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Abstract

Dimethyl fumarate (DMF) is a widely used oral disease-modifying therapy for multiple sclerosis (MS). Its efficacy and safety profiles are supported by over a decade of experience. Differences exist between Asia and Europe/United States in the prevalence and characteristics of MS; most data for DMF are derived from populations outside Asia. DMF was recently (2021) approved for use in China. The objectives of this review were to evaluate the evidence for DMF’s profile, to provide an update to healthcare providers on current knowledge surrounding its use and to assess the relevance of existing data to use in China. This study used a modified Delphi method based on the insights of a scientific Steering Committee (SC), with a structured literature review conducted to assess the data of DMF. The literature review covered all papers in English (from 01 January 2011 to 21 February 2022) that include ‘dimethyl fumarate’ and ‘multiple sclerosis’, and their MeSH terms, on PubMed, supplemented by EMBASE and Citeline searches. Papers were categorized by topic and assessed for relevance and quality, before being used to formulate statements summarizing the literature on each subject. SC members voted on/revised statements, requiring ⩾80% agreement and ⩽10% disagreement for inclusion. Statements not reaching this level were discussed further until agreement was reached or until there was agreement to remove the statement. A total of 1030 papers were retrieved and used to formulate the statements and evidence summaries considered by the SC members. A total of 45 statements were agreed by the SC members. The findings support the positive efficacy and safety profile of DMF in treating patients with MS. Limited Chinese patient data are an ongoing consideration; however, based on current evidence, the statements are considered applicable to both the global and Chinese populations. DMF is a valuable addition to address unmet MS treatment needs in China.

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Keywords

China Delphi method dimethyl fumarate multiple sclerosis review

Introduction

Differences in the incidence, prevalence, presentation and prognosis of multiple sclerosis (MS) have been observed between East Asian populations and the rest of the world.^{1,2,3,4,5,6,7,8} For example, the prevalence of MS is estimated as 2.39/100,000 in China, 8.62/100,000 in Southeast Asia, 142.81/100,000 in Europe and 43.95/100,000 globally.⁹

Dimethyl fumarate (DMF) is a fumaric acid ester used to treat MS.^10,11,12,13 DMF (Tecfidera^®; Biogen-Idec, Cambridge, MA, USA) was approved for treatment of MS in the United States in March 2013^14,15 and the European Union (EU) in January 2014 (starting with 120 mg oral capsules, administered twice daily for 7 days, followed by a twice daily 240 mg maintenance dose).^10,15 In Asia, DMF was approved in South Korea in July 2016 and in Japan in December 2016.^16,17 DMF has been approved in other Asian locations including, but not limited to, India (February 2015), Hong Kong (March 2016), Singapore (July 2016) and Thailand (March 2020).^18,19,20,21 DMF is a widely used oral disease-modifying therapy (DMT) for MS,²² having been prescribed to approximately 580,500 persons globally in the clinical trial and post-market settings, corresponding to 1,267,327 person-years of exposure through 30 June 2022 (data on file; published 2021 data),²³ and was approved for use in the People’s Republic of China in 2021.³

Although there are more than 13 years of DMF data, including long-term follow-up from its pivotal clinical trials (DEFINE, CONFIRM) and the long-term extension study (ENDORSE),^{24,25,26,27,28} comparatively little of this data has been derived from East Asia.²⁵ It is therefore relevant to consider whether DMF performs similarly in treating these populations, as elsewhere in the world.

Early treatment of MS with DMT is part of the strategy to improve patient prognosis. It is important to continually assess what is known about different DMTs in the light of additional clinical trials and post-marketing studies and real-world experience, to evolve clinical practice. For example, MS organizations and working groups have demonstrated the value of updating practice through agreed statements on the use of DMTs during COVID-19.²⁹ With the recent approval of DMF in China, it is an opportune time to review global and Asian DMF practice. Therefore, the objective of this work was to use a modified Delphi method to assess the current use of DMF in clinical practice and identify considerations relevant for its use going forward, in China and other countries, so that these serve as a valuable resource to sharing up-to-date evaluation of evidence supporting good clinical practice for treatment of MS.

Methods

This study used a modified Delphi method (Figure 1) based on the insights of a scientific Steering Committee (SC). First, a structured literature review was performed to identify relevant evidence addressing the question, ‘How is DMF used in the treatment of MS?’ The literature review considered results from a PubMed search (from 01 January 2011 to 21 February 2022) including the core search terms ‘dimethyl fumarate’ AND ‘multiple sclerosis’ and their MeSH terms (search strings are detailed in Supplemental material; literature search strategy in Figure 2). Additional terms were used to categorize results into relevant topics.

Figure 1.

Study flow for this modified Delphi process.

Figure 2.

Literature search strategy.

The main search was supplemented by additional searches of EMBASE and Citeline. The topics of interest were categorized as: efficacy, safety, mechanism of action, pharmacokinetics/pharmacodynamics (PK/PD), treatment sequencing, adverse event (AE) management, infection, progressive multifocal leukoencephalopathy (PML) risk, effects on haematological parameters, effects on organ systems, drug-drug interactions, pregnancy/lactation, COVID-19 and paediatric populations.

The literature was first screened by title and abstract by editorial support staff from MIMS Limited for relevance and quality. Due to the known level of variation in the formulation of compounded products,³⁰ only papers using commercially produced DMF were included. Quality was based on the totality of several factors: type of publication (guidelines > systematic reviews > meta-analyses > opinion pieces > case reports), study design (randomized controlled trials (RCTs) > observational or cohort studies > case studies; and direct comparisons were considered superior evidence to indirect comparisons) and study size (more than 500 participants > fewer than 500 participants). Funding sources were also noted. The culmination of these factors was reflected in an overall evidence rating (high, medium high, moderate, medium low and low). Statements were developed based on the evidence and reviewed by SC members along with the supporting evidence and evidence rating.

The SC comprised 14 expert members (neurologists) representing clinical expertise from Germany (n = 1), United Kingdom (n = 1), Australia (n = 1), Spain (n = 2), Japan (n = 1), Switzerland (n = 1) and China (n = 7). SC members were selected based on their clinical experience with MS, publication record and any previous contributions to MS treatment guidelines. For practicality, topics were split into two sets: Set 1 topics, for Statements 8–24, 29–33 and 40–41, were discussed at the first meeting and Set 2 topics, for Statements 1–7, 25–28, 34–39 and 42–46, were discussed at the second meeting (Figures 1 and 3a, 3b, 3c). Each topic set underwent two or more anonymous voting rounds with thresholds for agreement of ⩾80% and disagreement of ⩽10%. Statements not meeting the criteria were discussed at one of two online SC meetings for revision (Figure 1).

Figure 3a.

Figure 3b.

Figure 3c.

Summary of voting responses and guiding statements on clinical use of dimethyl fumarate in treating multiple sclerosis.

Voting administration, collation of responses, collating meeting minutes and statement revision were conducted by the editorial support team to negate bias. In addition to ‘Agree’ and ‘Disagree’, SC members could indicate agreement ‘with revision’, with suggestions provided as free-text entries, which were collated for discussion with highlighting of the incorporated updates (examples given in Figure 1). Statements discussed during meetings were revised and re-circulated for a second round of voting. For statements with a response exceeding the disagreement threshold, the second round had a voting option for statement deletion. After two voting rounds for each statement set, statements requiring higher levels of agreement were revised and voted on in the same round until agreement was reached on either a revised wording or deletion of the statement. Where the level of disagreement was below the threshold, the statement was included, as such statements reflect majority opinion, although not necessarily unanimity. In situations where practice or evidence differed significantly between regions, statements about global and Chinese or East Asian populations are presented separately.

Results

A total of 965 papers were retrieved with the search terms and a further 70 distinct references (one duplicate was removed) were used to supplement the search from additional sources. The number of participants voting in each round and the levels of agreement attained are summarized in Figures 1 and 3a, 3b, 3c, respectively.

In the first round of voting on Set 1 statements (expressed as per cent responses on total number of votes received on all statements), there was 81% agreement, 13% agreement with revisions, 3% requesting further discussion at the meeting and 3% disagreement. The level of overall agreement increased to 88% by the second vote, with a further 6% agreeing with revisions (4% disagreement and 2% suggested deletions).

For the Set 2 statements, at round 1 there was 70% overall agreement, 17% agreement with revision and 12% disagreement. After the second vote there was 94% overall agreement on the statements, 5% agreement with revision and 1% disagreement.

The most common reason for disagreement in both sets was a perceived lack of supporting evidence. Agreement with revision was typically for the correction of language-related issues such as simplifying wording. In total, 45 statements were finally included (Figure 3a, 3b, 3c).

