Abstract
Background and purpose
The long-term benefit of natalizumab on brain atrophy progression in multiple sclerosis (MS) patients is unknown. Our aim was to investigate its effect over 5 years.
Methods
This prospective study included 60 relapsing MS patients who started natalizumab treatment in years 2006−2007.
Results
At the 5-year follow-up, 20 patients discontinued natalizumab after an average of 29.5 cycles, 27 continued natalizumab treatment with some periods of honeymoon (average of 38.4 infusions) and 13 never stopped natalizumab (average of 60.6 infusions). In multiple linear regression analysis, adjusted for age, sex and baseline magnetic resonance imaging (MRI) status, the number of natalizumab infusions was associated with decrease of relapse rate (adjusted P = 0.037), but no association was found with the progression of disability, accumulation of lesion burden or brain volume loss. However, only one (8%) patient in the continuous monthly group experienced disability progression compared to 10 (37%) in the non-continuous and seven (35%) in the discontinuation natalizumab groups. At the follow-up, two patients had died [one from a fatal case of progressive multifocal leukoencephalopathy (PML) and one from a car accident] and 15 patients were lost to follow-up. There was another case of non-fatal PML over the follow-up.
Conclusions
In line with previous reports, MS patients with longer and continuous use of natalizumab had fewer relapses and remained stable in their disability status. No difference in lesion burden accumulation or brain atrophy development was found in relation to the duration of natalizumab use. PML occurred in 2.5% of patients in this small sample cohort. Given the increased risk of PML and uncertain benefit of prolonged natalizumab use on clinical and MRI outcomes of disease progression found in this study, a careful risk−benefit therapeutic assessment is mandatory.
Introduction
Natalizumab (Tysabri®) is a highly specific α4-integrin antagonist which improves clinical and magnetic resonance imaging (MRI) outcomes by reducing the relapse rate and disability progression in patients with relapsing−remitting (RR) multiple sclerosis (MS) [1]. Natalizumab is recommended for patients who have very active disease or who fail first-line disease-modifying therapy (DMT) [1], because its use has been linked to a serious adverse event, progressive multifocal leukoencephalopathy (PML) [2, 3].
In phase III clinical trials, natalizumab reduced inflammation in MS patients, as evidenced by a decrease in T2, T1 and contrast-enhancing (CE) lesion activity and lesion burden [4-7]. Compared with placebo, natalizumab reduced CE lesions by 92%, new/enlarging T2-hyperintense lesions by 83% and T1-hypointense lesions by 76% over 2 years [5]. Brain volume loss was greater in year 1 and less in year 2 in natalizumab-treated patients [5]. Over 2 years of treatment, the mean percentage of brain volume loss was similar between the natalizumab and placebo groups. The higher rate of brain volume loss in the first year compared to the second year of treatment was attributed to the changes in water shifts (pseudoatrophy effect) [8] induced by the potent anti-inflammatory effect of natalizumab [9]. Post-marketing observational studies corroborated that higher loss of brain volume in natalizumab patients is probably due to the pseudoatrophy effect [10-13]. The early brain volume loss (over 2 years) was attributed to the loss in white matter and not gray matter volume, as was reported in a study that included 45 MS patients on natalizumab therapy followed over 2 years, data supporting a water shift effect related to decrease of inflammation [13].
The long-term safety and effectiveness of natalizumab reported in a prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) study showed that serious adverse events, the stability of Expanded Disability Status Scale (EDSS) scores and a low relapse rate over 5 years were consistent with its known safety and efficacy profile [14]. As brain volume measure was shown to be one of the best surrogates for MS clinical disease stability, measuring the long-term effect of DMT on this specific metric could provide a more convincing therapeutic risk−benefit ratio assessment [8, 9].
Whilst the benefit of natalizumab therapy in patients with relapsing MS is well established, its use over 2 years was linked to an increased risk of PML and therefore many patients have chosen to discontinue the therapy after 2–3 years of treatment [3, 15-19]. The overall PML incidence was 3.73 cases per 1000 patients in a recently published prospective open-label study [3], which is consistent with the most recently reported PML risk in the post-marketing setting, being 4.03 cases per 1000 patients (95% confidence interval 3.71–4.36 per 1000 patients), as of 4 September 2015 [20]. The highest risk for PML in natalizumab-treated patients is in those who are John Cunningham virus (JCV) positive, have received prior immunosuppression and who exceeded a treatment duration of 24 months [20].
