Evaluating the effectiveness of initial therapies
There are many disease-modifying therapies available for multiple sclerosis – from the moderately potent (the injectables and orals) to the most potent (infusion drugs such as Lemtrada, Ocrevus and Tysabri). The efficacy of a drug is important, but it’s only part of a broader picture of effectiveness, a term that combines efficacy, tolerability, side effects and quality of life (Lynd and colleagues. Int J MS Care 2018;20:269-277).
Drug efficacy is based on its ability to slow worsening disability, control relapses and reduce inflammatory lesions in the brain. But a drug also needs to have acceptable side effects (ones you can live with), should be safe (unlikely to cause serious side effects), and ideally improve a person’s quality of life.
As more potent medications have become available, a greater emphasis has been placed on using these medications early in the disease course – a “stitch in time” approach. The reasoning is that the first five years after a diagnosis of MS is when (current) treatments are most effective, so it’s important to hit the disease hard to prevent later disability. However, a recent study has questioned whether the early use of potent drugs is best for everyone (Bsteh and colleagues. Mult Scler Relat Disord 2019;39:101908).
In fact, in the real world outside of clinical trials, most people start with a medium-potency drug, such as Copaxone, an interferon (Avonex, Betaseron/Extavia, Rebif, Plegridy) or one of the oral therapies (Aubagio, Tecfidera). A recent UK study looked at medication use over a 5-year period and found that 83% of people started with a medium-potency drug (Harding and colleagues. JAMA Neurol 2019;76:536-541). Over time, about 25% switched to another medium-potency drug, and 11% went on to take a higher-potency drug. So over a 5-year span, 72% of people were adequately served with one of the medium-potency drugs.
Also instructive is a long-term study of clinically isolated syndrome (CIS), in which MS-like signs and symptoms don’t meet the diagnostic criteria for MS but there is a high risk of developing MS. Over a 30-year period, one-third never developed MS (Chung and colleagues. Ann Neurol 2020;87:63-74). In the group that did develop MS, the long-term outcomes fell into three camps: 44% did not develop significant disability, 33% developed progressive disability, and 23% died (from MS or other causes). No MS treatment was available when the study started, and people generally remained untreated for the duration of their illness. These outcomes suggest that while some people with aggressive MS need to a powerful drug, many people can be adequately treated with a medium-potency therapy.
Comparing starting treatments
Copaxone: Many people start treatment with one of the older injectable medications. Copaxone (and its no-name successors) remains popular largely because it’s very safe, has a long track record and presents fewer problems if the person becomes pregnant. However, it’s the only MS medication that hasn’t been shown to slow worsening disability, which limits its overall effectiveness. A common reason for quitting Copaxone is its lack of efficacy (Salacinska and colleagues. Pol Merkur Lekarski 2019;47:221-225). Switching to an oral therapy such as Tecfidera has been shown to reduce relapses even in people who have been on Copaxone for many years (Kresa-Reahl and colleagues. Clin Ther 2018;40:2077-2087). The most troublesome side effect with Copaxone is skin reactions caused by the injections, which can include dents or pits in the skin (called lipoatrophy).
Interferons: There are five different formulations of beta-interferons from which to choose. They appear to have similar effectiveness (Einarson and colleagues. Curr Med Res Opin 2017;33:579-593), so the main consideration will be how often they’re taken: every other day (Betaseron/Extavia), three times a week (Rebif), once a week (Avonex), or once every two weeks (Plegridy). Some studies have suggested that interferons are more efficacious than Copaxone, most notably in reducing inflammatory lesions in the brain (La Mantia and colleagues. Cochrane Database Syst Rev 2016;11:CD009333). The impact of interferons on disability is unclear: some studies have found they slow disability (Drulovic and colleagues. Neurol Sci 2019;40:1627-1636. Trojano and colleagues. Ann Neurol 2007;61:300-306), while others have not (Shirani and colleagues. JAMA 2012;308:247-256. Zhang and colleagues. Eur J Neurol 2015;22:990-1000).
In recent years, oral therapies (Aubagio, Tecfidera) have become the most common starting therapies, in large part because people prefer taking a pill and are wary of needles. Many on an injectable also opt for an oral because they tire of injecting themselves (Evans and colleagues. Clin Ther 2012;34:341-350). Fortunately, there doesn’t appear to be a risk of an MS flare-up if you do decide to switch to an oral drug (Spelman and colleagues. Eur J Neurol 2016;23:729-736). For people who prefer a pill, there are two options that can be used initially.
Aubagio: This once-daily medication has been reported to somewhat comparable to the injectables but less effective than Tecfidera (Longbrake and colleagues. Mult Scler J Exp Transl Clin 2016; epublished November 1, 2016). Its chief advantage is a high level of satisfaction with the drug and improvements in quality of life (Coyle and colleagues. Mult Scler Relat Disord 2017;17:107-115). The main disadvantages are hair loss, a low risk of a carpal tunnel-like tingling in the extremities, and a risk of severe liver injury (a rare occurrence). Pregnancy is contraindicated: a reliable method of contraception is essential (for men and women) while on treatment and the drug must be actively washed out of the body before the couple plans to conceive.
Tecfidera: This twice-daily medication appears to be the most efficacious of the first-line options (Buron and colleagues. Neurology 2019;92:1811-1829. Laplaud and colleagues. Neurology 2019;93:e635-e646. Hutchinson and colleagues. Curr Med Res Opin 2014;30:613-627). Many people are able to remain relapse-free and people report greater well-being (Berger and colleagues. Mult Scler J Exp Transl Clin 2019;5:2055217319887191. Ozel and colleagues. Patient Relat Outcome Meas 2019;10:373-384). One study found that people taking Tecfidera had better productivity at work and improved quality of life compared to those taking an injectable MS medication (Lee and colleagues. Neurol Ther 2017;6:79-90). The main difficulties with Tecfidera are flushing (feeling hot and red-faced) and stomach upset. An Aspirin beforehand and taking the drug with food may help (Narapureddy and colleagues. Patient Prefer Adherence 2019;13:1655-1666).
There is no ideal medication for any given person with MS. The best option will depend on the individual. The minority of people with severe MS may be better off with a more potent drug right from the start. For the majority with less severe disease, it’s important to review the options carefully with the neurologist and MS nurse. The goal is to select the treatment that will be most effective: a good balance of efficacy and safety, a regimen that fits the person’s lifestyle and a drug that will improve quality of life.
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