Panimmunoglobulin and IgE-selective extracorporeal immunoadsorption in patients with severe atopic dermatitis
Authors: Kristian Reich, Julia Deinzer, Anne-Kathrin Fiege, Valerie von Gruben, Anna-Lena Sack, Alice Thraen, Peter Weisenseel, Kristine Breuer, Stefan Jäckle, Markus Meier
Journal: Journal of Allergy and Clinical Immunology (2016)

Atopic dermatitis (AD) is a pruritic, usually eczematous inflammatory skin disease that involves skin barrier dysfunction in concert with immunologic abnormalities driven by dendritic cells, T cells, and eosinophils and characterized by the presence of distinct cytokine and chemokine circuits.1Esaki H. Ewald D.A. Ungar B. Rozenblit M. Zheng X. Xu H. et al.Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection.J Allergy Clin Immunol. 2015; 135: 153-163Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar There is a high unmet therapeutic need, especially for patients with persistent severe disease.2Bieber T. Straeter B. Off-label prescriptions for atopic dermatitis in Europe.Allergy. 2015; 70: 6-11Crossref PubMed Scopus (25) Google Scholar A currently discussed new treatment strategy aims at reducing circulating IgE levels, which are often increased in patients with severe chronic AD and correlate with disease severity.3Liu F.T. Goodarzi H. Chen H.Y. IgE, mast cells, and eosinophils in atopic dermatitis.Clin Rev Allergy Immunol. 2011; 41: 298-310Crossref PubMed Scopus (314) Google Scholar The anti-IgE antibody omalizumab has been tried,4Quist S.R. Ambach A. Göppner D. Quist J. Franke I. Bonnekoh B. et al.Long-term treatment of severe recalcitrant atopic dermatitis with omalizumab, an anti-immunoglobulin E.Acta Derm Venereol. 2013; 93: 206-208Crossref PubMed Scopus (11) Google Scholar but results in patients with AD have not been definitive. In a small pilot study using extracorporeal immunoadsorption with columns that bind all immunoglobulin classes (panimmunoglobulin [pan-Ig] immunoadsorption), parameters of cutaneous inflammation normalized parallel to a clinical improvement in AD.5Kasperkiewicz M. Schmidt E. Frambach Y. Rose C. Meier M. Nitschke M. et al.Improvement of treatment-refractory atopic dermatitis by immunoadsorption: a pilot study.J Allergy Clin Immunol. 2011; 127: 267-270Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Here we compared the clinical effects of pan-Ig immunoadsorption with those of IgE-selective immunoadsorption using newly developed columns selective for human IgE in 50 adult patients (>18 years old) with severe recalcitrant AD. Immunoadsorption is an approved therapeutic procedure in Germany, and treatment costs for these refractory cases were covered by public and private health insurers. Data collection and analysis were done as part of an immunoadsorption registry in the setting of an open-label comparative trial. Extracorporeal pan-Ig (n = 24) and IgE-selective immunoadsorption (n = 26) were managed by an interdisciplinary team of dermatologists, nephrologists, and specially trained nurses. Each patient received a total of 10 immunoadsorption sessions over a 2-month period divided into 3 cycles of 4 consecutive days in week 1, 3 days in week 4, and 3 days in week 8. Patients were hospitalized for each immunoadsorption cycle and assessed before immunoadsorption (visit 1), between the second and third cycles (visit 2), and at approximately 1 month (visit 3) and 6 months (visit 4) after immunoadsorption (Fig 1). Details of patients' characteristics (see Table E1 in this article's Online Repository at www.jacionline.org) and management, severity definitions, registry settings, and immunoadsorption procedures are presented in the Methods section in this article's Online Repository at www.jacionline.org. The mean Eczema Area and Severity Index (EASI) was 21.3, and the majority of patients had excessive IgE levels of between 5,000 and 10,000 kU/L before therapy. Both immunoadsorption types reduced peripheral IgE levels by approximately 85% to 90% per immunoadsorption cycle, but only pan-Ig immunoadsorption also had significant effects on circulating IgG levels (see Fig E1 and further details in the Results section in this article's Online Repository at www.jacionline.org). The main effects, as measured by reductions in EASI and Dermatology Life Quality Index (DLQI), occurred between visits 1 and 2 and remained stable up to visit 4 (Fig 2, upper panels). The median EASI reductions in the IgE-selective immunoadsorption group were 47% (95% CI, 31% to 59%) at visit 2, 45% (95% CI, 20% to 57%) at visit 3, and 60% (95% CI, 17% to 66%) at visit 4 (all P < .005), which is similar to reductions seen in the pan-Ig immunoadsorption group (visit 2: 39% [95% CI, 11% to 58%], visit 3: 52% [95% CI, 30% to 66%], and visit 4: 61% [95% CI, 29% to 71%]; all P < .005). Almost 50% of the patients treated with either immunoadsorption procedure achieved an EASI50 response (ie, an at least 50% reduction of the baseline EASI) by visit 2, and approximately 30% achieved a DLQI of 5 or less (mild effect of the disease). As shown in the lower panels of Fig 2, these percentages remained stable until visit 4 in the IgE-selective immunoadsorption group and slightly increased in the pan-Ig immunoadsorption group. Improvements in EASI and DLQI were paralleled by reductions in the clinical signs domain of the SCORAD index (objective SCORAD) and the Patient-Oriented Eczema Measure (POEM, see Fig E2 in this article's Online Repository at www.jacionline.org). At visit 3, pruritus and sleep scales indicated mean improvements among EASI50 responders of 54% and 55%, respectively. Of the 12 patients with systemic therapy at visit 1, treatment could be stopped in 6 by visit 3 and reduced in another 2 (see also Table E1). Logistic regression analysis revealed 3 dichotomous baseline variables to influence EASI50 response by visit 3. If systemic therapy was present at baseline, the IgE less was less than 6700 kU/L (sample median), and the EASI was 17 or greater (sample median), the probability of achieving an EASI50 response was 75% compared with 15% in the absence of any of these factors (see Fig E3 in this article's Online Repository at www.jacionline.org). While there were no major differences in clinical effects between the 2 immunoadsorption treatment groups, 2 adverse events (AEs) were recorded in the IgE-selective immunoadsorption group, neither of which are considered related to immunoadsorption, compared with 8 AEs in 7 patients in the pan-Ig immunoadsorption group, all of which were considered related to immunoadsorption. The latter included 2 mild cases of herpes labialis and 3 severe infectious AEs that required systemic therapy: 1 case each of herpes keratitis caused by HSV-1, bacterial conjunctivitis caused by Staphylococcus aureus, and bacterial sinusitis. The results of our findings suggest that IgE-selective immunoadsorption is a potential treatment option in patients with severe AD that deserves further investigation. The available data for another new promising treatment for AD, the IL-4 receptor α chain antagonist dupilumab, indicate that EASI50 responses might be achievable in more than 80% of patients after 16 weeks of weekly injections,6Thaçi D. Simpson E.L. Beck L.A. Bieber T. Blauvelt A. Papp K. et al.Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.Lancet. 2016; 387: 40-52Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar but the results are difficult to compare with those reported here because of differences in the treated patient populations. The exact mechanisms underlying the clinical response in patients with AD to immunoadsorption are incompletely understood. Importantly, comparisons of skin-bound and peripheral IgE levels in the earlier pilot trial5Kasperkiewicz M. Schmidt E. Frambach Y. Rose C. Meier M. Nitschke M. et al.Improvement of treatment-refractory atopic dermatitis by immunoadsorption: a pilot study.J Allergy Clin Immunol. 