Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

Detecting clinically-relevant changes in progressive multiple sclerosis.

OBJECTIVE: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS). METHODS: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy's Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS. RESULTS: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW. CONCLUSION: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS.

Walking speed, rather than Expanded Disability Status Scale, relates to long-term patient-reported impact in progressive MS.

OBJECTIVE: To study the relationships between 1-2 year changes in well-known physician-rated measurements (Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT)) and the long-term (≥ 5 years) outcome in patient-reported outcome (PRO) measures (Multiple Sclerosis Impact Scale (MSIS-29), Multiple Sclerosis Walking Scale (MSWS-12)) that reflect the patient-perceived impact of disease, in progressive MS. METHODS: We selected all progressive patients having at least two complete visits within 1-2 years, from a larger cohort of prospectively-followed MS patients. These were invited for another visit, at least 5 years later, consisting of another series of similar examinations, plus 2 PRO scales: the MSIS-29 and MSWS-12. We explored associations between early changes in physician-rated measurements and the long-term outcome as per the PRO measures. RESULTS: In this study,134 patients fulfilled the selection criteria. We found that early change in T25FW was the only physician-rated change that was significantly related to long-term physical impact experienced by the patient, as was assessed by MSIS-29 (Kruskal-Wallis test: χ(2)=7.8, p=0.020). Early T25FW change, and to a lesser degree early 9HPT change, were significantly related to the reported long-term walking limitations, as assessed by MSWS-12 (Kruskal-Wallis test: χ(2)=13.8 and p=0.001 for T25FW, χ(2)=6.5 and p=0.038 for 9HPT). None of the early physician-rated changes were related to the long-term psychological impact experienced by the patient. CONCLUSION: Early changes on physician-rated scales do have long-term impact in terms of potentially predictive value of outcomes for groups of patients in progressive MS, regarding walking limitations and more global physical impact. Surprisingly, early change in T25FW, rather than early change in EDSS, was significantly associated with longer-term patient-reported disease impact. Our study data support the value of using early physician-rated examinations in clinical trials in progressive MS.

Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis.

BACKGROUND: The interleukin 7 receptor (IL7R) has been recognized as a susceptibility gene for Multiple Sclerosis (MS). Analysis of rs6897932 (the most strongly MS-associated single nucleotide polymorphism (SNP)), showed effects of genotype on the relative expression of membrane-bound to total amount of IL7R mRNA. OBJECTIVE: We assessed the relevance of IL7R on MS phenotype (including clinical and magnetic resonance imaging (MRI) parameters) at DNA and mRNA level in Dutch patients with MS. METHODS: The genotype of rs6897932 was analyzed in 697 patients with MS and 174 healthy controls. The relevance of genotype and carriership of the C allele on MS phenotype (disease activity and severity, using clinical and MRI parameters) was assessed. In addition, relative gene expression of membrane-bound to total IL7R mRNA was analyzed with respect to disease phenotype in a subgroup of 95 patients with early relapsing MS. RESULTS: In particular, homozygosity for the risk allele is a risk factor for MS in our population (OR(CC vs CT and TT) = 1.65 (95% CI: 1.18-2.30), two-sided p = 0.004). However, no effect of genotype or the relative expression of membrane-bound IL7R (presence of exon 6-7) to total amount of IL7R mRNA (presence of exon 4-5) was found on MS phenotype. DISCUSSION: Homozygosity for the IL7R exon 6 rs6897932 C allele is associated with a higher risk for MS in our Dutch population. No effect was found of genotype or mRNA expression on disease phenotype.

Disease progression in multiple sclerosis: combining physicians' and patients' perspectives?

BACKGROUND: To assess disease progression in multiple sclerosis (MS) several outcome measures are available. The interrelation of changes on different scales has not been studied extensively and the concept of combining scales has only recently been introduced in MS. OBJECTIVE: To explore combining different clinical outcome measures in the evaluation of disease progression in MS. METHODS: In 553 patients we studied the presence of relevant changes according to standard definitions on the Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) and the Multiple Sclerosis Impact Scale (MSIS-29). We examined 'exclusive worsening' (worsening on one measure while not worsening on any other measure) and 'opposing changes' (worsening on one measure while improving on another measure). Finally, we investigated the impact of combining assessments. RESULTS: Based on the EDSS alone, 140 patients progressed. However, almost twice as many (275) showed worsening on any of the clinical outcome measures. Exclusive worsening was observed in 37 patients on the EDSS, 13 on the 9HPT, 39 on the T25FW and 44 on the MSIS physical. Of all worsened patients 76 (28%) showed opposing changes, a phenomenon predominantly observed when combining physician-based and patient-derived outcome measures. CONCLUSION: When assessing disease progression in MS, sensitivity to change can be increased by combining different outcome measures. The added value is especially present when combining measures from different perspectives. However, further research is needed to evaluate the optimal way to combine outcome measures before implementing this strategy in clinical studies.

