Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis

Abstract

Acute and subacute inflammation, the mechanisms by which demyelination and axonal loss occur in multiple sclerosis (MS), result from the migration of activated immune cells into the central nervous system parenchyma. The triggering antigen is unknown, but the process involves deregulated immune response of T and B lymphocytes, macrophages, and mediators with expansion of autoreactive T cells creating a shift in the balance of pro- and anti-inflammatory cytokines favoring inflammation. Ongoing disease activity and exacerbations early in the course of relapsing-remitting MS may prevent full remission and propagate future progressive disability. A key strategy of immune therapy is timely initiation of treatment to achieve remission, followed by maintenance of remission. In this context, treatment with high-dose methylprednisolone (MP) is currently recommended to induce a faster recovery from a clinical exacerbation that results from an acute inflammatory attack. Adrenocorticotropic hormone (ACTH or corticotropin) gel is an alternative for patients who do not respond to or do not tolerate corticosteroids. ACTH is a universal agonist in the melanocortin (MC) system and, as such, among other functions, stimulates the adrenal cortex to produce cortisol. MCs are a family of peptides that includes ACTH and other MC peptides. This system has five classes of receptors, all of which show a strong affinity for ACTH, suggesting a more complex and dynamic mechanism than only inducing endogenous corticosteroid production. ACTH and MCs regulate processes relevant to MS, including anti-inflammatory and immunomodulatory functions involving lymphocytes, macrophages, the sympathetic nervous system involved in inflammatory processes, and reduction of pro-inflammatory cytokines. The clinical implications of the mechanistic differences between corticosteroid and ACTH gel treatment remain to be elucidated. Recent data show that patients experiencing an acute exacerbation, who previously had suboptimal response to or were unable to tolerate MP treatment, showed positive clinical outcomes with fewer adverse events with ACTH gel.

Keywords: ACTH; adrenal cortex hormones; melanocortins; multiple sclerosis/immunology; multiple sclerosis/therapy.

Figure 1.

Cytokine imbalance in MS. The healthy immune system maintains a balance between pro- and anti-inflammatory cytokines, whereas individuals with MS have an imbalance of cytokines related to increased Th1 immune response and decrease in Th2/Treg function characterized by increased expression of pro-inflammatory cytokines IFN-γ, IL-12, TNF, and IL-17. IFN, interferon; IL, interleukin; MS, multiple sclerosis; TGF, tumor growth factor; TNF, tumor necrosis factor; Treg, regulatory T cells. Adapted from Boppana et al. [2011]. Reprinted with permission. Glatiramer acetate and interferon-B enhance Treg function and help to restore the imbalance between pro-inflammatory and anti-inflammatory cytokines.

Figure 2.

Physician-reported response of patients to ACTH after failing treatment with MP. Categorization of response is based on clinical evaluation of each patient after treatment with ACTH. Reproduced with permission from Berkovich et al. [2012].