Therapeutic Decision Making in a New Drug Era in Multiple Sclerosis

B. Mark Keegan, MD, FRCP(C)

Disclosures

Semin Neurol. 2013;33(1):5-12. 

In This Article

Deciding on Which Medication

Determine Therapeutic Goals

The main therapeutic goals of immunomodulatory MS therapies are to reduce clinical relapses and accumulation of new MRI lesions. MRI findings of encouraging therapeutic response include reduction in the development of new T2 lesions, gadolinium-enhancing T1 lesions, and T1 hypointensities, as well as brain and spinal cord atrophy that may either accompany focal MS lesions or be diffuse. An additional goal is to reduce short-term relapse-related disability with a long-term promise (continuing to be controversial) of reducing long-term disability regardless of relapse or progression-related etiology. Controversy remains evidenced by somewhat conflicting study findings; some support a long-term beneficial effect for initial immunomodulatory medications such as β interferons, while others do not.[19,20]

How do you Determine if Therapeutic Goals are Being Met?

A detailed clinical history will document a relapse rate prior to and following initiation of MS therapy. However, caution needs to be used as patient recall may be incomplete. Clinicians also need to be aware of the tendency for regression to the mean number of attacks: Simply by nature of the disease, patients with a prior high relapse rate will tend to experience fewer "baseline" attacks even without altering therapy. Additionally, RRMS patients will experience fewer attacks as they age.

Gauging improvement or stability in neurologic impairment is gained both from history and neurologic examination. Assessing functional ambulatory limitations is often a key historical element. The clinician may assess functional ambulatory limitations by history indicating progressive disease. As years go on, the leg dragging or ataxia will be noticed progressively earlier at the one mile, half mile, quarter mile mark that indicates clinical progression.

MRI findings may inform the clinician regarding especially ongoing and new inflammatory activity. This is evidenced by gadolinium-enhancing T1 lesions, accumulating new T2 lesions, and T1 hypointensities. Brain and spinal cord atrophy on MRI may also become apparent progressively over time. Although an ideal interval for serial MRI evaluations is not defined; some physicians recommend every 12 to 24 months for "average-activity" MS patients to assess radiologic stability, worsening, or improvement over time relating to the patients' therapies. Some patients with highly active MS or those on natalizumab (especially to check for early progressive multifocal leukoencephalopathy [PML] development) may require brain MRI more frequently.

Certainly, if the goals of immunomodulatory or symptomatic therapy are being met, then no changes would be required unless there are significant problems with medication tolerability. This remains a challenge for all the immunomodulatory MS medications to varying degrees (Table 1). A detailed evaluation of common and idiopathic side effects associated with the medication will be required and further switching of medications based on adherence and tolerability may be needed.

If Goals are not Being Met

There are several reasons why therapeutic goals may not be being achieved. If the pretherapy relapse rate is not improved, a therapeutic switch may be indicated. Importantly though, the relapse rate is an incomplete indicator of the ongoing inflammatory disease activity. Brain and spinal cord MRI may be revealing of an active inflammatory component that is incompletely controlled even when the relapse rate is improved or relapses are nonexistent. An alteration and switch of medications to a more powerful antiinflammatory medication in these patients may be indicated despite the lack of clinical attacks or definitive worsening disability if the MRI shows therapy-resistant inflammatory disease.

Is Clinical Worsening Due to Attack-related Disease or Progression?

If patients are clinically worsening (an indication of not meeting therapeutic goals), it must be distinguished whether this is due to relapse-related disease or relatively noninflammatory MS progressive disease. If it is due to progression only, it is generally presumed that pathophysiologically the disease is neurodegenerative in nature or is due to subclinical (and subradiologic) inflammation that is not clearly responsive to our currently available therapies. If it is solely due to progressive disease, then it appears that switching to an alternative MS therapy is unlikely to benefit. Conversely, if clinical impairment is strongly associated with ongoing relapses or marked new inflammatory MRI activity, then enhancing antiinflammatory effectiveness by an "upgrade" in intensity of immunomodulatory therapy would be needed.

How are MS Medications Selected?

Various preparations of injectable β interferons and glatiramer acetate remain the first-line immunomodulatory medications for many clinicians (Fig. 2).[21] These injectable therapies come along with now decades of use and corresponding comfort regarding manageable side-effect profiles with a minimum of serious side effects. Approved β interferons are interferon β-1a subcutaneously thrice weekly (Rebif, EMD Serono, Inc., Rockland, Massachusetts) or intramuscularly once weekly (Avonex, Biogen Idec, Weston, Massachusetts) and interferon β-1b subcutaneous every other day injections (Betaseron/Betaferon, Bayer HealthCare, Leverkeusen, Germany; Extavia, Novartis, Basel, Switzerland). Glatiramer acetate (Copaxone, Teva Pharmaceuticals, Petah Tikva, Israel) is given subcutaneously on a once daily basis. Each of these injectable medications is effective in reducing clinical attacks and new MRI lesions. Parenteral therapy and mode of injection, however, is the main drawback of these medications. Interferon-specific side effects include flu-like symptoms (myalgias, headache, malaise) often improving within 2 to 3 months of therapy. Liver enzyme monitoring is recommended in patients treated with the interferon medications. Rarely, depression may worsen in these patients. Glatiramer acetate overall is well tolerated; however, flushing, eosinophilia, and rare allergic reactions may complicate therapy. Additionally, injection-site reactions may evolve into skin lipoatrophy. Combination therapy with interferon β-1aintramuscularly once weekly and glatiramer acetate does not appear to be significantly more efficacious than monotherapy.[22]

Figure 2.