2011; 127: 267-270Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar indicated that reductions in the latter are transient but associated with and probably responsible for more sustainable reductions in the former. Because decreases in skin-bound IgE levels correlated with immunologic and clinical improvements, we speculate that this indirect effect contributes to AD improvement caused by immunoadsorption. At the time the pan-Ig proof-of-concept study was performed, IgE-selective immunoadsorption columns were not yet available. Pan-Ig immunoadsorption is potentially associated with removal of protective immunoglobulin, a drawback in patients with severe AD, who have an increased susceptibility to skin infections by pathogens such as S aureus and Herpes simplex. The results of the present study in conjunction with earlier case reports7Kasperkiewicz M. Süfke S. Schmidt E. Zillikens D. IgE-specific immunoadsorption for treatment of recalcitrant atopic dermatitis.JAMA Dermatol. 2014; 150: 1350-1351Crossref PubMed Scopus (19) Google Scholar, 8Daeschlein G. Scholz S. Lutze S. Eming R. Arnold A. Haase H. et al.Repetitive immunoadsorption cycles for treatment of severe atopic dermatitis.Ther Apher Dial. 2015; 19: 279-287Crossref PubMed Scopus (12) Google Scholar indicate that IgE-selective immunoadsorption is indeed as effective as pan-Ig immunoadsorption but probably safer with regard to infectious events. We thank all patients participating in this observational study and acknowledge the expert assistance of the nurses at the Nephrology Centre Reinbek and Geesthacht, namely Luis Viana, Evelyn Pechler, Silke de Jong, Nadine Alt, and Petra Dahlhaus. We also thank Miltenyi Biotec GmbH for their support in this study. All patients were originally seen in a special outpatient clinic for patients with difficult AD at the Dermatologikum Hamburg. The collected data included a detailed medical history; assessments of disease severity, such as EASI and scores on the clinical signs domain of the SCORAD index (objective SCORAD); and assessments of health-related quality of life (HR-QoL), including DLQI and POEM score, according to current recommendations for the management of severe AD.E1Schmitt J. Langan S. Deckert S. Svensson A. von Kobyletzki L. Thomas K. et al.Harmonising Outcome Measures for Atopic Dermatitis (HOME) Initiative.J Allergy Clin Immunol. 2013; 132: 1337-1347Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, E2Eichenfield L.F. Tom W.L. Chamlin S.L. Feldman S.R. Hanifin J.M. Simpson E.L. et al.Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis.J Am Acad Dermatol. 2014; 70: 338-351Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar Pruritus and sleep were assessed by using a 0- to 10-point numeric rating scale.E3Phan N.Q. Blome C. Fritz F. Gerss J. Reich A. Ebata T. et al.Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.Acta Derm Venereol. 2012; 92: 502-507Crossref PubMed Scopus (350) Google Scholar Adults (>18 years) with severe recalcitrant active AD of the extrinsic type (IgE >150 kU/L)E4Tokura Y. Extrinsic and intrinsic types of atopic dermatitis.J Dermatol Sci. 2010; 58: 1-7Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar were offered treatment with either pan-Ig or IgE-selective immunoadsorption. In the absence of a broadly accepted definition of severe AD and a low correlation between absolute EASI and DLQI (data not shown), we considered patients who, despite expert management, either had an EASI of greater than 10 and/or a DLQI of greater than 10 (severe effect on HR-QoL)E5Hongbo Y. Thomas C.L. Harrison M.A. Salek M.S. Finlay A.Y. Translating the science of quality of life into practice: what do dermatology life quality index scores mean?.J Invest Dermatol. 2005; 125: 659-664Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar to be in alignment with the disease severity classification used for psoriasis.E6Finlay A.Y. Current severe psoriasis and the rule of tens.Br J Dermatol. 