Melanocortin system
Immune effects of ACTH-MCR interactions
ACTH vs. steroids
Commentary by Dr. Daniel Selchen, University of Toronto, Canada
NeuroSens Survey
A few decades ago, adrenocorticotropic hormone (ACTH) was routinely used for managing acute relapses in patients with multiple sclerosis. The efficacy of this approach was demonstrated in what was perhaps the first multicentre placebo-controlled study in MS, which also introduced the Disability Status Scale (DSS) as an endpoint (Rose et al. Trans Am Neurol Assoc 1969;94:126-133).
Subsequent studies comparing ACTH to intravenous methylprednisolone (IVMP) found that the two therapies provided similar benefits (Abbruzzese et al. Ital J Neurol Sci 1983;4:169-172; Thompson et al. Neurology 1989;39:969-971).A Cochrane analysis of six trials concluded that both ACTH and IVMP improved recovery after an acute MS relapse within the first five weeks (odds ratio 0.37 for both), and reduced EDSS scores in the week following treatment (mean -1.47) (Filippini et al. Cochrane Database Syst Rev 2000;(4):CD001331). A separate meta-analysis found that both ACTH and corticosteroids improved disability and visual acuity in patients with MS or optic neuritis in the 30 days post-relapse (Brusaferri & Candelise. J Neurol 2000;247:435-442).
IVMP became more widely used for acute relapses due to a shorter treatment course and other factors. Ease of administration was further improved following a pooled analysis of steroid trials, which found that oral and IV administration provided comparable benefits with respect to time to recovery, hospitalization and ambulation (Burton et al. Cochrane Database Syst Rev 2009 Jul 8;(3):CD006921). While the optimal steroid dosing has not been determined, the usual regimen for acute relapses is IVMP 500-1000 mg/day for 3-5 days, or oral prednisone 1000-1250 mg/day for five days (National MS Society 2008). In Canada, a five-day course is most commonly used, according to a survey of the Canadian Network of MS Clinics (Morrow et al. Can J Neurol Sci 2009;36:213-215).
In light of more recent studies, the option of ACTH may be re-considered for the treatment of acute relapses in patients with a poor response/tolerability with a corticosteroid. A long-acting synthetic ACTH formulation (Synacthen Depot) is approved in Canada. The typical dosing is 0.5-1.0 mg intramuscular (IM) twice-weekly or 1 mg IM for three days for acute relapses, with maintenance dosing of 0.5-1.0 mg IM every 2-3 days, as needed.
The use of ACTH as an alternative to corticosteroids was initially based on the assumption that the anti-inflammatory activity of ACTH was due primarily to its corticotrophic effects. However, more recent findings show that ACTH retains its anti-inflammatory effects in adrenalectomized rats, which has drawn attention to an additional cortisol-independent mechanism of action (Getting et al. Arthritis Rheum 2002;46:2765-2775). A further observation was that the efficacy of ACTH in conditions such as infantile spasms and opsoclonus-myoclonus could not be explained by ACTH’s corticotrophic effects (Stafstrom et al. J Child Neurol 2011;11:1411-1421; Pranzatelli et al. Pediatr Neurol 2005;33:121-126). These observations led to the investigation of the immunomodulatory effects of melanocortins and their role in MS.
Melanocortin system
The melanocortin (MC) system is involved in eye/skin pigmentation, regulation of immune modulation, body weight and blood pressure (Montero-Melendez T. Semin Immunol 2015; epublished February 25, 2015). MCs, such as ACTH and melanocyte stimulating hormone (MSH, -alpha, -beta, -gamma), are derived from the prohormone pro-opiomelanocortin (POMC). POMC deficiency may be associated with childhood-onset obesity, adrenal insufficiency, and red hair (Challis & Millington. Gene Reviews 2013; Dec. 12, 2013). Five receptor subtypes (MC1-5R) have been identified ((Mountjoy et al. Science 1992;257:1248-1251). ACTH is the only peptide that interacts with all five MCR subtypes. Steroidogenic effects are due to its interaction with MC2R (also called the ACTH receptor).
Immune effects of ACTH-MCR interactions
Of particular importance to MS is MCR expression on immune cells such as Th1 cells, monocytes and glial cells (MC1R), macrophages (MC2R, MC3R), and B cells (MC1R, MC2R, MC3R) (reviewed in Ross et al. Front Neurol 2013;4:21; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3591751/pdf/fneur-04-00021.pdf).
In vitro studies have demonstrated that ACTH and other MC peptides reduce production of inflammatory cytokines/chemokines, such as IL-1, IL-8, and tumour necrosis factor (TNF)-alpha (Delgado et al. J Leukoc Biol 1998;63:740-745; Taherzadehetal et al. Am J Physiol 1999;276:R1289-1294). IL-1β has been proposed as a link between inflammation and neurodegeneration due to the correlation of IL-1β in CSF with cortical lesion load (Seppi et al. J Neuroimmunol 2014;270:56-60). Elevated levels of IL-8 and TNF-alpha have been observed in primary-progressive MS (Ukkonen et al. Mult Scler 2007;13:701-707; Rossi et al. Mult Scler 2014;20:304-312). Moreover, ACTH has been shown to induce expression of regulatory T cells (Tregs) in experimental autoimmune encephalomyelitis (EAE) (Brod & Hood. J Neuroimmunol 2011;232:131-135). This effect may be mediated through the modulation of MC5R on activated T cells (Taylor & Namba. Immunol Cell Biol 2001;79:358-367).
