Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS

Abstract

Background:

The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS).

Objective:

To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study.

Methods:

Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients (n = 40) were compared to those 6 months after onset of DMF treatment (n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year under treatment.

Results:

Stable patients showed significantly lower lymphocytes, CD4+ and CD8+ T cells as well as CD19+ B cells compared to active patients under DMF treatment. Furthermore, an increased CD4/CD8 ratio (p < 0.025) in stable patients indicated a disproportionate reduction of CD8+ T cells relative to CD4+ T cells. Reduced lymphocytes, CD8+ T cells, and CD19+ B cells 6 months after DMF start allowed prediction of the treatment response in the first year.

Conclusion:

DMF treatment response is reflected by lower circulating lymphocytes and specific lymphocyte subsets. Changes in the cellular immune profiles under DMF treatment are clinically relevant and might serve as a surrogate marker of treatment response.

Keywords

Multiple sclerosis dimethyl fumarate treatment response lymphocyte subsets CD8+ T cells

Get full access to this article

View all access options for this article.

References

Gold

Kappos

Arnold

et al . Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367(12): 1098–1107.

Schilling

Goelz

Linker

et al . Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 2006; 145(1): 101–107.

Treumer

Zhu

Glaser

et al . Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol 2003; 121(6): 1383–1388.

Schimrigk

Brune

Hellwig

et al . Oral fumaric acid esters for the treatment of active multiple sclerosis: An open-label, baseline-controlled pilot study. Eur J Neurol 2006; 13(6): 604–610.

Vandermeeren

Janssens

Borgers

et al . Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. Biochem Biophys Res Commun 1997; 234(1): 19–23.

Metz

Traffehn

Strassburger-Krogias

et al . Glial cells express nuclear nrf2 after fumarate treatment for multiple sclerosis and psoriasis. Neurol Neuroimmunol Neuroinflamm 2015; 2(3): e99.

Scannevin

Chollate

Jung

et al . Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 2012; 341(1): 274–284.

Fox

Miller

Phillips

et al . Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367(12): 1087–1097.

Spencer

Crabtree-Hartman

Lehmann-Horn

et al . Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2015; 2(3): e76.

10.

Longbrake

Cross

AH.

Dimethyl fumarate associated lymphopenia in clinical practice. Mult Scler 2015; 21(6): 796–797.

11.

Ermis

Weis

Schulz

JB.

PML in a patient treated with fumaric acid. N Engl J Med 2013; 368(17): 1657–1658.

12.

Sweetser

Dawson

Bozic

Case reports of PML in patients treated for psoriasis. N Engl J Med 2013; 369(11): 1080–1081.

13.

Rosenkranz

Novas

Terborg

PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med 2015; 372(15): 1476–1478.

14.

Polman

Reingold

Banwell

et al . Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2): 292–302.

15.

Schumacher

Beebe

Kibler

et al . Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci 1965; 122: 552–568.

16.

Kappos

Giovannoni

Gold

et al . Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis. Eur J Neurol 2015; 22(4): 664–671.

17.

Youden

WJ.

Index for rating diagnostic tests. Cancer 1950; 3(1): 32–35.

18.

DeLong

Clarke-Pearson

DL.

Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach. Biometrics 1988; 44(3): 837–845.

19.

Hoxtermann

Nuchel

Altmeyer

Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology 1998; 196(2): 223–230.

20.

Fox

Chan

Gold

et al . Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS: Patient management considerations. Neurol Clin Pract 2016; 6(3): 220–229.

21.

Nieuwkamp

Murk

van Oosten

et al . PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N Engl J Med 2015; 372(15): 1474–1476.

22.

Nemecek

Zimmermann

Rubenthaler

et al . Flow cytometric analysis of T cell/monocyte ratio in clinically isolated syndrome identifies patients at risk of rapid disease progression. Mult Scler 2015; 22: 483–493.

23.

Longbrake

Ramsbottom

Cantoni

et al . Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler 201; 22: 1061–1070.

24.

Gross

Schulte-Mecklenbeck

Klinsing

et al . Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3(1): e183.

25.

Lundy

Wang

et al . Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets. Neurol Neuroimmunol Neuroinflamm 2016; 3(2): e211.

26.

Fox

Chan

Gold

et al . Characterization of absolute lymphocyte count profiles in MS patients with delayed-release dimethyl fumarate: Considerations for patient management. Neurology 2015; 85: e48.

27.

Longbrake

Naismith

Parks

et al . Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance. Mult Scler J Exp Transl Clin. Epub ahead of print 31 July 2015. DOI: 10.1177/2055217315596994.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB

0.07 MB

0.01 MB