Therefore the aim of this study was to define the effect of long-term natalizumab therapy on the development of brain atrophy and progression of disability in relapsing MS patients treated with natalizumab over 5 years. The effect of continuous natalizumab therapy on the accumulation of lesion burden and relapses over 5 years was also investigated.
Methods
Study design and participants
This was a prospective, observational, MRI-blinded, longitudinal study, which re-evaluated at the 5-year time point natalizumab-treated relapsing MS patients who participated in an initial prospective study of voxel-wise magnetization transfer ratio (VWMTR) [21]. The original cohort consisted of 77 relapsing MS patients who initiated natalizumab therapy [21].
The baseline inclusion criteria for the 5-year follow-up study were participation in the natalizumab VWMTR study [21], age 18–65 years, diagnosis of MS according to the McDonald 2005 criteria [22] of either RR or relapsing secondary-progressive (RSP) disease type, [23] EDSS score ≤6.5, disease duration <30 years, received >1 cycle of natalizumab and fulfilled the TOUCH® (TYSABRI® Outreach: Unified Commitment to Health) enrollment requirements [24]. The exclusion criteria were the presence of relapse and steroid treatment in the 30 days preceding the 5-year MRI scan, pre-existing medical conditions known to be associated with brain pathology (cerebrovascular disease, positive history of alcohol abuse) and pregnancy.
Standard protocol approvals, registrations and patient consents
The study was approved by the Ethical Standards Committee and written consent was obtained from all study subjects (Clinicaltrials.gov identifier number NCT01847287).
Interventions
All MS patients initiated monotherapy with intravenous natalizumab (300 mg infusion every 4 weeks). Use of other DMTs was allowed upon discontinuation of natalizumab and was determined by clinician/patient decision, with no randomization. Relapses were treated with 1 g intravenous methylprednisolone for 3−5 days. Therapy for symptoms of MS, including fatigue, spasticity, depression, bowel and bladder dysfunction, pain, cognitive problems and sexual dysfunction, was allowed.
End-points
The primary end-points of the study were to determine the association between the number of natalizumab cycles and brain volume loss, lesion burden, disability progression and relapse rate over 5 years. The secondary outcomes of the study were to determine MRI and clinical changes between those patients who received natalizumab treatment for 5 years continuously on a monthly basis (continuous monthly group), those patients who received natalizumab treatment with some periods of honeymoon (non-continuous monthly group) and those patients who discontinued natalizumab treatment at some point during the follow-up and may have switched to some other DMT (discontinuation group).
Clinical and laboratory assessments
Physical examinations and neurological assessments were conducted at the baseline and the 5-year follow-up. Disability progression was defined at the 5-year visit as any 0.5-point increase in the EDSS score in patients who had a baseline EDSS score of ≥5.5, a 1.0-point increase in the EDSS score in patients who had a baseline EDSS score of ≥1.0, or any ≥1.5-point increase in the EDSS score in patients who had a baseline EDSS score of 0.0. How many RR and RSP patients progressed to secondary-progressive (SP) disease type was also evaluated.
When concerns of suspected PML were raised, the patient underwent an MRI and/or cerebrospinal fluid evaluation. Because JCV STRATIFY antibody testing was not available at baseline, it was conducted routinely only from the second and third years onwards.
