Progressive multifocal leukoencephalopathy and multiple sclerosis: Lessons from natalizumab

Three patients have developed progressive multifocal leukoencephalopathy while being treated with natalizumab for their autoimmune diseases. One patient had relapsing-remitting multiple sclerosis (RRMS), one had Crohn’s disease, and one (who had been enrolled in an RRMS phase III trial) had no evidence of multiple sclerosis on autopsy. The patient with RRMS now has severe, permanent neurologic damage and the other two patients died. In this article, we recommend revised entry and diagnostic criteria to prevent enrollment of RRMS patients with a favorable prognosis or questionable diagnosis into trials of drugs with unknown safety profiles. In light of the risk of progressive multifocal leukoencephalopathy, we strongly recommend that RRMS patients who are at low risk of disability not be treated with natalizumab. Finally, we discuss what additional natalizumab efficacy data need to be presented before any decisions should be made about treating RRMS patients with a high risk of developing long-term disability.     

Progressive multifocal leukoencephalopathy and natalizumab

Natalizumab (TYSABRI^®), a specific α4-integrin antagonist, is approved as a second-line treatment of relapsing-remitting MS (RRMS) patients who fail therapy with interferons or as first-line treatment of patients with highly active relapsing-remitting disease. Since the market introduction of natalizumab as a monotherapy in July of 2006, 111 cases of PML have been reported in natalizumab-treated MS patients as of April 2011. This review focuses on the available data regarding risk stratification for PML under long-term natalizumab therapy, and summarizes the current approach for PML management, as a natalizumab treatment complication is not necessarily associated with a fatal outcome. There is a need for development of surrogate markers that would help to better define the risk of PML in individual patients.     

Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing‐remitting multiple sclerosis

Background: Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease‐modifying treatments (DMTs). Methods: A retrospective, observational study was carried out. All patients (n = 45) initiated natalizumab after experiencing at least 1 relapse in the previous year under interferon‐beta (IFNB) or glatiramer acetate (GA) treatments. The patients also had at least 1 gadolinium‐enhancing (Gd+) lesion on their baseline brain MRI. Expanded Disability Status Scale (EDSS) scores, and performance on the Timed 25‐Foot Walk Test and on the Timed 100‐Metre Walk Test were prospectively collected every 4 weeks during 44 weeks of natalizumab treatment. Brain MRI scans were performed after 20 and 44 weeks of treatment. Results: Sixty‐two per cent of patients showed no clinical and no radiological signs of disease activity, and 29% showed a rapid and confirmed EDSS improvement over 44 weeks of natalizumab therapy. Patients with improvement on the EDSS showed similar levels of baseline EDSS and active T1 lesions, but had a significantly higher number of relapses, and 92% of them had experienced relapse‐mediated sustained EDSS worsening in the previous year. A clinically meaningful improvement in ambulation speed was observed in approximately 30% of patients. Conclusions: These results indicate that natalizumab silences disease activity and rapidly improves disability status and walking performance, possibly through delayed relapse recovery in patients with RRMS who had shown a high level of disease activity under other DMTs.     

Efficacy of natalizumab in second line therapy of relapsing–remitting multiple sclerosis: results from a multi-center study in German speaking countries

Background:  Natalizumab has been recommended for the treatment of relapsing–remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population.
Method:  Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab ≥12 months prior to study conduction.
Results:  Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 ± 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >/= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>/= 2 relapses in the year and >/= 1 Gadolinium (Gd)+ lesion at study entry, n  = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity).
Conclusion:  Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.     

Disease reactivation after switching from natalizumab to daclizumab

Discontinuation of natalizumab can lead to severe rebound of disease activity in patients with relapsing–remitting multiple sclerosis (RRMS); nevertheless, the treatment regimen in this clinical situation remains controversial. We report the case of a 25-year-old male patient with RRMS who was clinically stable under 3 years of natalizumab before treatment was stopped due to progressive multifocal leucencephalopathy (PML) safety concerns. After initiation of daclizumab, the patient suffered from disease reactivation, which was ultimately controlled by intravenous methylprednisolone and alemtuzumab treatment. Therefore, in some patients, daclizumab might not be sufficient to control disease activity after discontinuing natalizumab treatment.     