Mechanism of action

Two statements were proposed on the mechanism of action of DMF. DMF’s effects on the immune system are complex and multi-faceted (Figure 3a, 3b, 3c, Statements 1 and 2); DMF influences both B cell and T cell populations and pro-inflammatory cytokine production to reduce inflammatory activity.^{31,32,33,34,35,36,37} One of the main pathways of activity of DMF is via nuclear factor erythroid 2–related factor 2 (Nrf2), which has anti-oxidative and anti-inflammatory effects.^{13,38,39,40,41,42} The anti-oxidative and anti-inflammatory effects of the Nrf2 pathway may contribute to the cytoprotective abilities of DMF.^38,39 DMF may prevent demyelination and axonal loss through reduction in pro-inflammatory reactive astrocytes.⁴³ Changes in immune cell populations, including a reduction in pro-inflammatory Th17 cells and increase in Th2 naïve/anti-inflammatory cells, induced by DMF produce a net shift away from a pro-inflammatory immune state.⁴⁴ Reductions in memory T and B cells similarly reduce overactive immune responses and the resulting neuronal damage in MS.^36,44

PK/PD and dosing

Upon ingestion, DMF is rapidly metabolized to monomethyl fumarate (MMF), which can cross the blood-brain barrier to exert its effects (Figure 3a, 3b, 3c, Statements 3–6).^39,40,45 MMF does not accumulate in the body, owing to a short terminal half-life of ~1 h.⁴⁵ A high-calorie and fat-rich meal delays T_max by hours and reduces C_max by approximately 40%.⁴⁵ However, area under the curve is not affected by taking DMF with a meal, which enables DMF to maintain efficacy, while reducing side effects.^10,45 The impacts of having a meal on T_max and C_max reduce both gastrointestinal (GI) AEs and flushing, thereby alleviating DMF’s most common undesired effects.^46,47 Patients with severe renal or hepatic dysfunction were excluded from the pivotal clinical trials of DMF. However, neither condition is expected to influence the level of exposure to MMF.^10,12

Situation in China/East Asia

The studies in East Asian patients used the same dose regimen and reported a consistent AE profile for DMF, as the pivotal trials, which largely included Caucasian patients.^16,48,49,50 No change in dosing is required for this population.

Efficacy statements

Three efficacy statements were included (Figure 3a, 3b, 3c, Statements 7–9). The overall level of evidence for the efficacy of DMF was considered high, albeit with varying ratings for individual parameters. For relapse rate/annualized relapse rates (ARRs), radiological evidence of disease activity and disability progression, the data are derived from several large RCTs, meta-analyses and systematic reviews,^{25,26,27,28,49,51,52,53} and have been incorporated into guidelines from all major MS organizations, including in Japan.^16,54,55,56 The pivotal clinical trials most convincingly demonstrated improvements in relapse rate/ARR with DMF treatment.^25,26,27,28 Long-term data support that DMF treatment results in reductions in disability progression, with few overall relapses, but members of the SC considered this to have less strong support than the stated effects on ARR.⁵⁷ Radiological evidence of disease activity is perhaps the least well-supported parameter of this set, given more variability in magnetic resonance imaging (MRI) assessment across centres and studies and therefore a lower quality of evidence.⁵¹ Despite the varying level of evidence for different aspects of efficacy, the overall position of the SC is that data exist for improvements on each of these parameters.

The importance of initiating a DMT soon after diagnosis is highlighted in several international guidelines^54,55 and is supported by convincing evidence from both individual trials (including DMF specifically) and reviews.^58,59,60 The SC noted the strong evidence for this statement and encourages early, appropriate initiation of a DMT.

Serum neurofilament light chains (sNFLs) are a marker of neuroinflammation and are thought to represent a proxy measure for axonal damage in MS.⁶¹ sNFL is reduced by DMTs in MS,⁶² and lower baseline sNFL levels in a small (n = 80) observational trial predicted a greater response to DMF treatment, assessed by achieving no evidence of disease activity (NEDA) and reducing effector immune cells.⁶¹ The study concords with a slightly larger trial (n = 127) which showed that DMF reduced NFL in the blood and cerebrospinal fluid (CSF) of treatment-naïve patients and could normalize the CSF levels in 73% of participants.⁶³ As a comparatively new outcome measure with limited use in clinical practice, sNFL relevance for prognosis or disease outcomes requires further research. Nonetheless, DMF has shown some effects on this marker, and it may be a potential proxy measure for treatment response or prognosis.

Situation in China/East Asia

Evidence for efficacy of DMF in the East Asian population comes primarily from Japan, which contributed the majority (80%) of the East Asian population (n = 142) in the APEX study, followed by South Korea (14%).^48,49 A post hoc sub-analysis of Asian data from Fox et al.² has also been performed, confirming treatment efficacy and positive benefit-risk balance. In general, treatment results are similar between East Asian and Caucasian/rest-of-the-world populations, although there is lower incidence of MS but potentially poorer prognosis in Asian populations, possibly due to increased frequency of spinal lesions in this population and incomplete resolution of first attacks. There is no predicted difference for Asian populations which would lead to preferring later treatment initiation, and considering a higher potential first-year relapse rate and poorer prognosis,^2,64 it may be high priority to initiate treatment of Asian patients early in the clinical course. Many patients with MS in China do not initiate a DMT at the earliest opportunity⁴ for reasons of cost,³ perception of the condition as ‘mild’ and the advice of neurologists and other healthcare professionals.^3,4 The treatment pattern in China continues to evolve, with early diagnosis and sustained use of DMTs during periods of remission becoming more common.³

Haematologic parameters and infection risk

Seven statements on haematological parameters and infection risk achieved agreement (Figure 3a, 3b, 3c, Statements 10–17). In general, the risk of lymphopenia with DMF was recognized – but also that this did not translate to a substantial increase in risk of infections. Very rare occurrences of PML warrant clinical vigilance.

Lymphopenia

DMF studies consistently show a ~30% decline in mean absolute lymphocyte count in treated patients, which typically stabilizes within 6–12 months of treatment initiation.^48,65,66,67 Lymphopenia is a risk factor for (serious) opportunistic infections and associated mortality in the general population.^68,69 For this reason, it is important to monitor lymphocyte counts in patients receiving a therapy which may induce lymphopenia, such as DMF.^70,71 However, the degree of lymphopenia induced by DMF has not been associated with increased incidence of serious infections,^44,65,72 despite some case reports and database review findings of opportunistic infections.^{69,73,74,75,76,77,78,79,80} Degree of lymphopenia has also been proposed by some to predict better responses to DMF, as a proxy measure for a less overactive immune response and pro-tolerogenic profile,^{44,70,71,81,82} but most of the data have come from relatively small studies. The data are equivocal, as some studies (e.g. Longbrake et al.³¹) including larger controlled trials have found no relationship between lymphopenia and therapeutic efficacy of DMF.^31,44,65 It has also been determined that CD4⁺ and CD8⁺ T cell counts correlate with absolute lymphocyte counts, suggesting that separate monitoring is not required.⁶⁷ After treatment discontinuation, most patients with lymphopenia experience recovery of lymphocyte count; the extent and duration of lymphopenia influence the time required to attain this.⁸³ In the opinion of the SC, the data are insufficient to conclusively link lymphopenia with therapeutic efficacy, and lymphopenia is not recommended for use as a prognostic factor.

Vaccination response

Potential suppression of the immune system by DMTs is a risk factor not only for infections but also for a blunted response to vaccination, resulting from a reduced humoral and/or cellular response.^29,84,85 The PROCLAIM study assessed immunoglobulin levels in patients initiating DMF and found no impact of DMF on immunoglobulin levels.⁴⁴ Similarly, immune response to vaccination was found to be similar between DMF and interferons.^86,87 The SC therefore supports the conclusion that DMF does not interfere with vaccination.

Tuberculosis

Active tuberculosis infections need to be excluded before starting DMF treatment. In the EU/European Economic Area (EEA), tuberculosis has been estimated to occur at approximately 9.6 cases per 100,000 population (2019).⁸⁸ In comparison, the rates in China are estimated to be as high as 58 per 100,000 population, with substantially higher rates of latent infection (2019).⁸⁹ In general, screening for latent tuberculosis may be considered before initiating DMF;^90,91,92 however, DMF is not one of the DMTs for which screening is mandatory.^90,91,92,93 The risk for reactivation of latent tuberculosis infection appears to be low,^91,93,94 and the decisions regarding testing ultimately lie with the treating physician.

Progressive multifocal leukoencephalopathy

Several DMTs have been associated with PML, caused by reactivation and viral replication of John Cunningham Virus (JCV) in glial cells, which then causes demyelination.^23,95,96 PML is very rare and, in the cases that exist, occurs more commonly in immunocompromised patients.⁹⁵ As of 1 September 2022, there have been 12 cases of PML reported in approximately 580,500 patients treated with DMF, a rate of ~1/50,000 patients (0.9/100,000 patient years of DMF exposure)^23,95 (data shown: on file; previous data referenced).²³

Prolonged Grade 3 lymphopenia is a risk factor for PML and a reason to discontinue DMF therapy.^29,97 Based on reported trial data, it is estimated that around 5–10% of patients treated with DMF will experience Grade 3 lymphopenia, and 2.2% of patients will have prolonged (⩾6 months) Grade 3 lymphopenia.^65,98 However, only a few cases have been reported of patients experiencing complications from prolonged severe lymphopenia.^65,97,99,100 Age ⩾50 years is another risk factor for PML; however, neither age ⩾50 years nor severe prolonged lymphopenia are absolute identifiers of those at increased risk of PML, with recorded case reports in patients without these characteristics.^{95,101,102,103}

Closer monitoring of patients with a higher risk of PML is recommended. This includes monitoring for lymphopenia^23,29 and regular (every 6–12 months) MRI scans.^16,103 Discontinuing the suspected causative agent is recommended when patients develop PML.¹⁰⁴

Situation in China/East Asia

The high incidence of latent tuberculosis infection in China^89,105 and infrastructural challenges in the availability of testing pose a practical obstacle to implementing routine screening before initiating DMF. However, as the risk of reactivation is considered very low,^91,93,94 the recommendation for China is that screening for latent infections is not mandated.

