Although the exact mechanism(s) of action (MoA) of all the agents is not well understood, their role in MS disease control is believed to be primarily exerted by immunomodulation (though some may have inherent immunosuppressive capabilities), in that they affect immune system processes that are felt to contribute to the inflammatory events that cause damage to the CNS in MS as discussed in Chapter 2. Table 5.1 shows data on current DMD with their postulated MoA.

No single drug has proven yet to be universally efficacious in abrogating all measures of disease activity in MS and halting the disability progress. Furthermore, there are limited comparative data among current MS DMD to guide clinicians to choose the best option as an initial therapy. Nevertheless, data derived from a few active comparator studies evaluating the efficacy of DMD revealed that high-dose, high-frequency IFN-β preparations are superior to low-dose once weekly IFN-β, but were not shown to be superior to GA. Comparison of fingolimod to low-dose IFN-β-1a IM weekly injection demonstrated superiority of efficacy of fingolimod, albeit with a different and occasional serious side effect profile.

We use a classification of these agents into several groups based on risk benefit, yielding to the designation of first line, second line, or further. The first-line drugs are those with long postmarketing safety records and consist of the various IFN-β preparations and GA. In our practice, the second-line group currently consists of natalizumab, mitoxantrone, and fingolimod (though regulatory approval of fingolimod and natalizumab allows for first-line use in the USA), which are agents that might be more potent than first-line drugs but carry a higher risk of major side effects. All are associated with rare but life-threatening side effects.

Window

It is proposed that MS is essentially a two-stage disease: an early inflammatory stage, characterized by focal inflammation both in white and gray matter, and a later neurodegenerative stage, which is founded on the neuroaxonal damage caused by the inflammatory process that has already attained a level that is irreversible and progressive and cannot be adequately repaired. In fact, recent evidence indicates that attacks in the first 1 or 2 years may have a major influence on later stage progression, while attacks occurring later may have less influence on disease progression. This suggests that an important early window of opportunity is present for initiation of disease-specific treatment that can minimize the inflammatory-induced damage, as is the goal of all DMD, accomplished through modulation of inflammatory events (manifest as clinical relapse and MRI activity). Effective early therapeutic intervention appears, therefore, key to diminishing the pathological process and preventing or slowing disability progression. Figure 5.1 depicts the window of opportunity.

Prognostic factors

Several studies have shown that a poorer prognosis can be anticipated in cases with some of the following characteristics: male gender; a later age at onset; motor, cerebellar, and sphincter involvement at onset; a progressive course at onset; a short interattack interval; a high number of early attacks; and a relevant early residual neurologic deficit. Some paraclinical measures might also confer prognostic considerations such as MRI, cerebrospinal fluid (CSF) analysis, and evoked potentials. These tend to not only predict the early conversion to a relapsing course in CIS patients but also indicate which patients may have an earlier progression (e.g., MRI).

In addition to giving us a prognosis, some of these features might also help to place a particular patient into the window of therapy by indicating whether it is early, warranting a safe but mild treatment, or late, where more aggressive therapy may be more effective.

The pivotal studies that established current therapies, together with postmarketing monitoring of their efficacy in last two decades, have revealed that they are not curative but can offer partial efficacy in terms of disease control with a variable degree of response among patients. There is no indication as yet of an a priori profile in a patient’s biologic or clinical characteristics to guide us to the best choice of therapy that will produce the optimal response in a given patient, but recently, researchers have suggested some biological markers that might predict treatment response or be used for monitoring treatment in MS patients in the future.

Overall, the research offers tantalizing data, and we anxiously await the results of larger studies on bigger cohorts of patients for maturation of the novel idea of biomarkers in MS treatment optimization, and until then, we must rely on common markers of disease activity (relapse, disability progression, and MRI activity) in our clinical practice.

Therapy

The major factors that affect our decision-making for choosing an option in MS treatment are:

1. Clinical course of MS: We do not have evidence-based medicine in treatment of PPMS, but CIS, RRMS, and early SPMS are our target patients for treatment.
   
2. The stage of patient in the window of opportunity for treatment: Estimated by considering prognostic factors, history, and physical examination (EDSS) and MRI.
   
3. The early aggressive course of disease: Especially if aggressive, warrants a different approach regardless of the patient’s early status in time frame of window of opportunity.

After starting patients on DMD, we enter into a dynamic and sometimes challenging phase of treatment monitoring. The main purposes of this phase are to determine a patient’s adherence to the regimen, which is a prerequisite for effectiveness, and to assess disease response.

