A Narrative Review of the Immunomodulatory Effects of Acthar® Gel Beyond Its Steroidogenic Properties

Corticosteroids have long been a standard-of-care treatment for chronic immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, corticosteroids are associated with potentially serious adverse effects and may be ineffective in cases of resistant or refractory disease. Acthar® Gel, a naturally sourced complex mixture of porcine pituitary peptides, is a noncorticosteroid alternative that is approved by the US Food and Drug Administration to treat a variety of IMIDs and autoimmune conditions. These include infantile spasms, systemic lupus erythematosus, exacerbations of multiple sclerosis and rheumatoid arthritis, and several ocular inflammatory disorders. Preclinical and clinical studies have shown that the immunomodulatory effects of Acthar Gel are distinct from those of corticosteroids and other adrenocorticotropic hormone (ACTH)–class therapeutics. For example, Acthar Gel stimulates both steroid-dependent and steroid-independent pathways that may mitigate inflammation. In this narrative review, we summarize the immunomodulatory effects of Acthar Gel, with a focus on its potential mechanisms in immune cells, such as B cells, T cells, and macrophages. These effects are thought to be mediated by binding and activation of transmembrane melanocortin receptors expressed on these immune cells. Receptor binding initiates an intracellular signal transduction cascade that ultimately regulates the expression of anti-inflammatory genes. Collectively, the experimental and clinical studies reviewed here suggest that Acthar Gel acts as an immunomodulator via melanocortin receptors and may be an effective anti-inflammatory therapeutic option for patients with IMIDs who are refractory or intolerant to corticosteroids. Graphical Abstract available for this article. Steroids, also known as corticosteroids, are medications that can help reduce inflammation and treat diseases where the body’s immune system mistakenly attacks its own healthy tissue, such as rheumatoid arthritis and multiple sclerosis. However, treatment with corticosteroids can cause harmful or unwanted side effects and may not work well for some patients. Acthar® Gel is an alternative to corticosteroids that is approved by the US Food and Drug Administration to treat diseases that affect the immune system, including infantile spasms, systemic lupus erythematosus, flare-ups of multiple sclerosis and rheumatoid arthritis, and certain eye inflammations. Research studies have shown that Acthar Gel’s mechanism of action is distinct from corticosteroids, with both direct activity on immune cells and induction of low levels of natural corticosteroids produced by the body. This review paper summarizes the effect of Acthar Gel on immune system cells, such as B cells, T cells, and macrophages, and how this treatment interacts with specific targets called melanocortin receptors on these immune cells. This interaction initiates a series of signals inside the cells that ultimately reduce inflammation. The research studies discussed in this review paper suggest that Acthar Gel helps regulate the immune system by acting on the melanocortin receptors. Acthar Gel may be an appropriate treatment option to help reduce inflammation for patients with immune system diseases who are unresponsive or unable to receive corticosteroids.

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