Through the risk stratification process for PML with natalizumab, clinicians in China may be aware of the use of the JCV antibody index. Based on high JCV antibody positivity detected in MS patients from Hong Kong, JCV seropositivity is expected to be high in China.¹⁰⁶ However, JCV seropositivity does not play a role in risk stratification for DMF. For clinical practice in China, it is important to note that JCV index testing is not required with DMF; age and lymphopenia are sufficient criteria for determining PML monitoring.^16,29,95 Clinical vigilance for this condition remains very important, despite its rarity.

Comorbidities, organ function and cancer risk

Four statements on comorbidities and organ function were approved, mostly with a focus on cardiovascular and hepatic safety (Figure 3a, 3b, 3c, Statements 18–22). As MS causes progressive disability, patients are encouraged to maintain a healthy lifestyle, including a balanced diet combined with an exercise programme at a tolerable level.¹⁰⁷ Patients with MS are at higher risk of several forms of cardiovascular disease, including myocardial infarction and heart failure.¹⁰⁸ DMF is not associated with cardiovascular AEs such as arrhythmia or hypertension and is unlikely to contribute to cardiovascular morbidity in patients with MS.^109,110

Drug-induced liver injury is a recognized risk for patients receiving DMTs for MS.¹¹¹ Alanine transaminase (ALT)/aspartate aminotransferase (AST) elevations have been reported in major trials of most DMTs, including DMF.^{25,26,48,50,112,113} With DMF, persistent or severe ALT/AST derangement or discontinuation due to liver toxicity occurred in <1–2% of clinical trial participants.^28,112 Post-marketing evidence has identified ALT/AST elevation as relatively common; however, outright liver injury/hepatotoxicity has been recorded in very few DMF-treated patients (n = 4–14).^109,112 In light of the low risk of liver toxicity with DMF, periodic laboratory testing (up to regular 6-monthly testing) is sufficient to monitor for liver toxicity.^29,112 To date, the number of reported cases of hepatotoxicity with DMF is limited to 14, plus one case of acute hepatitis E virus infection.^112,114,115 Of those 14 cases, the earliest elevations of ALT/AST were recorded shortly after treatment initiation; liver injury was mild (six patients) or moderate/severe (eight patients) and there were no cases of liver failure.¹¹⁵

In patients with liver disease, DMF may be used with caution, at its normal dosage, as it is metabolized independently of the cytochrome P450 system.¹¹² Any risk of exacerbation or reactivation of hepatitis B virus (HBV)/hepatitis C virus (HCV) infection is mitigated in part by screening for these infections before initiation of most DMTs.¹¹²

Situation in China/East Asia

HBV and HCV are more common in China than in the EU,¹¹⁶ meaning that the requirement to screen for these viruses may yield positive results more frequently. With positive results, antiviral therapy and adjustments to the initiation of DMT should be considered; specialist assistance from hepatology or infectious disease colleagues is required to determine the appropriate course of action.¹¹²

Cancer risk

A single statement was proposed for cancer risk (Figure 3a, 3b, 3c, Statement 23). An increased risk of malignancy in patients with MS has been investigated repeatedly, including in those with long-term use of DMTs.¹¹⁷ Overall, the malignancy rate in patients treated with DMF is similar to age- and sex-matched individuals without MS.¹¹⁸ Duration of DMF treatment was concluded as a risk protective factor against neoplasms, in a small Spanish study.¹¹⁹ Recent database analyses have produced conflicting results, with one finding no evidence of an increased cancer risk¹²⁰ and the other being the first publication to find an increased risk of neoplasm with DMF.¹²¹ Consequently, it may be prudent to be vigilant in checking for cancer in DMF-treated patients, but this does not yet support a malignancy rate higher than the general population.¹¹⁸

Treatment initiation and decision-making

Location and licencing determine the permitted indications for DMF. If permitted by the local label, DMF can be used in both patients with relapsing-remitting multiple sclerosis (RRMS) and patients with clinically isolated syndrome (CIS).¹² The efficacy and tolerability of DMF are well balanced, and it is suitable as an initial therapy.^{27,28,122,123,124,125,126,127,128,129,130,131,132} The SC proposed four statements on this topic (Figure 3a, 3b, 3c, Statements 24–27).

Early-in-treatment challenges with tolerability are the largest reason for the discontinuation of DMF.^133,134 To mitigate the risk of AEs, a more gradual up-titration to the target dose may be considered for up to 4 weeks.^{10,135,136,137} It is important to note that the full dose is required for efficacy. Positive relationships between healthcare providers and patients are an important part of goal setting, partly through enhancing adherence. Self-management by patients may be improved by participation in a shared decision-making process.¹³⁸ Treatment selection will partly depend on the goals of the patient.^{138,139,140,141} These aspects of positive patient relationships may help to enhance tolerability when starting a new therapy. As treatments for MS have advanced, the achievable treatment goals/targets have evolved. NEDA-3 (no relapses, no new radiological evidence of disease activity, no disability progression) is the current benchmark proxy for best disease control.^{142,143,144,145} It may be beneficial to explain this as a target to patients as part of the goal-setting process.

Treatment switching

Five treatment switching statements were approved (Figure 3a, 3b, 3c, Statements 28–32). Evidence for the profile of DMF was initially established in comparison with both placebo and glatiramer acetate in the DEFINE, CONFIRM and ENDORSE trials.^{25,26,27,28,113} ENDORSE re-randomized patients previously treated with glatiramer acetate to DMF, with similar efficacy and tolerability results to those reported in treatment-naïve patients.²⁸ Outside pivotal clinical trials, these findings are further supported by observational studies of patients switching from other first-line therapies to DMF.^{122,124,132,146,147,148,149,150,151} Based on these results, horizontal switching, especially from injectable therapies, is a viable use of DMF.

Early (versus later) initiation of an effective DMT is linked to better long-term outcomes for patients with MS (see efficacy statements, Figure 3a, 3b, 3c, Statements 7–9), exemplified by achieving NEDA-3 with DMF.^{49,54,55,58,151} Treatment inertia may delay switching, and latency to initiation of an effective therapy may result in poorer outcomes, meaning that in addition to initiating DMTs early, switches should be considered if a therapy has proved intolerable or has shown a lack of efficacy in the judgement of the treatment team.^29,142

When switching to a new therapy it is important to consider its characteristics, to properly prepare the patient for the switch.⁵⁶ The most common AEs of DMF treatment are GI symptoms and flushing.^26,46,152 Discontinuation of DMF is more commonly attributable to tolerability issues (68% of discontinuing patients cited this as the main reason for discontinuation) than to a lack of efficacy (15% of patients).^134,153 However, a study of 886 patients in Spain reported similar rates of DMF discontinuation as a consequence of AEs and lack of efficacy (13.2% and 13.5% of patients, respectively).^133,150 Side effects resulting in discontinuation most commonly occur early in treatment,^153,154 suggesting that particular attention can be paid to mitigating AEs and promoting tolerability in the early period of treatment. Rarely, discontinuation may be due to lymphopenia. As a general principle, if a therapy is discontinued for a particular AE, switching to a therapy with a similar AE profile may not be the most appropriate choice. With DMF, limited evidence from a small observational study has suggested that lymphocyte counts may not recover in patients who discontinued therapy and switched to other lymphodepleting agents, because of lymphopenia.¹⁵⁵ Out of caution, such switches should be avoided if possible. A United States study reports that most patients who discontinued DMF with lymphopenia experienced lymphocyte count reconstitution.⁸³

Situation in China/East Asia

In China, as many as 58% of patients do not initiate DMTs upon their diagnosis of MS.³ The reasons include cost, a historical lack of available DMTs and low patient acceptance of therapy for what they may erroneously perceive as a ‘mild’ condition.⁴ Many patients will therefore be initiating DMF treatment while DMT-naïve. There are no contraindications to initiating therapy with DMF based on prior steroid or other therapies,^10,12 but the timing of initiation may depend on satisfactory condition of the patient, as judged by the neurologist, for example without lymphopenia from corticosteroid or azathioprine use.

Adverse event management and tolerability

As with treatment initiation, important considerations for AE management and tolerability are counselling, shared decision-making and mitigation strategies (Figure 3a, 3b, 3c, Statements 33–36). Forward planning, counselling and expectation setting all assist adherence with DMF by improving tolerability.^{46,136,137,156,157} Involving patients in goal setting and integrating their preferences into therapy management is beneficial for initiating DMTs in MS.^136,156

Mitigation of AEs primarily involves either GI symptoms or flushing.⁴⁶ Symptomatic therapies for GI AEs include proton pump inhibitors, antihistamines and assorted other agents for nausea such as metoclopramide, domperidone, diphenhydramine and dimenhydrinate.^46,135 Gradual up-titration (over 4 weeks) or temporary reductions in dose when an AE is encountered help to mitigate the risk of discontinuation.^136,137 The goal is still to achieve the full dose, consistently, as it is required for efficacy.⁴⁶ Taking DMF with food continues to be recommended to mitigate GI AEs.^136,157,158

For flushing, aspirin (75–325 mg) daily, or every second day, can be used typically as pre-treatment 30 min before DMF.^{11,46,136,159,160} Antihistamines are only rarely required but can also be used.^136,137 Metoprolol, acetaminophen, ibuprofen, cosmetics and counselling have been used for flushing by at least one respondent in a consensus statement.⁴⁶

There have been few reports of hypersensitivity in the literature, despite large numbers of patients treated with DMF.^{161,162,163,164,165} Where they have occurred, management has shown a response to steroid and antihistamine treatment.