2005; 152: 861-867Crossref PubMed Scopus (322) Google Scholar We found that the majority of patients fulfilling these criteria were (1) either patients with high EASI who did not respond to or had significant side effects or contraindications to treatment with systemic corticosteroids and cyclosporine or (2) patients with a DLQI of greater than 10 despite ongoing immunosuppressive therapy, such as cyclosporine, methotrexate, azathioprine, or mycophenolate mofetil. All clinical assessments were performed by a team initially blinded to the type of immunoadsorption. Topical and/or systemic treatments were continued and modified as needed. Patients were informed about the treatment procedure and the collection of data and provided written informed consent for both. The patients described in this article were treated between April 2012 and March 2015. Immunoadsorption was managed by an interdisciplinary team of dermatologists, nephrologists, and nurses who were specially trained for pan-Ig and IgE-selective immunoadsorption. A nephrologist carefully examined all patients to confirm eligibility for immunoadsorption and performed venous ultrasonography of both arms to determine venous access. Each patient received a total of 10 immunoadsorption sessions over a 2-month period divided into 3 cycles of 4 consecutive days in week 1, 3 days in week 4, and 3 days in week 8. Patients were hospitalized for each immunoadsorption cycle at the St. Adolf-Stift and closely monitored by the interdisciplinary immunoadsorption team. Patients received 2 g of cefazolin or, in the case of a history of cephalosporin intolerance, 1 g of fosfomycin as a prophylactic intravenous bolus on the first day of each cycle. Immunoadsorption was performed with reusable adsorption columns containing a matrix coated with either mouse anti-human IgE (TheraSorb IgE; Miltenyi Biotec, Teterow, Germany) or polyclonal sheep anti-human immunoglobulin antibodies (TheraSorb Ig-Flex, Miltenyi Biotec) and the LIFE 18 Apheresis Unit (Miltenyi Biotec). Two adsorption columns were used per patient, allowing for adsorber regeneration during immunoadsorption. The adsorbers have a binding capacity of approximately 0.6 g of total immunoglobulin and 5 million IU of IgE per plasma loading cycle, respectively, but total binding capacity per treatment is not limited because of repeated plasma loading and regeneration of the adsorbers. During each immunoadsorption session, at least the 2-fold plasma volume was processed, as calculated according to Sprenger et al.E7Sprenger K.B. Huber K. Kratz W. Henze E. Nomograms for the prediction of patient's plasma volume in plasma exchange therapy from height, weight, and hematocrit.J Clin Apher. 1987; 3: 185-190Crossref PubMed Scopus (42) Google Scholar When possible, the median cubital or cephalic veins of both arms were used for venous access, generating a blood flow of at least 70 mL/min. Of the 500 immunoadsorption sessions reported here, 55 (11%) sessions in 8 patients required a central venous catheter. Anticoagulation was achieved by a bolus injection of 5000 IU of sodium heparin and anticoagulant citrate dextrose, formula A (ACD-A; Baxter, Munich, Germany). The ratio of ACD-A to whole blood was adjusted to maintain a free calcium concentration in the extracorporeal circuit of less than 0.3 mmol/L, as determined by means of bedside testing every 30 minutes (GEM Premier 3000; Instrumentation Laboratories, Zaventem, Belgium). Intravenous calcium was substituted if the patient's free serum calcium concentration decreased to less than 0.9 mmol/L. The immunoadsorption session was terminated if the treatment time exceeded 4.5 hours or once the 2.8-fold plasma volume had been processed. To compare and confirm the specificity of the 2 different immunoadsorption procedures, IgE and IgG levels were determined immediately before and after each apheresis cycle. In addition, to determine the removal of proteins and immunoglobulins in each immunoadsorption session, the total eluate of the rinsed columns was collected in 5 patients of each treatment group over 1 cycle by using 10-L containers. A 10-mL sample of the mixed eluate was sent for laboratory diagnostic analysis, with all parameters analyzed within 12 to 24 hours (Aesculabor, Hamburg, Germany). Patients' characteristics, IgE levels, and clinical scores were described by summary statistics (sample size, mean ± SD, and/or median and related 95% CI, where applicable). Box-and-whisker