Patient adherence involves the combination of patient interest and enthusiasm in maintaining therapy, tolerance to side effects, and the regimen schedule. Adherence can be maximized through educational discussion in a realistic discussion about the expected efficacy of treatment and its usual side effects. Furthermore, adherence is aided through methods and instruments to improve injection techniques and lower the rate of injection site problems. Systemic side effects of IFN-β, such as flu-like symptoms, can be diminished by proper timing for injection according to a patient’s activity and premedication. Detecting drug side effects is partly based on a patient’s knowledge of symptoms, and this in turn requires up-front education about the medication and how it should be used.

Table 5.2 summarizes some laboratory tests that should be considered, depending on the individual, before starting the relevant therapy as part of premedication evaluation and after starting medication for side effect monitoring.

Disease response monitoring is by far the more challenging part of management, as there is no standardized evidence-based protocol for this and we rely mostly on treatment recommendations by consensus opinion. Unlike clinical trials, there is no placebo group with which to compare a patient’s response to therapy; thus, the best practice is to compare the patient’s clinical state to the pretreatment period. This is even more challenging in CIS patients, since we do not have any pretreatment phase of activity. Typically, we would monitor three parameters: relapse, disease progression (EDSS), and MRI, in addition to insuring that each patient is tolerant of the medication and not showing any signs of toxicity.

Relapse parameters that concern us as to the level of disease activity are the rate, severity, and degree of recovery of neurological dysfunctions following each attack.

The Kurtzke EDSS is the most common measurement of disease progression assessment that has been used both in the clinic and in clinical trials with MS patients. Any increase from the baseline could indicate progression of disease or residual effects from relapses that should be interpreted based on the baseline score and time course of disability establishment. A significant and sustained increase in EDSS following a relapse developing in a short period of time could indicate a more severe inflammatory process. EDSS increments sustained for more than 6 months are usually considered indicative of disability progression. MRI measures of disease activity such as contrast-enhancing lesion(s) (CEL), new or enlarging T₂-hyperintense lesion(s), T₁-hypointense lesion(s) (or black holes), and atrophy have all been examined, but new T₂ lesions +/− CEL are the most consistent and validated measures of disease activity. MRI has already been utilized as a surrogate marker of treatment efficacy in drug trials. A meta-analysis of 23 randomized placebo-controlled trials in RRMS, involving a total of 6591 patients, identified a strong correlation between the effect of treatment on relapses and number of MRI lesions measured. More than 80% of the variance in treatment effects on relapses was explained by the variance in MRI measures. Contrast enhancement and new or newly enlarging lesions identified with T₂ have greater utility in evaluating effectiveness of treatment, and MRI metrics (atrophy and T₁ black holes) have weak predictive value for future disability and correlate poorly with T₂ lesion burden in progressive disease.

None of the current guidelines for monitoring therapy have been standardized in large cohort of patients in long prospective studies but are based on clinical and MRI data that indicates inflammatory or degenerative activity of MS in patients, reflecting the temporary or permanent damage in myelin and neuroaxonal tissues. One practical recommendation is a simplified version of the Rio score instrument, a tool that uses the same clinical and MRI measures over the first year of treatment to predict response to therapy. The Rio scoring system was found to be useful for predicting response to SC IFN-β-1a among 373 patients with RRMS who were followed for 4 years in the PRISMS study. The patients were classified at 1 year using the Rio criteria, which determine response based on a score of 0 (responsive) or a score of 1–3 (unresponsive) when 1 point is assigned to each of the following:

• >2 active T2 lesions on MRI
  
• ≥1 relapse
  
• An EDSS score increase ≥1 (confirmed after 6 months)

After 1 year of treatment, the patients were classified using a simplified Rio scoring system (EDSS not included) in which 1 point is assigned to the presence of ≥2 active T2 lesions between months 6 and 12 and relapse is scored as follows:

• 0 relapses = 0
  
• 1 relapse = 1 and ≥2 relapses = 2

After 1 year, 29.9% of patients were Rio responders, and 37.3% were responders according to the simplified score. Both the Rio score and the simplified Rio score significantly predicted subsequent relapse frequency (p < 0.001 for each) as well as disease progression (p = 0.03 and p = 0.002, respectively).

Such a practical guideline can be applied in clinical practice to monitor the response to therapy and determine the status of patient as a responder or nonresponder for planning the future of management.