Immunoadsorption Research Articles

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates.

Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure. The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate.

Immunoadsorption in nephrotic syndrome: Where are we now and where are we going from here?

Idiopathic nephrotic syndrome (INS) is characterized by three different entities, namely minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). While there is an increasing understanding of primary MN with the discovery of antibodies directed against phospholipase A2 receptor (PLA2R Ab) and thrombospondin type 1 domain-containing 7A, circulatory factors causative of inducing MCD and FSGS remain in part elusive. Extracorporeal treatment forms (mostly plasma exchange) have been reserved for patients with either a disease course refractory to commonly prescribed immunosuppressive drugs or to patients with recurrence after kidney transplantation. There is a paucity of data supporting the use of immunoadsorption (IAS) in the management of MCD and MN and evidence to perform LDL-apheresis in the former is limited to reports from Japan. Treatment with IAS in primary FSGS has shown mixed responses, possibly biased by including treatment-resistant cases in the absence of genetic testing. In those with recurrence of the disease following kidney transplantation, IAS has shown high remission rates with an acceptable safety profile. There is a need to compare IAS to plasma exchange (PLEX) in this indication and due to a higher amount of plasma processed during one session, IAS may have advantages over PLEX. Removal of PLA2R Ab by IAS is currently being tested in a phase II clinical trial. More clinical trials in a prospective and randomized fashion need to be designed to prove the concept that IAS may be a treatment option for INS. While PLEX is still the leading extracorporeal treatment form in these indications, this review aims to highlight the efficacy and safety of IAS in the management of INS.

Effectiveness of different immunoadsorption columns for anti-A/B antibody depletion

ObjectiveIn recent studies, semi-selective compared to antigen-specific immunoadsorption (IA) columns showed comparable effectiveness in anti-A/B antibody removal before incompatible living donor kidney transplantation. Semi-selective columns allow a greater number of IA treatments at lower costs. They are also capable of removing potentially harmful human leukocyte antigen alloantibodies. Nevertheless, additional plasma exchange treatments are often necessary to reach the preoperative target titer, most likely due to an inadequate anti-A/B IgM antibody depletion. MethodsWe compared the effectiveness of immunoglobulin and anti-A/B antibody reduction by different semi-selective (Therasorb Ig-flex, Therasorb Ig-omni5, Immunosorba) and antigen-specific (Glycosorb) IA columns during the desensitization of 63 ABO-incompatible living donor kidney transplant candidates with a total of 375 IA treatments. Fifty-three patients were eventually transplanted. ResultsTotal IgM reduction during the first IA treatment was significantly greater with the Therasorb Ig-omni5 compared to the Therasorb Ig-flex (mean: −71.3 vs −41.6; p = 0.001) or Immunosorba columns (mean: −71.3 vs −42.8; p = 0.03). During a median of 5.5–6 pre-transplant IA treatments, Therasorb Ig-flex and Therasorb Ig-omni5 columns were equally effective in the reduction of total IgM while both showed superior IgM reduction compared to the Immunosorba columns (Therasorb Ig-flex, mean: −81.2 vs −72.2; p = 0.01; Therasorb Ig-omni5, mean: −88.2 vs −72.2; p = 0.02). IgG reduction was not significantly different between groups. Likewise, anti-A/B IgM antibody reduction (titer Saline) during the first IA treatment was significantly greater with the Therasorb Ig-omni5 compared to the Therasorb Ig-flex (mean titer reduction: −1.9 vs −1.1; p = 0.02) and tended to be greater than with Immunosorba or Glycosorb columns. During a median of 5–6 pre-transplant IA treatments, overall anti-A/B IgM antibody reduction was significantly greater when IA was performed with the Therasorb Ig-flex (mean titer reduction: −3.8 vs −1.3; p < 0.001) or Therasorb Ig-omni5 (mean titer reduction: −4.3 vs −1.3; p = 0.01) compared to the Immunosorba columns with no differences compared to the Glycosorb columns. Again, anti-A/B IgG antibody reduction (titer Coombs) was not significantly different between groups. ConclusionsThe semi-selective Therasorb Ig-omni5 device offers potential advantages in reducing total IgM as well as anti-A/B IgM antibodies.

Therapeutic Immunoadsorption and Conventional Plasma Exchange in ABO-incompatible Renal Transplant: An Exculpatory Evidence.

