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Immunoglobulin E–Selective Immunoadsorption Reduces Peripheral and Skin-Bound Immunoglobulin E and Modulates Cutaneous IL-13 Expression in Severe Atopic Dermatitis

Open AccessPublished:October 23, 2018DOI:https://doi.org/10.1016/j.jid.2018.09.020

      Abbreviations:

      AD (atopic dermatitis), EASI (Eczema Area and Severity Index), IA (immunoadsorption), Ig (immunoglobulin), SD (standard deviation)
      To the Editor
      Elevated immunoglobulin (Ig) E levels may interfere with skin inflammation in atopic dermatitis (AD) at different levels. One hypothesis is that IgE binding to dendritic cells via the high-affinity IgE receptor, FcεRI, activates the release of pro-inflammatory mediators and facilitates stimulation of allergen-specific cutaneous T-cell responses (
      • Reich K.
      • Heine A.
      • Hugo S.
      • Blaschke V.
      • Middel P.
      • Kaser A.
      • et al.
      Engagement of the FcεRI stimulates the production of IL-16 in Langerhans cell-like dendritic cells.
      ,
      • Werfel T.
      • Heratizadeh A.
      • Niebuhr M.
      • Kapp A.
      • Roesner L.M.
      • Karch A.
      • et al.
      Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge chamber.
      ). In a pilot trial, extracorporeal immunoadsorption (IA) with columns that bind all Ig classes reduced parameters of cutaneous inflammation and improved the clinical phenotype of AD (
      • Kasperkiewicz M.
      • Schmidt E.
      • Frambach Y.
      • Rose C.
      • Meier M.
      • Nitschke M.
      • et al.
      Improvement of treatment-refractory atopic dermatitis by immunoadsorption: a pilot study.
      ). In a subsequent trial with 50 recalcitrant AD patients, pan-Ig IA was compared with IgE-selective IA; both procedures strongly reduced peripheral IgE levels and showed similar clinical effects, with approximately half of the patients achieving an Eczema Area and Severity Index (EASI) 50 response (
      • Reich K.
      • Deinzer J.
      • Fiege A.K.
      • von Gruben V.
      • Sack A.L.
      • Thraen A.
      • et al.
      Panimmunoglobulin and IgE-selective extracorporeal immunoadsorption in patients with severe atopic dermatitis.
      ). There was evidence that IgE-selective IA was better tolerated, as there were five infectious adverse events, three of them severe, among 24 patients in the pan-Ig IA compared to none in the IgE-selective IA group, in which peripheral IgG levels remained largely unchanged. In these and other reports, IgE-selective IA was carried out with reusable columns, with individual patients receiving up to five repetitive cycles of 3–5 days, each applied several weeks apart (reviewed by
      • Kasperkiewicz M.
      • Schmidt E.
      • Ludwig R.J.
      • Zillikens D.
      Targeting IgE antibodies by immunoadsorption in atopic dermatitis.
      ). Although clinical responses occasionally lasted for many months after the last IA (
      • Reich K.
      • Deinzer J.
      • Fiege A.K.
      • von Gruben V.
      • Sack A.L.
      • Thraen A.
      • et al.
      Panimmunoglobulin and IgE-selective extracorporeal immunoadsorption in patients with severe atopic dermatitis.
      ), single-day retreatments on an outpatient basis will be a likely requirement to achieve long-term control in severe cases.
      In this open-label pilot trial, we tested the IgE-removing capacity of a single-use IgE-specific column (IgEnio; Fresenius Medical Care, Bad Homburg, Germany). The column is based on a single-chain variable fragment, ScFv12, which is specific for IgE, does not cross-link IgE on mast cells and basophils, and is produced in E. coli under Good Manufacturing Practice conditions (
      • Lupinek C.
      • Roux K.H.
      • Laffer S.
      • Rauter I.
      • Reginald K.
      • Kneidinger M.
      • et al.
      Trimolecular complex formation of IgE, FcεRI, and a recombinant nonanaphylactic single-chain antibody fragment with high affinity for IgE.
      ). Biopsies taken from eczematous target lesions before and after IA were investigated by routine dermatopathology (spongiosis, acanthosis, hyperkeratosis), immunohistochemistry (CD1a, CD3, CD11c, IgE, HLA-DR, Ki-67, IL-17A), and quantitative reverse transcriptase PCR (IL-4, IL-13, IL-17A, IFN-γ) (
      • Reich K.
      • Papp K.A.
      • Matheson R.T.
      • Tu J.H.
      • Bissonnette R.
      • Bourcier M.
      • et al.
      Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis.
