Fumaric acid derivatives have strong effects on the immune system. They also help lower swelling and protect cells from damage. Dimethyl fumarate and monomethyl fumarate turn on Nrf2 and work with HCAR2. This helps control how immune cells act. This process helps treat psoriasis and multiple sclerosis. Studies show fewer CD4+ and CD8+ T-lymphocytes in psoriasis. They also show NF-κB is blocked in human cells. Nerve tissue stays healthy in multiple sclerosis models.
| Evidence Type | Description |
|---|---|
| Clinical Evidence | There are fewer CD4+ and CD8+ T-lymphocytes in psoriasis patients. This happens because of apoptosis. |
| In Vitro Evidence | DMF stops NF-κB from turning on TNF-α genes in human endothelial cells. This shows it lowers swelling. |
| Animal Model Evidence | Myelin and axonal density stay safe in mice with experimental autoimmune encephalomyelitis. This is linked to Nrf-2 being turned on. |
| Clinical Trial Evidence | A phase II trial in RRMS patients treated with DMF showed fewer gadolinium-enhancing lesions. This means DMF helps the immune system and protects nerves. |
Learning how fumaric acid works and how it acts in the body is important. This helps make treatment safer and work better.
Fumaric Acid Derivative Overview
Definition and Types
Fumaric acid derivatives are part of a group called dicarboxylic acids. Each one has two carboxylic acid groups and a double bond. Scientists can change these molecules by adding new chemical groups. For example, making esters creates dimethyl fumarate. Making salts gives fumarates with different features. These changes affect how the molecules act in the body and with other chemicals.
The main fumaric acid derivatives used in medicine are dimethyl fumarate, diroximel fumarate, and monomethyl fumarate. All of them have monomethyl fumarate as the active metabolite. Doctors use these for treating psoriasis and multiple sclerosis. Fumaderm is a mix of ethyl hydrogen fumarates and dimethyl fumarate. It is given to people with severe psoriasis. Fumaderm has been safe and helpful for many years.
Tip: Changing fumaric acid derivatives can help them dissolve better and work well in the body.
Clinical Uses in Psoriasis and Multiple Sclerosis
Doctors first gave fumaric acid esters to people with severe psoriasis. These medicines are taken by mouth and go into the small intestine. Later, scientists learned that dimethyl fumarate and other fumarates help control the immune system. This led to their use for multiple sclerosis, especially relapsing-remitting multiple sclerosis.
Studies show that fumaric acid esters lower swelling and protect nerve cells. In psoriasis, clinical trials found lower PASI scores after 12 to 16 weeks. The table below shows results from different studies:
| Study (year) | Study Design | Patient Population | Treatment Arms | Number of Patients | Duration (weeks) | Efficacy Results |
|---|---|---|---|---|---|---|
| Altmeyer et al (1994) | Multicenter double-blind RCT | Psoriasis with BSA <10% | FAE (Fumaderm) vs Placebo | 50 vs 50 | 16 | PASI reduced by 50% (from 21.6 to 10.8) |
| Dutch RCT (1990) | Placebo-controlled RCT | Psoriasis patients | FAE (Fumaderm), Octyl fumarate, Placebo | 39 total | N/A | 68% reduction in body surface area affected with Fumaderm |
| Gollnick et al (2002) | Multicenter double-blind RCT | Severe psoriasis | FAE (Fumaderm) + calcipotriol ointment vs FAE + placebo ointment | 68 vs 66 | 13 | PASI reduction 76.1% vs 51.9% |
| Fallah Arani et al (2011) | Multicenter RCT | Moderate-to-severe psoriasis (PASI <10) | FAE (Dutch formulation) vs MTX | 30 vs 30 | 12 | PASI reduction 42% (FAE), 54% (MTX) |
| Balak et al (2014) | Single center double-blind RCT | Moderate-to-severe psoriasis (PASI <10) | FAE + cetirizine vs FAE + placebo | 25 vs 25 | 12 | Mean PASI change ~65%, PASI-75 response 20% |
Doctors also use dimethyl fumarate to treat multiple sclerosis. In relapsing-remitting multiple sclerosis, studies showed fewer brain lesions and less disease activity. Dimethyl fumarate changes how immune cells act and lowers swelling. Scientists found that fumaric acid esters help protect nerve cells in animal tests. The long-term safety of fumaric acid esters in psoriasis supports their use in sclerosis.
- Fumaric acid derivatives have helped people with psoriasis and sclerosis for many years.
