Dimethylfumarat: Oral Immunomodulator in Multiple Sclerosis and Psoriasis
Dimethylfumarat (DMF) is an orally available immunomodulator. In Europe, the active substance was initially approved in 1994 under the name Fumaderm for moderate to severe plaque psoriasis, and since 2014 it has been available as Tecfidera (Biogen) for the treatment of relapsing remitting multiple sclerosis (RRMS). Generic formulations and the salt form dimethylfumarat (Vumerity) have been added later.
Dimethylfumarat has changed the MS treatment landscape because it represents an effective oral first line therapy that patients can use without injections or infusions. The efficacy against relapses and disability progression is between classical interferon beta preparations and highly effective therapies such as natalizumab or ocrelizumab. In psoriasis, DMF is an established systemic option, especially in patients with comorbidities who cannot receive biologics.
Mechanism of Action
Dimethylfumarat is a methyl ester of fumaric acid and is rapidly hydrolyzed in the intestine by esterases to monomethylfumarat (MMF), the actual active metabolite. MMF activates the transcription factor Nrf2 (Nuclear Factor Erythroid 2 related factor 2), which switches on numerous antioxidative and cytoprotective genes. The result is a reduction of oxidative damage in cells and a modulated immune response.
Furthermore, DMF shifts the Th1 and Th17 dominated proinflammatory immune response towards a Th2 dominated antiinflammatory reaction. Blood lymphocyte count typically decreases by 20 to 40 percent, with a more pronounced reduction in CD8 positive T cells. This lymphopenia is clinically relevant because it increases the risk of opportunistic infections, particularly progressive multifocal leukoencephalopathy (PML) through JC virus reactivation.
Pharmacokinetically, DMF is rapidly metabolized to MMF. Half-life of MMF approximately one hour, but the effect persists much longer through downstream gene activation. Elimination predominantly pulmonary as CO2 after further metabolism.
Applications
- Relapsing Remitting Multiple Sclerosis (RRMS): First line therapy
- Moderate to Severe Plaque Psoriasis: in adults when topical therapy is insufficient
- Off-label: sarcoidosis, cutaneous lupus erythematosus, granuloma annulare
Dosage and Administration
Multiple Sclerosis: Titration over 7 days from 120 mg twice daily to 240 mg twice daily (maintenance dose). Taking with fatty meals reduces gastrointestinal side effects and flushing considerably.
Psoriasis: Titration schedule starting from 30 mg daily in the first week to 720 mg daily in the ninth week, then individual dose adjustment. Often lower maintenance doses.
Renal Insufficiency and Hepatic Insufficiency: caution and possible dose adjustment in moderate to severe functional impairment.
Side Effects
Very common: flushing (hot flushes with skin reddening) especially in the first weeks, gastrointestinal complaints including nausea, abdominal pain, diarrhea, usually improving over time. Lymphopenia.
Common: pruritus, skin rash, increase in liver transaminases, proteinuria, eosinophilia.
Serious, Rare: progressive multifocal leukoencephalopathy (PML) from JC virus reactivation with prolonged lymphopenia below 500 lymphocytes per microliter, opportunistic infections, lymphomas (rare), acute liver damage, anaphylactic reactions.
Important: in prolonged severe lymphopenia (lymphocytes below 500 per microliter for longer than six months), therapy discontinuation should be considered as the PML risk increases significantly.
Drug Interactions
- Other Immunosuppressive Agents: additive infection and lymphopenia risk, avoid combination
- Live Vaccines: contraindicated during therapy
- Aspirin (325 mg before administration): can reduce flushing, clinically relevant in the first weeks
- Hepatotoxic Agents: additive liver damage, regular monitoring of liver transaminases
- Other Fumarates (Methyl Hydrogen Fumarate, Calcium Fumarate): additive effects, avoid combination
Special Precautions
Pregnancy: Data on the use of DMF in pregnancy are limited, animal data show no definite teratogenicity, nevertheless use in pregnancy is recommended only after strict indication assessment. Reliable contraception is recommended, MS patients with desire for children should discuss therapy individually with their neurologist. Breast-feeding: not recommended as MMF passes into breast milk.
Before Starting Therapy: blood count with differential, liver transaminases, creatinine, urinalysis. In preexisting lymphopenia below 800 per microliter, the indication should be critically reconsidered.
Monitoring: blood count and liver transaminases every 3 months. With lymphopenia below 500 per microliter, more intensive monitoring, if persistence persists for 6 months therapy review. Patients must be informed about warning signs of PML (cognitive changes, motor deficits, visual symptoms).
Flush Management: the characteristic flushing in the first weeks is usually mild and disappears after 4 to 8 weeks. Taking with fatty meals, slow titration, and 325 mg aspirin 30 minutes before the dose can help.
You May Also Be Interested In
- Teriflunomide, further oral MS therapy
- Glatiramer Acetate, parenteral MS base therapy
- Ocrevus, Ocrelizumab as highly effective MS therapy
- Methotrexate, classical psoriasis system therapy
- Adalimumab, TNF antibody in psoriasis
Frequently Asked Questions
What is flushing and how long does it last?
Flushing is a hot flush with skin reddening, often on the face and upper body, sometimes with pruritus or burning. It occurs in many patients in the first weeks after taking DMF, usually within 30 to 60 minutes and lasting one to two hours. Flushing typically improves after 4 to 8 weeks. Aspirin 325 mg 30 minutes before the dose and taking with fatty meals reduce the severity.
What is PML and why must I pay attention to it?
Progressive multifocal leukoencephalopathy is a rare but potentially fatal brain infection caused by JC virus, which remains inactive with a normal immune system but can reactivate with lymphopenia. Symptoms include cognitive decline, speech disorders, motor deficits, visual disturbances, often gradual in onset. With any new neurological symptoms during DMF therapy, immediate neurological evaluation with MRI is required.
How quickly does DMF work in Multiple Sclerosis?
DMF reduces the annual relapse rate in registration studies (DEFINE, CONFIRM) by approximately 45 to 50 percent compared to placebo. Initial efficacy assessment occurs after 6 to 12 months based on clinical relapses and MRI. Efficacy is comparable to glatiramer acetate and interferon beta, while highly effective therapies such as natalizumab and ocrelizumab are more effective in more active disease.
Can I take DMF when planning pregnancy?
With desire for children, therapy is discussed individually with the neurologist. DMF is not sufficiently studied in pregnancy, animal data show no definite teratogenicity. In practice, DMF is often paused or switched to other therapies when planning pregnancy, if the disease allows.
Sources
- EMA, Tecfidera (Dimethylfumarat) EPAR
- DGN Guideline Multiple Sclerosis
- Gelbe Liste, Dimethylfumarat Active Substance Profile
- BfArM, Federal Institute for Drugs and Medical Devices
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