- •Low baseline lymphocyte counts in patients with MS (pwMS) who are on dimethyl fumarate (DMF) is predictive of future lymphopenia.
- •High baseline monocyte counts in pwMS on DMF is predictive of disease activity, including clinical relapse and/or new gadolinium-enhancing lesion on MRI.
- •High baseline eosinophil counts in pwMS on DMF is predictive of common adverse events, such as gastrointestinal dysfunction and flushing.
Dimethyl fumarate (DMF) is a first-line oral therapy for relapsing-remitting multiple sclerosis (RRMS). This retrospective study aims to determine the utility of routine complete blood counts (CBC) in predicting lymphopenia, adverse effects and efficacy in a real-world clinical setting.
The Calgary Multiple Sclerosis (MS) Clinic manages over 1800 people with MS on disease-modifying therapies (DMT). Data of patients with relapsing-remitting MS (pwMS) who initiated DMF between July 1, 2013 and December 31, 2014 were included. Patients were followed for one year. DMT use is carefully monitored and pwMS need a screening CBC and have regular CBCs done at follow-up. Demographic, clinical, MRI and relapse information are collected prospectively in a clinic database. We analyzed CBCs at baseline and month 3.
We identified 139 pwMS in the study period who started DMF. Median follow-up time on-drug was 12 (0.16–12) months. In our study, 15.8% of pwMS developed lymphopenia grade 2 or higher. Baseline lymphocyte counts and older age were significant predictors of lymphopenia. Higher baseline eosinophil counts predicted flushing/gastrointestinal adverse effects, and higher baseline monocyte counts were predictive of breakthrough disease activity. Neutrophil and platelet to lymphocyte ratios, markers that have been associated with overall mortality in the general population, were increased at month 3.
Routinely obtained CBCs during the screening and monitoring of people with MS starting DMF offer clinically useful information and generate interesting hypotheses. Age and baseline lymphocyte counts are reinforced as clinically useful predictors of lymphopenia. Our novel findings that baseline eosinophil and monocyte counts could offer insights into usual adverse effects and efficacy, respectively, should be further investigated as a potentially new set of biomarkers.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Multiple Sclerosis and Related Disorders
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Effectiveness and safety of dimethyl fumarate treatment in relapsing multiple sclerosis patients: real-world evidence.Neurol. Ther. 2017; 6 (PMID: 28780745; PMCID: PMC5700902): 189-196https://doi.org/10.1007/s40120-017-0080-x
- Average values and racial differences of neutrophil lymphocyte ratio among a nationally representative sample of United States subjects.PLoS ONE. 2014; 9 (PMID: 25375150; PMCID: PMC4223021)e112361https://doi.org/10.1371/journal.pone.0112361
- The neutrophil-to-lymphocyte ratio as disease actvity marker in multiple sclerosis and optic neuritis.Mult. Scler. Relat. Disord. 2017; 18 (PMID: 29141813): 213-217https://doi.org/10.1016/j.msard.2017.10.009
- Fingolimod and dimethyl-fumarate-derived lymphopenia is not associated with short-term treatment response and risk of infections in a real-life MS population.CNS Drugs. 2020; 34 (PMID: 32193826): 425-432https://doi.org/10.1007/s40263-020-00714-8
- Delayed and recurrent dimethyl fumarate induced-lymphopenia in patients with multiple sclerosis.Mult. Scler. Relat. Disord. 2022; 63103887https://doi.org/10.1016/j.msard.2022.103887
- Safety and persistence of dimethyl fumarate as a treatment for relapsing-remitting multiple-sclerosis.Farm Hosp. 2020; 45 (PMID: 33709887): 73-76https://doi.org/10.7399/fh.11567
- Time course of lymphocyte repopulation after dimethyl fumarate-induced grade 3 lymphopenia: contribution of patient age.Ther. Adv. Neurol. Disord. 2019; 12 (PMID: 31105768; PMCID: PMC6506915)1756286419843450https://doi.org/10.1177/1756286419843450
- Eosinophil-mediated cardiac injury possibly due to dimethyl fumarate.JACC Cardiovasc. Imaging. 2016; 9 (PMID: 26299674): 752-753https://doi.org/10.1016/j.jcmg.2015.05.003
- Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis.Mult. Scler. J. Exp. Transl. Clin. 2020; 6 (PMID: 32440353; PMCID: PMC7227148)2055217320918619https://doi.org/10.1177/2055217320918619
- Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes.Nat. Commun. 2019; 10 (PMID: 31300673; PMCID: PMC6626021): 3081https://doi.org/10.1038/s41467-019-11139-3
- Dimethyl fumarate induced lymphopenia in multiple sclerosis: a review of the literature.Pharmacol. Ther. 2021; 219 (PMID: 33091427)107710https://doi.org/10.1016/j.pharmthera.2020.107710
- Immunological predictors of dimethyl fumarate-induced lymphopenia.Ann. Neurol. 2022; 91: 676-681https://doi.org/10.1002/ana.26328
- Gut microbiota composition as a candidate risk factor for dimethyl fumarate-induced lymphopenia in multiple sclerosis.Gut Microbes. 2022; 14: 1https://doi.org/10.1080/19490976.2022.2147055
