Real-life experience with Dimethyl Fumerate (Tecfidera)

Why is DMF so poorly tolerated? 

Mult Scler Relat Disord. 2018 Jun 2;24:42-46. doi: 10.1016/j.msard.2018.05.007. [Epub ahead of print]

Real-life persistence and tolerability with dimethyl fumarate.

Sejbaek T1, Nybo M2, Petersen T3, Illes Z4.


Dimethyl fumarate (DMF) has been registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). Differences in tolerability between multiple sclerosis clinics in patients treated with DMF has not been examined.

We examined real-world tolerability to DMF, and also compared adherence data between two MS clinics.


Adverse events (AE), discontinuation rates, and causes of discontinuation were investigated.


253 patients participated in this retrospective study. In the total cohort, 27.7% of the patients discontinued DMF. Higher rate of discontinuation was associated with higher number of previous disease modifying treatments (p < 0.001). Reasons for discontinuation were primarily flushing (15%) and gastrointestinal AEs (51%). Grade III lymphopenia was detected only in 6 cases (2.4%). We observed differences between the two clinics: discontinuation because of AEs was different (Odds ratio 6.13, 95% CI: 3.0-12.7, p < 0.001), the mean treatment duration also differed (305.3 ± 186.3 vs 140.5 ± 114.4 days, p < 0.001), and dissimilarities in adherence were mainly related to flushing, gastrointestinal AEs, and consideration of lymphopenia (p < 0.0001). Better adherence was associated with prospectively planned management of gastrointestinal AEs and flushing.


Adherence in real-life was similar to pivotal trials. Differences in discontinuation rates at two MS clinics underline importance of AE management.

Another successful year for Biogen, not least because of SPINRAZA (nusinersen, an antisense oligonucleotide) in spinal muscular atrophy (SMA). But in MS, they won a patent dispute on Tecfidera filed by Kyle Bass a hedge fund manager last year, banking a revenue of $987 million this quarter alone. All said and done, for PwMS and their clinicians the most important thing is safety and tolerability. Judging across the board, however, compared to other oral therapies, some of Tecfidera’s side effects, such as the gastrointestinal symptoms and lymphopaenia, may limit its usage and adherence to therapy.

Here, authors Sejbaek et al. investigate the real-world tolerability of Tecfidera in RRMS at two MS centers.

They report in total 80% of 253 PwMS experienced side effects, whilst ~28% discontinued therapy. By comparison, less than a quarter discontinued therapy because of treatment failure (i.e. secondary to a clinical relapse). So side effects are a real problem with Tecfidera. The majority of side effects were gastro-intestinal, although skin flushing was also problematic. Low lymphocyte counts (lymphopaenia), both transient and persistent ones were also noted, with grade I/II lymphopaenia (<0.8 × 10−9 cells/L) affecting less than a quarter of PwMS. But, discontinuation of therapy because of this was low.

Not surprisingly, those who have discontinued previous therapies were also more likely to discontinue on Tecfidera also (constant switching of therapies gives rise to poor MS prognosis in the long-run based on MS database reviews).

In view of the impact of these side effects on adherence therapy, the authors have suggested some solutions, which can be found in the tale below. If you experience some of these side effects with Tecfidera it’s worth trying.

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Neuro Doc Gnanapavan


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  • My spouse is on DMF and tolerates it well when he absolutely adheres to a firm schedule of food and dose. He literally eats the same breakfast at the same time every day, likewise dinner. The only time he gets flushing is when some invitation or restaurant meal ends up changing the timing.

  • The whole story may have not been told. The following is a poster presented this week at EAN. Lymphopenia may be more prevalent in the real world and time to recovery can be has long as 27 months:

    Background and aims:
    Dimethyl fumarate (DMF) is an oral drug for the treatment of RRMS. About 6% of patients on DMF had an absolute lymphocyte count equal to or less than 500/mL in trials. Progressive multifocal leucoencephalopaty (PML) cases have been reported in patients on DMF with moderate and permanent lymphopenia. It seems that durable moderate lymphopenia is a risk factor of PML in patients treated with DMF

    Our objetive is to analyse the characteristic of the patients with lymphopenia in a real world MS cohort treated with DMF.