Magnetic resonance imaging acquisition and analyses
Magnetic resonance imaging assessments were performed at baseline and the 5-year follow-up using the same 1.5-T General Electric Signa 4x/Lx unit (Milwaukee, WI, USA) which did not undergo hardware or software upgrades over the follow-up. For each session, a dual echo proton density/T2-weighted image (WI), fluid-attenuated inversion recovery (FLAIR), spin-echo (SE) T1-WI with and without contrast and three-dimensional spoiled gradient-recalled T1-WI were acquired using the same protocol at baseline and follow-up. The axial dual echo sequence was acquired with echo time (TE) 12/90 ms, repetition time (TR) 3000 ms, number of excitations (NEX) 1, echo train length (ETL) 14, field of view (FOV) 24 × 18 cm, matrix 192 × 256, 3 mm slice thickness (th) with a total of 48 slices, no gap. The axial FLAIR was acquired with FOV 24 × 24 cm, matrix 192 × 256, 48 slices, 3 mm th, no gap, TE 128 ms, inversion time 2000 ms, TR 8002 ms, ETL 22, NEX 1. The axial SE T1-WI was acquired with FOV 24 × 18 cm, matrix 192 × 256, 48 slices, 3 mm th, no gap, TE 9 ms, TR 600 ms, NEX 2. The contrast-enhanced SE T1-WI sequence was acquired 5 min after injection of a single dose intravenous bolus of 0.1 mmol/kg gadopentetate dimeglumine. Axial three-dimensional T1-WI scans with FOV 24 × 18 cm, matrix 192 × 256, 1.5 mm th, 128 slices, no gap, TE 7 ms, TR 24 ms, NEX 1, flip angle 30° were also acquired.
The MRI analyses were blinded to patients’ clinical characteristics or natalizumab group status. Volumetric measures were determined on three-dimensional spoiled gradient-recalled T1-WIs that were modified by using an in-house developed inpainting technique to avoid tissue misclassification [25]. Total brain tissue volume, normalized for head size, was calculated using the SIENAX method, whereas for longitudinal changes the SIENA method was applied to calculate the percentage brain volume change (PBVC) [26].
The number of brain CE lesions was based on semi-automated tracing on the digital images [27]. T2, T1 and CE lesion volumes (LVs) were measured using a semi-automated edge detection contouring-thresholding technique, as previously described [21].
Statistical analyses
Statistical analyses were performed using SPSS 21.0 (IBM, Armonk, NY, USA).
For the primary outcomes of the study multiple linear regression analysis was used in which the change in whole brain volume, CE lesion number, T2-LV, T1-LV, disability progression and relapse rate over 5 years were used as dependent variables, and the number of natalizumab cycles over 5 years was used as the independent variable. The models were run with and without adjusting for age, sex, disability status and the appropriate MRI variable at baseline, if applicable. Dependent measures were tested for normality using Q−Q plots and the Shapiro–Wilk test. To satisfy model assumptions several measures were square root transformed (T2-LV, T1-LV) or alternative statistical methods were used (CE lesion number, ordinal; disability progression and MS type, logistic; relapse rate, Poisson). The results were tested separately for all MS patients and those with RR and RSP disease type at baseline.
The secondary outcomes of the study were to determine changes in clinical and MRI measures over 5 years between continuous monthly, non-continuous monthly (discontinued more than 12 weeks) and the discontinuation natalizumab groups.
Demographic and clinical differences between the study groups over 5 years were calculated using the chi-squared test, Student’s t test and anova, and for ordinal measures using Kruskal–Wallis or Mann–Whitney U tests. Analysis of MRI characteristics over 5 years between the study groups was corrected for the respective baseline measure and, as with regression analysis, data were transformed or ranked to satisfy normality assumptions where necessary.
The minimum significance level for entry and inclusion in the final model was P < 0.05. All P values were based on two-tailed tests.
Results
Study sample, discontinuation, safety and JCV antibody status
Sixty (78%) of the original 77 relapsing MS patients enrolled in the VWMTR study [21] who initiated natalizumab treatment between 2006 and 2007 were reassessed as part of this 5-year follow-up study. Of the 17 patients lost to follow-up, two patients died whilst the other 15 patients’ data were not available as they moved from the area or left our practice. The two deaths were related: one to PML diagnosed at 4 months after completing the VWMTR study; the other death was the result of a car accident in the fourth year of the follow-up.
Demographic and disease characteristics at baseline were similar across relapsing MS patients participating in the original study [21] and in the 5-year follow-up study. At baseline, the mean age of the 5-year cohort was 41.3 years, the mean disease duration was 12.7 years and the median EDSS was 3.0. At baseline 47 patients had RR and 13 RSP disease type. At the 5-year follow-up, a total of eight MS patients developed SP disease type (Table 2).
