Clinical baseline factors predict response to natalizumab: their usefulness in patient selection

The marketing of natalizumab (Tysabri, Biogen Idec) for the treatment of relapsing remitting multiple sclerosis (RR MS) has been one of the major changes in the treatment of MS in recent years, due to its high efficacy [1]. However, the risk of the severe, sometimes fatal, disease called progressive multifocal leukoencephalopathy (PML), in about 2:1000 treated patients raises concerns [2, 3]. Optimal pre-treatment patient selection is therefore required to minimize the risk-benefit ratio of such treatment. While longitudinal cohorts of patients treated with natalizumab have been published so far, results could be biased by issues related to the characteristics of the natural history of MS before and after initiation of treatment.

Due to the fluctuating course of MS, methodological pitfalls may affect the analysis of changes in relapse rate. Published studies on natalizumab effect report a marked decrease in mean relapse rate in treated patients, compared to pre-treatment (see for instance [4‐7]). However, such phenomenon could be, at least partially, explained by the regression to the mean phenomenon, which is observed in patients with high relapse rate (such as in patients selected for treatment with natalizumab in European countries), as shown in placebo arms of clinical trials in MS [8]; alternatively, transition to a secondary progressive (SP) course might cause a decrease in relapse rate over time [9]. Moreover, descriptors used to characterize the clinical response to natalizumab, like the change in disability scores over time, appear sometimes inadequate because they do not include an analysis of the pre-treatment period.

The objective of this study was to analyze and describe clinical characteristics that might reflect a positive response to natalizumab in a cohort of MS patients, to test a new parameter for evaluating disability changes over time in MS patients and to provide clinicians and patients with baseline factors that could influence the treatment outcome, with a critical attention to methodological pitfalls.

The study is composed of two parts. In the first part, we analyzed the characteristics of the clinical response to natalizumab in the first two years of treatment; in the second part, we looked for baseline parameters that would predict treatment response in the first year. The cohort was composed of all patients with relapsing MS treated monthly with natalizumab (300 mg by intravenous infusion) in the Liguria region, North-West of Italy, for at least one year by November 11, 2010 (N = 62). These patients had been followed for at least one year prior to treatment. An additional six patients had been enrolled in the cohort but interrupted the treatment at various times before the end of the first year, due to allergic reactions in four patients, “natalizumab inefficacy” in one patient and presence of anti-natalizumab antibodies in the remaining patient. A “worst scenario” additional analysis was performed assuming that these patients had been followed for one year of treatment with a negative outcome. Demographics, disease history, and clinical data of the 62 patients for the year prior to treatment were recorded at baseline (Table 1). Follow-up data were prospectively acquired at 6, 12, and 24 months after the start of treatment, and included disability, measured with the Expanded Disability Status Scale (EDSS), number of relapses, and side effects. At the time of the analysis, 30 of the 62 MS patients studied had been treated for at least 12 months and the remainder 32 for at least 24 months.For the description of clinical response to natalizumab, we analyzed the changes in annualized relapse-rate (ARR) and EDSS for the first and second year of treatment and the proportion of patients with relapses or at least 1-point of EDSS change compared to baseline. EDSS scores were acquired in relapse-free phase. We defined “clinically disease free” the subjects without relapses or 1-point EDSS increase during the first year of therapy. Improvement or stabilization of EDSS after treatment, compared to baseline EDSS, are usually evaluated as markers of response to the therapy. However, such measures do not consider the EDSS trend in the pre-treatment period and, therefore, may overestimate the effect of treatment on disability. Hence, we devised a new qualitative score as a tool to describe the effect of the treatment in decreasing the disability gain compared to the pre-treatment. In detail, we recorded the EDSS score 12 months before the start of treatment (“EDSS T-12”), at the start of treatment (“EDSS T0”), and 12 months after the start of treatment (“EDSS T + 12”) (N = 53 patients). We defined “Better EDSS trend” (BET) score a qualitative index of the trend in disability course from one year pre-treatment to one year after treatment. BET score values would be “1” in case of a decrease by at least one point in the extent of worsening in EDSS during the year of treatment as compared to that in the year prior to treatment, and “0” otherwise. Thus, BET = 1 is taken as (EDSS T0 - EDSS T-12) – (EDSS T + 12 - EDSS T0) ≥ 1. According to this definition, patients experiencing stability in the pre-treatment year and then throughout the first year of treatment have a BET score = 0. Figure 1 is given as an example.

In the second part of the study, we studied whether baseline parameters, including demographics and disease characteristics, were associated with the occurrence of relapses, disease freedom or BET score in the first year of treatment, using a logistic regression analysis.