AimThe objective of this study was to compare the efficacy of immunoadsorption (IA) with conventional therapeutic plasma-exchange (cTPE) in ABO-incompatible (ABOi) renal transplant.MethodsData of patients from July 2015 to June 2017 (category-I, number of patients (N) = 11; IA±cTPE) on the average length of stay (ALOS), number of cTPE/IA, antibody-titers (AT), creatinine, patient and graft survival at one year were compared retrospectively with patients in period from February 2012 to June 2015 (category-II, N = 29; cTPE only). AT of patients not decreasing to less than one fold after two cTPE were shifted for IA. For patients undergoing IA, real-time AT was done and IA stopped after target titer (TT <1:8) was achieved. Post-transplant cTPE was done if, titers rebounded to ≥1:8. Intravenous immunoglobulin (IVIG) was given after every cTPE/IA. Cost comparisons were made.ResultsIn category-I, seven patients (63.63%) were shifted to IA from cTPE. The mean cTPE procedures in category I and II are 3.5 ± 2.4 and 4.8 ± 2.5, respectively (p = 0.206). The mean IA procedures in category-I are 1.6 ± 0.5. The number of patients requiring post-operative TPE was less in category-I than category-II, i.e., N = 5, 45.5% vs N = 20, 69%, respectively (p = 0.171). The expense of IA in category-I vs cTPE in category-II was statistically not significant (p = 0.422) but had significant lesser ALOS (p = 0.044). Expenses, when a patient undergoes both cTPE and IA (category-I), are significantly higher to category-II (p = 0.003). The two groups were comparable in AT, creatinine value, graft and patient survival rates at one year.ConclusionContrary to the general judgment of IA being expensive than cTPE, this study shows equivalent expenditures with comparable therapeutic outcomes.

Immunoadsorption for Acute Symptomatic Antibody-Mediated Rejection after Heart Transplantation

Purpose Antibody-mediated rejection (AMR) after heart transplantation (HTX) is associated with adverse outcomes . A standardized therapeutic regimen has not yet been defined. Immunoadsorption (IA) has shown promising results in AMR after kidney transplantation . We present our results with IA for acute symptomatic AMR after HTX. Methods This retrospective single-center study included all consecutive patients with proven and treated symptomatic AMR between 2006 and 2016. Survival from AMR, incidence of cardiac allograft vasculopathy (CAV) as well as donor specific anti-HLA-antibody (DSA) cumulative mean fluorescence intensity (MFI) assessed by LUMINEX single antigen bead assay are described. Results 22 patients were designated to undergo extracorporeal antibody removal for symptomatic AMR and received IA (n=18, 81,8 %) or plasmapheresis (PP; n=1, 4,5 %). One patient was switched to IA after one initial PP. In two patients IA/PP was not initiated due to unfavorable prognosis. Concomitant therapy was methylprednisolone (100 %), IVIg (9 %) and rituximab (4,5 %). AMR occurred after a median of 5.65 months (IQR 0.43-21.4) from HTX. Overall survival after a median follow up of 4.85 years from AMR diagnosis was 63.6 %. Mortality 30 days, 1 year and 5 years after AMR onset was 27.3 %, 31.8 % and 31.8 %. 4 patients (18.2 %) developed severe CAV (ISHLT grade ≥ 2) after a median time of 30.5 months after AMR onset. 21 patients had positive DSA at the time of AMR diagnosis (HLA I only: 13.6 %, HLA II only: 50 %, HLA I+II: 31.8%). Conclusion Despite high early mortality, long-term outcome of patients surviving the acute phase is encouraging, however we observed an increased burden of CAV. Due to the oftentimes fulminant clinical course, rapid diagnosis and therapy, facilitated by close interdisciplinary cooperation of intensivists , cardiac surgeons and nephrologists is crucial. Next steps include a detailed characterization of DSAs over the treatment period as well as endomyocardial biopsy specimens of patients with AMR.