Of the 60 patients participating in the 5-year follow-up, 20 patients discontinued natalizumab, 27 continued natalizumab treatment with some periods of honeymoon (more than 12 weeks) and 13 never stopped natalizumab (Table 1). Significant differences were found in the number of natalizumab infusions amongst the three study groups (Table 2). All MS patients in the discontinuation group received fewer than 50 cycles of natalizumab except one patient who received 55 and one who received 63 cycles, with the mean and median being around 30 cycles. In contrast, the mean and median of natalizumab cycles in the continuous monthly group was around 60, a double amount of total natalizumab infusions received compared to the discontinuation group, whilst the mean and median of the non-continuous monthly group was around 40 cycles (Table 2).
| Total (n = 60) | Continuous monthly group (n = 13) | Non-continuous monthly group (n = 27) | Discontinuation group (n = 20) | P | |
|---|---|---|---|---|---|
|
|||||
| Female, n (%) | 42 (70) | 10 (77) | 17 (63) | 15 (75) | 0.557 |
| Disease type, n (%) | |||||
| RR | 47 (78.3) | 9 (69) | 23 (85) | 15 (75) | 0.469 |
| RSP | 13 (21.7) | 4 (32) | 4 (15) | 5 (25) | |
| Age in years, mean (SD) | 41.3 (10.0) | 41.9 (8.5) | 40.4 (10.5) | 42.3 (10.7) | 0.812 |
| Disease duration in years, mean (SD) | 12.7 (8.0) | 12.7 (7.7) | 12.7 (9.3) | 12.6 (6.7) | 0.999 |
| EDSS, median (min−max) | 3.0 (0–7) | 2.5 (1–6.5) | 2.5 (0–7) | 3.25 (1.5–6.5) | 0.730 |
| CE positivity, n(%) | 11 (18) | 2 (15) | 6 (22) | 3 (15) | 0.780 |
| CE lesion number, mean (SD) | 1.0 (2.9) | 0.2 (0.6) | 0.9 (1.9) | 1.6 (4.5) | 0.767 |
| CE lesion volume, ml, mean (SD) | 0.2 (0.5) | 0.05 (0.1) | 0.2 (0.7) | 0.09 (0.2) | 0.745 |
| T2 lesion volume, ml, mean (SD) | 16.7 (18.3) | 18.3 (15.7) | 18.1 (20.7) | 13.8 (16.7) | 0.490 |
| T1 lesion volume, ml, mean (SD) | 4.8 (6.3) | 8.7 (8.9) | 3.8 (5.1) | 3.5 (4.9) | 0.042 |
| NBV, ml, mean (SD) | 1489.5 (104.4) | 1494.4 (103.8) | 1471 (98.5) | 1494.9 (112.4) | 0.778 |
| Total (n = 60) | Continuous monthly group (n = 13) | Non-continuous monthly group (n = 27) | Discontinuation group (n = 20) | P | |
|---|---|---|---|---|---|
|
|||||
| Number of natalizumab infusions, mean (SD), median
(min−max) |
40.2 (17.3) 45
(2–72) |
60.6 (5.3) 61
(50–72) |
38.4 (9.8) 39
(15–50) |
29.5 (19.2) 30.5
(2–63) |
<0.0001 |
| JCV antibody status, n (%) | |||||
| Positive | 26 (43) | 2 (15) | 9 (33) | 15 (75) | 0.001 |
| Negative | 34 (56) | 11 (84) | 18 (66) | 5 (25) | |
| Disease type, n (%) | |||||
| RR | 47 (78) | 10 (77) | 20 (74) | 17 (85) | 0.819 |
| RSP | 5 (8) | 1 (9) | 3 (11) | 1 (5) | |
| SP | 8 (13) | 2 (15) | 4 (15) | 2 (10) | |
| Disease-modifying treatment, n (%) | |||||
| Natalizumab | 40 (67) | 13 (100) | 27 (100) | 0 (0) | NA |
| Interferon-beta | 7 (12) | 7 (35) | |||
| Glatiramer acetate | 4 (7) | 4 (20) | |||
| Fingolimod | 1 (2) | 1 (5) | |||
| Othera | 5 (8) | 5 (15) | |||
| No therapy | 3 (5) | 3 (15) | |||