    Retrospective observational study including patients with RRMS on DMF and analyzethe clinical features of those patients, who have presented lymphopenia during at least 3months of treatment.

    188 patients were studied. 57 (30,31%) presented lymphopenia for more than three months. 42 (73,7%) were women. The average age was 44,05 (23-70), and 17 were older than 50 years. The mean time from the start of treatment to the onset of lymphopenia was 8.73 months (1-26). The grades of significant lymphopenia: Grade 2: 20 patients (35,1%); Grade 3: 24 patients (42,1%); Grade 4: 1(1,8%). The rate of lymphocytes no recovery was 82,50%. Because of safety reasons, DMF was withdrawn in 33 patients. Of the patients who recovered from lymphopenia, the average recovery time was 10 months (2-27) after withdrawal.

    In the real world analysis, one third of patients presented lymphopenia and from these patients more than a half had to stop the drug for risk of PML. Moreover, the recovery of the number of lymphocytes was very slow, and must be taken into account for the choice of the next disease modifying drug.

    • This abstract picks upon the sequencing of therapies. Given the prolonged recovery in white counts (on average 6 months in my experience), Teriflunomide is a holding option, although you have to wait for the lymphopenia to recover to a degree before commencing other treatments.

    • I promised myself not to keep droning on about lymphopaenia post interferon and dmf but to be consigned to the SPMS scrapheap at 45 with tlc 0.5 is no joke. That was 2.5 years ago, latest tlc 0.6, no chance of off-label cladribine 🙁

      Personal whinging aside, should less effective lymphocyte depleters be avoided if using them early on will preclude more effective treatments later? Especially as these less effective treatments must be depleting the 'wrong' lymphocytes forever more….

  • From what I see from patients experiences on fb, they change it due to effectiveness issues and not tolerance ones.

    I wonder how innocent this study is, being released a little before the expiring of the DMF patent together with the release of a very similar drug with less tolerance issues from Biogen. I suspect the two are connected.

    • Yes, there is marketing to consider…but I like to debate these things; there’s more to drug selection than simply relapse rate reduction. If the findings are not what you like to see/hear the data has a way of presenting itself!

  • I'm on DMF and haven't had any problems with it. My theory about the GI issues and flushing is that it's due to a candida die off. The idea being that DMF is a potent anti-fungal substance and that the common side effects are shared by people who do things like candida diets. Personally I try to eat a lot of unpasteurized fermented foods and avoid refined sugars.

  • I have been successfully self medicating with 98% dimethyl fumarate crystals for psoriasis and psoriatic arthropathy since December 2012. I experimented with the dosage and eventually found 800mg doses to be most effective. Twice weekly dosing with this amount was coincident with a lymphocyte count of 1 to 1.1 and excellent control of disease. However, from late August 2016 to mid December 2016, the count reduced from 0.9 to 0.6. Initially I believed the cause to be sun exposure, but despite dose reduction and sun avoidance, I was unable to increase the count above 0.9. Taking a range of supplements also proved fruitless, as did a four week break from dosing. The upshot was that I could only take one dose of 800mg weekly: While this controlled the psoriasis well, it was insufficient for the psoriatic arthropathy, so it was frustrating for me. An unexpected blood hemoglobin value after several weeks of increased exercise lead me to suspect a problem with iron. Three weeks and a few days of twice daily iron supplementation followed by thrice weekly iron supplementation was coincident with an increase in WBC count from 5.2 to 7.1 and an increase in lymphocytes from 0.88 to 1.28. I now take 800mg of dimethyl fumarate twice weekly and iron three times weekly. I will have another blood test in five weeks. It will be interesting to see whether the lymphocyte count is maintained.



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