- Dimethyl fumarate is now an important medicine for multiple sclerosis.
- Fumarate compounds keep showing good safety and work well in studies.
Pharmacokinetics and Metabolism
Absorption and Bioavailability
Fumaric acid derivatives enter the body in special ways. Dimethyl fumarate is a common one. When you swallow it, it changes fast in your body. It turns into fumaric acid and its mono-methyl ester. Fumaric acid cannot get into cells well, so it mostly stays in your gut. The amount in your blood does not show how well it works or how long it lasts. These medicines work because of what happens in the gut and what their breakdown products do.
Many things affect how these medicines get into your body:
- How oily the molecules are changes how they are absorbed.
- Monoesters that are more oily go through the gut faster but break down quickly.
- Dimethyl fumarate can get into cells easily in lab tests, but it breaks down before it is absorbed.
- Enzymes in your gut, called methyl esterases, change dimethyl fumarate to monomethyl fumarate fast.
- Longer chains on the molecule make it more oily and easier to break down, which helps balance absorption.
- The length of the chain, how oily it is, gut enzymes, and how easy it is to cross the gut wall all matter for absorption.
Knowing these things helps us understand how these medicines work and why they help people.
Metabolic Pathways and Elimination
The body breaks down fumarate derivatives in different ways. Dimethyl fumarate and diroximel fumarate are prodrugs. They quickly turn into monomethyl fumarate, which is the active part. Monomethyl fumarate does not last long in the body, only about one hour. Most of it leaves the body as carbon dioxide when you breathe out, which is about 60% of the dose. The kidneys get rid of some, and only a little comes out in poop. Monomethyl fumarate goes through the tricarboxylic acid cycle and becomes carbon dioxide, fumaric acid, citric acid, and glucose. These steps show how the body handles these medicines.
There are three main ways the body breaks down fumarate derivatives:
- One way uses the citric acid cycle to change pyruvate to oxaloacetate, then to fumarate with malate dehydrogenase.
- Another way changes pyruvate to acetyl-CoA, then to succinate and fumarate with succinate dehydrogenase.
- The glyoxylate shunt changes isocitrate to succinate and glyoxylate, then to malate and fumarate.
These steps show how fumarate is part of cell energy and medicine actions.
Role of the Citric Acid Cycle
Fumarate is very important in the citric acid cycle. The enzyme fumarase changes fumarate to malate inside the mitochondria. This step is needed to make energy. Succinate dehydrogenase makes fumarate from succinate. This can go backward if there is not much oxygen, which changes NADH and ATP levels. Fumarate also helps in the purine nucleotide cycle, which connects energy making to other cell jobs. If fumarate metabolism does not work right, it can cause diseases like cancer. Too much fumarate can block some enzymes and keep HIF1α stable, which makes cells act abnormally.
Dimethyl fumarate and monomethyl fumarate join the citric acid cycle after they are broken down. They do not change the cycle enzymes directly. But they help cells by making antioxidant defenses stronger and keeping mitochondria healthy. These actions help cells handle stress and stay balanced. The table below shows how fumarate works in the citric acid cycle:
| Evidence Aspect | Description |
|---|---|
| Fumarate as an Intermediate | Fumarate is made again each time the citric acid cycle goes around, so it is part of metabolism. |
| Hydration Step | Fumarate changes to malate by adding water, which is important for making energy. |
| Anaplerotic and Cataplerotic Reactions | Adding or taking away fumarate changes oxaloacetate, which changes how much ATP is made. |
| Regulatory Role via HIF | Fumarate can block prolyl hydroxylases, which keeps HIF stable and connects metabolism to oxygen control. |
How fumarate derivatives work depends on how they fit into these cell pathways.
Mechanisms of Action
Fumaric acid esters work in cells in several ways. These ways help explain how they lower swelling, change the immune system, and protect cells. Knowing these actions helps us see why fumarate medicines help with psoriasis and multiple sclerosis.
Nrf2 Pathway Activation
The Nrf2 pathway helps keep cells safe from stress. Normally, Nrf2 is stuck to Keap1 in the cell fluid. This keeps Nrf2 turned off and ready to be broken down. Fumaric acid esters, like dimethyl fumarate and monomethyl fumarate, act on Keap1. They stick to cysteine groups on Keap1 and break the link to Nrf2. This lets Nrf2 move into the cell’s nucleus. Inside, Nrf2 joins other proteins and sticks to AREs in DNA. This turns on genes that fight stress and lower swelling.