| Number of relapses, mean (SD) | 1.5 (1.9) | 0.3 (0.5) | 1.6 (1.4) | 2.4 (1.7) | 0.024 |
| EDSS, median (min−max) | 3.0 (0–7) | 3.0 (6.5) | 3.0 (6.0) | 3.3 (6.5) | 0.879 |
| Absolute change, mean (SD) | 0.1 (1.5) | −0.4 (1.7) | 0.3 (1.5) | 0.2 (1.5) | 0.443 |
| Disability progression,n (%) | 18 (30) | 1 (7.7) | 10 (37) | 7 (35) | 0.138 |
| CE positivity, n (%) | 1 (2) | 0 (0) | 0 (0) | 1 (5) | 0.380 |
| CE lesion number, mean (SD)b | 0.4 (2.8) | 0 | 0 | 1.1 (4.7) | 0.342 |
| T2 lesion volume, ml, mean (SD)c | 18.0 (22.3) | 19.8 (19.5) | 16.4 (18.9) | 18.5 (28.7) | 0.227 |
| Absolute change, ml, mean (SD) | 1.1 (10.3) | 1.5 (5.4) | −1.6 (6.9) | 4.8 (15.1) | 0.151 |
| T1 lesion volume, ml, mean (SD)c | 6.6 (8.4) | 8.6 (8.3) | 5.5 (7) | 6.8 (10.3) | 0.206 |
| Absolute change, ml mean (SD) | 1.9 (0.7) | 0.1 (2.9) | 1.7 (3.5) | 3.2 (6.6) | 0.052 |
| PBVC, mean (SD) | −4.6 (2.5) | −3.9 (2.5) | −5 (1.8) | −4.7 (3.2) | 0.496 |
Of the 20 patients who discontinued natalizumab, one patient developed breast cancer and was discontinued from natalizumab in the first 2 years, as previously reported [21]. Another natalizumab-treated patient (a 43-year-old female with RRMS) developed PML and was discontinued over the third year of treatment. This patient survived without important physical impairment and participated in the 5-year follow-up study. The reasons for natalizumab discontinuation in the other 18 MS patients were JCV positive antibody testing (13) and/or use of immunosuppressive therapy in the past (two), patient decision (two) and non-compliance to treatment regimen (one). The type of DMT used after stopping natalizumab is listed in Table 2.
At the 5-year follow-up, 26 (43%) patients were JCV antibody positive (Table 1). Of those, only 15 JCV antibody positive patients discontinued the drug and 11 continued the therapy (Table 2).
Primary outcomes – multiple regression analyses findings
Table 3 shows unadjusted and adjusted multiple regression analysis according to the treatment status at the 5-year follow-up. In baseline models adjusted for age, sex, disability status and the appropriate MRI variable at baseline, no associations between the number of natalizumab infusions over 5 years and change in T2-LV (P = 0.951), T1-LV (P = 0.136), PBVC (P = 0.418), EDSS score absolute change (P = 0.335), disability progression (P = 0.210) or MS disease type (P = 0.614) were found (Table 3). However, there was a relationship between the higher number of natalizumab infusions and lower relapse rate (P= 0.037). In baseline unadjusted models, no associations between the number of natalizumab infusions over 5 years and change in MRI measures was found (Table 3). However, a relationship between the higher number of natalizumab infusions and lower relapse rate was found (P = 0.007). No association between change in EDSS absolute score or disability progression and the higher number of natalizumab infusions was found in either unadjusted or adjusted regression models (Table 3).
