On March 8, 2023, Nature released a new paper titled "Macrophage fumarate hydratase restrains mtRNA-mediated interferon production." Researchers from Trinity College Dublin in Ireland and the University of Cambridge in the United Kingdom have achieved a crucial breakthrough in understanding how the body changes throughout the development of inflammatory disorders, identifying a possible new therapeutic target in the process.

These researchers discovered that the enzyme fumarate hydratase is blocked in macrophages. Macrophages are an inflammatory cell type that has been linked to a number of disorders such as lupus, arthritis, sepsis, and COVID-19.

"No one has previously linked fumarate hydratase to inflammatory macrophages, and we feel that targeting this process may treat debilitating diseases such as lupus," said Luke O'Neill, co-corresponding author of the paper and professor of biochemistry at Trinity College Dublin. Lupus is a nasty autoimmune disease that damages multiple parts of the body, including the skin, kidneys, and joints.

The most prevalent kind of lupus and autoimmune disease is systemic lupus erythematosus (SLE), in which the immune system attacks its own tissues, producing extensive inflammation and tissue destruction in the afflicted organs. It affects the joints, the skin, the brain, the lungs, the kidneys, and the blood vessels. Patients have symptoms such as fatigue, skin rashes, fevers, and joint discomfort or swelling. For some people, flares of SLE symptoms may occur often, sometimes even years apart, and then disappear at other times (called remission). Some people, on the other hand, have SLE flares more regularly throughout their lives. SLE also causes sun sensitivity, mouth ulcers, arthritis, lung issues, heart problems, renal problems, seizures, psychosis, and blood cell and immunological abnormalities. The causes of SLE are unclear. However, it is widely assumed that environmental, genetic, and hormonal factors are involved. SLE may vary in severity from mild to life-threatening.

In models of sepsis, it was shown that fumarate hydratase was inhibited. Sepsis is a systemic inflammatory condition that may develop as a result of bacterial or viral infections, and it often results in fatalities. Similarly, there is a significant decrease in the amount of the enzyme fumarate hydratase seen in blood samples taken from lupus patients. Therefore, restoring fumarate hydratase or targeting melanoma differentiation-associated protein 5 (MDA5) or toll-like receptor 7 (TLR7) in these disorders provides great potential for much-needed novel anti-inflammatory drugs, according to Professor O'Neill.

The most commonly used medications currently available, including small molecules and monoclonal antibodies, are:

Nonsteroidal anti-inflammatory drugs (NSAIDs) like naproxen sodium (Aleve) and ibuprofen (Advil, Motrin IB, and others) can be used to treat lupus-related pain, edema, and fever.
Antimalarial drugs, such as hydroxychloroquine (Plaquenil), have an effect on the immune system and can reduce the risk of lupus flares.
Corticosteroids. Prednisone and other corticosteroids can alleviate the inflammation caused by lupus.
Immunosuppressants. In severe cases of lupus, immunosuppressive drugs are beneficial. These drugs include azathioprine (Imuran, Azasan), mycophenolate mofetil (CellCept), and methotrexate. (Trexall).
Biologics. Intravenous administration of Belimumab (Benlysta) reduces lupus symptoms in some patients. Rituximab (Rituxan) is advantageous in cases of lupus resistance.