Scientists saw that dimethyl fumarate turns on Nrf2 in nerve cells. This gives strong nerve protection. In animal tests, mice with more fumarate had more Nrf2 and better heart safety. Mice without Nrf2 did not get this help, even with treatment. In people with multiple sclerosis, dimethyl fumarate raises Nrf2 activity and helps protect nerves.
Note: Fumaric acid esters can turn on Nrf2 because of their special chemical nature. This helps boost the cell’s defenses.
NF-κB Inhibition
NF-κB is a protein that helps make many swelling signals. When it is turned on, it goes into the nucleus and starts genes that cause swelling. Fumaric acid esters, mostly dimethyl fumarate, stop this from happening. They block NF-κB from going into the nucleus and sticking to DNA. This lowers the making of signals like TNF-α, IL-6, and IL-1β.
Tests show dimethyl fumarate can block NF-κB in many cells. These include airway muscle cells, skin cells, T cells, and fibroblasts. In skin cells, dimethyl fumarate lowers swelling gene activity by blocking NF-κB. This way of stopping swelling does not need the Nrf2 pathway. This makes dimethyl fumarate different from other fumaric acid esters.
- Blocking NF-κB helps control immune cells and lowers swelling.
- This action helps fumarate medicines work in autoimmune diseases.
Glutathione Modulation
Glutathione (GSH) is a main cell protector. Fumaric acid esters, like dimethyl fumarate and diethyl fumarate, react with GSH. This makes GSH levels drop in the cell. When GSH drops, the cell makes more HO-1, a protein that fights swelling. Later, the Nrf2 pathway helps make more enzymes to bring GSH back up.
In brain cells, dimethyl fumarate first lowers GSH, then turns on Nrf2, which later raises GSH. This helps stop swelling and keeps cells safe. In T cells, less GSH means more ROS in mitochondria, which stresses the cell and can cause cell death. Giving extra GSH or its parts can stop these effects. This shows that GSH loss is key to how fumaric acid esters work. This explains why these drugs help the immune system and protect cells.
HCA2 Receptor Binding
The HCA2 receptor is found on many immune cells. After you take dimethyl fumarate, it changes to monomethyl fumarate. Monomethyl fumarate turns on HCA2. When this happens, Gi proteins are turned on. This lowers cAMP and slows down adenylate cyclase. This makes immune cells move less and lowers swelling.
Animal tests show that mice with HCA2 get less immune cell buildup and milder skin problems after dimethyl fumarate. Mice without HCA2 do not get these good effects. Turning on HCA2 also changes other cells, like fat cells, liver cells, and dendritic cells. In some cells, HCA2 stops NF-κB and lowers swelling signals. In dendritic cells, it raises IL-10 and helps regulatory T cells grow, which helps control the immune system.
| Cell Type / Tissue | Downstream Effects of HCA2 Activation by Fumaric Acid Esters | Signaling Pathways / Mechanisms |
|---|---|---|
| Adipocytes | Fat breakdown slows, so fewer fatty acids go into the blood. | Gi proteins slow adenylate cyclase, cAMP drops, PKA drops, HSL slows down. |
| Hepatocytes | Liver makes less new fat and stores less fat. | PKC-ERK signals, AMPK gets turned on, ACC slows down. |
| Intestinal Epithelial Cells (IECs) | NLRP3 inflammasome turns on, IL-18 is made, NF-κB is blocked. | NLRP3 turns on, NF-κB is blocked. |
| Macrophages | Less swelling, NF-κB is blocked, cells move less. | NF-κB is blocked, Gβγ signals are blocked, F-actin is blocked. |
| Microglia and Monocytes | Less swelling, NF-κB is blocked, fewer swelling signals (IL-6, TNFα, MCP-1). | NF-κB p65 is blocked. |
| Dendritic Cells (DCs) | IL-6 drops, IL-10 rises, RALDH1 goes up, more regulatory T cells. | Cytokines change, RA is made by RALDH1. |
| Neutrophils | More cell death happens by raising BAD. | PKA slows down, BAD goes up. |
| Retinal Pigment Epithelium | Can lower swelling or cause cell death, depending on dose. | Gi/cAMP/NF-κB lowers swelling, Gβγ/Ca2+/NOX4/ROS/JNK causes cell death. |
| Langerhans Cells | Skin flushing happens by making prostaglandins. | Gi turns on, Gβγ goes up, Ca2+ rises, PGD2 and PGE2 are made. |
All these actions together show why fumaric acid esters work so well. By turning on Nrf2, blocking NF-κB, changing glutathione, and using HCA2, these drugs lower swelling, change the immune system, and protect cells. These ways help explain why fumaric acid esters are safe and helpful in the clinic.
