Major Research Findings

Monomethyl fumarate (MMF), a metabolite of dimethyl fumarate (DMF), is a potent agonist for hydroxycarboxylic acid receptor 2 (HCAR2), which plays a role in both suppressing cell activation and inducing inflammation. 1 MMF has shown better gastrointestinal tolerability compared to DMF. 2 Both DMF and MMF have the potential to treat various diseases like multiple sclerosis (MS), cancer, and others by enhancing antioxidant pathways and inhibiting reactive oxygen species. 4 DMF and its metabolite, methylhydrogenfumarate (MHF), have been shown to enhance antibacterial superoxide-anion generation in human monocytes, suggesting their role in innate immune defense against microorganisms. 5 6

Reasons for Side Effects

Electrophilic compounds like DMF can lead to severe systemic side effects due to non-specific S-alkylation of cysteine thiols, causing glutathione depletion. 3 Therefore, understanding the balance between therapeutic effects and side effects is crucial for DMF treatment.

Common Side Effects

Gastrointestinal

The primary side effects of DMF are related to the gastrointestinal system. 3 Nausea, vomiting, diarrhea, and abdominal pain are commonly reported. 2 MMF is considered to have better gastrointestinal tolerability compared to DMF. 2

Skin

DMF can cause skin redness, rash, and itching. 1 This is attributed to inflammatory responses mediated by HCAR2. 1

Immune System

DMF may cause lymphopenia. 5 This is thought to be due to DMF's ability to suppress immune cell activity. 4 However, DMF has also been shown to enhance antibacterial superoxide-anion generation in monocytes. 5

Side Effect Management

Gastrointestinal

Dietary and pharmacological approaches can be used to mitigate gastrointestinal side effects. 2 Dietary changes include consuming easily digestible foods and increasing meal frequency. 2 Pharmacotherapy may involve antiemetics and antidiarrheals. 2

Skin

Steroid ointments are used to reduce skin side effects. 1

Immune System

Immunosuppressants are employed to manage immune system side effects. 5

Comparison Across Studies

Commonalities

Several studies suggest that DMF and its metabolite MMF have potential therapeutic value for various diseases, including MS, by enhancing antioxidant pathways and inhibiting reactive oxygen species. 4

Differences

There are differences in the gastrointestinal tolerability of DMF and MMF, with MMF demonstrating better tolerance. 2 DMF has been shown to induce skin inflammation through HCAR2. 1

Considerations for Real-Life Applications

DMF is an approved treatment for MS and should be taken under the guidance of a doctor. 3 Side effects of DMF vary among individuals, so it's essential to consult with a doctor and receive appropriate treatment. 3

Current Research Limitations

There are still many unanswered questions regarding the mechanisms of action and side effects of DMF and MMF, necessitating further research. 3

Future Research Directions

Future research should focus on elucidating the mechanisms of action of DMF and MMF in detail and developing new drugs that can reduce side effects. 3 Clinical trials are also needed to assess the safety and efficacy of DMF and MMF. 3

Conclusion

DMF and MMF hold promise as therapeutic agents for various diseases, including MS. 4 However, DMF can cause side effects affecting the gastrointestinal system, skin, and immune system. 3 Side effects of DMF can vary among individuals, so it's crucial to consult with a doctor and receive appropriate treatment. 3 Future research should focus on thoroughly understanding the mechanisms of action of DMF and developing new drugs that minimize side effects. 3