Safety and efficacy of immunoadsorption versus plasma exchange in steroid-refractory relapse of multiple sclerosis and clinically isolated syndrome: A randomised, parallel-group, controlled trial

Johannes Dorst, Tanja Fangerau, Daniela Taranu, Pia Eichele, Jens Dreyhaupt, Sebastian Michels, Joachim Schuster, Albert C Ludolph, Makbule Senel, Hayrettin Tumani, Johannes Dorst, Tanja Fangerau, Daniela Taranu, Pia Eichele, Jens Dreyhaupt, Sebastian Michels, Joachim Schuster, Albert C Ludolph, Makbule Senel, Hayrettin Tumani

Abstract

Background: Plasma exchange (PE) constitutes the standard therapy for steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome. Immunoadsorption (IA) is an alternative method of apheresis which selectively removes immunoglobulines (Ig) while preserving other plasma proteins. Although IA is regarded as a well-tolerated, low-risk procedure, high-level evidence for its efficacy is lacking. Therefore, we sought to investigate whether IA is superior to PE in patients with acute relapse of multiple sclerosis or clinically isolated syndrome who had insufficiently responded to high-dose intravenous methylprednisolone (MP).

Methods: Patients with acute relapse of multiple sclerosis or clinically isolated syndrome and without complete clinical remission of symptoms after at least one cycle of high-dose intravenous MP therapy were enrolled to our randomised, controlled, parallel-group, monocentric trial. Eligible patients were aged at least 12 years and had no clinical or laboratory signs of systemic infection. Eligible patients were randomly assigned (1:1) to receive either IA or PE. Patients in both groups received 5 treatments on 5 consecutive days. In the IA group, the 2.0-fold individual total plasma volume was processed on day 1, and the 2.5-fold on days 2-5. In the PE group, 2 liters of plasma (corresponding to the 0.69 ± 0.12-fold individual total plasma volume) were removed each day and substituted by 5% human albumin solution. Patients were followed up directly after last apheresis as well as 2 and 4 weeks after last treatment. The primary endpoint was change of the Multiple Sclerosis Functional Composite (MSFC) after 4 weeks compared to baseline. Analyses of primary outcome and safety measures were done in all patients who received at least one treatment (intention-to-treat-population). The trial is registered with ClinicalTrials.gov, number NCT02671682.

Findings: Between January 21, 2016, and October 26, 2018, 63 patients were screened for eligibility, and 61 patients were randomly assigned to receive IA (n = 31) or PE (n = 30). All randomised patients were included in the intention-to-treat-analysis. For the primary outcome, the median improvement of MSFC after 4 weeks compared to baseline was 0.385 (IQR 0.200-0.675; p < 0.001) in the IA group and 0.265 (IQR 0.100-0.408; p < 0.001) in the PE group. Improvement in the IA group was significantly larger (p = 0.034) compared to PE. Response rates after 4 weeks were 86.7% in the IA group and 76.7% in the PE group. One deep venous thrombosis occurred in each group.

Interpretation: Both IA and PE were safe in patients with steroid-refractory relapse and resulted in significant improvements of the primary outcome MSFC after 4 weeks compared to baseline. IA patients showed significantly larger improvements of MSFC compared to PE patients after 4 weeks. The results indicate a potential superiority of IA compared to PE in treatment of steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome, which has to be confirmed by future studies.

Funding: Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

Keywords: Immunoadsorption; Multiple sclerosis; Relapse; Therapeutic plasma exchange.

Conflict of interest statement

JDo reports personal fees and research grants from Fresenius Medical Care GmbH, Fresenius Medical Care Deutschland GmbH and Miltenyi Biotec GmbH. MS has received consulting or speaker honoraria as well as travel reimbursements from Bayer, Biogen, Celgene, Roche, Sanofi Genzyme and TEVA and research funding from the Hertha-Nathorff-Program and University of Ulm, none related to this study. HT reports personal fees and/or research grants from Fresenius Medical Care GmbH and Fresenius Medical Care Deutschland GmbH, Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, Teva, DMSG, and BMBF. DT has received speaker honoraria from Sanofi-Genzyme and Novartis, as well as travel and accommodation reimbursements from Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, and TEVA, none related to this study. TF, PE, JDr, SM, JS, and ACL report no conflicts of interest.

© 2019 Published by Elsevier Ltd.

Figures

Fig. 1
Fig. 1
Trial profile. * One patient was lost to follow-up; this patient was included in ITT analysis, but one more patient was recruited for this treatment arm in order to obtain the required number of patients according to power calculation for primary endpoint analysis.
Fig. 2
Fig. 2
MSFC difference to baseline in intention-to-treat population. IA=immunoadsorption. PE=plasma exchange. V1=directly after apheresis. V2=2 weeks after apheresis. V3=4 weeks after apheresis. MSFC=Multiple Sclerosis Functional Composite.
Fig. 3
Fig. 3
Development of MSFC (left) and response rates (right) in intention-to-treat population. IA=immunoadsorption. PE=plasma exchange. V0=baseline. V1=directly after apheresis. V2=2 weeks after apheresis. V3=4 weeks after apheresis. p < 0.001. n.s.=not significant.
Fig. 4
Fig. 4
Reduction rates of immunoglobulins. IA=immunoadsorption. PE=plasma exchange. Ig=immunoglobulin.