Effects on Cell Types
T Cells and Apoptosis
Fumarate changes how T cells act in autoimmune diseases. People with psoriasis or multiple sclerosis often have fewer T cells after taking fumarate. This happens because fumarate makes some T cells, like memory and CD8+ T cells, die by apoptosis. Dimethyl fumarate goes after active T cells and makes them die more easily. It does this by blocking the NF-κB pathway and lowering Bcl-2, a protein that helps cells live. This effect is stronger in T cells that are already working. So, fumarate can target the bad cells that cause autoimmune diseases. By removing these cells, fumarate helps people get better and lowers inflammation.
B Cells and Immune Modulation
B cells help the immune system by making antibodies and sending messages to other cells. Fumarate can change how B cells act. It lowers the number of some B cell types and makes them send out fewer signals that cause swelling. This helps balance the immune system and helps treat diseases like psoriasis. When B cells are less active, the body has fewer bad immune reactions. This means symptoms get better and there is less damage to tissues.
Keratinocytes in Psoriasis
Keratinocytes are skin cells that make a barrier to protect the body. In psoriasis, these cells grow too fast and send out signals that bring in immune cells. Fumarate can slow down how fast keratinocytes grow in lab tests. This helps lower the thick, scaly skin patches seen in psoriasis. By changing how keratinocytes act, fumarate helps skin get better and adds to its value as a treatment. Being able to target both immune and skin cells makes fumarate a good choice for treating psoriasis.
Endothelial and Other Cells
Fumarate also changes how endothelial cells work. These cells line blood vessels. Fumarate stops them from making molecules that help white blood cells stick and cause swelling. The table below shows some main ways fumarate acts on endothelial cells:
| Effect/Action | Description |
|---|---|
| Inhibition of adhesion molecules | Fumarate lowers VCAM-1, ICAM-1, and E-selectin, so fewer white blood cells stick. |
| NF-κB pathway inhibition | Fumarate blocks NF-κB, which means less swelling. |
| Anti-angiogenic effect | Fumarate lowers VEGFR-2, so new blood vessels grow slower. |
| Reduction of vascular inflammation | Fumarate lowers swelling in blood vessels and helps protect the heart. |
Fumarate also changes how neutrophils act. It makes them less active, lowers harmful molecules, and keeps them from moving into tissues. These actions help lower swelling and help people with autoimmune diseases feel better.
Note: Fumarate works on many cell types, which is why it helps with psoriasis and other diseases.
Dimethyl Fumarate and dimethylfumarate
Key Features and Differences
Dimethyl fumarate is special among fumaric acid esters. It has unique features and uses in medicine. Doctors use dimethyl fumarate for psoriasis and multiple sclerosis. In the body, it quickly changes to monomethyl fumarate. Monomethyl fumarate is the main active part. Other fumarate types, like diroximel fumarate, also change to monomethyl fumarate. But they have different side effects.
- Dimethyl fumarate is the main compound in most treatments.
- Diroximel fumarate was made to help with stomach comfort. It still causes some stomach problems, but less than dimethyl fumarate.
- Both dimethyl fumarate and diroximel fumarate are safe. Diroximel fumarate causes fewer days with bad stomach symptoms.
- Monoethyl fumarate does not work as well as dimethyl fumarate. Mixing it with dimethyl fumarate does not help and may cause more side effects.
Dimethyl fumarate often causes stomach problems. Some people stop taking it because of this. Lymphopenia means fewer white blood cells. Many people get this, and it links to feeling better. Dimethyl fumarate and other esters can change liver and kidney function. These changes are mild and go away.