- Lower lymphocyte counts and older age are associated with reduced multiple sclerosis disease activity during dimethyl fumarate treatment.Mult. Scler. Relat. Disord. 2021; 49 (PMID: 33524927)102781https://doi.org/10.1016/j.msard.2021.102781
- Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years’ follow-up of DEFINE, CONFIRM, and ENDORSE.Ther. Adv. Neurol. Disord. 2020; 13 (PMID: 32426039; PMCID: PMC7222239)1756286420915005https://doi.org/10.1177/1756286420915005
- Patient-specific factors modulate leukocyte response in dimethyl fumarate treated MS patients.PLoS ONE. 2020; 15 (PMID: 32045436; PMCID: PMC7012426)e0228617https://doi.org/10.1371/journal.pone.0228617
- Sequencing of disease-modifying therapies for relapsing-remitting multiple sclerosis: a theoretical approach to optimizing treatment.Curr. Med. Res. Opin. 2018; 34 (PMID: 29583054): 1419-1430https://doi.org/10.1080/03007995.2018.1458023
- The neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios are independently associated with neurological disability and brain atrophy in multiple sclerosis.BMC Neurol. 2019; 19 (PMID: 30755165; PMCID: PMC6371437): 23https://doi.org/10.1186/s12883-019-1245-2
- Gadolinium enhancement on cranial MRI in multiple sclerosis is age dependent.J. Neurol. 2020; 267 (PMID: 32388832): 2619-2624https://doi.org/10.1007/s00415-020-09895-0
- Reference values of neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, and mean platelet volume in healthy adults in South Korea.Medicine. 2018; 97 (PMID: 29952958; PMCID: PMC6039688): e11138https://doi.org/10.1097/MD.0000000000011138
- Safety of dimethyl fumarate for multiple sclerosis: a systematic review and meta-analysis.Mult. Scler. Relat. Disord. 2020; 46 (PMID: 33296968)102566https://doi.org/10.1016/j.msard.2020.102566
- Dimethyl fumarate-associated lymphopenia: risk factors and clinical significance.Mult. Scler. J. Exp. Transl. Clin. 2015; 1 (PMID: 26550483; PMCID: PMC4636217)2055217315596994https://doi.org/10.1177/2055217315596994
- Predictors of lymphocyte count recovery after dimethyl fumarate-induced lymphopenia in people with multiple sclerosis.J. Neurol. 2021; https://doi.org/10.1007/s00415-021-10412-0
- Lymphocyte count and body mass index as biomarkers of early treatment response in a multiple sclerosis dimethyl fumarate-treated cohort.Front. Immunol. 2019; https://doi.org/10.3389/fimmu.2019.01343
- Safety and efficacy of dimethyl fumarate in multiple sclerosis: an Italian, multicenter, real-world study.CNS Drugs. 2018; 32 (PMID: 30022464): 963-970https://doi.org/10.1007/s40263-018-0543-3
- Dimethyl fumarate induces a persistent change in the composition of the innate and adaptive immune system in multiple sclerosis patients.Sci. Rep. 2018; 8 (PMID: 29844361; PMCID: PMC5974280): 8194https://doi.org/10.1038/s41598-018-26519-w
- Risk factors for lymphopenia in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate.J. Neurol. 2020; 267 (Erratum in: J Neurol. 2019 Nov 23; PMID: 31583427): 125-131https://doi.org/10.1007/s00415-019-09557-w
- Oral dimethyl fumarate induces changes within the peripheral neutrophil compartment of psoriasis patients that are linked with skin improvement.Br. J. Dermatol. 2021; (PMID: 33657656)https://doi.org/10.1111/bjd.19899
- Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study.Br. J. Dermatol. 1998; 138 (German Multicentre Study) (PMID: 9580799): 456-460https://doi.org/10.1046/j.1365-2133.1998.02124.x
- Common Terminology Criteria for Adverse Events v4.0, NCI, NIH, DHHS.NIH publication, Bethesda, MD2009
- Evaluation and differential diagnosis of marked, persistent eosinophilia.Immunol. Allergy Clin. N. Am. 2007; 27: 529-549https://doi.org/10.1016/j.iac.2007.07.008
Paul A., Comabella M., Gandhi R. Biomarkers in multiple sclerosis. Cold Spring Harb Perspect Med. 2019 Mar 1;9(3):a029058. doi: 10.1101/cshperspect.a029058.
- Eosinophilic gastroenteritis in a woman with multiple sclerosis on dimethyl fumarate.Neurology. 2016; 87 (PMID: 27466473): 952-953https://doi.org/10.1212/WNL.0000000000003045
- Factors associated with dimethyl fumarate-induced lymphopenia.J. Neurol. Sci. 2019; 398 (PMID: 30658226): 4-8https://doi.org/10.1016/j.jns.2019.01.007
- Neutrophil-to-lymphocyte ratio and mortality in the United States general population.Sci. Rep. 2021; 11 (PMID: 33431958; PMCID: PMC7801737): 464https://doi.org/10.1038/s41598-020-79431-7
- Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate.Neurol. Neuroimmunol. Neuroinflamm. 2015; 2 (PMID: 25738172; PMCID: PMC4335821): e76https://doi.org/10.1212/NXI.0000000000000076
- Association of lymphopenia and eosinophilia with dimethylfumarate treatment efficacy and tolerability in psoriasis: a retrospective study.J. Dermatol. Treat. 2020; 31 (PMID: 30957595): 378-381https://doi.org/10.1080/09546634.2019.1605135
- Transferring clinically established immune inflammation markers into exercise physiology: focus on neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index.Eur. J. Appl. Physiol. 2021; https://doi.org/10.1007/s00421-021-04668-7
Published online: April 02, 2023
Accepted: April 2, 2023
Received in revised form: March 28, 2023
Received: December 18, 2022
© 2023 Elsevier B.V. All rights reserved.