Progression on the Multiple Sclerosis Functional Composite in multiple sclerosis: what is the optimal cut-off for the three components?

For the Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT), components of the Multiple Sclerosis Functional Composite (MSFC), cut-off points of 20% change have previously been defined as meaningful endpoints of functional decline. Recently, however, a 15% change of MSFC components was introduced. The objective of this study was to determine optimal cut-offs for all MSFC components to indicate clinical disease progression in a primary progressive (PP) multiple sclerosis (MS) population. T25FW, 9HPT and the Paced Auditory Serial Addition Test (PASAT) were performed in 161 patients with PPMS with a 2-year interval. Absolute and relative differences in test scores were calculated. For each cut-off point of relative change, proportions of patients who progressed (deterioration beyond cut-off value) and improved (improvement beyond cut-off value) were calculated. Further, we calculated the ratio of 'improved' versus 'progressed' patients. Line graphs were created indicating: percentage progressed patients, percentage improved patients, and ratio of improved versus progressed patients. The optimal cut-off was determined by searching the cut-off point with the lowest ratio of improved versus progressed patients, while at the same time capturing a substantial amount of progression. For both T25FW and 9HPT, the ratio between patients that improved and worsened clearly decreased between the cut-offs of 15% and 20%. For the PASAT, the ratio between patients improved and worsened was persistently poor. In conclusion, a cut-off of 20% for both T25FW and 9HPT has a better signal-to-noise ratio than lower values (e.g. 15%) and is therefore preferable for the assessment of disease progression. No satisfactory cut-off point for the PASAT could be determined.

Gender differences in multiple sclerosis: cytokines and vitamin D.

The disproportional increase of the female:male ratio in relapse-onset (relapsing remitting (RR) and secondary progressive (SP)) multiple sclerosis (MS) patients in the last 20 years has further raised scientific interest in gender difference in MS. It has been suggested that the immune system, especially cytokines, plays an important role in the gender issue, as can also be seen in other autoimmune diseases. The immune system is influenced by different factors including hormones and seasonal fluctuations (vitamin D). This overview will highlight the gender differences in MS, with emphasis on the cytokines and vitamin D.

The search for responsive clinical endpoints in primary progressive multiple sclerosis.

OBJECTIVE: To determine whether in primary progressive multiple sclerosis (PPMS) combining scores of Expanded Disability Status Scale (EDSS) with data from Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT) would produce a clinical endpoint that has a higher event rate than EDSS alone. METHODS: In a group of 161 PPMS patients, EDSS, T25FW, and 9HPT were performed at three time points over 2 years. We calculated how many patients showed clinically meaningful deterioration (or improvement) on individual and combined scales. We defined improvements on one scale with deterioration on the other as "opposing changes." We investigated the possible effect of baseline disability on the definition of our endpoint by dividing the population into two subsets of patients determined by baseline EDSS level. RESULTS: On individual scales, event rates were highest on T25FW: 34% and 46% 1 year and 2 years after baseline. On a combination of two scales, at 1 year the event rate was highest on T25FW/9HPT (46%; with a high rate of opposing changes) and at 2 years on T25FW/EDSS (57%; with a lower rate of opposing changes). In both subsets, event rates were highest on T25FW and (at 2 years) on the combination of T25FW/EDSS. CONCLUSIONS: T25FW has the highest event rate as a single scale, independent of baseline disability level. A term of 2 years turned out to be more meaningful to observe than 1 year. "Worsening on either T25FW or EDSS" is the most appropriate composite endpoint in this patient group.

Serum homocysteine levels in relation to clinical progression in multiple sclerosis.

BACKGROUND: Elevated homocysteine levels are associated with various neurodegenerative diseases and have even been identified as a risk factor for some of these. Homocysteine levels may be elevated in patients with multiple sclerosis (MS) but large studies are lacking and the relation with disease progression remains to be determined. AIM: The aim of the study was to investigate homocysteine levels in patients with MS and in controls, and to study the relationship between homocysteine levels and clinical progression in MS. METHODS: Serum homocysteine levels were compared between MS subtypes (n = 219) and controls (n = 152). Homocysteine levels were associated with baseline and follow-up clinical severity scores. RESULTS: The results showed that serum homocysteine values were similar in patients with MS and controls. Baseline scores on the Expanded Disability Status Scale were higher in patients with secondary progressive MS (SPMS) in the top compared with the bottom quartile of homocysteine levels (p = 0.02). The baseline scores on the Multiple Sclerosis Functional Composite (MSFC) and Paced Auditory Serial Addition Test (PASAT), which measures cognitive functioning, were lower in patients with SPMS in the top compared with the bottom quartile of homocysteine levels (MSFC, p = 0.02; PASAT, p = 0.02). High homocysteine levels were associated with a decline in PASAT scores during follow-up in patients with primary progressive MS (p = 0.009). CONCLUSION: Serum total homocysteine levels are associated with several measures of disease progression in MS but are not elevated in patients with MS compared with controls. The association of homocysteine levels with cognition in patients with progressive MS raises the question of whether homocysteine directly impacts on MS or reflects a more general neurodegenerative process.

Responsiveness and predictive value of EDSS and MSFC in primary progressive MS.

INTRODUCTION: We studied the responsiveness and predictive value of two widely used clinical outcome measures that document multiple sclerosis (MS) disease progression-the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC)-in patients with primary progressive (PP) MS. Disease course in PPMS shows less fluctuation than in relapsing remitting (RR) MS. METHODS: In a group of 161 patients with PPMS, EDSS and MSFC were performed at three timepoints. To assess responsiveness, mean change scores and variances were plotted against baseline scores and effect sizes were calculated. Predictive value was determined by calculating sensitivity, specificity, and likelihood ratios (LRs) of 1-year changes to predict changes over 2 years. Furthermore, multivariate logistic regression models were used to assess the predictive value of short-term worsening on EDSS and MSFC. RESULTS: Responsiveness of both EDSS and MSFC was shown to be limited and mean changes were highly dependent on the baseline scores. Effect sizes for EDSS and MSFC were small and inconclusive (0.239 and 0.161). The predictive value of a short-term worsening (baseline to year 1) to predict worsening in the long term (baseline to year 2) was expressed for EDSS by a sensitivity of 0.55 and a LR+ of 8.64. For MSFC, sensitivity was 0.68 and LR+ was 3.14. However, short-term worsening was a poor predictor of subsequent worsening (year 1 to year 2) for EDSS (LR+ 1.06) and this relationship was actually inverse for MSFC (LR+ 0.61). CONCLUSION: In this study over a period of 2 years in primary progressive multiple sclerosis, the Multiple Sclerosis Functional Composite (MSFC) was less responsive than the Expanded Disability Status Scale (EDSS). The predictive value of neither EDSS nor MSFC was very powerful.

Clinical impact of 20% worsening on Timed 25-foot Walk and 9-hole Peg Test in multiple sclerosis.

INTRODUCTION: Quantitative tests of motor function, like the Timed 25-foot Walk (T25FW) and 9-hole Peg Test (9HPT), are increasingly being applied as outcome measures in multiple sclerosis (MS) clinical trials. The quantitative nature of the data has a favorable impact on responsiveness, but the clinical impact of the changes is uncertain. The goal of this study was to assess whether a change on T25FW and 9HPT does indeed have a clinical meaning. This was accomplished by comparing 20% changes on these quantitative measurements to concomitant changes on the Guy's Neurological Disability Scale (GNDS), a scale which measures patient-perceived daily life disability. METHODS: From a longitudinal database, we selected patients with at least two measurements of T25FW, 9HPT and GNDS with a minimal time interval of 350 days. In those patients who experienced at least a 20% change on T25FW or 9HPT, GNDS score changes were examined more closely. RESULTS: Of 527 patients, 143 experienced a >20% worsening on their T25FW and 71 on their 9HPT, respectively. Patients with a 20% increase in T25FW or 9HPT had more GNDS worsening than patients without such an increase. GNDS worsening associated with an increase in T25FW was mainly due to an increase in perceived disability related to lower extremity function and fatigue; GNDS worsening associated with an increase in 9HPT was more diffuse with respect to domains involved. CONCLUSION: Worsening on T25FW or 9HPT has a clinical impact on disability, as perceived by MS patients during daily life functioning.

A subtype of multiple sclerosis defined by an activated immune defense program.

Given the heterogeneous nature of multiple sclerosis (MS), we applied DNA microarray technology to determine whether variability is reflected in peripheral blood (PB) cells. In this study, we studied whole-blood gene expression profiles of 29 patients with relapsing-remitting MS (RRMS) and 25 age- and sex-matched healthy controls. We used microarrays with a complexity of 43K cDNAs. The data were analyzed using sophisticated pathway-level analysis in order to provide insight into the deregulated peripheral immune response programs in MS. We found a remarkable elevated expression of a spectrum of genes known to be involved in immune defense in the PB of MS patients compared to healthy individuals. Cluster analysis revealed that the increased expression of these genes was characteristic for approximately half of the patients. In addition, the gene signature in this group of patients was comparable with a virus response program. We conclude that the transcriptional signature of the PB cells reflects the heterogeneity of MS and defines a sub-population of RRMS patients, who exhibit an activated immune defense program that resembles a virus response program, which is supportive for a link between viruses and MS.

Proxy measurements in multiple sclerosis: agreement between patients and their partners on the impact of multiple sclerosis in daily life.

BACKGROUND: The use of self-report measurements in clinical settings has increased. The underlying assumption for self-report measurements is that the patient understands the questions fully and is able to give a reliable assessment of his or her own health status. This might be problematic in patients with limitations that interfere with reliable self-assessment such as cognitive impairment or serious mood disturbances, as may be the case in multiple sclerosis. In these situations proxies may provide valuable information, provided we can be certain that proxies and patients give consistent ratings. OBJECTIVE: To examine whether patients with multiple sclerosis and their partners agree on the impact of multiple sclerosis on the daily life of the patient by using the Multiple Sclerosis Impact Scale (MSIS-29). METHODS: 59 patients with multiple sclerosis and their partners completed the MSIS-29. Agreement was examined, comprehensively at scale score levels and item functioning, using both traditional and less conventional psychometric methods (Rasch analysis). RESULTS: Agreement between patients and partners was good for the physical scale, and slightly less but still adequate for the psychological scale. Mean directional differences did not show considerable systematic bias between patients and proxies. Intraclass correlation coefficients (ICCs) satisfied the requirements for agreement, but were higher for the physical scale (0.81) than for the psychological scale (0.72). These findings were supported by Rasch analyses. CONCLUSION: In this sample, albeit small, partners provided accurate estimates of the impact of multiple sclerosis. This supports the value of self-rating scales and indicates that partners might be useful sources of information when assessing the impact of multiple sclerosis on the daily life of patients.

How similar are commonly combined criteria for EDSS progression in multiple sclerosis?

INTRODUCTION: Measuring disease progression is an important aspect of multiple sclerosis (MS) clinical trials. Commonly applied disability endpoints include time to clinically meaningful Expanded Disability Status Scale (EDSS) change, or the number of patients in whom such a change has occurred. Typically, clinically meaningful EDSS change has been defined as a change of 1.0 point on Kurtzke's EDSS in patients with an entry EDSS score of 5.5 or lower, or 0.5 point in patients with a higher EDSS score. Our goal was to evaluate whether these changes can be considered as similar. Therefore, we compared EDSS changes to corresponding changes in the Guy's Neurological Disability Scale (GNDS), which is a measure of patient perceived disability, and the Multiple Sclerosis Functional Composite (MSFC), which is an examination-based quantitative scoring of neurological impairment. METHODS: From a large longitudinal database, we selected two groups of patients with a clinically meaningful change in EDSS score according to the usual criteria: patients with EDSS change > or = 1.0 for baseline EDSS < or = 5.5 and patients with EDSS change > or = 0.5 for baseline EDSS > or = 6.0. We compared changes in GNDS sum score and in MSFC score between both groups. RESULTS: In the group with baseline EDSS > or = 6.0, GNDS and MSFC changes were higher than in patients with baseline EDSS < or = 5.5. The difference in change was 1.00 (95% confidence interval (CI): -0.35 to 2.36) for the GNDS and 0.412 (95% CI: 0.300-0.525) for the MSFC. CONCLUSION: Our results indicate that a 0.5 point EDSS change in patients with baseline EDSS > or = 6.0 cannot be considered equal to a 1.0 point change in patients with baseline EDSS < or = 5.5.

Psychometric evaluation of the multiple sclerosis impact scale (MSIS-29) for proxy use.

BACKGROUND: There may be difficulties in the use of self report measurements in patients with cognitive impairment or serious mood disturbances which interfere with reliable self assessment, as may be the case in multiple sclerosis (MS). In such cases proxies may provide valuable information. However, before using any questionnaires in a proxy sample, the questionnaire should be evaluated for proxy use. OBJECTIVE: To evaluate the psychometric properties of the 29 item Multiple Sclerosis Impact Scale (MSIS-29) when used by proxies of MS patients. METHODS: A sample of 62 partners of MS patients completed the MSIS-29. The data were evaluated for the psychometric criteria of the MSIS-29, including data quality, scaling assumptions, acceptability, reliability, validity, and responsiveness. RESULTS: Psychometric evaluation was satisfactory; data quality was high, and scaling assumptions and acceptability were good. Reliability was high (alpha>0.80). Findings were consistent with results of a psychometric evaluation in a patient sample. CONCLUSIONS: The MSIS-29 can be used reliably in proxies of patients with MS. As a next step the relation between data obtained from patients and proxies needs to be studied, focusing on factors that may affect agreement and discrepancies.