      ) (see also Supplementary Repository online). The study was approved by the Ethical Committee of the Medical Association, Hamburg, Germany, and written informed consent was obtained from all patients.
      Eleven patients (mean age 40.3 years; range 29–67 years) with severe recalcitrant AD (mean ± standard deviation [SD] baseline EASI 25.9 ± 11.3, objective Severity Scoring of Atopic Dermatitis Index 49.0 ± 11.6; Dermatology Life Quality Index 15.2 ± 4.5; and Patient-Oriented Eczema Measure 20.9 ± 4.1; and mean ± SD disease duration 31.1 years ± 11.7 years) with largely elevated peripheral IgE levels (13,881.6 kU/l; range 1,811–53,447 kU/l) were treated with three cycles of extracorporeal IgE-selective IA (3-3-2 days) over a period of approximately 6–9 weeks in an open-label pilot trial (see Supplementary Repository). All patients had been treated with systemic therapies before (including corticosteroids, cyclosporine, azathioprine, and alitretinoin), but did not receive systemic therapy for at least 4 weeks before IA. Topical therapies, including low- to mid-potent corticosteroids and calcineurin inhibitors, were allowed and were kept stable or reduced during IA. Primary endpoint was the reduction of peripheral IgE at the end of the third IA compared to baseline. All other endpoints and biopsies were assessed approximately 1 month after the third IA and compared to baseline. After three cycles with single-use columns, peripheral IgE levels were significantly reduced to 30.4% ± 18.5% (P = 0.001, Wilcoxon matched-pairs signed rank test; Figure 1a), while peripheral IgG levels remained largely unaffected (data not shown). Three patients achieved an improvement of at least 50% of their baseline EASI (EASI 50 response; mean ± SD decrease 56.7% ± 6.9%), five patients improved, but did not achieve EASI 50 (partial response, mean ± SD decrease 34.1% ± 13.8%), two patients showed no change in clinical activity, and one patient worsened (non-response, mean ± SD increase 47.2% ± 49.7%). EASI reductions were generally reflected by improvements of other outcome parameters, including objective Severity Scoring of Atopic Dermatitis Index, Dermatology Life Quality Index, Patient-Oriented Eczema Measure, pruritus, and sleep disturbance. Extracorporeal IA with single-use columns was well tolerated and no infectious or serious adverse events were observed. Only patients with EASI 50 response showed consistent reductions of skin-infiltrating CD3+ T cells and CD11c+ cells (P = 0.012 and P = 0.034, respectively, Stuart–Maxwell test), while numbers of these cells remained largely unchanged or increased in partially responding and nonresponding patients. Similarly, skin-bound IgE and cutaneous IgE+ cells (mostly dermal dendritic cells; compare Figure 1b) consistently decreased in responding (P = 0.044; Stuart–Maxwell test), but not in partially responding or nonresponding patients. Cellular changes were associated with changes in the expression of T-helper cytokine pathways. Cutaneous mRNA levels of IL-13 and IFNγ clearly decreased in all patients with EASI 50 response during IgE-selective IA (P = 0.006 and P = 0.005, respectively, Wilcoxon matched-pairs signed rank test), but increased in all nonresponding patients, while partially responding patients showed intermediate effects (Figure 2a). There was a good correlation between the individual clinical response and the reduction of cutaneous IL-13 mRNA expression (Figure 2b). No consistent pattern was observed with regard to the other immunohistochemical markers or skin mRNA levels of IL-4 and IL-17A.
      Figure thumbnail gr1
      Figure 1Peripheral and cutaneous immunoglobulin E levels. (a) Effects of extracorporeal immunoadsorption with a single-use immunoglobulin E–selective absorber column on peripheral levels of immunoglobulin E before and after three cycles performed several weeks apart. (b) Example of immunoglobulin E staining of a biopsy taken from a representative eczematous lesion before (baseline; upper picture) and 4 weeks after the third immunoadsorption cycle (picture below). Scale bars = 100 μm. The peripheral immunoglobulin E values of this patient (Patient 9; clinical responder) are marked in (a) with a rectangle. IA, immunoadsorption; Ig, immunoglobulin.
      Figure thumbnail gr2