References

    1. Burton J.M., O'Connor P.W., Hohol M., Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2009;(3)
    1. Oliveri R.L., Valentino P., Russo C. Randomised trial comparing two different high doses of methylprednisolone in MS: a clinical and MRI study. Neurology. 1998;50(6):1833–1836.
    1. Weinshenker B.G., O'Brien P.C., Petterson T.M. A randomised trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. 1999;46(6):878–886.
    1. Keegan M., Pineda A.A., McClelland R.L., Darby C.H., Rodriguez M., Weinshenker B.G. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology. 2002;58(1):143–146.
    1. Keegan M., Konig F., McClelland R. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet. 2005;366(9485):579–582.
    1. Ruprecht K., Klinker E., Dintelmann T., Rieckmann P., Gold R. Plasma exchange for severe optic neuritis: treatment of 10 patients. Neurology. 2004;63(6):1081–1083.
    1. Bramlage C.P., Schroder K., Bramlage P. Predictors of complications in therapeutic plasma exchange. J Clin Apheresis. 2009;24(6):225–231.
    1. Basic-Jukic N., Kes P., Glavas-Boras S., Brunetta B., Bubic-Filipi L., Puretic Z. Complications of therapeutic plasma exchange: experience with 4857 treatments. Ther Apher Dial. 2005;9(5):391–395.
    1. Hohenstein B., Passauer J., Ziemssen T., Julius U. Immunoadsorption with regenerating systems in neurological disorders –a single center experience. Atheroscler Suppl. 2015;18:119–123.
    1. Belak M., Borberg H., Jimenez C., Oette K. Technical and clinical experience with protein a immunoadsorption columns. Transfus Sci. 1994;15(4):419–422.
    1. Zollner S., Pablik E., Druml W., Derfler K., Rees A., Biesenbach P. Fibrinogen reduction and bleeding complications in plasma exchange, immunoadsorption and a combination of the two. Blood Purif. 2014;38(2):160–166.
    1. Schneider-Gold C., Krenzer M., Klinker E. Immunoadsorption versus plasma exchange versus combination for treatment of myasthenic deterioration. Ther Adv Neurol Disord. 2016;9(4):297–303.
    1. Kohler W., Bucka C., Klingel R. A randomised and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis. J Clin Apheresis. 2011;26(6):347–355.
    1. Hauser S.L., Waubant E., Arnold D.L. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676–688.
    1. Hauser S.L., Bar-Or A., Comi G. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221–234.
    1. Egg R., Reindl M., Deisenhammer F., Linington C., Berger T. Anti-MOG and anti-MBP antibody subclasses in multiple sclerosis. Mult Scler. 2001;7(5):285–289.
    1. Dendrou C.A., Fugger L., Friese M.A. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–558.
    1. Howell O.W., Reeves C.A., Nicholas R. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain J Neurol. 2011;134(Pt 9):2755–2771.
    1. Grigoriadis N., van Pesch V. A basic overview of multiple sclerosis immunopathology. Eur J Neurol. 2015;2:3–13. the official journal of the European Federation of Neurological Societies.
    1. Stern J.N., Yaari G., Vander Heiden J.A. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014;6(248)
    1. Stork L., Ellenberger D., Beissbarth T. Differences in the reponses to apheresis therapy of patients with 3 histopathologically classified immunopathological patterns of multiple sclerosis. JAMA Neurol. 2018;75(4):428–435.
    1. Koziolek M.J., Tampe D., Bahr M. Immunoadsorption therapy in patients with multiple sclerosis with steroid-refractory optical neuritis. J Neuroinflammation. 2012;9:80.
    1. Faissner S., Nikolayczik J., Chan A., Gold R., Yoon M.S., Haghikia A. Immunoadsorption in patients with neuromyelitis optica spectrum disorder. Ther Adv Neurol Disord. 2016;9(4):281–286.
    1. Schimrigk S., Faiss J., Kohler W. Escalation therapy of steroid refractory multiple sclerosis relapse with tryptophan immunoadsorption - Observational Multicenter study with 147 patients. Eur Neurol. 2016;75(5-6):300–306.
    1. Muhlhausen J., Kitze B., Huppke P., Muller G.A., Koziolek M.J. Apheresis in treatment of acute inflammatory demyelinating disorders. Atheroscler Suppl. 2015;18:251–256.
    1. Heigl F., Hettich R., Arendt R., Durner J., Koehler J., Mauch E. Immunoadsorption in steroid-refractory multiple sclerosis: clinical experience in 60 patients. Atheroscler Suppl. 2013;14(1):167–173.
    1. Lipphardt M., Muhlhausen J., Kitze B. Immunoadsorption or plasma exchange in steroid-refractory multiple sclerosis and neuromyelitis optica. J Clin Apheresis. 2019;30(10):21686.
    1. Sprenger 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 Apheresis. 1987;3(3):185–190.
    1. Deschamps R., Gueguen A., Parquet N. Plasma exchange response in 34 patients with severe optic neuritis. J Neurol. 2016;263(5):883–887.
    1. Baggi F., Ubiali F., Nava S. Effect of igg immunoadsorption on serum cytokines in mg and lems patients. J Neuroimmunol. 2008;201-202:104–110.
    1. Faissner S., Nikolayczik J., Chan A. Plasmapheresis and immunoadsorption in patients with steroid refractory multiple sclerosis relapses. J Neurol. 2016;263(6):1092–1098.

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