Concomitant therapies

Two statements summarize DMF use with symptomatic treatment (Figure 3a, 3b, 3c, Statements 37 and 38). Corticosteroids are commonly used in the treatment of acute relapses in patients with MS.^16,54,145 While DMTs aim to avoid relapses, if they occur it is important that the DMT does not prevent acute or symptomatic therapy from being undertaken. DMF has no known drug-drug interactions,^10,11,12,166 including with single doses of interferon beta-1a (IFN-b1a) and glatiramer acetate, or aspirin. The former characteristic facilitates switching, whereas the latter facilitates symptomatic mitigation of flushing symptoms.⁴⁶ GI adverse effects and flushing are the most common side effects with DMF.⁴⁶ Symptomatic therapies such as antihistamines (flushing), proton pump inhibitors (GI) and aspirin (flushing), among others, can be used to mitigate these AEs and improve tolerability.^46,137,152 Aspirin mitigates flushing without increasing GI AEs.¹⁵⁹

In total, the lack of drug-drug interactions means that AEs and relapses may both be managed without concern for the patient’s DMF use.

COVID-19 and vaccinations

The use of DMTs during the COVID-19 pandemic has been an important and vibrant topic of clinical consideration. The SC considered two statements on this topic and was aligned with recommendations from numerous societies worldwide (Figure 3a, 3b, 3c, Statements 39 and 40). First, patients treated with DMF have not shown an increased risk of severe COVID-19 infection.¹⁶⁷ It is recommended that DMT selection should continue to be based on the activity and severity of the MS²⁹ and that the risks from MS outweigh those of COVID-19 in most cases.^85,168,169 Patients with MS may experience a diminished response to vaccines, depending on the DMT which they are receiving and its mechanism of action.^{29,87,170,171} The patient response to vaccination, including for COVID-19, has been found to be intact during treatment with DMF, and the AE profiles of the influenza and COVID-19 vaccines have not been shown to be influenced by DMF.^{29,87,172,173} DMF does not interact with vaccines for COVID-19 and patients taking DMF should continue therapy, independent of vaccination timing.^29,167 Data attained with influenza vaccination suggest that vaccine use does not increase the risk of subclinical disease activity in DMF-treated patients.⁸⁷

Pregnancy/lactation

Overall, the lack of accumulation of DMF/MMF makes it suitable for use in proximity to pregnancy, although it should still be discontinued during pregnancy (Figure 3a, 3b, 3c, Statements 41–44).

DMF has shown some developmental toxicity at clinically relevant doses in animal studies but not in human populations.^{174,175,176,177,178,179,180} In the United States, DMF is pregnancy category C, meaning it should be discontinued when a patient wants to become pregnant.^{10,11,12,55,175} In humans, there is no evidence of reduced fertility or increased risk of congenital malformation or miscarriage rates with inadvertent exposure to DMF in pregnant patients within the first trimester.^{174,175,176,177,178,179,180} Clinical evidence is limited, meaning that the characteristics of DMF’s formulation contribute to its recommended use. Namely, DMF does not accumulate, so no washout period is required before patients who have been treated with DMF wish to attempt pregnancy.¹⁸¹

There are very few published works considering the issue of DMF during breastfeeding. Any potential use of DMF during breastfeeding will need to balance the benefits and potential risks.^10,11,12,182 The primary active metabolite of DMF (MMF) has been detected in small quantities in breast milk in a small case study of two lactating patients.¹⁸³ The authors concluded the risk to the infant was likely to be low, considering the low concentration levels, but there is too little evidence to be confident in this regard.¹⁸³

Aside from pregnancy and breastfeeding, avoiding pregnancy via contraception may be influenced by DMT choice. Norgestimate/ethinyl estradiol oral contraceptives have been studied in a small RCT in combination with DMF, without impact on the efficacy or tolerability of either class of agent.¹⁶⁶ These study findings accord with the DMF prescribing information, which indicates no drug-drug interactions.^10,11,12 A United Kingdom consensus on MS and pregnancy also advises that DMF does not reduce the effectiveness of hormonal contraception.¹⁷⁹

Situation in China/East Asia

The DMF prescribing information in China notes that there are no adequate data on developmental risk in pregnant women.¹⁰ The evidence above suggests that therapy should not be continued during pregnancy and that discontinuation of DMF can occur close to pregnancy confirmation and does not need to be stopped (washed out) for a long period in advance of attempts to become pregnant.¹⁸¹ For breastfeeding, the Chinese label agrees that the risks and benefits of treatment on the mother and the breastfed infant should be considered when making treatment decisions. Family planning and fertility are very important considerations for female MS patients in China, but no differences in practice with DMF are likely based on the generated data.

Paediatrics

DMF has only limited data in paediatric populations, with trial data generated only from the FOCUS and CONNECTED studies of ~20 paediatric patients. In these trials, DMF performed similarly as in adult populations in terms of both efficacy and tolerability (Figure 3a, 3b, 3c, Statement 45).^184,185 In the FOCUS trial, AEs that were common with DMF in paediatric patients included headache (n = 4, 18%), dysmenorrhea (n = 2, 9%), GI disorders (n = 12, 55%) and respiratory, thoracic and mediastinal symptoms such as cough (n = 3, 14%) and upper respiratory tract infection (n = 2, 9%).¹⁸⁴ Data from a limited number of case reports, cohort studies and retrospective observational studies support the similarity of DMF performance in paediatric and adult populations (Figure 3a, 3b, 3c, Statement 45).^{186,187,188,189} The CONNECT study, a phase III open-label randomized clinical trial of DMF (n = 78) against IFN-b1a (n = 72), has recently shown that DMF was well tolerated, with favourable MRI and adjusted ARR for DMF-treated paediatric patients;¹⁹⁰ noting it was published after this article’s evidence review and it will be considered more completely in future work.

Discussion

More than half a million patients have been treated with DMF since its launch in 2013 (data on file).²³ The statements agreed in this article were generated by reviewing over a decade of literature on DMF, spanning the original pivotal clinical trials through to the most recent post-marketing data. The data for DMF have remained largely consistent over time.²⁶ In terms of safety, no new signals have emerged since existing reviews. A small number of PML cases have accumulated, but the condition remains very rare (data on file).⁹⁵ The expert opinion of the SC, therefore, supports the positive efficacy and safety profile of DMF as a first-line and switch therapy agent in patients with RRMS and, if permitted by the local label, CIS.

The most recent estimates of MS prevalence in China are 2.39 per 100,000, meaning a potential MS population within the country of more than 34,000.³ This represents a large new population of patients who could potentially be exposed to and/or benefit from DMF.

Despite over a decade of experience with DMF, data from ethnically Chinese populations comprise a small fraction of the existing data,³ which presents challenges for understanding how DMF will be used in practice in this country.⁴⁸ Post-marketing data from within China will be valuable for further understanding the characteristics of DMF in this population. Important differences within China may include the background prevalence of relevant diseases such as hepatitis and tuberculosis,^89,116 differences in the MS treatment armamentarium available, prevailing practices on patient acceptance of DMTs and healthcare professional attitudes towards MS management and its relative importance as a rare disease.³ Monitoring infrastructure for serial (follow-up) neuroimaging and/or serology for hepatitis and tuberculosis may also be impacted by regional differences in availability and implementation priority.

The possibility of drug interactions with as-yet-unidentified Chinese medicine products cannot be categorically excluded, and the real-world use patterns of DMF along with the Chinese diet and cultural practices regarding traditional medicine will be a source of new data following its increased use in the country. Nonetheless, with the evidence generated to date, it is anticipated that DMF will behave similarly in the Chinese population as with the rest-of-the-world population. This is consistent with the confidence of the Chinese regulatory agencies in approving DMF for use in MS treatment,¹⁰ based on similar predictions of maintained safety and efficacy in the population.

Obstacles to rational uptake in China will be confusion regarding the monitoring and testing requirements; for example, about whether JCV and latent tuberculosis testing need to be conducted. It should be made clear that neither JCV nor latent tuberculosis testing needs to be performed. Despite this, it is important that clinicians remain vigilant for PML risk alongside any other AEs.

The panel considered additional statements on the role of the gut microbiome in the aetiology of MS and potential influence on DMF efficacy but found insufficient evidence to proceed. This will be a topic of interest in the future as more evidence accumulates.^191,192,193 Similarly, data from paediatric populations and in patients who are pursuing pregnancy or who are breastfeeding are also sparse; it is hoped that more data will be generated in these groups.

Thus, the limitations of the study include the sparsity of data in Asian patients as well as the level and quality of evidence in some areas, making it difficult to make conclusive recommendations on those topics. As more patients in China are treated with DMF and more experience is gathered, a repeated analysis and update of the information presented here should be conducted.

This project revealed a consistency of data suggesting DMF remains a valuable part of the MS treatment armamentarium. This evidence summary hopes to clarify all relevant aspects for more effective use in China.

Conclusion

A decade of experience with DMF continues to support its positive efficacy and safety profile in treating patients with MS. Although there is a paucity of high-quality evidence from China itself, the limited data that exist from East Asian populations support a similar profile and suggest that DMF will be a valuable addition to the MS therapeutic armamentarium and will help address unmet treatment needs in China. This review of the most recent and extensive previous literature to form conclusive summary statements is aimed to provide a relevant overview to all clinicians treating patients with MS, with the aims of optimizing care and patient outcomes.