Anti-inflammatory effects may also be due to inhibition of cytokines (e.g. IL-8) that induce nuclear factor (NF)-kappaB signalling, as demonstrated in a murine model of acute brain inflammation (Ichiyama et al. Brain Res 1999;836:31-37). NF-kappaB inhibition has also been proposed as one of the mechanisms of action of disease-modifying therapies used in MS, such as teriflunomide and dimethyl fumarate (Manna et al. J Immunol 1999;162:2095-2102; di Nuzzo et al. Drug Des Devel Ther 2014;8:555-568; Loewe et al. J Immunol 2002;168:4781-4787).
A less explored area is the role of the sympathetic nervous system (SNS) in MS. Lymphocytes, macrophages and microglia express beta-adrenergic receptors (Schorr & Arnason. Brain Behav Immun 1999;13:271-278), and beta-adrenergic agonists have been shown to inhibit macrophages and suppress experimental autoimmune encephalomyelitis (EAE) (Wiegmann et al. J Neuroimmunol 1995;56:201-206). SNS modulation was explored in a pilot study of the beta-agonist albuterol as add-on therapy to glatiramer acetate, which showed significant improvement in one-year outcomes (Khoury et al. Arch Neurol 2010;67:1055-1061; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2954052/pdf/nihms240840.pdf). ACTH potentiates SNS pathways, increases norepinephrine synthesis in the CNS and modulates the release of other neurotransmitters, which inhibits microglial activation and release of nitric oxide (Chang et al. Brain Res Bull 2000;52:525-530).
More recent studies have investigated the in vitro effects of ACTH on oligodendrocyte proliferation and survival. In a study of rat brain cultures incubated with cytotoxic agents, ACTH demonstrated dose-dependent effects on glial cell survival, reducing oligodendrocyte death by 30-60% (Benjamins et al. Glia 2013;61:1206-1217). ACTH effects appeared to be mediated by MC4R receptors on oligodendrocytes. The authors subsequently reported that ACTH promoted the proliferation and differentiation of oligodendrocyte progenitor cells (Benjamins et al. J Neurosci Res 2014;92:1243-1251).
These results may explain in part the observation two decades ago that an induction regimen of ACTH/cyclophosphamide with periodic boosters produced significant stabilization for up to 30 months in younger patients with progressive MS (Weiner et al. Neurology 1993;43:910-918). In contrast, two trials of cyclophosphamide alone or in combination with oral prednisone failed to demonstrate any benefit in progressive MS (Likosky et al. J Neurol Neurosurg Psychiatry 1991;54:1055-1060; Canadian Cooperative Multiple Sclerosis Study Group. Lancet 1991;337:441-446). In a recent review of immunosuppression trials, the authors of the ACTH/cyclophosphamide study stated that their positive results may be largely attributable to patient selection, notably a higher proportion of patients with inflammatory disease activity (Stankiewicz et al. Neurotherapeutics 2013;10:77-88). A further difference, however, was the use of ACTH rather than prednisone as add-on therapy. This raises the intriguing suggestion that the MCR-mediated immunomodulatory effects of ACTH on glial cells rather than its corticotrophic effects may have clinical relevance.
While the potential neuroprotective effects of ACTH have not been firmly established, a recent review concluded that there was a need for additional studies of ACTH in RRMS or secondary-progressive MS (SPMS) (Arnason et al. Mult Scler 2013;19:130-136; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3573675/pdf/10.1177_1352458512458844.pdf). A phase II trial of pulsed ACTH therapy in progressive MS is currently recruiting subjects. A phase IV study is also investigating the impact of ACTH versus IVMP on axonal injury and retinal nerve fibre layer (RNFL) thickness in patients with optic neuritis.
ACTH vs. steroids
Emerging evidence of the effects of ACTH on the melanocortin system have prompted a reappraisal of its potential benefits in MS. While corticosteroids and ACTH are generally viewed as comparable in overall efficacy, the unique MC-mediated effects of ACTH provide a rationale for its use in patients with an inadequate response to steroids. ACTH may also be more acceptable to patients who cannot tolerate steroids. Side effects of both agents may include fluid retention, alterations in glucose metabolism, blood pressure changes, infections and weight gain.
In contrast to steroids, ACTH stimulates MC2R on osteoblasts and promotes osteoblast differentiation, which may be associated with a lower risk of osteoporosis and avascular necrosis (Arnason 2013).As a result, ACTH may also be a suitable alternative for patients at risk of osteoporosis due to frequent or prolonged steroid exposure.
Studies are now investigating the effect of ACTH in MS fatigue, and whether the melanocortin effects of ACTH improve recovery from cognitive dysfunction associated with MS relapse. For patients with MS relapse, ACTH remains an interesting and viable treatment alternative to oral or IV steroids.
For recent reviews see Berkovich R, Agius MA. Ther Adv Neurol Disord 2014;7:83-96, free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3932770/pdf/10.1177_1756285613518599.pdf; and Berkovich R. Neurotherapeutics 2013;10:97-105, free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3557364/pdf/13311_2012_Article_160.pdf.
Comment
Dr. Daniel Selchen: ACTH was once standard therapy for MS relapses. It was subsequently superseded by oral prednisone and IV methylprednisolone (and high-dose oral steroids) because of convenience rather than efficacy as ACTH was administered IM for up to 14 days.
The above described theoretical mechanistic advantages of ACTH in relation to the melanocortin system have spurred trials in multiple MS areas, including fatigue, adjunctive treatment in RRMS, progressive MS, as well as a head-to-head phase IV trial versus IV methylprednisolone in optic neuritis with quite “hard” OCT (optical coherence tomography)-based outcome measures.
In addition, if the theoretical potential benefits of ACTH are reflected in new studies, the availability of a depot preparation could have practical delivery advantages in the community in comparison to IVMP.
NeuroSens Survey
This poll is currently disabled.