Intraoperative neurophysiological monitoring during surgery for Chiari malformations

Natalizumab has been demonstrated to be highly effective in reducing measures of disease activity, such as clinical relapse rate, and gadolinium (Gd)-enhancing and new or enlarging T2 lesions appearance in patients with relapsing remitting multiple sclerosis (RRMS). Up to date, no data on the effect of natalizumab on cortical pathology have been published. We studied the efficacy of natalizumab in preventing the accumulation of new cortical lesions (CL) in 35 RRMS patients treated for 1 year. While confirming the high impact of natalizumab in reducing the relapse rate (>90%, 85% relapse-free patients) and white matter (WM) pathology (80% patients free from new T2 WM lesions, 97% patients free from new T1 Gd-enhancing lesions), we found that this monoclonal antibody was highly effective in reducing the appearance of new CL (86% patients free from new CL). Our findings indicate a relevant activity of natalizumab against cortical inflammation in RRMS.     

Evolución de una serie de pacientes con esclerosis múltiple remitente-recurrente tratados con natalizumab durante 7 años mediante el parámetro no evidencia enfermedad activa

IntroductionThe safety and effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in clinical trials. However, due to the limitations of these trials, it is important to know how the condition behaves under long-term clinical practice conditions.ObjectiveTo determine the long-term effectiveness of natalizumab in patients with RRMS by means of annual evaluation of the “no evidence of disease activity” (NEDA) parameter, which includes number of relapses, disability (measured with the Expanded Disability Status Scale), and brain MRI parameters.Patients and methodsWe performed a retrospective study of patients with RRMS from 3 centres who were treated with one or more doses of natalizumab. Each year, we evaluated NEDA status and safety based on the percentage of patients who discontinued treatment with natalizumab and experienced adverse reactions.ResultsThe study included 89 patients, most of whom received treatment for 2 to 4 years, with a follow-up period of up to 7 years. Natalizumab significantly reduces the radiological and clinical progression of the disease, as well as the annual rate of relapses. The NEDA parameter demonstrates the effectiveness of the drug, with values of 75.28% for year one and 66.67% for year 7. Twenty-five patients (28.1%) dropped out after a median of 4 years. Fourteen of these patients (56%) dropped out due to the appearance of anti–JC virus antibodies, either in isolation or associated with another cause. Four dropouts (16%) were due to treatment ineffectiveness, with one patient dying due to progressive multifocal leukoencephalopathy.ConclusionsNatalizumab is highly effective as measured by the NEDA long-term remission parameter.     

Latent tuberculosis seems not to reactivate in multiple sclerosis patients on natalizumab

Current safety recommendations for multiple sclerosis (MS) patients who are considered for natalizumab do not specify how to screen for latent tuberculosis (LTB). Only chest X-ray is recommended as a routine, and follow-up depends on its results. The incidence of TB in Spain is high and the risk of a LTB reactivation due to natalizumab is unknown. Our objective is to describe in our clinical practice if following the current recommendations for the MS population on natalizumab allows identifying patients with a LTB, as well as the risk for TB reactivation. Our study demonstrated that, in our environment, current recommendations are not sensitive enough to identify cases of LTB, though no cases of active TB were observed. Considering the lack of documented active TB cases worldwide among natalizumab patients, we suggest that these safety measures are probably unnecessary, even in countries with a high TB incidence.     

Demographic and clinic characteristics of French patients treated with natalizumab in clinical practice

Natalizumab is the first selective adhesion molecule inhibitor indicated for treatment of active relapsing-remitting multiple sclerosis (RRMS). Natalizumab has been available in France since April 2007. The aims of this study are to analyze demographic, clinical, and tolerance data from French patients with RRMS treated with natalizumab in actual clinical practice and to draw comparisons with patients in the pivotal AFFIRM study. All patients with RRMS in the Nord-Pas de Calais and Alsace regions of France treated with natalizumab at any time since April 2007 were included. Variables analyzed included previous treatments; disability status [Expanded Disability Status Scale (EDSS) score]; annualized relapse rate (ARR) at baseline and after 12 months of treatment; and adverse events. Data from 384 patients (72% female) were evaluated. Mean baseline EDSS score was 3.53 and mean baseline ARR was 2.19, both significantly greater than in AFFIRM. One hundred twenty-seven patients completed 12 months of treatment; mean EDSS score in this group was 3.02 (14% reduction) and mean ARR was 0.59 (73% reduction). Although these patients had significantly different baseline characteristics and greater disability compared with patients receiving natalizumab in AFFIRM, average disability remained stable and ARR declined by 73%. Tolerability was similar to that observed in AFFIRM.     