plots (with median, interquartile range box, and 10% and 90% whiskers) were applied to inspect the distributions of quantitative target variables. EASI and DLQI over time were intraindividually evaluated by using median values and related CIs. For comparison of both treatment groups, the Hodges-Lehmann point estimator and CI were chosen to estimate group differences.E8Hodges J.L. Lehmann E.L. Estimates of location based on rank tests.Ann Math Stat. 1963; 34: 598-611Crossref Google Scholar, E9Lehmann E.L. Nonparametric confidence intervals for a shift parameter.Ann Math Stat. 1963; 34: 1507-1512Crossref Google Scholar EASI and DLQI observed at visits 2 to 4 were intraindividually compared with baseline values by using the Wilcoxon signed-rank test, with P values of less than .05 set to indicate significance. Patients presenting at the follow-up visits with an individual 50% decrease in EASI compared with baseline or patients with DLQI of 5 points or less were considered responders and are listed with frequencies, percentages, and related CIs, if applicable. The EASI response distribution was investigated by using logistic regression to identify important prognostic factors that would explain differences in treatment response.E10Pocock S.J. Clinical trials, a practical approach. John Wiley & Sons, Chichester (NY)1991: 218-220Google Scholar A wide range of possible factors was included, such as sex, age, baseline clinical scores, IgE levels, and use of systemic medication. Finally, response probabilities were estimated for the set of events caused by these specific factors. Calculations were done with SAS statistical software (version 9.1.2 [2013]; SAS Institute, Cary, NC). Data evaluation was performed as an explorative analysis, applying robust estimators without the need for normal distributed data. Strategies to prevent bias caused by missing values were not considered because of the small number of missing values. The characteristics of the treated patients are presented in Table E1. The majority of patients had long-standing severe AD with largely impaired HR-QoL. Because of the heterogeneity of eligible patients, including patients with severe AD (EASI >10) with no systemic therapy possible and patients with significant disease (DLQI >10) despite ongoing systemic therapy (see the Methods section), there was some variation in clinical activity scores. Forty (80%) patients either had an EASI of greater than 20 or a DLQI of greater than 10, and 22 patients (44%) had both. More than 40% (22/50) of patients received systemic therapies in the last 3 months and more than 80% (42/50) of patients received systemic therapies in the last 12 months before immunoadsorption, with the majority of them being systemic corticosteroids or cyclosporine. Twelve (24%) patients had ongoing systemic therapy at baseline (visit 1), and 2 of these patients had more than 1 systemic therapy (Table E1). There were no major baseline differences between patients receiving pan-Ig and those receiving IgE-selective immunoadsorption, except that the latter tended to have lower clinical activity scores, possibly explained by a higher number of baseline patients with concurrent cyclosporine. Circulating IgE and IgG levels before and after each immunoadsorption cycle are shown in Fig E1. Peripheral immunoglobulin levels before immunoadsorption cycle 1 correspond to baseline levels before treatment. The majority of patients had excessive pretreatment IgE levels of between 5,000 and 10,000 kU/L, with comparable distributions of values in both immunoadsorption treatment groups. IgE-selective immunoadsorption decreased median peripheral IgE levels by approximately 90% with each treatment cycle and peripheral IgG levels by approximately 20%. Pan-Ig immunoadsorption reduced median peripheral IgE levels and also peripheral IgG levels by approximately 85% with each cycle. Effects of both immunoadsorption procedures on peripheral IgE and IgG levels were transient because precycle values remained similar over time. Based on the analysis of 1 immunoadsorption cycle for 5 patients