ABO-incompatible kidney transplantation: Indian working group recommendations

Expanding use of ABO-incompatible kidney transplant (ABOiKT) globally and in India demands harmonized protocols. With an aim to provide unified and standardized consensus for ABOiKT in Indian setting, a 14-member working group formulated this document on key critical areas to guide ABOiKT. The recommendations include the following: (i) Gel column agglutination test is a method of choice for antibody (Ab) titer assessment with tube method as acceptable alternative. Immunoglobulin G measurement is advised for clinical decision making. (ii) Assessment of one Ab titer before subjecting patient to Ab removal is recommended. Postplasmapheresis (PP) titers to be monitored anywhere between 2 and 12 h. (iii) Target Ab titer recommended is ≤1:16 irrespective of the method used for titer assessment. (iv) If cost and availability are not a concern, immunoadsorption (IA) should be preferred. (vi) Choice of replacement fluid depends on the method employed for Ab removal. (vii) Donor or AB-positive plasma transfusion can be considered to avoid coagulopathy and bleeding in posttransplant period. It also decreases the risk of coagulopathy associated with greater number of PP cycles performed during and after transplant. (viii) IA column can be reused if cleaned, sterilized and stored properly. (ix) Intravenous immunoglobulin (IVIG) is optional for use in ABOiKT. Choose IVIG batch with lowest ABO- Ab titers and use in low dose (~ 100 mg/kg). (x) Rituximab in a low dose of 100–200 mg is effective and its use (at-least 2 weeks prior to transplant) is at the discretion of treating renal transplant physician. (xi) Avoid, if possible, the combined used of antithymocyte globulin and rituximab as it increases risk of infections significantly. (xii) Posttransplant PP is needed if there is Ab mediated rejection with increasing titers. (xiii) Standard immunosuppression should be followed. These recommendations are first of a kind that aims to standardize the practice of ABOiKT, serve as a guiding tool to the transplant physicians in India.

Immunoadsorption in dermatology

Autoimmmune bullous diseases are mediated by pathogenetically relevant autoantibodies against components of the epidermis and/or superficial mucous membranes (in pemphigus) and structural proteins of the dermal-epidermal junction (in pemphigoid diseases). Using immunoadsorption (IA), an already well-established procedure in cardiac and rheumatic disorders, antibodies can be removed from the plasma. At present, most data on the adjuvant use of IA in dermatology are derived from patients with severe and/or refractory pemphigus vulgaris or pemphigus foliaceus and also from patients with pemphigoid diseases. Additionally, in the last few years different protocols for IA in patients with severe atopic dermatitis and elevated total serum IgE levels have been published. While panimmunoglobulin adsorbers are mainly used in dermatology, an IgE-specific adsorber has been used in some patients with atopic dermatitis and in the future, antigen-specific adsorbers are to be expected that will enable the specific reduction of autoantibodies.

Short-term and long-term effects of immunoadsorption in refractory chronic inflammatory demyelinating polyneuropathy: a prospective study in 17 patients.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, autoimmune-inflammatory disease of the peripheral nervous system. Recently, various immunoglobulin G4 (IgG4) type auto-antibodies have been described in patients with CIDP which can effectively be removed by immunoadsorption (IA). Therefore, we prospectively evaluated the therapeutic effect of IA in 17 patients with progressive CIDP not responding to other treatment. We prospectively evaluated the course of disease of 17 patients with CIDP who had insufficiently responded to steroids and/or IVIg previously and who received at least one cycle of IA. As clinical outcome parameter, we used a combined CIDP score of three validated scales comprising disability, motor score, and sensitivity. Seven patients received repeated treatments in regular intervals over a prolonged period up to 46 months. We observed a small, but significant improvement of the overall score after 2 weeks that mainly reflected an improvement of muscle strength. The median value of the combined CIDP score was 308.0 (266.0-374.5) points before IA and 330.0 (290.0-393.5) points 2 weeks after IA (p = 0.019). More importantly, all but one of seven progressive patients who received long-term immunoadsorption in regular intervals stabilized almost completely. Before IA, these patients lost 6.7 (3.0-13.1) points of combined CIDP score per month. During IA, they lost - 0.1 (0.0-0.8) points per month (p < 0.0001). Our results suggest that IA might constitute a promising and well-tolerated therapeutic alternative in CIDP for short-term and long-term treatment. We showed that long-term treatment with IA in regular intervals can stabilize the course of disease at least in a subgroup of patients.

