%, p<0.05) and the lipid content was smaller than in the control group (5.0 vs. 11.6%, p<0.05). Minimum lumen areas and maximum total vessel areas did not differ significantly between both groups. CONCLUSION: Results of this study suggest that, despite a severer risk profile for cardiovascular complications in LA-patients, chronic LA is associated with significantly lower lipid content in carotid plaques compared to plaques of patients without LA with similar degrees of stenosis, which is characteristic of clinically stable plaques.

Fibrinogen/LDL apheresis as successful second-line treatment of sudden hearing loss: a retrospective study on 217 patients.

BACKGROUND: Sudden sensorineural hearing loss (SSHL) may be caused by a reduction of cochlear perfusion. Cholesterol and fibrinogen negatively influence rheological properties of blood thus leading to alteration of microcirculation. Fibrinogen/LDL apheresis improves cochlear blood flow by acutely decreasing plasma cholesterol and fibrinogen. METHODS: Remission rates of 217 patients with SSHL were analysed retrospectively after single apheresis. All patients had been treated otherwise before without any improvement of hearing. We investigated data in regard to frequency of hearing loss and time between onset of symptoms and apheresis. RESULTS: 15% of all patients had complete remissions, whereas partial remissions were seen in 46%. No change of hearing threshold was seen in 33%, 2% worsened. Remission rates decreased from 70% for a time of 2 weeks between onset of SSHL and apheresis to 63% and 21% for 6 weeks and 3 months. CONCLUSION: The present study shows that apheresis was followed by complete or partial remissions in 61% of patients even as second line therapy. The window for good therapeutic success is approximately 6 weeks.

Indication and implementation of lipidapheresis, rheopheresis, or immunoadsorption (lessons learnt from Germany's largest apheresis center).

Efficient modes of extracorporeal blood purification are available today for apheresis treatment of progressive atherosclerosis, autoimmune disease, or for improving hemorheology. Advanced technology and sophisticated care render apheresis treatment selective, safe and tolerable. Our task is to constantly update indications for apheresis based on best evidence available and good clinical practice, as well as, to determine how apheresis therapy can be made available to those in need or with otherwise refractory disease. Presenting examples of lipid apheresis, rheopheresis, or immunoadsorption for treatment of hypercholesterolemia, hyperlipoproteinemia (a), acute hearing loss, refractory or exacerbating multiple sclerosis, we highlight real world obstacles for implementation of treatment, resulting in still too many patients with proven or recommended indication left untreated. Based on the experience of the largest apheresis center in Germany, with more than 3,300 treatments per year, we depict the necessary structure for identification of patients, defining indication, referral, implementation of therapy, and reimbursement. Apheresis is unfamiliar to most patients and many practitioners or consultants. Nephrologists, performing >90% of apheresis treatments in Germany, have to form a network for referral comprising all regional care-givers, general practitioners as well as the respective specialists (mainly, cardiologists, endocrinologists, diabetologists, ORL specialists, neurologists, ophthalmologists, or rheumatologists), and insurances or other cost-bearing parties for offering a scientifically approved therapeutic regimen and comprehensive care. We have realized this concept in a high volume apheresis center acting in a closely knit network characterized by an unrelenting effort at ongoing medical education. As a consequence, we include approximately 10 times more patients with appropriate diagnoses in our apheresis program as compared to the national average.