Changes in magnetic resonance imaging disease measures over 3 years in mildly disabled patients with relapsing-remitting multiple sclerosis receiving interferon β-1a in the COGnitive Impairment in MUltiple Sclerosis (COGIMUS) study

Magnetic resonance imaging (MRI) can provide valuable information on the type, extent and location of pathological lesions in patients with multiple sclerosis (MS). Increasingly, MRI is routinely used in the diagnosis and monitoring of MS, being integral to the McDonald criteria [1]. In addition, MRI measures have been widely used as secondary [2‐5] and, more recently, primary [6] outcome measures in large clinical trials of new MS therapies. In the pivotal PRISMS (Prevention of Relapses and disability by Interferon-β-1a Subcutaneously in Multiple Sclerosis) study, subcutaneous (sc) interferon (IFN) β-1a, 44 or 22 µg three times weekly (tiw), significantly reduced relapse-related outcomes in patients with relapsing-remitting MS (RRMS) [7]. Treatment with sc IFN β-1a was also found to significantly reduce MRI measures of disease at 2 years compared with placebo [7]. Significant effects included reductions in T2 burden of disease (BOD; P < 0.0001 for both doses vs placebo), the number of T2 active lesions (P < 0.0001 for both doses vs placebo), and the number of combined unique active (CUA) lesions (P < 0.0001 for both doses vs placebo) [4, 7]. Furthermore, a significant benefit of the higher over the lower dose was seen for some measures, including the number of active T2 lesions, as reported for clinical outcomes [7]. Beneficial effects of treatment with sc IFN β-1a on MRI measures of disease were also detected in this patient cohort after 7 to 8 years of follow-up, again with evidence of a dose effect [8].

In addition to long-term monitoring of treatment-related outcomes, MRI, unlike clinical measures, can detect early treatment effects. Recently, rapid benefits of IFN β-1a in RRMS were detected using MRI. Notably, patients receiving active treatment had 69% fewer CUA lesions than those receiving placebo after 16 weeks of treatment (P < 0.001) [6]. A post hoc analysis revealed a significant effect on the number of CUA lesions as early as week 4 after starting treatment [6]. The effect of IFN β-1a on 'newer' MRI measures including T1 black holes (BH), which indicate areas of axonal loss and permanent tissue damage, is less clear.

Although MRI provides valuable insights into MS, conventional MRI measures have tended to correlate poorly with clinical outcomes [9, 10]. This discrepancy is believed to arise for several reasons, such as the presence of clinically silent MRI lesions, functional plasticity, and the failure of neurological measures such as the Expanded Disability Status Scale (EDSS) to capture psychosocial symptoms and cognitive impairment.

Cognitive impairment is experienced by up to 65% of patients with MS [11] and can result in considerable disability, loss of social functioning, and reduced quality of life (QoL) [12, 13]. Previous studies in MS have reported associations between the development of brain MRI lesions and cognitive impairment [14, 15]. In the prospective, multicentre, observational COGIMUS (COGnitive Impairment in MUltiple Sclerosis) study of mildly disabled patients with RRMS, we reported that T2 hyperintense and T1 hypointense lesion volumes at baseline were significantly higher in patients with cognitive impairment than in those without [16]. Indeed, T2 lesion volume was also found to be a significant predictor of cognitive impairment at baseline [16]. In addition, weak associations were found between cognitive performance test results and specific MRI measures in this population [16].

In COGIMUS, ~20% of patients who received sc IFN β-1a were found to have cognitive impairment at baseline (22 µg sc tiw: 24.2%, 44 µg sc tiw: 18.6% [P = 0.145]) despite having only a low level of physical disability (mean [standard deviation; SD] EDSS score was 1.8 [1.0]) [16, 17]. Further, 3-year results from COGIMUS suggested that treatment with IFN β-1a, 44 or 22 µg sc tiw, may have a dose-dependent protective effect on cognition in this mildly disabled patient population [17, 18]. Here we report the results of a post hoc analysis of the longitudinal effects of treatment on MRI measures of disease over 3 years in the COGIMUS study. Associations between MRI measures and cognitive and patient-reported outcomes were assessed to explore whether beneficial treatment effects on MS lesions were related to those on cognition.

The beneficial effects of sc IFN β-1a on MRI measures of disease in patients with RRMS are well recognized. In this observational study, such effects were seen in patients being treated and assessed under normal clinical practice conditions, strengthening our results. Here we demonstrated significant effects of sc IFN β-1a on T2 and T1 Gd+ lesion volumes over 3 years in a large cohort of patients with mild physical disability (mean EDSS score: 2.0). Furthermore, most patients remained free from new T1 Gd+, T2 and BH lesions over the course of the study. A dose-dependent effect was seen in several MRI outcomes, with the 44 µg dose having a more pronounced benefit than the 22 µg dose. Treatment with the 44 µg dose of IFN β-1a also predicted better cognitive outcomes at Year 3. T2 lesion volume was found to be associated with poor cognitive and QoL outcomes.

Over the 3-year study, sc IFN β-1a treatment was associated with a significant reduction in T1 Gd+ and T2 lesion volumes, with a significant benefit of the 44 μg dose demonstrated for T2 lesion volume. These findings are consistent with those of the pivotal PRISMS study, in which sc IFN β-1a reduced T2 BOD and CUA lesion number over 2 years of treatment, with a dose-dependent effect on T2 lesion number and activity [4, 7]. Our data confirm that sc IFN β-1a has beneficial effects on MRI measures of disease in this cohort of mildly disabled patients with RRMS. It is interesting that no dose effect was observed for T1 Gd+ lesions. As Gd+ lesions are new lesions, it is possible that the lower 22 μg dose of IFN β-1a is able to inhibit initial inflammatory processes in these patients in the early stages of disease. Indeed, an effect of sc IFN β-1a on active MRI lesions was reported at Month 2 in the PRISMS study, during which patients received lower doses of IFN β-1a during titration up to the 44 µg tiw dose [4]. The dose effect may, however, become evident when assessing longer-term MRI measures such as T2 lesion volume, which capture both old and new lesions. It is possible that newer lesions are more susceptible to the effects of sc IFN β-1a than more established, chronic and inactive lesions.