      Figure 2Cutaneous cytokine expression and clinical response. (a) Ratio of cutaneous mRNA levels as determined by quantitative reverse transcriptase PCR in biopsies taken approximately 1 month after immunoadsorption compared to biopsies taken at baseline. A ratio of 1 corresponds to no change in response to immunoglobulin E–selective immunoadsorption, ratios >1 indicate increased, values <1 decreased expression (logarithmic scale). (b) Individual correlation of Eczema Area and Severity Index response (x-axis) and change of cutaneous IL-13 mRNA expression (y-axis, logarithmic scale). Colors of the circles represent clinical responses; red, patients with Eczema Area and Severity Index 50 response; light red, patients with improvement but not Eczema Area and Severity Index 50; gray, patients with no improvement or worsening of immunoadsorption. No biopsies were available from patient no. 5. Pat, patient.
      Our pilot trial indicates that peripheral IgE levels can significantly and selectively be reduced with a single-use IgE-selective absorber column. IgE-reducing effects were more prominent in patients with baseline IgE levels ≤6,000 kU/l (mean ± SD reduction 81.4% ± 9.7%) than in patients with baseline IgE levels >6,000 kU/l (mean ± SD reduction 48.8% ± 7.0%), however, two of the EASI 50 responders were in the latter group. Overall, the IgE-reducing capacity and clinical efficacy seemed lower than those recently observed in patients treated with reusable IgE-selective columns (
      • Reich K.
      • Deinzer J.
      • Fiege A.K.
      • von Gruben V.
      • Sack A.L.
      • Thraen A.
      • et al.
      Panimmunoglobulin and IgE-selective extracorporeal immunoadsorption in patients with severe atopic dermatitis.
      ), which might be explained by the reduced number of total and per-cycle treatment days and the inclusion of more patients with very high IgE levels in the present study. Although preliminary, the current study provides evidence that the clinical response of severe AD to IgE-selective IA is associated with a reduction of skin-bound IgE and numbers of cutaneous CD11c+ cells, which may be explained by the repetitive removal of peripheral IgE and decreased activation of dendritic cell subsets with IgE-binding capacity. We speculate that the reduction of infiltrating T cells and cutaneous IL-13 production results from a subsequent negative modulation of T-helper 2 cell activation. Interestingly, there was also a link between clinical response and downregulation of cutaneous IFN-γ production in line with previous observations that T-helper 1 pathways may also be activated in chronic eczematous lesions (
      • Fujita H.
      • Shemer A.
      • Suárez-Fariñas M.
      • Johnson-Huang L.M.
      • Tintle S.
      • Cardinale I.
      • et al.
      Lesional dendritic cells in patients with chronic atopic dermatitis and psoriasis exhibit parallel ability to activate T-cell subsets.
      ). In summary, our paper confirms the therapeutic value of IgE-selective IA in some patients with refractory AD. Optimal responses with the single-use columns tested here can probably be expected in patients with baseline IgE levels of up to 6,000 kU/l, but clinical effects may also be seen in patients with excessively elevated IgE that cannot be treated with other IgE-binding modalities (
      • Quist 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.
      ).

      Conflict of Interest

      K. Reich serves on advisory boards, receives research funding, and receives payments for lectures and educational development from AbbVie, Affibody, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Covagen, Forward Pharma, Fresenius Medical Care, GlaxoSmithKline, Janssen-Cilag, Kyowa Kirin, Leo, Lilly, Medac, Merck Sharp & Dohme, Miltenyi Biotec, Novartis, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Takeda, UCB, Valeant, Xenoport. Thomas M. Falk, Norbert Blödorn-Schlicht and M. Meier receive research funding from Fresenius Medical Care and Miltenyi Biotec. The remaining authors state no conflict of interest.

      Acknowledgments

      Fresenius Medical Care, Bad Homburg, Germany, provided an unrestricted research grant to the Interdisciplinary Apheresis Centre, Reinbek, Germany, used to support data collection and analysis. We thank all patients participating in this study and acknowledge the expert assistance of the nurses at the Nephrology Centre Reinbek and Geesthacht, namely Luis Viana, Evelyn Pechler, Franziska Schweitzer, Iris Wycisk, Celine Munsch, Nadine Heinrich, Silke de Jong, and Nadine Alt.

      Supplementary Material

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