in each immunoadsorption treatment group, more than 4 mg of IgE was removed on average per immunoadsorption session (1 day) with both immunoadsorption procedures compared with approximately 12.5 g of IgG with the pan-Ig immunoadsorption and 1.4 g of IgG with the IgE-selective immunoadsorption procedures, respectively (data not shown). Reduction of IgG plasma concentrations with IgE-selective immunoadsorption is explained by 2 effects: the dilution of plasma during treatment with the infused ACD-A solution and the small loss of plasma (on average, between 10 and 15 mL per adsorption cycle) that occurs during the switch between the 2 adsorber columns. Fig E2 shows that EASI and DLQI reductions at visit 3, approximately 1 month after the final immunoadsorption cycle, were paralleled by reductions in objective SCORAD and POEM scores, although the effects appeared to be less pronounced. Logistic regression analysis revealed 3 dichotomous baseline variables that influenced the EASI50 response to immunoadsorption by visit 3, namely systemic therapy (if present at baseline), an IgE baseline value of less than 6700 kU/L (corresponding to the sample median), and a baseline EASI of 17 or greater (corresponding to the sample median). As shown in Fig E3, the probability to achieve an EASI50 response was 15% in the absence of any of these factors but 75% in the presence of all 3 factors. The 8 AEs occurring in 7 patients in the pan-Ig immunoadsorption group included 2 mild cases of herpes labialis, 3 severe infectious AEs (1 case each of herpes keratitis caused by HSV-1, bacterial conjunctivitis caused by S aureus, and bacterial sinusitis, all requiring systemic therapy), and 3 serious AEs (1 case each of air embolism during central venous catheter placement, cubital vein thrombophlebitis, and generalized cutaneous allergic reaction to prophylactic antibiotic therapy, all requiring hospitalization). All AEs completely resolved during follow-up.Fig E2Comparison of clinical and HR-QoL scores used during immunoadsorption. Box plots and means of relative reductions of clinical scores (EASI and objective SCORAD scores) and HR-QoL parameters (DLQI and POEM scores) at visit 3 compared with baseline (visit 1) are shown.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E3Parameters influencing response to immunoadsorption. The illustration shows the estimated probability of the EASI50 response after immunoadsorption treatment related to the presence of 0, 1, 2, or 3 of the following baseline parameters determined by means of logistic regression analysis: (1) EASI of 17 or greater; (2) consumption of at least 1 systemic medication; and (3) peripheral IgE level of less than 6700 kU/L. The highest EASI50 response probability of 75% was calculated for patients with all 3 parameters at baseline.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Patients' characteristicsAll therapiesPan-IgIgE selectiveNo.502426Sex (M/F)30/2014/1016/10Age (y), mean ± SD45.6 ± 11.044.3 ± 12.546.8 ± 9.5Age (y), median (range)46.5 (21-75)46 (21-63)47 (24-75)Duration of AD (y), mean ± SD36.9 ± 13.335.0 ± 14.038.5 ± 12.7SCORAD score (mean ± SD)40.5 ± 14.246.3 ± 13.635.1 ± 12.7EASI (mean ± SD)21.3 ± 15.524.1 ± 15.218.7 ± 15.6DLQI (mean ± SD)15.3 ± 6.915.9 ± 7.314.8 ± 6.6POEM score (mean ± SD)20.4 ± 5.920.9 ± 5.319.9 ± 6.4Visit 1/2/3/4 (no.)50/49/49/4724/24/24/2226/25/25/25Concurrent therapies (visit 1/2/3/4) TopicalNone5/7/7/42/3/2/23/4/3/2TCS30/32/30/2816/17/16/1414/15/14/14TCI1/0/1/20/0/1/11/0/0/1TCS+TCI14/10/13/136/4/5/58/6/8/8 Systemic therapiesNone38/41/41/3919/21/21/1819/20/20/21SCS4/4/5/53/3/3/31/1/2/2CYA5/2/2/12/0/0/13/2/2/0MTX0/1/1/20/0/0/00/1/1/2MMF1/1/0/00/0/0/01/1/0/0COM2/0/0/00/0/0/02/0/0/0COM, Combination therapy; CYA, cyclosporine; MMF, mycophenolate mofetil; MTX, methotrexate; SCS, systemic corticosteroids; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids. Open table in a new tab COM, Combination therapy; CYA, cyclosporine; MMF, mycophenolate mofetil; MTX, methotrexate; SCS, systemic corticosteroids; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids.