PROs range from subjective measures, such as perceived quality of life or the ability to perform daily activities, to more objective and symptomatic measures, such as levels of physical disability. Some of these aspects are difficult to measure clinically, but nonetheless contribute considerably to the experience of MS. The effectiveness of a therapy in patients’ lives as a whole can therefore be assessed using PRO measures in addition to clinical data. Another factor impacting the effectiveness of a therapy that is difficult to address in a clinical trial is the heterogeneity of a general patient population, since certain patients groups (for example, those with comorbidities) that may confound the results in the trial are excluded. Real-world observational studies, therefore, complement evidence from clinical trials, and evidence of real-world effectiveness is becoming increasingly important in health technology assessments and in the development of treatment guidelines.
MS is associated with a multitude of mental and physical symptoms , which, despite being difficult to measure clinically, can be perceived as debilitating by patients. PROs can be used to assess the impact of these symptoms on patients’ lives. Natalizumab is an effective treatment that has been shown to reduce relapses and delay disability progression . This longitudinal study provides evidence that further supports the effectiveness of natalizumab and suggests a positive effect on PRO measures, which were observed from 3 months after treatment initiation and sustained over the 12-month study period.
At the start of the study, most patients reported that MS had a considerable negative impact on their lives, affecting both physical and psychological aspects, despite already having received an average of two DMTs. The patients’ general HRQoL scores were below the scores of the average US population, and the majority had problems with mobility and the ability to carry out daily activities. This poor health status is typical for MS patients, who consistently have a lower HRQoL than both the population without MS [3, 27, 28] and patients with other chronic diseases, such as diabetes, heart disease, stroke, and arthritis . Fatigue is also a common problem for MS patients; in fact, the majority describe fatigue as the worst or one of the worst symptoms . Fatigue can also exacerbate other symptoms, such as balance, vision, and cognitive problems [29, 30].
Because MS is a progressive disease, the absence of a worsening of symptoms is a positive outcome. Following initiation on natalizumab, 65% to 88% of patients reported scores indicating a positive outcome in all PRO measures assessed. What is more, not only was there no further deterioration of the PRO measures assessed, but symptoms were actually improved in a substantial proportion of the patients. Approximately half of patients reporting a positive outcome in their general and disease-specific HRQoL assessments had meaningful improvements in their scores after 12 months compared with baseline. This is consistent with improvements in HRQoL reported by natalizumab-treated patients in randomized clinical trials  and in a 3-month real-world study . Similarly, more than a quarter of patients reported improvements in their disability level, their ability to carry out daily activities, and the impact of MS on fatigue and cognition. Improvements such as these have previously been reported in small European studies, in which natalizumab was associated with decreased fatigue , a reduction in cognitive impairment , and improvements in mobility and reduced disease activity in patients previously treated with interferon beta or glatiramer acetate .
Improvements in all PRO measures investigated were already observed after three natalizumab infusions and were sustained over the 12-month study period. This indicates that the impact of natalizumab occurs rapidly. Post hoc analyses from the AFFIRM and SENTINEL clinical trials demonstrated that within the first 3 months of natalizumab treatment, a significant reduction in annualized relapse rate occurred, and that the reduced rate was maintained throughout the 2-year study period. This rapid effect of natalizumab on the annualized relapse rate has also been observed in the TOP study, a clinical practice–based observational study .
There are no universally acknowledged minimal score changes that correspond to clinically meaningful changes in patients for any of the PRO measures used in this study, with the exception of SF-12v2 (which, as it is normalized, is directly comparable to the scoring of SF-36, for which a score change of at least 5 constitutes a clinically meaningful change ). However, the steps in the FS and DS scales correspond to clearly defined levels of ability or disability (see Additional files 1 and 2) and a change of one step is therefore a clearly noticeable difference to the patient. Similarly, a MSIS-29 score change of at least one category, as defined by the creator of the measure, which corresponds to different degrees of problems caused by MS, would presumably be a meaningful difference for the patient. For both MOS-Cog and MFIS, a 1-point score corresponds to a defined category of how often MS impacts aspects of cognition and fatigue. It is therefore reasonable to assume that the score changes reported are meaningful to the patient.
This was an observational, single-arm prospective study and, as such, has recognized limitations. Since the data presented are longitudinal comparisons within the same population, it is uncertain whether the reported improvements in PROs are a direct result of treatment with natalizumab. However, evidence from randomized clinical trials has shown that, in contrast to natalizumab-treated patients, the HRQoL of MS patients receiving placebo worsens over time . Some of the PRO data could also be affected by recall bias, as the patients were asked to consider a period of up to 4 weeks in the past. In addition, results could be affected by selection bias, as the full set of 12-month data was only available for 333 of the 1,275 patients who were enrolled in the study. However, most of the patients were excluded from analysis because they did not meet study eligibility criteria. In addition, a sensitivity analysis comparing the demographics and characteristics of the patients completing the 12-month survey found that they were not significantly different from those of the patient group completing the baseline survey. Furthermore, a sensitivity analysis that included data for all available time points from all patients who received at least one natalizumab infusion showed similar sustained improvements over time. The self-reported MOS-Cog instrument used to determine cognitive impairment does not provide an objective measure of cognitive functioning similar to that obtained through neuropsychological testing. However, our intent in using the instrument was not to provide a quantitative measure of cognitive functioning but to determine how day-to-day cognitive impairment was perceived by patients and how those perceptions changed over time. In this regard, the MOS-Cog is a reliable scale . Although it is preferable to use the long form of the MFIS in evaluating the impact of fatigue, the abbreviated version, the MFIS-5, was developed for occasions when time is limited, such as in the survey reported here . The MFIS-5 consists of the five items most strongly correlated with the total MFIS score, and the items assess the impact of fatigue in terms of physical, cognitive, and psychosocial functioning. The use of the abbreviated scale thus provided a reliable snapshot of the effects of fatigue given the limited time available.