Patients with sarcoidosis have a hyperactive immune system that leads to widespread inflammation. The hallmark of sarcoidosis is the appearance of clumps of white blood cells, called granulomas, that can interfere with the function of the organs and tissues in which they develop, particularly the lungs, but also lymph nodes, skin, and eyes.

Immunosuppressants are a class of medications that can help dampen the immune response and relieve the symptoms of sarcoidosis.

How immunosuppressants work

Several components of the immune system, such as certain white blood cells called T-cells, are abnormally activated in sarcoidosis. Activated T-cells stimulate the production of cell-signaling molecules that promote inflammation, such as interleukin (IL)-2, interferon-γ, and tumor necrosis factor (TNF)-α.

Corticosteroids, such as prednisone, are typically the first-line therapy for treating inflammation in acute and chronic sarcoidosis. However, these medications are associated with many side effects when used over long periods. Immunosuppressants can be an alternative way of reducing immune system activity. Because they allow patients to lower their corticosteroid doses, these medications are also known as corticosteroid-sparing agents.

Types of immunosuppressants

Different types of immunosuppressants function in different ways. These include calcineurin inhibitors that block immune cell activation, antimetabolites that stop immune cells from multiplying, alkylating agents that destroy immune cells, and anti-TNF-α therapies that block the action of cell-signaling molecules that promote inflammation.

Calcineurin inhibitors

Calcineurin is a protein that is involved in activating T-cells and in the production of IL-2. By binding to calcineurin, calcineurin inhibitors can reduce the levels of these inflammatory molecules in sarcoidosis.

Cyclosporine is a calcineurin inhibitor usually used to treat ocular sarcoidosis.

Antimetabolites

Anti-metabolite medications generally work by preventing normal DNA synthesis, either directly or indirectly. Immune cells that are not able to make new DNA stop multiplying; fewer of these immune cells result in a less robust inflammatory response.

Imuran (azathioprine), Arava (leflunomide), and Cellcept (mycophenolate mofetil) interfere directly with DNA synthesis. Methotrexate works indirectly by preventing the action of an enzyme known as dihydrofolate reductase, which in turn stops production of folic acid, which is essential for DNA synthesis. These four antimetabolites are the most commonly used corticosteroid-sparing agents for sarcoidosis patients.

Alkylating agents

Cyclophosphamide is a type of chemotherapy that is usually reserved for people with severe sarcoidosis, because of its high risk of serious side effects. It binds directly to DNA, replacing key DNA molecules with alkyl molecules. This stops DNA from being read and proteins from being made, eventually causing the cell to die (a benefit in cancers). Immune cells are particularly sensitive to the effects of cyclophosphamide.

Anti-TNF-α therapies

Anti-TNF-α therapies work by specifically blocking the production of TNF-α, a key inflammatory cell-signaling molecule involved in the development and maintenance of granulomas in sarcoidosis.

Remicade (infliximab) and Humira (adalimumab) are two TNF-α inhibitors commonly used to treat sarcoidosis.

Further details

Most immunosuppressants need to be taken regularly for several months before any effects are observed.

Suppressing the immune response leaves the body vulnerable to certain types of infections, known as opportunistic infections. These are caused by microbes that ‘take advantage’ of the weakened immune state and can develop anywhere, including the lungs and skin.

Other general side effects of immunosuppressants are an increased risk of heart disease, reduced blood counts, and malignancies. Patients taking immunosuppressants are usually monitored closely to watch for the occurrence of side effects.

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