Why Alternatives to Systemic Steroids Deserve a Second Look

November 29, 2019
Alicia Bigica
Alicia Bigica

Alicia Bigica is the Associate Editorial Director for NeurologyLive. Prior to joining MJH Life Sciences in 2019, she helped launch leading resources for medical news in the neurology and dermatology specialties. Follow her on Twitter @aliciabigica or email her at abigica@neurologylive.com.

NeurologyLive, November 2019, Volume 2, Issue 7

The assistant professor of clinical neurology at Keck School of Medicine University of Southern California in Los Angeles sat down with NeurologyLive for a Q&A discussing using steroids as treatment for multiple sclerosis.

Althought the advent of highly effective disease-modifying treatments for multiple sclerosis [MS] has greatly reduced the risk of disease relapse, it’s still important that clinicians be armed and ready to treat MS exacerbations.

Treatment with systemic steroids is backed by long-standing clinical evidence, but what about patients who have trouble tolerating high-dose steroids or whose relapses persist? In an interview with NeurologyLiveTM, Regina Berkovich, MD, PhD, an assistant professor of clinical neurology at Keck School of Medicine at the University of Southern California in Los Angeles, sat down to review current MS relapse treatment standards and reveal why clinicians might want to consider using an alternative to resolve troublesome exacerbations.

Q: Given the solid track record of corticosteroids for treatment of MS relapse, why should clinicians consider other options?

The use of corticosteroids as a first-line therapy for MS relapse is, first of all, supported by scientific evidence. The clinical experience is vast, and it has been FDA-approved since 1979. A typical dose is 1 g or 1000 mg by IV [intravenously] once a day for 3 to 7 days. Usually, the practices are 3 to 5 days; that is the most-used regimen for daily administration. Lately, we have been aware of clinical data and some publications on the use of oral systemic steroids, but when it comes to the oral steroids, they also have to be used in high dosages, which are equivalent to 1 g of methylprednisolone. In that case, they can be used as an alternative. Although they are not specifically approved with as much clinical evidence as IV steroids, they appear to be a viable option.

The reasons for using alternatives to systemic steroids in my practice are limited mostly to intolerability to the systemic steroids or lack of efficacy. I must say that the lack of efficacy of systemic steroids and the hope that other medications still may work require deeper clinical evaluations and better scientific and clinical support. However, I’m basing this completely on my professional experience, when I have patients not responding to the steroids or being steroid resistant for various reasons. We have good experience accumulated over the years that those patients may respond to corticotropin or ACTH [adrenocorticotropic hormone]. We use the ACTH gel, which is known as Acthar Gel. Some of the cases will respond to that treatment option; I think the reason is that it has a completely different mechanism of action.

Q: What makes ACTH, or corticotropin injection, different from systemic steroids?

Repository corticotropin injection, or what we used to call ACTH, was approved in 1978 after an extensive, multicenter, placebo-controlled study by James Rose, PhD, who was a professor of neurology working at UCLA [University of California, Los Angeles]. He conducted the first clinical trial in multiple sclerosis and enrolled the largest number of participants at that time...This was the first study in which the Disability Status Scale was implemented. Many clinical metrics in relapse evaluations that we now understand as classical actually came from that first study. The study looked at the effects of corticotropin, and it showed that patients treated with ACTH had faster and more robust recovery from MS exacerbation compared with placebo.

I think that the important point for us to remember is that ACTH is not a steroid. It is a hormone, but it is not a steroid. It is a protein. If we remember the HPA [hypothalamic-pituitary-adrenal] axis, we recall that it is a regulatory hormone, which is at a much higher level than cortisol. That may explain why the mechanism of action and the targets of corticotropin are much more diverse than those with the adrenal hormones, such as systemic steroids or cortisol.

Although we know that systemic steroids, cortisol, methylpred- nisolone, and prednisone have a high affinity to the glucocorti- coid receptors, ACTH—as a protein and not a steroid—has affinity to a different type of receptors, which are called melanocortin receptors. The class of melanocortin receptors represented on adrenal glands is just 1 class of 5. The other receptors are distributed through blood cells, including lymphocytes, microglia, skin, and bone tissue. Their representation is extremely widespread. We used to think that ACTH activates the adrenal glands, and the adrenal glands produce cortisol. However, that seems to be just 20% of the story or maybe even less. ACTH works on different types of receptors spread throughout the body, as well as different tissues and cells.

The mechanism of engaging the anti-inflammatory effect is also different compared with the glucocorticoid receptors. It goes deeper into the anti-inflammatory mechanisms, and as a regulatory hormone, it is expected to have a completely different immunology from the outcomes that have been shown in some of the clinical trials.

"I think that the important point to remember is that ACTH is not a steroid. That may explain why the mechanism of action and the targets of corticotropin are much more diverse than those with adrenal hormones, such as systemic steroids or cortisol," said Regina Berkovich, MD, PhD.

Q: How would you advise incorporating treatment with repository corticotropin injection?

The use of repository corticotropin injection is mostly reserved for those cases in which we cannot use systemic steroids. Therefore, some of the comparisons between steroids and repository corticotropin injection, in terms of price and efficacy, really don’t seem to hit the target. At least in my practice, I don’t expect there to be competition between the 2. I use repository corticotropin injection when I’m restricted with systemic steroids and when systemic steroids are, unfortunately, not an option. In that situation, I consider repository corticotropin injection versus hospital admission for the plasma exchange, so that is where the comparison is going. Therefore, I think it’s important to remember that it’s a second- or third-line therapy. By definition, it means that other therapies, either tried before or contraindicated, did not show efficacy. This is a limited population of patients we’re talking about. That’s why comparison doesn’t seem to be correct.

When it comes to the dosing, my experience and my clinical recommendation would be to consider between 5 and 15 days. We’re talking about 1, 2, or, on rare occasions, 3 vials, because 1 vial is 5 mL and good for five 1-mL daily injections. It certainly can be used on a daily basis. Those patients who would need it every other day for various reasons can do that, as well. That can be decided clinically on an individual basis. My clinical experience has been that a course of 5 days or 5 mL may not be sufficient for the majority of MS-relapsing patients, and it may need to be extended to 7 to 10 days. I rarely use it more than 10 days. In my practice, I have experience giving 1 cc intramuscularly; there is evidence that it works just the same with respect to the bioavailability and pharmacokinetics compared with subcutaneous injections. It can be used intramuscularly or subcutaneously once a day.

Q: In terms of the risk-benefit ratio, for which clinical situations might repository corticotropin injection be considered?

Repository corticotropin injection is rarely, if ever, used as a first-line therapy; it should be reserved for those options or situations when systemic steroids are not feasible, are contraindicated, or failed previously. Specifically, repository corticotropin injection can be used in patients who have intolerable life-threatening adverse effects [AEs] such as steroid-induced acute psychosis. That would be the most vivid presentation of preference for using repository corticotropin injection.

The list of potential AEs of repository corticotropin injection resembles the list of potential AEs of systemic steroids. Methylprednisolone and repository corticotropin injection have the same list of psychiatric AEs; however, when it comes to the equivalent production of cortisol as a result of the stimulation of ACTH, that production is less than 3% compared with 1 g of meth- ylprednisolone, so you may expect the potential steroidogenic AEs to be just a fraction of what has been experienced in the setting of the systemic steroid use. That has been supported by my clinical experience. So those patients who, for example, had acute psychosis as an AE of the systemic steroids did not have a similar reaction in my practice when ACTH was used.