PMD110 - COST-EFFECTIVENESS OF IMMUNOADSORPTION FOR INCOMPATIBLE KIDNEY TRANSPLANTATION IN GERMANY

Kidney transplantation has been shown to offer superior outcomes over dialysis in the treatment of end-stage renal disease (ESRD). Medical technologies have been developed, aiming to overcome barriers often associated with (living) kidney transplantations (blood group incompatibility, highly sensitized patients). Immunoadsorption (IA) is one of these technologies. The analysis evaluates the cost-effectiveness of the therapy in patients undergoing incompatible kidney transplantation compared with remaining on treatment with dialysis. Quality-adjusted life years (QALY) and costs from a German health insurance perspective over a lifetime horizon were the primary outcome of the developed state-transition model. Additionally, the number of life years gained and the reduction of time in which the patients are dependent on dialysis have been part of the analysis. Current transplantation rates and potential future scenarios of increased incompatible transplantation rates enabled by IA have been analysed using various willingness-to-pay thresholds. A systematic review revealed a limited number of low quality studies on the effectiveness of IA. However, even when including high parameter uncertainty in sensitivity analyses, offering IA in incompatible kidney transplantations has been shown to be a dominant strategy with a probability of cost-effectiveness given a WTP of € 0 of 92,63 percent. IA might lead to an increase in QALYs per patient of 0,07; 0,1 and 0,25 for the base case analysis, scenario 1 and scenario 2, respectively, when increasing the number of incompatible transplantations. Cost reduction ranges between € 4.197,21 and € 15.505,58 resulting in overall cost savings of up to € 122.121.948,10 when extrapolating the findings to all waitlisted patients. Enabling incompatible living kidney transplantation in ESRD patients is a cost-effective approach resulting in better outcome at lower costs. An increase of the transplantation rate yields the opportunity of reduction of overall costs of renal replacement therapy for health care systems.

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.

ObjectiveTo analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).MethodsThis retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.ResultsTwo hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).ConclusionsOur findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.Classification of evidenceThis study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.

Adjuvant treatment of severe/refractory bullous pemphigoid with protein A immunoadsorption.

While depletion of circulating autoantibodies using immunoadsorption (IA) is an established therapeutic approach in patients with pemphigus vulgaris, IA has only sporadically been used in other autoimmune bullous disorders. Although bullous pemphigoid (BP) usually responds well to topical and systemic corticosteroids, rapid depletion of serum autoantibodies may be an effective adjuvant treatment option in patients with severe and/or refractory disease. Case series of 20 patients (13 women, 7 men; mean age 78.6 years; range 56-94 years) with severe or refractory BP. In addition to oral prednisolone (0.25-0.5 mg/kg/day), dapsone (1.0-1.5mg/kg/day), and clobetasol propionate 0.05% ointment (lesional application, twice daily), treatment consisted of proteinA IA (three sessions on consecutive days). The mean follow-up period was 33.6 months (1-84 months). The majority of patients showed a rapid and sustained response. One month after treatment, eight patients (42%; 19 patients were included in the follow-up) were in complete remission; at the last follow-up visit (after 1 to 84 months), that number was 13 (68%). Not only was there an initial drop in anti-BP180 autoantibodies (by 92%), the effect also continued after one and three months, with mean autoantibody levels at 26% and 13% of baseline, respectively (p<0.001). Both previously treated and treatment-naive patients showed a significant reduction in anti-BP180NC16A antibody levels throughout the observation period. Adverse events occurred in 13 of the 20 patients (65%). Three were severe of which two were likely or probably related to IA. Immunoadsorption is an effective adjuvant treatment option for (the usually elderly) patients with severe and/or refractory BP.

Effect of DNA immune absorption on lupus pneumonia

Objective To investigate the clinical application and efficacy of DNA immune absorption in patients with lupus interstitial pneumonia. Methods to collect randomized 18 patients with lupus patients with pneumonia were enrolled in the study and randomly divided into immunoadsorption group and traditional CTX treatment group, in order to observe the ESR, CRP, ANA quantitative monitoring at different time, pulmonary function test (diffusing capacity of the lung for carbon monoxide, DLCO), 6 min walking distance, procalcitonin(PCT). The difference between groups was statistically analyzed and the effect of DNA immunization was discussed. Results There were significant differences between immunoadsorption group and control group in ESR at the different time points before and after the treatment(Fgroup=7.841, P<0.05; Fcross=6.512, P<0.05; Finteraction=10.421, P<0.05), CRP(Fgroup=6.995, P<0.05; Fcross=5.847, P<0.05; Finteraction=8.847, P<0.05) and ANA quantitative monitoring(FgrouP=12.336, P<0.05; Fcross=11.214, P<0.05; Finteraction=15.847, P<0.05). At 1 and 2 weeks after treatment, CRP and ESR of the immunoadsorption group began to decrease, and the difference was statistically significant compared with those before treatment (P<0.05), while the difference between the control group and the treatment group was statistically significant after 4 weeks (P<0.05). After 2 weeks of treatment, there was a significant difference in ANA quantitative monitoring between the immunoadsorption group, compared with that before treatment.There was a significant difference between the control group before treatment and the 6 months after treatment (P<0.05). There was a significant difference between the immunoadsorption group and the control group in pulmonary function test(FgrouP=6.222, P<0.05; Fcross=7.154, P<0.05; Finteraction=8.527, P<0.05), 6 min walking distance(FgrouP=8.669, P<0.05; Fcross=7.154, P<0.05; Finteraction=11.547, P<0.05) and PCT( FgrouP=5.621, P<0.05; Fcross=4.125, P<0.05; Finteraction=7.554, P<0.05.The pulmonary function and 6 min walking distance of 2-week treatment in the immunoadsorption group.There showed a significant difference compared with that before treatment.The difference between the control group after 4 weeks of treatment and that before treatment was statistically significant (P=<0.05). There was a significant difference between the 2 weeks PCT treatment in the immunoadsorption group and that before treatment (P<0.05). There was a significant difference between the control group after 3 months of treatment and before treatment(P<0.05). Conclusion The treatment of lupus interstitial pneumonia in traditional regimens is ineffective, and the efficacy of DNA is better than that of conventional regimens, and reduces the risk of infection. Key words: Systemic lupus erythematosus; Lupus pneumonia; Interstitial pneumonia; DNA immunosorbent; Plasma exchange