Patients gave informed consent for data on their clinical history and follow-up to be used for the study. The study was approved by the Ethical Committee of San Martino University Hospital, Genova.

In this study, we followed a cohort of MS patients treated with natalizumab for one to two years, with the aim of identifying the best markers of response to the treatment and defining the characteristics of responders. Most published studies on this topic are descriptive [5, 7, 10‐16]. Few research papers have attempted to correlate baseline data with outcome towards prediction of treatment response, and results are not always consistent between studies, possibly due to the methodological biases that might affect uncontrolled longitudinal studies. Among predictors of decreased relapse rate, Fernandez et al. report baseline EDSS lower than 6 [17], while according to another study, which failed to find an association with baseline disability categories (similar ARR under natalizumab in subjects with EDSS 0–3.5 and subjects with EDSS 3.5–6.5), patients with shorter disease course have the lowest relapse rate under natalizumab [18]. Sargento-Freitas and co-authors found that patients with “optimal response” to natalizumab (those with sustained, relapse-independent reduction in EDSS score of at least 1 point or a reduction in ARR of more than 1 during NTZ treatment) had higher relapse-rate in the pre-treatment year compared to those with suboptimal or no response to treatment [19]. Prosperini et al. report that patients with fewer pre-treatment relapses or lower EDSS are more likely to be disease-free after two years of treatment [20].

In the cohort we report here, as well as in others published so far [4‐7], mean ARR decreased to a very low value after natalizumab (0.26/year). As a consequence, the magnitude of changes in the ARR were directly proportional to the pre-treatment disease activity (the higher the relapse rate in the year prior to treatment, the greater the improvement). This might lead to misleading conclusions, such as considering natalizumab less effective in subjects with lower pre-treatment relapse rate (and higher EDSS). Therefore, we focused our analysis on predictors of relapse occurrence. About one-fourth of subjects had a relapse in the first year of treatment. We found that a high pre-treatment disease activity, as defined by at least two relapses and concomitant 1-point EDSS gain, increased the risk of a relapse in the first year of therapy, which was independent from baseline disability. Importantly, the patient population with a relapse under natalizumab had a similar mean decrease in EDSS after one year compared to those without relapse: therefore, relapses upon treatment did not lead to permanent EDSS worsening. If these data will be confirmed in a longer follow-up, this would differentiate natalizumab from interferon-beta, since relapses under treatment with interferon beta predict disability accumulation in the long-term [21]. We did not find predictors of disease freedom under treatment, differently from what reported by others [20], possibly due to the different definition of freedom from disease activity employed in our study (not including magnetic resonance imaging data).

High pre-treatment disease activity, as defined above, was associated to 1-point EDSS decrease after treatment, similar to what has been reported by the work by Belachew and co-authors [22]. While the same authors did not find associations between baseline disability and EDSS improvement, we found that baseline mild-moderate disability (EDSS 3.0-3.5) was a predictor of EDSS decrease under treatment; different ways of categorizing disability classes may explain this.

From the patient’s point of view, the decrease in disability is not the only relevant endpoint. Stabilization of disease, as well as slower progression, could significantly improve the quality of life. This observation prompted us to create a novel outcome, which we called BET, that describes an improved EDSS trend in the first year under treatment, compared to the year prior to treatment. We found that about half treated patients had a BET score = 1 (improved EDSS trend) after one year of treatment with natalizumab. We show that BET score = 1 correlated with relapse rate before treatment, indicating again that subjects with active disease in the pre-treatment were best responders. Baseline disability did not influence the BET score. It is important to note that, since the BET score describes the EDSS trend over time, it has some limitations associated to the EDSS scale (i.e. the non-linearity of the disability scale); at the same time, BET is easy to calculate in clinical practice, where EDSS is widely used. We suggest that BET score, which compares disability changes in two subsequent time frames, could be used as a tool for analyzing the impact of disease-modifying treatments in disability trends compared to the pre-treatment.

In conclusion, we demonstrated that patients who would most likely improve their neurological status after a one-year treatment with natalizumab had a high disease activity in the year prior to treatment, i.e. at least two relapses and a 1-point increase in EDSS (independent of baseline disability), or a moderate disability (EDSS 3.0 to 3.5) at the time of natalizumab initiation. High pre-treatment disease activity increased the risk of a relapse during the therapy, but this did not impact upon the overall neurological improvement at one year after treatment. Therefore, we suggest that the occurrence of a relapse during natalizumab should not be considered as treatment failure. We propose BET score as an additional tool to describe the response to treatments in MS.