Supplemental Material

sj-docx-1-tan-10.1177_17562864231180734 – Supplemental material for Clinical use of dimethyl fumarate in multiple sclerosis treatment: an update to include China, using a modified Delphi method

Supplemental material, sj-docx-1-tan-10.1177_17562864231180734 for Clinical use of dimethyl fumarate in multiple sclerosis treatment: an update to include China, using a modified Delphi method by Ralf Gold, Michael Barnett, Andrew Chan, Huiyu Feng, Kazuo Fujihara, Gavin Giovannoni, Xavier Montalbán, Fu-Dong Shi, Mar Tintoré, Qun Xue, Chunsheng Yang and Hongyu Zhou in Therapeutic Advances in Neurological Disorders

Footnotes

Acknowledgements

The Steering Committee authors acknowledge and thank all experts who contributed to the voting and discussion, refining the draft statements. Jeffrey Martin and Rachael Profit (MIMS, Hong Kong and Pte Limited) contributed to the literature search, project administration, visualization of the voting data and medical writing assistance to the manuscript preparation.

Declarations

ORCID iD

Gavin Giovannoni

Supplemental material

Supplemental material for this article is available online.

References

Chan

Tsang

, et al. Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese. Clin Neurol Neurosurg 2011; 113: 617–622.

Fox

Gold

Phillips

, et al. Efficacy and tolerability of delayed-release dimethyl fumarate in black, Hispanic, and Asian patients with relapsing-remitting multiple sclerosis: post hoc integrated analysis of DEFINE and CONFIRM. Neurol Ther 2017; 6: 175–187.

Jia

Zhang

Yang

. The incidence and prevalence, diagnosis, and treatment of multiple sclerosis in China: a narrative review. Neurol Sci 2022; 43: 4695–4700.

Zhou

Zeng

Yang

, et al. Status of immunotherapy acceptance in Chinese patients with multiple sclerosis: analysis of multiple sclerosis patient survival report 2018. Front Neurol 2021; 12: 651511.

Cheng

Miao

Zhang

, et al. A population-based survey of multiple sclerosis in Shanghai, China. Neurology 2007; 68: 1495–1500.

GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18: 269–285.

Howard

Trevick

Younger

. Epidemiology of multiple sclerosis. Neurol Clin 2016; 34: 919–939.

Rosati

. The prevalence of multiple sclerosis in the world: an update. Neurol Sci 2001; 22: 117–139.

Walton

King

Rechtman

, et al. Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition. Mult Scler 2020; 26: 1816–1821.

10.

Biogen-Idec. TECFIDERA® prescribing information (China), https://www.biogen.cn/content/dam/corporate/cn_CN/pdf/%E5%AF%8C%E9%A9%AC%E9%85%B8%E4%BA%8C%E7%94%B2%E9%85%AF%E8%82%A0%E6%BA%B6%E8%83%B6%E5%9B%8A%E8%AF%B4%E6%98%8E%E4%B9%A6.pdf (2022, accessed 30 October 2022).

11.

Biogen-Idec. TECFIDERA® summary of product characteristics (EMA), https://www.ema.europa.eu/en/documents/product-information/tecfidera-epar-product-information_en.pdf (2022, accessed 30 October 2022).

12.

Biogen-Idec. TECFIDERA® prescribing information (United States), https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204063s027lbl.pdf (2022, accessed 21 November 2022).

13.

Linker

Lee

Ryan

, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011; 134: 678–692.

14.

Cada

Levien

Baker

. Dimethyl fumarate. Hospital Pharmacy 2013; 48: 668–679.

15.

Temple

. NDA approval, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/204063Orig1s000ltr.pdf (2013, accessed 31 October 2022).

16.

Niino

Ohashi

Ochi

, et al. Japanese guidelines for dimethyl fumarate. Clin Exp Neuroimmunol 2018; 9: 235–243.

17.

Lee

. Pricing and reimbursement pathways of new orphan drugs in South Korea: a longitudinal comparison. Healthcare 2021; 9: 296.

18.

Biogen Idec gets DCGI nod for multiple sclerosis oral drug, 2015, https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/biogen-idec-gets-dcgi-nod-for-multiple-sclerosis-oral-drug/articleshow/46215644.cms?from=mdr (2015, accessed 30 October 2022).

19.

MIMS. Local product insert, https://www.mims.com/thailand/drug/tecfidera/local-product-insert/TH%20Package%20leaflet_TECFIDERA_Thai%20PIL_rev3Mar2020-clean_(rev16Mar20).pdf (2020, accessed 31 October 2022).

20.

HKDoH. Compendium of pharmaceutical products, https://www.drugoffice.gov.hk/eps/do/tc/doc/Compdium.pdf (2020, accessed 1 November 2022).

21.

HSA. New drug approvals Singapore July 2016, https://www.hsa.gov.sg/announcements/new-drug-approval/new-drug-approvals-jul-2016 (2016, accessed 1 November 2022).

22.

San-Juan-Rodriguez

Good

Heyman

, et al. Trends in prices, market share, and spending on self-administered disease-modifying therapies for multiple sclerosis in Medicare part D. JAMA Neurol 2019; 76: 1386–1390.

23.

Lyons

Hughes

McCarthy

, et al. Progressive multifocal leukoencephalopathy outcomes in patients with multiple sclerosis treated with dimethyl fumarate. Mult Scler J Exp Transl Clin 2022; 8: 20552173221132469.

24.

Fox

Kita

Cohan

, et al. BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety. Curr Med Res Opin 2014; 30: 251–262.

25.

Gold

Kappos

Arnold

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

26.

Gold

Arnold

Bar-Or

, et al. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: final ENDORSE study results. Mult Scler 2022; 28: 801–816.

27.

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: 1087–1097.

28.

Gold

Arnold

Bar-Or

, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: interim analysis of ENDORSE, a randomized extension study. Mult Scler 2017; 23: 253–265.

29.

Wiendl

Gold

Berger

, et al. Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper). Ther Adv Neurol Disord 2021; 14: 17562864211039648.

30.

Boulas

. Compounded formulations of dimethyl fumarate show significant variability in product characteristics. Drug Res 2016; 66: 275–278.

31.

Longbrake

Cantoni

Chahin

, et al. Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count. Mult Scler 2018; 24: 728–738.

32.

Liebmann

Korn

Janoschka

, et al. Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity. Brain 2021; 144: 3126–3141.

33.

Holm Hansen

Højsgaard Chow

Sellebjerg

, et al. Dimethyl fumarate therapy suppresses B cell responses and follicular helper T cells in relapsing-remitting multiple sclerosis. Mult Scler 2019; 25: 1289–1297.

34.

Holm Hansen

Højsgaard Chow

Christensen

, et al. Dimethyl fumarate therapy reduces memory T cells and the CNS migration potential in patients with multiple sclerosis. Mult Scler Relat Disord 2020; 37: 101451.

35.

Breuer

Herich

Schneider-Hohendorf

, et al. Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium. Mult Scler 2018; 24: 1871–1882.

36.

Mansilla

Navarro-Barriuso

Presas-Rodríguez

, et al. Optimal response to dimethyl fumarate is mediated by a reduction of Th1-like Th17 cells after 3 months of treatment. CNS Neurosci Ther 2019; 25: 995–1005.

37.

McGuire

Ruiz-Zorrilla Diez

Emmerich

, et al. Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Sci Rep 2016; 6: 31159.

38.

Brennan

Matos

Richter

, et al. The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes. Sci Rep 2017; 7: 42054.

39.

Edwards

Kamath

Button

, et al. A pharmacokinetic and biomarker study of delayed-release dimethyl fumarate in subjects with secondary progressive multiple sclerosis: evaluation of cerebrospinal fluid penetration and the effects on exploratory biomarkers. Mult Scler Relat Disord 2021; 51: 102861.

40.

Gopal

Mikulskis

Gold

, et al. Evidence of activation of the Nrf2 pathway in multiple sclerosis patients treated with delayed-release dimethyl fumarate in the phase 3 DEFINE and CONFIRM studies. Mult Scler 2017; 23: 1875–1883.

41.

Suneetha

Raja Rajeswari

. Role of dimethyl fumarate in oxidative stress of multiple sclerosis: a review. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1019: 15–20.

42.

Wipke

Hoepner

Strassburger-Krogias

, et al. Different fumaric acid esters elicit distinct pharmacologic responses. Neurol Neuroimmunol Neuroinflamm 2021; 8: e950.

43.

Yadav

Ito

Soin

, et al. Dimethyl fumarate suppresses demyelination and axonal loss through reduction in pro-inflammatory macrophage-induced reactive astrocytes and complement C3 deposition. J Clin Med 2021; 10: 857.

44.

Longbrake

Mao-Draayer

Cascione

, et al. Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity. Mult Scler 2021; 27: 883–894.

45.

Narapureddy

Dubey

. Clinical evaluation of dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis: efficacy, safety, patient experience and adherence. Patient Prefer Adherence 2019; 13: 1655–1666.

46.

Phillips

Hutchinson

Fox

, et al. Managing flushing and gastrointestinal events associated with delayed-release dimethyl fumarate: experiences of an international panel. Mult Scler Relat Disord 2014; 3: 513–519.

47.

Fox

Vasquez

Grainger

, et al. Gastrointestinal tolerability of delayed-release dimethyl fumarate in a multicenter, open-label study of patients with relapsing forms of multiple sclerosis (MANAGE). Int J MS Care 2016; 18: 9–18.

48.

Saida

Yamamura

Kondo

, et al. A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries. BMC Neurol 2019; 19: 5.

49.

Kondo

Kawachi

Onizuka

, et al. Efficacy of dimethyl fumarate in Japanese multiple sclerosis patients: interim analysis of randomized, double-blind APEX study and its open-label extension. Mult Scler J Exp Transl Clin 2019; 5: 2055217319864974.

50.