| Unadjusted | Adjusted for age, sex, EDSS and MRI | |||||||
|---|---|---|---|---|---|---|---|---|
| Estimate | 95% CI | P | R2 | Estimate | 95% CI | P | R2 | |
|
||||||||
| PBVC | 0.010 | −0.030, 0.049 | 0.449 | .005 | 0.016 | −0.023, 0.055 | 0.418 | .131 |
| CE-LN change | 0.055 | −0.082, 0.191 | 0.433c | .021 | 0.050 | −0.174, 0.273 | 0.663c | .605 |
| T2-LV change, cm3 | −0.013 | −0.178, 0.152 | 0.914 | .001 | −0.014 | −0.174, 0.146 | 0.951 | .455 |
| T1-LV change, cm3 | −0.026 | −0.096, 0.044 | 0.149 | .034 | −0.032 | −0.102, 0.037 | 0.136 | .203 |
| EDSS change | −0.011 | −0.033, 0.011 | 0.311 | .016 | −0.011 | −0.033, 0.011 | 0.335 | .101 |
| Relapse rate | −0.014 | −0.024, −0.004 | 0.007a | .123 | −0.011 | −0.022, −0.001 | 0.037a | .317 |
| Disability progression | 1.023 | 0.990, 1.057 | 0.173b | .044 | 1.021 | 0.988, 1.056 | 0.210b | .087 |
| MS type (RR to RR/SP) | 0.995 | 0.690, 1.031 | 0.784b | .002 | 0.989 | 0.947, 1.033 | 0.614b | .264 |
To test whether there were differences in RR or RSP disease type, the primary outcome multiple regressions were recalculated separately for each group. Confirmatory analyses within separate RR and the small RSP disease groups yielded similar MRI results (data not shown), whereas the effect of natalizumab on reducing relapse rate was significant only in the RR disease type (P = 0.002).
Secondary outcomes – differences at 5 years between continuous monthly, non-continuous monthly and the discontinuation natalizumab groups
Demographic, clinical and MRI characteristics at baseline are listed in Table 1. No differences were found between the three study groups except for higher T1-LV in the continuous monthly group (P = 0.042).
Group-wise (three level) clinical and MRI outcomes at 5 years are listed in Table 2. There was a higher number of natalizumab infusions, as expected, in the continuous natalizumab group (P < 0.001). Patients who discontinued treatment with natalizumab had more frequent JCV antibody positivity testing (P = 0.001). There was a higher number of relapses over 5 years in the groups who discontinued natalizumab (P = 0.024). No differences in change in EDSS absolute score, disability progression and MS disease type at the 5-year follow-up were found between the three treatment groups. However, the MS patients remained stable with only one (8%) patient in the continuous monthly group experiencing disability progression compared to 10 (37%) in the non-continuous and seven (35%) in the discontinuation natalizumab groups. No MRI differences on lesion burden or PBVC were found between the three treatment groups at the 5-year follow-up.
Discussion
This study examined the effect of natalizumab infusions on the evolution of various MRI and clinical outcomes in relapsing MS patients over 5 years. The main findings of the study are that MS patients who continued natalizumab therapy for a longer period of time (>4 years) showed fewer relapses and remained stable from a disability point of view. In the continuous monthly group, only one MS patient had disability progression, supporting a long-term benefit of natalizumab [14]. The discontinuation and non-continuous monthly groups showed higher disability progression rates (35% and 37%, respectively), but these differences did not reach significance compared to the continuous monthly natalizumab group. It cannot be excluded that the most aggressive cases were selected out of the continuous treatment group, which could have contributed to better clinical outcomes in patients who did continue natalizumab therapy for 5 years. This is less likely as, of 20 MS patients who discontinued treatment with natalizumab during the study, 13 (65%) did so because of JCV antibody status positivity, five (25%) because of their own decision and two (10%) because of the safety issues.
One of the central aims of this study was to investigate the effect of natalizumab on long-term brain volume loss. Because the pseudoatrophy effect [8] of a potent anti-inflammatory therapy like natalizumab can affect water shift fluids over 2 but not 3 years [12], it was hypothesized that the 5-year follow-up would be sufficiently long to examine the effect of natalizumab infusions on brain atrophy progression. The number of natalizumab infusions did not show a significant effect on the accumulation of lesion burden and on brain atrophy progression over 5 years in the regression analysis. When data were analyzed according to treatment status, no significant differences were found between the three groups, although the continuous monthly group developed less brain volume loss (3.9%) compared to the discontinuation (4.7%) and non-continuous monthly (5%) natalizumab groups. Future larger long-term studies should explore the rate of brain volume changes and disability progression in patients treated with natalizumab and other DMTs.