Mechanisms in Treatment
Dimethyl fumarate works in the body in many ways. It turns on the Nrf2 pathway. This helps cells fight stress and lowers swelling. It also blocks the NF-κB pathway. This lowers signals that cause swelling. Dimethyl fumarate changes the immune system. It makes it less proinflammatory and more balanced. Monomethyl fumarate, the active part, can cross into the brain. It protects nerve cells. This makes dimethyl fumarate good for multiple sclerosis.
| Aspect | Dimethyl Fumarate / Monomethyl Fumarate | Other Fumaric Acid Esters |
|---|---|---|
| Clinical Use | Used for psoriasis and multiple sclerosis; strong effects in the central nervous system | Mainly used for psoriasis; less effect on the brain |
| Mechanism | Activates Nrf2, blocks NF-κB, shifts immune response, depletes and restores glutathione, activates HCAR2, crosses blood-brain barrier | Similar effects but less focus on brain protection |
| Immunomodulation | Reduces memory T cells, increases naïve T cells, lowers CD8 and CD19 cells | Immunomodulation present but less studied in the brain |
| Side Effects | Flushing, stomach issues, lymphopenia | Side effects vary; less is known about their mechanisms |
Dimethyl fumarate changes both metabolism and the immune system. It can reach the brain, which makes it different from other treatments. This wide action helps explain why dimethyl fumarate works well for psoriasis and multiple sclerosis.
Clinical Implications
Therapeutic Outcomes
Dimethyl fumarate works well for psoriasis and multiple sclerosis. Studies show patients often get much better. Many people see their symptoms drop a lot. Some studies show PASI scores go down by 22% to 86%. About half or more reach PASI-75 after 16 weeks. After 36 months, 82% of people have clear or much better skin. Studies show dimethyl fumarate works better than a placebo. The medicine changes the immune system from T-helper 1 to T-helper 2 cells. This helps lower swelling and makes treatment work well. Dimethyl fumarate also protects nerve cells, which is another good effect.
- Patients often get better quickly in their skin or nerves.
- Dimethyl fumarate keeps working well over time.
- Studies show it is a good choice for people with autoimmune diseases.
Safety and Adverse Effects
Most people do not have big problems with dimethyl fumarate. Some get side effects. The most common are stomach problems like nausea, diarrhea, and cramps. Many people also get flushing. Other mild effects are feeling tired, itchy skin, low white blood cells, and protein in urine. These problems usually start early and get better later. Studies show dimethyl fumarate is safe for most people. No big problems have been seen in large groups. The safety is about the same for different diseases like lupus and psoriasis.
Tip: Most side effects are mild and go away. Tell your doctor if you get new or bad symptoms.
Dose Escalation and Monitoring
Doctors give a small dose at first and raise it slowly. This helps stop side effects and makes the medicine work better. If a patient cannot take a higher dose, doctors lower it. When the patient gets better, the dose can go down to a steady level. Doctors check blood often during treatment. They look for low white blood cells. They also check liver, cholesterol, fat, and kidney health. If there are big problems, doctors may stop the medicine. Studies say this careful plan keeps people safe and helps the medicine work.
- Start with a small dose and raise it each week.
- Check blood and liver health often.
- Change the dose if needed for side effects or how the patient feels.
Fumaric Acid Derivative Treatment in Practice
Protocols and Preparations
Doctors often pick dimethyl fumarate first for psoriasis and multiple sclerosis. They use a clear plan to help patients get good results. Most plans start with a small dose of dimethyl fumarate. The dose goes up slowly over weeks. This helps lower stomach problems and flushing. Patients take the medicine by mouth, usually with food to help with side effects.
A common plan looks like this:
- Begin with a small dose, like 120 mg once or twice a day.
- Raise the dose each week until reaching the main dose, usually 240 mg two times a day.
- Watch for side effects and change the dose if needed.
Doctors do blood tests before and during treatment. They check for changes in white blood cells and liver health. This careful way helps keep patients safe and helps them get better.
Tip: Eating food with dimethyl fumarate can help stop stomach pain.
Patient Considerations
Each person reacts differently to this kind of treatment. Doctors think about age, other health issues, and past problems with medicine. Some people need a slower dose increase if their stomach is sensitive. Regular visits help see how well the medicine works and find side effects early.
Dimethyl fumarate helps many people with psoriasis. It also helps people with multiple sclerosis feel better in their nerves. Patients should tell their doctor about any new symptoms. Talking with the doctor helps make treatment work better.
Doctors may change to another treatment if the medicine does not help or if side effects are too strong. They always try to find the safest and best plan for each patient.
Fumaric acid derivatives help cells by starting antioxidant pathways and stopping inflammation. These effects help people with diseases like psoriasis and multiple sclerosis. Dimethyl fumarate changes into a form that protects nerves and lowers attacks from the immune system. Scientists are working to make these medicines easier to use and safer for long-term treatment. New research looks at how these drugs might help other autoimmune diseases and cancer.