Ochi

Niino

Onizuka

, et al. 72-week safety and tolerability of dimethyl fumarate in Japanese patients with relapsing-remitting multiple sclerosis: analysis of the randomised, double blind, placebo-controlled, phase III APEX study and its open-label extension. Adv Ther 2018; 35: 1598–1611.

51.

Zhang

Sun

, et al. Dimethyl fumarate for multiple sclerosis. Cochrane Database Syst Rev 2015; 22: CD011076.

52.

Salter

Lancia

Cutter

, et al. A propensity-matched comparison of long-term disability worsening in patients with multiple sclerosis treated with dimethyl fumarate or fingolimod. Ther Adv Neurol Disord 2021; 14: 17562864211021177.

53.

Zhang

, et al. Comparative efficacy and acceptability of disease-modifying therapies in patients with relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis. J Neurol 2020; 267: 3489–3498.

54.

Freedman

Devonshire

Duquette

, et al. Treatment optimization in multiple sclerosis: Canadian MS working group recommendations. Can J Neurol Sci 2020; 47: 437–455.

55.

Montalban

Gold

Thompson

, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler 2018; 24: 96–120.

56.

Rae-Grant

Day

Marrie

, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology 2018; 90: 777–788.

57.

Salter

Lancia

Cutter

, et al. Characterizing long-term disability progression and employment in NARCOMS registry participants with multiple sclerosis taking dimethyl fumarate. Int J MS Care 2021; 23: 239–244.

58.

Gold

Giovannoni

Phillips

, et al. Sustained effect of delayed-release dimethyl fumarate in newly diagnosed patients with relapsing-remitting multiple sclerosis: 6-year interim results from an extension of the DEFINE and CONFIRM studies. Neurol Ther 2016; 5: 45–57.

59.

Cerqueira

Compston

DAS

Geraldes

, et al. Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? J Neurol Neurosurg Psychiatry 2018; 89: 844–850.

60.

Hänninen

Viitala

Atula

, et al. Initial treatment strategy and clinical outcomes in Finnish MS patients: a propensity-matched study. J Neurol 2022; 269: 913–922.

61.

Walo-Delgado

De la Maza

Villarrubia

, et al. Low serum neurofilament light chain values identify optimal responders to dimethyl fumarate in multiple sclerosis treatment. Sci Rep 2021; 11: 9299.

62.

Delcoigne

Manouchehrinia

Barro

, et al. Blood neurofilament light levels segregate treatment effects in multiple sclerosis. Neurology 2020; 94: e1201–e1212.

63.

Sejbaek

Nielsen

Penner

, et al. Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients. J Neurol Neurosurg Psychiatry 2019; 90: 1324–1330.

64.

West

Wyatt

High

, et al. Are initial demyelinating event recovery and time to second event under differential control? Neurology 2006; 67: 809–813.

65.

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: 220–229.

66.

Goldman

Dwyer

Coleman

, et al. Patient-specific factors modulate leukocyte response in dimethyl fumarate treated MS patients. PLoS ONE 2020; 15: e0228617.

67.

Mehta

Miller

Arnold

, et al. Effect of dimethyl fumarate on lymphocytes in RRMS: implications for clinical practice. Neurology 2019; 92: e1724–e1738.

68.

Warny

Helby

Nordestgaard

, et al. Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study. PLoS Med 2018; 15: e1002685.

69.

Kim

Croteau

Brinker

, et al. Expanding spectrum of opportunistic infections associated with dimethyl fumarate. Mult Scler 2021; 27: 1301–1305.

70.

Garbo

Lorenzut

Del Negro

, et al. Lower lymphocyte counts and older age are associated with reduced multiple sclerosis disease activity during dimethyl fumarate treatment. Mult Scler Relat Disord 2021; 49: 102781.

71.

Tsantes

Curti

Ferraro

, et al. Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis. Eur J Neurol 2021; 28: 269–277.

72.

Boffa

Bruschi

Cellerino

, et al. 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: 425–432.

73.

Perini

Rinaldi

Puthenparampil

, et al. Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient. Mult Scler Relat Disord 2018; 26: 68–70.

74.

Greenstein

. Diffuse dermatophytosis occurring on dimethyl fumarate therapy. Mult Scler 2018; 24: 999–1001.

75.

Workel

Wolfhagen

MJHM

Bouwhuis

, et al. Cryptococcal meningitis in a patient with multiple sclerosis on dimethyl fumarate treatment: a case report. Mult Scler Relat Disord 2020; 42: 102137.

76.

Scotto

Reia

Buonomo

, et al. Risk of invasive fungal infections among patients treated with disease modifying treatments for multiple sclerosis: a comprehensive review. Expert Opin Drug Saf 2021; 20: 925–936.

77.

Kogel

Gold

Schneider

. CMV meningitis associated with dimethyl fumarate therapy-induced lymphopenia in a multiple sclerosis patient. J Neurol 2021; 268: 4374–4375.

78.

Rastas

Sirignano

Barner

, et al. Legionella infection associated with dimethyl fumarate used for treatment of multiple sclerosis. J Neurol 2019; 266: 2867–2868.

79.

Lorefice

Fenu

Cabras

, et al. An unusual infection in MS patient treated with dimethyl fumarate: a case report of omphalitis. Mult Scler Relat Disord 2016; 7: 65–67.

80.

Berkovich

Weiner

. Effects of dimethyl fumarate on lymphocyte subsets. Mult Scler Relat Disord 2015; 4: 339–341.

81.

Manni

Iaffaldano

Lucisano

, et al. Lymphocyte count and body mass index as biomarkers of early treatment response in a multiple sclerosis dimethyl fumarate-treated cohort. Front Immunol 2019; 10: 1343.

82.

Medina

Villarrubia

Sainz de la Maza

, et al. Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile. Mult Scler 2018; 24: 1317–1327.

83.

Chan

Rose

Alvarez

, et al. Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS. Neurol Clin Pract 2020; 10: 510–519.

84.

Monschein

Hartung

Zrzavy

, et al. Vaccination and multiple sclerosis in the era of the COVID-19 pandemic. J Neurol Neurosurg Psychiatry 2021; 92: 1033–1043.

85.

Szepanowski

Warnke

Zu Hörste

, et al. Secondary immunodeficiency and risk of infection following immune therapies in neurology. CNS Drugs 2021; 35: 1173–1188.

86.

Von Hehn

Howard

Liu

, et al. Immune response to vaccines is maintained in patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2018; 5: e409.

87.

Moser

Seiberl

Feige

, et al. Tetravalent influenza vaccine is not associated with neuroaxonal damage in multiple sclerosis patients. Front Immunol 2021; 12: 718895.

88.

European Centre for Disease Prevention and Control. Tuberculosis surveillance and monitoring in Europe 2021–2019 data, https://www.ecdc.europa.eu/en/publications-data/tuberculosis-surveillance-and-monitoring-europe-2021-2019-data (2021, accessed 9 October 2022).

89.

Jia

. Estimating the incidence of tuberculosis – Shanghai, China, 2025−2050. China CDC Wkly 2020; 2: 995–998.

90.

Baldassari

Feng

Macaron

, et al. Tuberculosis screening in multiple sclerosis: effect of disease-modifying therapies and lymphopenia on the prevalence of indeterminate TB screening results in the clinical setting. Mult Scler J Exp Transl Clin 2019; 5: 2055217319875467.

91.

Dantas

Pereira

Gauza

, et al. Latent tuberculosis infection reactivation in patients with multiple sclerosis in use of disease-modifying therapies: a systematic review. Mult Scler Relat Disord 2021; 55: 103184.

92.

Epstein

Dunn

Deresinski

. Infectious complications of multiple sclerosis therapies: implications for screening, prophylaxis, and management. Open Forum Infect Dis 2018; 5: ofy174.

93.

Fragoso

Adoni

Anacleto

, et al. How do we manage and treat a patient with multiple sclerosis at risk of tuberculosis? Expert Rev Neurother 2014; 14: 1251–1260.

94.

Getahun

Matteelli

Chaisson

, et al. Latent mycobacterium tuberculosis infection. N Engl J Med 2015; 372: 2127–2135.

95.

Jordan

Yang

Fisher

, et al. Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients. Mult Scler 2022; 28: 7–15.

96.

Berger

. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord 2017; 12: 59–63.

97.

Diebold

Altersberger

Décard

, et al. A case of progressive multifocal leukoencephalopathy under dimethyl fumarate treatment without severe lymphopenia or immunosenescence. Mult Scler 2019; 25: 1682–1685.

98.

Lucchini

Prosperini

Buscarinu

, et al. Predictors of lymphocyte count recovery after dimethyl fumarate-induced lymphopenia in people with multiple sclerosis. J Neurol 2021; 268: 2238–2245.

99.

Caldito

O’Leary

Stuve

. Persistent severe lymphopenia 5 years after dimethyl fumarate discontinuation. Mult Scler 2021; 27: 1306–1308.

100.

Wood

Robertson

Htet

, et al. Incidence of persistent lymphopenia in people with multiple sclerosis on dimethyl fumarate. Mult Scler Relat Disord 2022; 58: 103492.

101.

Gieselbach

R-J

Muller-Hansma

Wijburg

, et al. Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. J Neurol 2017; 264: 1155–1164.

102.

Motte

Kneiphof

Straßburger-Krogias

, et al. Detection of JC virus archetype in cerebrospinal fluid in a MS patient with dimethylfumarate treatment without lymphopenia or signs of PML. J Neurol 2018; 265: 1880–1882.

103.

Vola

Petracca

Cocozza

, et al. Possible progressive multifocal leukoencephalopathy and active multiple sclerosis under dimethyl fumarate: the central role of MRI in informing therapeutic decisions. BMC Neurol 2021; 21: 146.