The presence of BH indicates areas of axonal loss (neurodegeneration). Although we did not find a significant effect on BH lesion volume from baseline to Year 3 in the whole cohort, a significant difference between the two treatment groups was seen regarding the change in BH volume: BH volume increased in the 22 µg group, but decreased in the 44 µg group over the 3-year study. Whether IFN β-1a is neuroprotective is still a subject of some debate; however, our findings may suggest that the 44 µg dose of sc IFN β-1a could have neuroprotective effects. This is a particularly interesting finding as BH were not measured in earlier studies of DMDs, and hence how BH are associated with long-term treatment-related clinical outcomes is not known [8].

At Year 3, only 11.8% of patients had impaired performance on ≥3 cognitive tests. This is slightly lower than the proportion reported in the parent COGIMUS study [17], which may reflect differences between patients who underwent MRI scans and those who did not. Treatment with the 44 µg dose of IFN β-1a was associated with better cognitive outcomes, whereas higher T2 lesion load predicted cognitive decline. An association between T2 lesions and cognitive impairment has been reported previously [16, 25‐28]. As we saw a clear, dose-related effect of treatment on MRI measures and an association between T2 lesions and cognition, it is interesting to speculate on how the effect on different MRI lesion types may translate into cognitive benefits. Loss of axons (BH) could result in loss of neuronal connectivity, whereas T2 lesions might indicate reduced efficiency of neurotransmission owing to myelin degradation. Mapping the distribution of MS lesions and assessment of those in regions known to govern cognitive processes could provide further insights into how the effects of IFN β-1a treatment on MRI parameters are associated with cognitive benefits. Metabolic studies may also further explain the relation between treatment effects on MRI parameters and cognitive outcomes. In one study using positron emission tomography, the cortical rate of glucose metabolism was shown to be reduced significantly in patients with MS compared with healthy controls, and was inversely correlated with T2 BOD and cognitive performance [29]. White matter lesions could denervate cortical areas and be responsible for the observed reduction in cortical glucose metabolism resulting in clinical symptoms.

Decreased T2 lesion volume also predicted better QoL scores. Associations between MRI parameters (white matter lesion loads and brain atrophy) and QoL outcomes have been described in a cross-sectional analysis of patients with MS [30]. Here, we have assessed longitudinal treatment effects on QoL and MRI disease measures. Together, our and previous observations suggest that treatment-related reductions in MS lesion burden may have a positive effect on patients' daily lives. It is also possible that starting treatment may have positive psychological effects due to the patient's expectation that their treatment will reduce relapses and protect against worsening disability and cognitive impairment that lead to improved QoL. No associations were found between MRI measures and fatigue, depressive symptoms or social functioning in our analysis. However, higher fatigue at baseline did predict worsening QoL. These findings demonstrate the complexity of MS and the importance of measuring both pathological and symptomatic parameters to understand fully the impact of MS on the patient.

The limitations of this analysis should be considered. This was a post hoc analysis of data from an observational study, and there was no untreated comparator group; treatment effects should therefore be interpreted with caution. Consequently, differences observed between the lower and higher doses of sc IFN β-1a may have been affected by selection bias, although treatment groups were balanced with regard to main demographic variables. In addition, MRI data at Year 3 were missing for approximately half of the patients with baseline MRI data. Furthermore, among those patients from whom MRI data were collected over 3 years' follow-up, data for some parameters were missing. Despite this, we collected MRI and cognition data for >300 patients at baseline and for >150 patients at Year 3, making this a valuable data set, particularly considering the mild disability and short disease duration in this cohort. Notably, there were some important differences between patients with and without 3-year MRI data, including the proportion who had cognitive impairment, and in EDSS scores. This finding may have influenced the other results reported here and highlights the difficulties that can be encountered with data collection in longitudinal studies. Concerning MRI parameters, we did not assess cortical pathology (inflammatory lesions and atrophy), which has recently been shown to contribute considerably to neuropsychological symptoms in MS [31, 32]. As the importance of cortical pathology in MS, particularly with respect to cognitive outcomes, emerged after the start of the COGIMUS study it was not possible to include such assessments in this analysis. In addition, it should be noted that Gd+ lesions can only be detected for a time period of around 1 month at most, so it is possible that some of these lesions may not have been counted due to the scans being performed annually; however, this interval was dictated by routine practice due to the observational nature of the study. Finally, due to low patient numbers, it was necessary to define cognitive impairment as impaired performance on ≥2 cognitive tests to investigate associations between MRI parameters and cognitive status, whereas the definition in the parent COGIMUS study required impairment on ≥3 tests.

These findings demonstrate that sc IFN β-1a has a beneficial effect on MRI measures of disease in a population of patients with early RRMS and mild physical disability in a normal clinical setting. A dose effect was seen on MRI outcomes, notably on BH, an indicator of neurodegeneration, and was greater with the 44 µg than with the 22 µg dose of sc IFN β-1a. T2 lesion load and treatment with the higher dose of sc IFN β-1a predicted preserved cognitive function over the 3-year study. These results confirm the efficacy of sc IFN β-1a in RRMS and suggest that effects on MRI measures may underlie potential cognitive and QoL benefits of this treatment.