It is important to note that a somewhat higher rate of brain volume loss detected in the discontinuation natalizumab group may also be related to a possibly more significant pseudoatrophy effect after the third and fourth year of treatment, because of a switch from natalizumab treatment to other DMTs due to JCV positivity. An additional concern is the disease reactivation after natalizumab discontinuation. A return to the pre-study disease activity was reached by 4 months after discontinuation of natalizumab, during the therapy cessation period [28]. The concern of a possible ‘rebound’ effect after natalizumab discontinuation can be identified more frequently on MRI [29]. In the current study, only one patient presented with 21 CE lesions 8 months after discontinuing natalizumab. Because increase in inflammation may have an impact on brain volume measures, the primary analyses were repeated by excluding this patient; however, the findings remained similar.
The current study was designed to include MS patients who participated in the VWMTR study and were enrolled in a relatively short period of time (14 months) between years 2006 and 2007 [21]. This allowed us to follow all patients for a minimum of 5 years. When the study started, the risk of PML in the general JCV positive population was unknown. During the follow-up years, the risk tolerance of patients and their caregivers has changed, as the risk for PML became better defined [3]. The concern of increased risk for PML is limiting long-term use. In anti-JCV antibody negative patients the risk is <1/1000 [20]. A recent Food and Drugs Administration re-evaluation of the natalizumab package insert indicated that the estimated risk for developing PML in patients treated with natalizumab for 24 cycles who are anti-JCV antibody positive remains 1/1000 in patients with prior immunosuppressant use and <1/1000 in patients without prior immunosuppressant use [30]. However, the risk is increased to 12/1000 in patients with prior immunosuppressant use after exposure to 25−48 cycles and 3/1000 in patients without prior immunosuppressant use. Even higher exposure of 49–72 months was found to be associated with a risk of 13/1000 in patients with prior immunosuppressant use and 6/1000 in patients without prior immunosuppressant use [20]. Of the 77 original patients participating in the VWMTR study [21], two (2.5%) patients developed PML, for one of whom it was fatal. The availability for JCV STRATIFY testing became a very important tool in monitoring patients treated with natalizumab in recent years. None of the JCV negative patients developed PML over 5 years in the current study.
The strength of this study is that the long-term follow-up retained almost 80% of the original study sample. However, there are also limitations to this study, the main one of which is a relatively small sample size, especially in the RSP group, although no formal power calculations regarding the number of MS patients needed to show changes in brain atrophy have been conducted beyond 36 months of follow-up [31]. Whilst the MRI evaluators were blinded to the clinical characteristics, the clinical personnel were not. In addition, changes in brain volume can be influenced by factors such as dehydration, smoking, increased titer of Epstein−Barr virus, cardiovascular risk factors, decreased vitamin D, altered lipid profile, the presence of cardiovascular risk factors and oligoclonal bands, amongst others [32-38], which were not taken into account in the analyses of the brain volume changes. Another potential limitation of this study is related to the introduction of other DMTs upon discontinuation of natalizumab, which could have reduced between-group differences in outcome variables. Finally, the results of the study could have been interpreted in a more appropriate fashion if a control MS group on homogeneous DMT followed with identical study procedures was included in the original design of the study.
Multiple sclerosis patients with longer use of natalizumab had fewer relapses and remained stable in their disability status. No difference in lesion burden accumulation or brain atrophy development was found in relation to the duration of natalizumab use. These findings should be interpreted with caution, given that a substantial number of patients were lost to follow-up, discontinued natalizumab over the follow-up or received natalizumab treatment with some periods of honeymoon. PML occurred in 2.5% of patients in this sample cohort. Given the increased risk of PML and the uncertain benefit of prolonged natalizumab use on clinical and MRI outcomes of disease progression found in this study, a careful risk−benefit therapeutic assessment is mandatory.
ARYAN'S BLOG 