104.

Dunham

Schmidt

Clifford

. Treatment of progressive multifocal leukoencephalopathy using immune restoration. Neurotherapeutics 2020; 17: 955–965.

105.

Cheng

Sun

Y-N

Zhang

C-Y

, et al. Incidence and risk factors of tuberculosis among the elderly population in China: a prospective cohort study. Infect Dis Poverty 2020; 9: 13.

106.

Lau

Qiu

Kermode

, et al. High prevalence and indexes of anti-John Cunningham virus antibodies in a cohort of Chinese patients with multiple sclerosis. Mult Scler J Exp Transl Clin 2018; 4: 2055217318788699.

107.

Fanara

Aprile

Iacono

, et al. The role of nutritional lifestyle and physical activity in multiple sclerosis pathogenesis and management: a narrative review. Nutrients 2021; 13: 3774.

108.

Rapp

Michels

Schöpe

, et al. Associations between multiple sclerosis and incidence of heart diseases: systematic review and meta-analysis of observational studies. Mult Scler Relat Disord 2021; 56: 103279.

109.

Kingwell

Zhang

Zhu

, et al. Short-term laboratory and related safety outcomes for the multiple sclerosis oral disease-modifying therapies: an observational study. Expert Opin Drug Saf 2021; 20: 481–487.

110.

Guarnera

Bramanti

Mazzon

. Comparison of efficacy and safety of oral agents for the treatment of relapsing-remitting multiple sclerosis. Drug Des Devel Ther 2017; 11: 2193–2207.

111.

Antonazzo

Poluzzi

Forcesi

, et al. Liver injury with drugs used for multiple sclerosis: a contemporary analysis of the FDA adverse event reporting system. Mult Scler 2019; 25: 1633–1640.

112.

Biolato

Bianco

Lucchini

, et al. The disease-modifying therapies of relapsing-remitting multiple sclerosis and liver injury: a narrative review. CNS Drugs 2021; 35: 861–880.

113.

Gold

Giovannoni

Phillips

, et al. Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS). Mult Scler 2015; 21: 57–66.

114.

Diebold

Fischer-Barnicol

Tsagkas

, et al. Hepatitis E virus infections in patients with MS on oral disease-modifying treatment. Neurol Neuroimmunol Neuroinflamm 2019; 6: e594.

115.

Muñoz

Kulick

Kortepeter

, et al. Liver injury associated with dimethyl fumarate in multiple sclerosis patients. Mult Scler 2017; 23: 1947–1949.

116.

Yue

Zhang

Cai

, et al. Trends in the disease burden of HBV and HCV infection in China from 1990–2019. Int J Infect Dis 2022; 122: 476–485.

117.

Lebrun

Rocher

. Cancer risk in patients with multiple sclerosis: potential impact of disease-modifying drugs. CNS Drugs 2018; 32: 939–949.

118.

Gómez-Moreno

Sánchez-Seco

Moreno-García

, et al. Cancer diagnosis in a Spanish cohort of multiple sclerosis patients under dimethylfumarate treatment. Mult Scler Relat Disord 2021; 49: 102747.

119.

Gil-Bernal

González-Caballero

Espinosa-Rosso

, et al. Potential risk of disease modifying therapies on neoplasm development and coadjutant factors in multiple sclerosis outpatients. Sci Rep 2021; 11: 12533.

120.

Stamatellos

Siafis

Papazisis

. Disease-modifying agents for multiple sclerosis and the risk for reporting cancer: a disproportionality analysis using the US Food and Drug Administration adverse event reporting system database. Br J Clin Pharmacol 2021; 87: 4769–4779.

121.

Dolladille

Chrétien

Peyro-Saint-Paul

, et al. Association between disease-modifying therapies prescribed to persons with multiple sclerosis and cancer: a WHO pharmacovigilance database analysis. Neurotherapeutics 2021; 18: 1657–1664.

122.

Repovic

Robertson

Kresa-Reahl

, et al. Effectiveness of dimethyl fumarate in patients with relapsing multiple sclerosis switching after suboptimal response to glatiramer acetate, including patients with early multiple sclerosis: subgroup analysis of RESPOND. Neurol Ther 2021; 10: 169–182.

123.

Deleu

Mesraoua

Canibaño

, et al. Oral disease-modifying therapies for multiple sclerosis in the Middle Eastern and North African (MENA) region: an overview. Curr Med Res Opin 2019; 35: 249–260.

124.

Chan

Cutter

Fox

, et al. Comparative effectiveness of delayed-release dimethyl fumarate versus glatiramer acetate in multiple sclerosis patients: results of a matching-adjusted indirect comparison. J Comp Eff Res 2017; 6: 313–323.

125.

Paolicelli

Manni

Iaffaldano

, et al. Efficacy and safety of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs 2020; 34: 65–92.

126.

D’Amico

Zanghì

Sciandra

, et al. Dimethyl fumarate vs teriflunomide: an Italian time-to-event data analysis. J Neurol 2020; 267: 3008–3020.

127.

Condé

Moisset

Pereira

, et al. Dimethyl fumarate and teriflunomide for multiple sclerosis in a real-life setting: a French retrospective cohort study. Eur J Neurol 2019; 26: 460–467.

128.

Braune

Grimm

Van Hövell

, et al. Comparative effectiveness of delayed-release dimethyl fumarate versus interferon, glatiramer acetate, teriflunomide, or fingolimod: results from the German NeuroTransData registry. J Neurol 2018; 265: 2980–2992.

129.

Laplaud

Casey

Barbin

, et al. Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis. Neurology 2019; 93: e635–e646.

130.

Buron

Chalmer

Sellebjerg

, et al. Comparative effectiveness of teriflunomide and dimethyl fumarate: a nationwide cohort study. Neurology 2019; 92: e1811–e1820.

131.

Buron

Kalincik

Sellebjerg

, et al. Effect of lateral therapy switches to oral moderate-efficacy drugs in multiple sclerosis: a nationwide cohort study. J Neurol Neurosurg Psychiatry 2021; 92: 556–562.

132.

Granqvist

Burman

Gunnarsson

, et al. Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS. Mult Scler 2020; 26: 1532–1539.

133.

Sabin

Urtiaga

Pilo

, et al. Tolerability and safety of dimethyl fumarate in relapsing multiple sclerosis: a prospective observational multicenter study in a real-life Spanish population. J Neurol 2020; 267: 2362–2371.

134.

Wicks

Rasouliyan

Katic

, et al. The real-world patient experience of fingolimod and dimethyl fumarate for multiple sclerosis. BMC Res Notes 2016; 9: 434.

135.

Campbell

Lefaux

Mayer

, et al. Nursing management of gastrointestinal adverse events associated with delayed-release dimethyl fumarate: a global Delphi approach. J Neurosci Nurs 2020; 52: 72–77.

136.

Mayer

Fink

Sammarco

, et al. Management strategies to facilitate optimal outcomes for patients treated with delayed-release dimethyl fumarate. Drug Saf 2018; 41: 347–356.

137.

Sejbaek

Nybo

Petersen

, et al. Real-life persistence and tolerability with dimethyl fumarate. Mult Scler Relat Disord 2018; 24: 42–46.

138.

Lenzen

Daniëls

van Bokhoven

, et al. Setting goals in chronic care: shared decision making as self-management support by the family physician. Eur J Gen Pract 2015; 21: 138–144.

139.

Askari

Pappas

De Smit

, et al. Comparison of goals set by people with multiple sclerosis during two fatigue management interventions. Scand J Occup Ther 2022; 30: 684–692.

140.

Carrithers

. Update on disease-modifying treatments for multiple sclerosis. Clin Ther 2014; 36: 1938–1945.

141.

Ben-Zacharia

Adamson

Boyd

, et al. Impact of shared decision making on disease-modifying drug adherence in multiple sclerosis. Int J MS Care 2018; 20: 287–297.

142.

Rodrigues

Rocha

Bonifácio

, et al. Therapeutic inertia in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2021; 55: 103176.

143.

Fox

Rhoades

. New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis. Curr Opin Neurol 2012; 25(Suppl.): S11–9.

144.

Pandit

. No evidence of disease activity (NEDA) in multiple sclerosis – shifting the goal posts. Ann Indian Acad Neurol 2019; 22: 261–263.

145.

Giovannoni

Gold

Fox

, et al. Relapses requiring intravenous steroid use and multiple-sclerosis-related hospitalizations: integrated analysis of the delayed-release dimethyl fumarate phase III studies. Clin Ther 2015; 37: 2543–2551.

146.

Barros

Sequeira

de Sousa

, et al. Real-word effectiveness and safety of dimethyl fumarate in a multiple sclerosis Portuguese population. Clin Neuropharmacol 2020; 43: 55–60.

147.

Ontaneda

Nicholas

Carraro

, et al. Comparative effectiveness of dimethyl fumarate versus fingolimod and teriflunomide among MS patients switching from first-generation platform therapies in the US. Mult Scler Relat Disord 2019; 27: 101–111.

148.

Miclea

Leussink

Hartung

, et al. Safety and efficacy of dimethyl fumarate in multiple sclerosis: a multi-center observational study. J Neurol 2016; 263: 1626–1632.

149.

Lanzillo

Moccia

Palladino

, et al. Clinical predictors of dimethyl fumarate response in multiple sclerosis: a real life multicentre study. Mult Scler Relat Disord 2020; 38: 101871.

150.

Pilo de la Fuente

Sabín

Galán

, et al. Three-year effectiveness of dimethyl fumarate in multiple sclerosis: a prospective multicenter real-world study. CNS Drugs 2020; 34: 1275–1286.