Treatment algorithm for selection and switching of approved immunomodulatory multiple sclerosis (MS) medications. Note most selection and switching of MS medications lack strong evidence-based recommendations. Natalizumab should be used only with extreme caution in JCV Ab positive patients. JCV, John Cunningham virus; Ab, antibodies.

Since 2010, a new era has begun in the treatment of RRMS with the availability and approval of oral medications. Oral MS medications are now an attractive option for some patients and new agents continue to be introduced and approved. MS patients resistant to injection therapy in particular may select from an increasing number of oral medications now available. Currently approved oral MS medications are fingolimod (Gilenya, Novartis, Basel, Switzerland),[23] teriflunomide (Aubagio, Genzyme, Cambridge, MA),[24] and BG-12 (Tecfidera, Biogen Idec, Weston, Massachusetts). Each oral medication comes with their own side-effect profiles that need to be tailored to the individual patient. With fingolimod, first-dose monitoring of heart rate and blood pressure for minimum of 6 hours is required as is serological evaluation for varicella zoster virus immunity, ophthalmologic evaluation for macular edema both at baseline and repeated in 3 to 4 months and annually in those with diabetes mellitus or uveitis.[25] Rare, initially unexplained sudden deaths have occurred in patients taking fingolimod; therefore, evaluation of cardiac status and antihypertensive regimens are required. Health-related warnings for teriflunomide include that of elevated liver enzymes and possible hepatoxicity and risk of teratogenicity. BG-12 may be associated with flushing.

Natalizumab (Tysabri, Biogen Idec, Weston, Massachusetts) is generally considered a second-line MS medication for patients with treatment-resistant disease, given its highly robust reduction in clinical relapses and MRI lesions.[26] Occasionally, it is considered a useful first-line option if a highly inflammatory process is seen at onset with multifocal or severe repeated attacks early in the disease course. Natalizumab is prescribed through the TYSABRI Outreach: Unified Commitment to Health (TOUCH) prescribing program for patients in the United States given its association in some patients with the development of PML.[27] Testing for prior exposure to the John Cunningham virus (JCV) by an enzyme-linked immunosorbent assay- (ELISA-) based serological test is recommended. JCV seronegative patients are at a greatly reduced risk of PML, but need to be retested every 6 months to assure against new JCV exposure. Those patients seropositive for JCV Ab and particularly those with prior exposure to immunosuppressive drugs and treated for 2 years or more are at elevated risk for PML. Natalizumab should be discontinued in patients suspected to have PML and where plasma exchange to remove the drug is recommended.[28] Discontinuation of natalizumab requires caution; an immune reconstitution inflammatory syndrome (IRIS) may occur.[29] IRIS is a poorly understood corticosteroid-responsive inflammatory condition.

Alemtuzumab may be approached as a potential second-line medication; there are some safety concerns such as autoimmune thyroid disease and idiopathic thrombocytopenic purpura.[30,31] Mitoxantrone (Novantrone, EMD Serono, Inc., Rockland, Massachusetts) may be considered a second- or third-line agent even though it has current FDA approval; it is associated with severe side effects such as dose-related cardiotoxicity and delayed hematologic malignancies. Additional third-line agents such as cyclophosphamide[32] or rituximab[33]currently lack definitive therapeutic approval, but may be occasionally considered where a rapid and reliable antiinflammatory effect is desired and the approved medications are not options.

How are MS Medications Switched?

Parallel switching may be a convenient term for recommending a change in MS medications entirely within a drug class or between drug classes where lack of therapeutic efficacy was attributed simply to medication dosage or within a therapeutic "level" of antiinflammatory property where treatment-specific side effects are the main drawback (Fig. 2). An example of parallel switching within a drug class would be cases where a patient with lower therapeutic effect than desired went from a lower dose interferon β-1a intramuscular injection once weekly to interferon β-1a subcutaneous preparation given thrice weekly.[34] Alternatively, if interferon-specific side effects, number of injections per week or subcutaneous skin reactions were the concern an opposite switch between β − interferon preparations could be considered. An example of parallel switching between drug classes within a presumed similar level of antiinflammatory property would be evidenced when tolerability of interferon-specific side effects was the main concern and a switch to noninterferon glatiramer acetate could be considered. The development of interferon-neutralizing antibodies that limit their antiinflammatory effect may also indicate a parallel switch to glatiramer acetate.[35]

Changing MS medications from first-line agents to second-line therapies may be needed when greater antiinflammatory potency is deemed to be required. This may be at the risk of a more-concerning side-effect profile. A balance has to be struck between arresting a severe inflammatory process where patients likely will have accrual of disability and the possibility of exposing the patient to greater side effects.

Intolerability of immunomodulatory medications remains common, and an assessment of whether immunomodulatory therapy is entirely necessary in every MS patient needs to be considered. Those with exceedingly low or no relapses over many years and those with few, if any, new accrual of MRI lesions—especially if they are experiencing the immunomodulatory medication side effects—could be considered for a discontinuation of therapy and observance off of the medications. Some patients maintain a relatively benign disease course based on accrual of clinically evident disability off immunomodulatory medications and this needs to be kept in mind.

When Should Patients Stop Using Immunomodulatory Therapy?

There are no definitive guidelines to assess when a continuation of a drug is futile or not. Both initiation and discontinuation of MS therapies require a shared decision-making model between the patient and his or her physician.[36] This includes reviewing the therapeutic goals and reexamination of the patient's current clinical course, particularly as to whether they have developed SPMS. As none of the immunomodulatory medications convincingly arrest or favorably alter SPMS, these patients may be considered as candidates for possible discontinuation, perhaps particularly when ambulatory impairment milestones have been accrued and in older patients where a recurrence of clinically significant new inflammatory disease is less common. MRI findings may assist in this evaluation as well, when patients have had few, or no, new inflammatory MS lesions over a prolonged interval.

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