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME

IntroductionInfection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases.Methods10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry.ResultsIgG levels dropped to median 0.73 g/l (normal 7–16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6–12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.ConclusionsIA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

THE DNA-BASED THERAPEUTIC AGENT BC 007 COMPLETELY NEUTRALIZES AGONISTIC AUTOANTIBODIES DIRECTED AGAINST β1-ADRENOCEPTORS: RESULTS OF A PHASE 1 TRIAL

80 percent of patients with non-ischemic heart failure (HF) and reduced ejection fraction have autoantibodies against β1-adrenoceptos (β1-AAB), which cause and/or sustain HF. The removal of β1-AAB by immunoadsorption (IA) leads to an improvement of cardiac function and significantly reduced

Targeting IgE Antibodies by Immunoadsorption in Atopic Dermatitis.

One major hallmark of atopic dermatitis (AD) is the elevated level of total serum IgE, which has been reported to be partly of the autoreactive type in a subset of patients. Immunoadsorption (IA) has been successfully applied in various classical autoantibody-mediated diseases such as pemphigus. Recent reports proposed the use of IA also for patients with severe AD and high total serum IgE levels. In this mini-review, we summarize the current knowledge about this novel treatment approach for AD and briefly discuss the so far incompletely known role of autoreactive IgE as potential target of IA therapy in this common inflammatory skin disorder.

IgE-Selective Immunoadsorption for Severe Atopic Dermatitis

Recent reports proposed the application of immunoadsorption (IA) for patients with recalcitrant atopic dermatitis (AD) and high-serum IgE levels. However, experience with this novel treatment approach, especially with the newly available IgE-specific adsorber, is limited and recommendation for its use in clinical practice awaits evidence from more studies. Patients with severe AD (SCORAD ≥ 60) and total serum IgE levels ≥750 kU/L were included in this study. The treatment protocol consisted of two cycles of five consecutive treatments with IgE-selective IA 3 weeks apart. Ten patients were enrolled and four patients completed the study. The mean SCORAD was significantly improved by up to 43% within a few weeks and until the end of a 6-month follow-up period, with 50% of patients achieving an at least 50% individual reduction of the baseline SCORAD. Each IA cycle induced a temporal average decrement of total serum levels of IgE, IgM, IgA, and IgG by 92, 43, 38, and 35%, respectively. Except for one case of Staphylococcus aureus septicemia, no major adverse events occurred. Although limited by a considerable withdrawal rate, our observations strengthen our and other recent results further suggesting that IgE-selective IA is an effective treatment option for patients severely affected by AD with highly elevated IgE levels.

Prognosis and its risk factors in ANCA-associated glomerulonephritis patients treated with initial renal replacement therapy