151.

Lorefice

Casaglia

Fronza

, et al. The dimethyl fumarate experience: a handy drug with broad clinical utility. Front Neurol 2021; 12: 679355.

152.

Phillips

Selmaj

Gold

, et al. Clinical significance of gastrointestinal and flushing events in patients with multiple sclerosis treated with delayed-release dimethyl fumarate. Int J MS Care 2015; 17: 236–243.

153.

Lorscheider

Benkert

Lienert

, et al. Comparative analysis of dimethyl fumarate and fingolimod in relapsing-remitting multiple sclerosis. J Neurol 2021; 268: 941–949.

154.

Eriksson

Cars

Piehl

, et al. Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study. Eur J Clin Pharmacol 2018; 74: 219–226.

155.

Khatri

Tarima

Essig

, et al. Delayed lymphocyte re-population following discontinuation of dimethyl fumarate and after switching to other disease modifying drug therapies. Mult Scler Relat Disord 2017; 18: 60–64.

156.

Lahdenperä

Soilu-Hänninen

Kuusisto

, et al. Medication adherence/persistence among patients with active multiple sclerosis in Finland. Acta Neurol Scand 2020; 142: 605–612.

157.

Min

Cohan

Alvarez

, et al. Real-world characterization of dimethyl fumarate–related gastrointestinal events in multiple sclerosis: management strategies to improve persistence on treatment and patient outcomes. Neurol Ther 2019; 8: 109–119.

158.

Soelberg Sorensen

. Safety concerns and risk management of multiple sclerosis therapies. Acta Neurol Scand 2017; 136: 168–186.

159.

O’Gorman

Russell

, et al. Effect of aspirin pretreatment or slow dose titration on flushing and gastrointestinal events in healthy volunteers receiving delayed-release dimethyl fumarate. Clin Ther 2015; 37: 1402–1419.e5.

160.

Sheikh

Nestorov

Russell

, et al. Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther 2013; 35: 1582–1594.

161.

Gelibter

Orrico

Moiola

, et al. Allergy and dimethyl fumarate treatment in a patient with multiple sclerosis. J Neurol Sci 2020; 418: 117104.

162.

Antolin-Amerigo

Sánchez-González

Barbarroja-Escudero

, et al. Delayed hypersensitivity reaction to oral dimethyl fumarate. J Investig Allergol Clin Immunol 2018; 28: 201–203.

163.

Algahtani

Shirah

Marghalani

, et al. Erythema nodosum in a patient with multiple sclerosis on dimethyl fumarate. Mult Scler Relat Disord 2019; 28: 155–158.

164.

Boullosa-Lale

González-Freire

Martínez-Martínez

, et al. Safety and persistence of dimethyl fumarate as a treatment for relapsing-remitting multiple-sclerosis. Farm Hosp 2020; 45: 73–76.

165.

Di Bona

Albanesi

Giliberti

, et al et al. Desensitization for immediate hypersensitivity to oral dimethyl fumarate (tecfidera). J Allergy Clin Immunol Pract 2017; 5: 821–822.

166.

Zhu

Nestorov

Zhao

, et al. Evaluation of potential drug-drug interaction between delayed-release dimethyl fumarate and a commonly used oral contraceptive (norgestimate/ethinyl estradiol) in healthy women. Clin Pharmacol Drug Dev 2017; 6: 604–613.

167.

Mantero

Abate

Basilico

, et al. COVID-19 in dimethyl fumarate-treated patients with multiple sclerosis. J Neurol 2021; 268: 2023–2025.

168.

Centonze

Rocca

Gasperini

, et al. Disease-modifying therapies and SARS-CoV-2 vaccination in multiple sclerosis: an expert consensus. J Neurol 2021; 268: 3961–3968.

169.

Korsukewitz

Reddel

Bar-Or

, et al. Neurological immunotherapy in the era of COVID–19 – looking for consensus in the literature. Nat Rev Neurol 2020; 16: 493–505.

170.

Reder

Centonze

Naylor

, et al. COVID-19 in patients with multiple sclerosis: associations with disease-modifying therapies. CNS Drugs 2021; 35: 317–330.

171.

Sormani

De Rossi

Schiavetti

, et al. Disease-modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. Ann Neurol 2021; 89: 780–789.

172.

Inshasi

Alroughani

Al-Asmi

, et al. Expert consensus and narrative review on the management of multiple sclerosis in the Arabian Gulf in the COVID-19 era: focus on disease-modifying therapies and vaccination against COVID-19. Neurol Ther 2021; 10: 539–555.

173.

Achiron

Mandel

Dreyer-Alster

, et al. Humoral immune response in multiple sclerosis patients following PfizerBNT162b2 COVID19 vaccination: up to 6 months cross-sectional study. J Neuroimmunol 2021; 361: 577746.

174.

Gold

Phillips

Havrdova

, et al. Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience. Neurol Ther 2015; 4: 93–104.

175.

Biotti

Ciron

. First-line therapy in relapsing remitting multiple sclerosis. Rev Neurol 2018; 174: 419–428.

176.

Amato

Portaccio

. Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs. CNS Drugs 2015; 29: 207–220.

177.

Yeh

Widyastuti

Van der Walt

, et al. Natalizumab, fingolimod and dimethyl fumarate use and pregnancy-related relapse and disability in women with multiple sclerosis. Neurology 2021; 96: e2989–e3002.

178.

Hellwig

Rog

McGuigan

, et al. Interim analysis of pregnancy outcomes after exposure to dimethyl fumarate in a prospective international registry. Neurol Neuroimmunol Neuroinflamm 2022; 9: e1114.

179.

Dobson

Dassan

Roberts

, et al. UK consensus on pregnancy in multiple sclerosis: ‘Association of British Neurologists’ guidelines. Pract Neurol 2019; 19: 106–114.

180.

Varyte.

Zakarevicˇiene.

Ramašauskaite.

, et al. Pregnancy and multiple sclerosis: an update on the disease modifying treatment strategy and a review of pregnancy’s impact on disease activity. Medicina 2020; 56: 49.

181.

Wang

Alwan

, et al. A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis. CNS Drugs 2014; 28: 89–94.

182.

Capone

Albanese

Quadri

, et al. Disease-modifying drugs and breastfeeding in multiple sclerosis: a narrative literature review. Front Neurol 2022; 13: 851413.

183.

Ciplea

Datta

Rewers-Felkins

, et al. Dimethyl fumarate transfer into human milk. Ther Adv Neurol Disord 2020; 13: 1756286420968414.

184.

Alroughani

Das

Penner

, et al. Safety and efficacy of delayed-release dimethyl fumarate in pediatric patients with relapsing multiple sclerosis (FOCUS). Pediatr Neurol 2018; 83: 19–24.

185.

Alroughani

Huppke

Mazurkiewicz-Beldzinska

, et al. Delayed-release dimethyl fumarate safety and efficacy in pediatric patients with relapsing-remitting multiple sclerosis. Front Neurol 2020; 11: 606418.

186.

Krysko

Graves

Rensel

, et al. Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US. Neurology 2018; 91: e1778–e1787.

187.

Krysko

Graves

Rensel

, et al. Real-world effectiveness of initial disease-modifying therapies in pediatric multiple sclerosis. Ann Neurol 2020; 88: 42–55.

188.

Makhani

Schreiner

. Oral dimethyl fumarate in children with multiple sclerosis: a dual-center study. Pediatr Neurol 2016; 57: 101–104.

189.

Saijo

Abe

Oikawa

, et al. Successful treatment with dimethyl fumarate in a child with relapsing-remitting multiple sclerosis. Brain Dev 2022; 44: 353–356.

190.

Vermersch

Scaramozza

Levin

, et al. Effect of dimethyl fumarate vs interferon β-1a in patients with pediatric-onset multiple sclerosis. JAMA Netw Open 2022; 5: e2230439.

191.

Dello Russo

Scott

Pirmohamed

. Dimethyl fumarate induced lymphopenia in multiple sclerosis: a review of the literature. Pharmacol Ther 2021; 219: 107710.

192.

Katz Sand

Zhu

Ntranos

, et al. Disease-modifying therapies alter gut microbial composition in MS. Neurol Neuroimmunol Neuroinflamm 2019; 6: e517.

193.

Shah

Locca

Dorsett

, et al. Alterations of the gut mycobiome in patients with MS. EBioMedicine 2021; 71: 103557.

Supplementary Material

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Clinical use of dimethyl fumarate in multiple sclerosis treatment: an update to include China,using a modified Delphi method

Abstract

Keywords

Introduction

Methods

Results

Mechanism of action

PK/PD and dosing

Situation in China/East Asia

Efficacy statements

Situation in China/East Asia

Haematologic parameters and infection risk

Lymphopenia

Vaccination response

Tuberculosis

Progressive multifocal leukoencephalopathy

Situation in China/East Asia

Comorbidities, organ function and cancer risk

Situation in China/East Asia

Cancer risk

Treatment initiation and decision-making

Treatment switching

Situation in China/East Asia

Adverse event management and tolerability

Concomitant therapies

COVID-19 and vaccinations

Pregnancy/lactation

Situation in China/East Asia

Paediatrics

Discussion

Conclusion

Supplemental Material

sj-docx-1-tan-10.1177_17562864231180734 – Supplemental material for Clinical use of dimethyl fumarate in multiple sclerosis treatment: an update to include China, using a modified Delphi method

Footnotes

Acknowledgements

Declarations

ORCID iD

Supplemental material

References

Supplementary Material