Objective: To explore the prognosis and its risk factors in anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) patients who needed initial renal replacement therapy (RRT). Methods: One hundred patients [54 females, 46 males, with a median age of 54(41, 60) years] with biopsy-proven AAGN and requiring initial RRT between January 1996 and December 2016 in Nanjing Jinling Hospital were included. Intensive immunotherapy indicated that the patients received corticosteroids in combination with cyclophosphamide or mycophenolate mofetil, or immunoadsorption (IA) or double filtration plasmapheresis (DFPP). The clinical and histological risk factors for renal survival were analyzed. Results: Forty-one patients were free of RRT after a median time of 1 (0.5, 2) month treatment (dialysis-independent group), and the remaining 59 patients were on maintenance dialysis (dialysis-dependent group). The multivariate logistic analysis revealed that the proportion of normal glomeruli <8% (OR=5.95, P=0.002) and global sclerotic glomeruli ≥50% (OR=4.87, P=0.003), and not receiving intensive immunotherapy (OR=7.81, P=0.004) were the risk factors for the renal recovery in these patients. During a median follow-up time of 22 (10, 50) months, 15 patients(36.6%) in the dialysis-independent group progressed into maintenance dialysis, and the 1 and 3 year renal survival rate were 86% and 60%, respectively. During a median follow-up time of 6 (2, 24) months, 12 (12%) patients died, among whom four patients died of therapy. The multivariate Cox regression analysis revealed that IA/DFPP treatment (HR=10.85, P=0.034) and low albumin level (HR=1.26, P=0.009) significantly associated with a higher risk of therapy-related death. Conclusions: The renal recovery rate in AAGN patients with initial RRT was low. The proportion of normal and global sclerotic glomeruli, receiving intensive immunotherapy or not were associated with renal outcome, and IA/DFPP treatment as well as lower albumin level were independently associated with therapy-related death.

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica

Background:Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce.Methods:In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON).Results:A total of 24 patients were analyzed, 23 with relapsing–remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7–10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments.Conclusions:Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.

Safety and Efficacy of Immunoadsorption as an Add-On to Medical Treatment in Patients with Severe Idiopathic Pulmonary Arterial Hypertension

Background: Despite optimized medical therapy, severe idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease with a poor outcome. Autoantibodies have been detected in IPAH that can contribute to worsening of the disease. Objectives: The objective of this prospective, open-label, single-arm, multicenter trial was to evaluate the safety and efficacy of immunoadsorption (IA) as an add-on to optimized medical treatment for patients with IPAH. Methods: A total of 10 IPAH patients received IA over 5 days. Their clinical parameters, including hemodynamics measured by right heart catheter, were assessed at baseline and after 3 and 6 months. The primary endpoint was the change in pulmonary vascular resistance (PVR). Secondary endpoints included the change in 6-min walking distance, quality of life, safety, and plasma levels of IgG and autoantibodies. Results: The evaluation of the 10 IPAH patients (75% female; 51 ± 12 years; 166 ± 10 cm; WHO functional class III; 53% on combination therapy) revealed that IA was a safe procedure that efficiently removed IgG and autoantibodies from the circulation. After 3 months, the mean PVR improved significantly by 13.2% (p = 0.03) and the cardiac index improved by 13.1%, but no significant changes were found in 6-min walking distance. The quality of life physical functioning subscale score significantly improved after 6 months. The serious adverse events in 3 patients were possibly related to IA and included pneumonia, temporary disturbance in attention, and thrombocytopenia. Conclusions: IA as an add-on to targeted medical treatment for IPAH is a safe procedure with beneficial effects on hemodynamics, especially in patients with high levels of autoantibodies. Larger-scale controlled studies are needed to assess its efficacy in IPAH and to identify responders.

Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric kidney transplantation: a multicentre French cohort.

Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (KTx) in children. This can lead to delayed graft loss. As the management of children with recurrent FSGS is not well established, apheresis strategies could be a cornerstone to control the disease. Immunoadsorption (IA) is a recent apheresis therapy. There have been few studies examining IA in this setting. We report the results of IA for management of recurrent FSGS after KTx in children in France. We included all children treated with IA for early FSGS recurrence after KTx between January 2011 and June 2014 in France. We excluded genetic forms of FSGS. Patients' characteristics and technical data on IA were retrospectively collected. Recurrence was defined as nephrotic proteinuria during the post-transplantation period. Partial and complete remissions were defined when urine protein:creatinine ratios were less than 0.2 and 0.05 g/mmol, respectively. Twelve patients, from six paediatric KTx units, presenting with FSGS recurrence between 0 and 21 days after KTx were treated with IA. Ten of 12 children were responders: 2 achieved partial remission and 8 complete remission. The decrease of proteinuria rapidly occurred within the first 10 sessions after initiating IA. After 3 months of IA, two patients maintained remission without IA and eight became IA dependent. No severe side effects were reported. Our study reports on the efficacy of IA in the recurrence of FSGS after KTx in children. Further prospective controlled studies are required to confirm these results and to optimize the management of FSGS recurrence after paediatric KTx.