Natalizumab prevents the accumulation of cortical lesions in relapsing remitting multiple sclerosis: a preliminary report

Natalizumab has been demonstrated to be highly effective in reducing measures of disease activity, such as clinical relapse rate, and gadolinium (Gd)-enhancing and new or enlarging T2 lesions appearance in patients with relapsing remitting multiple sclerosis (RRMS). Up to date, no data on the effect of natalizumab on cortical pathology have been published. We studied the efficacy of natalizumab in preventing the accumulation of new cortical lesions (CL) in 35 RRMS patients treated for 1 year. While confirming the high impact of natalizumab in reducing the relapse rate (>90%, 85% relapse-free patients) and white matter (WM) pathology (80% patients free from new T2 WM lesions, 97% patients free from new T1 Gd-enhancing lesions), we found that this monoclonal antibody was highly effective in reducing the appearance of new CL (86% patients free from new CL). Our findings indicate a relevant activity of natalizumab against cortical inflammation in RRMS.

     

Kinetics and incidence of anti-natalizumab antibodies in multiple sclerosis patients on treatment for 18 months

Natalizumab is a monoclonal antibody shown to be highly effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Patients treated with natalizumab can develop antibodies directed against this agent that may affect the efficacy and safety of the drug. In this observational study, the kinetics of the appearance and the incidence of anti-natalizumab antibodies were followed prospectively for 18 months in a cohort of 64 consecutive patients treated with natalizumab for relapsing MS. Blood samples were drawn immediately before starting natalizumab therapy and each month afterwards. The presence of antibodies against natalizumab was assessed by enzyme-linked immunosorbent assay (ELISA) in all patients. Anti-natalizumab antibodies were detected in nine (14.1%) natalizumab-treated patients, three (4.68%) of whom were transiently positive while six (9.37%) were persistently positive (these patients discontinued natalizumab). All positive titres were observed during the first 4 months of treatment. One patient with a hypersensitivity reaction also had persistent antibodies. We conclude that antibodies against natalizumab develop early, within the first 6 months of therapy with natalizumab. Although no antibodies were detected after 4 months of therapy in this particular study, this does not rule out their development later on in exceptional cases.     

Early relapses after the first dose of natalizumab in active multiple sclerosis patients

BackgroundNatalizumab is prescribed in Italy in patients who experienced at least two clinical relapses during a 12-month therapy with other approved immunomodulatory agents.ResultsIn 7 of 35 patients selected on the basis of these recommendations, we have observed clinical relapses occurring within 24 h after the first dose of natalizumab.ConclusionThe mechanism by which a first injection of natalizumab may precipitate a clinical relapse in patients with MS is unknown. We speculate that natalizumab can promote the release of inflammatory mediators from lymphocytes present in the central nervous system at the time of the first infusion, thus favoring the clinical manifestation of a pre-existing active lesion.     

Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring

Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.     

Natalizumab reduces serum pro-angiogenic activity in MS patients

Angiogenesis has been implicated in the pathobiology of multiple sclerosis (MS). Osteopontin exerts a pro-angiogenetic effect and is increased in body fluid of MS patients. To evaluate the effect of 1 year natalizumab treatment on serum pro-angiogenic activity and on plasma osteopontin levels in relapsing (RR) MS patients. Ten RRMS patients scheduled for natalizumab treatment were enrolled and evaluated at baseline and after 1-year natalizumab treatment. Pro-angiogenic activity was assessed by a chick embryo chorioallantoic membrane assay (CAM), osteopontin levels were evaluated by an enzyme-linked immunosorbent assay. Plasma and serum samples of 10 treatment-naïve RRMS and 10 healthy controls (HCs) were used as controls of baseline evaluations. Both treatment-naïve and natalizumab scheduled RRMS patients had higher baseline vessel density (22.0?±?3.9 and 22.5?±?2.6, p?<?0.0001) and higher osteopontin levels (65.7?±?24.3 ng/ml and 65.9?±?16.6 ng/ml, p?=?0.019 and p?=?0.029, respectively) than HCs (9.0?±?2.2; 48.5?±?7.8 ng/ml, respectively). Baseline osteopontin levels and vessel density were significantly correlated (rs?=?0.373, p?=?0.043). After 1 year of treatment, the number of vessels and the osteopontin levels, were significantly reduced (11.9?±?2.1, p?<?0.005; 49.3?±?20.0 ng/ml, p?=?0.028). Our results suggest that natalizumab could exert its anti-inflammatory properties also by inhibiting the angiogenetic mechanisms in RRMS patients.     

Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

The clinical and radiologic impact of natalizumab (Tysabri) as therapy for multiple sclerosis (MS) is assessed. On the basis of Class I evidence, natalizumab has been demonstrated to reduce measures of disease activity and to improve measures of disease severity in patients with relapsing-remitting (RR) MS (Level A). The relative efficacy of natalizumab compared to current disease-modifying therapies cannot be defined accurately (Level U). Similarly, the value of natalizumab in the treatment of secondary progressive (SP) MS is unknown (Level U). The value of combination therapy using natalizumab and interferon in the treatment of RRMS is also unknown (Level U). There is an increased risk of developing progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy) and possibly an increased risk of other opportunistic infections (Level C). The PML risk in a pooled clinical trial cohort has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this figure could change in either direction with more experience with the drug.     

Effect of natalizumab on clinical and radiological disease activity in a French cohort of patients with relapsing-remitting multiple sclerosis

"Disease activity free" in relapsing-remitting multiple sclerosis (RRMS) is a new concept introduced by the results of the AFFIRM study. Our objective was to analyze the clinical and radiological efficacy of natalizumab treatment in actual clinical practice and compare it with the post hoc analysis of the AFFIRM study. All patients with RRMS who began treatment with natalizumab at our two French MS centres between April 2007 and May 2008 were included and followed-up for at least 2 years. No measurable disease activity ("disease activity free") was defined as no activity on clinical measures (no relapses and no sustained disability progression) and radiological measures (no gadolinium-enhancing lesions and no new T2-hyperintense lesions on cerebral MRI). A total of 193 patients were included. Natalizumab was discontinued in 25.9% of cases before the completion of 2 years of treatment. In our cohort, we observed patients with more severe disease than in the AFFIRM study. The proportion of patients remaining free of clinical activity during 2 years of treatment was lower than in the AFFIRM study (37.8% vs. 64.3%). The proportion of patients remaining free of radiological activity during 2 years of treatment was higher than in the AFFIRM study (68.9% vs. 57.7%), while the proportion of patients remaining free of disease activity during 2 years of treatment was comparable to the AFFIRM study (33.3% vs. 36.7%). Natalizumab seems to be as effective in a real-life setting as in pivotal and post hoc studies. The confirmation of such benefits is important because of the progressive multifocal leukoencephalopathy risk.     

Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients

A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3–12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval [CI] 0.88–1.00), 0.47 (95 % CI 0.43–0.52) during natalizumab therapy, 0.63 (95 % CI 0.51–0.76) 1–6 months after natalizumab and 0.55 (95 % CI 0.42–0.70) 7–12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.     

What happens when natalizumab therapy is stopped?

Natalizumab is an α-4 integrin antagonist used for the treatment of relapsing multiple sclerosis (MS). Concerns with the drug have a risen owing to a heightened risk of progressive multifocal leukoencephalopathy, which has caused some physicians to interrupt or stop treatment altogether. The article under review evaluates the safety of natalizumab treatment interruption, including the rate and magnitude of the return of MS disease activity toward baseline levels by clinical and MRI measures. The investigators found that by 4-7 months after natalizumab treatment interruption, MS disease activity began to reach baseline levels, which is consistent with the known elimination kinetics of natalizumab. The duration of prior natalizumab exposure or alternate MS treatments during interruption was demonstrated to not affect return of disease activity. Despite nearly similar disease activity after natalizumab treatment, patients with highly active disease prior to treatment had a return of disease activity that was greater in magnitude when compared with those with less active disease. Most significantly, the study did not show evidence of rebound following natalizumab cessation. We agree with these conclusions, but note that a subgroup of MS patients may demonstrate highly active disease after natalizumab cessation.     

Differential Effects of Fingolimod and Natalizumab on Magnetic Resonance Imaging Measures in Relapsing–Remitting Multiple Sclerosis

Fingolimod and natalizumab are approved disease-modifying drugs in relapsing–remitting multiple sclerosis (RRMS). The two drugs have different modes of action and may therefore influence different aspects of MS-related tissue damage. In this retrospective cohort study, we longitudinally compared patients treated with fingolimod and patients treated with natalizumab by measures based on structural magnetic resonance imaging (MRI). We included patients with RRMS given that two standardized MRI scans under the same drug were available with an interval of at least 6 months both from therapy start to baseline scan and from baseline scan to follow-up scan. After matching for age, baseline and follow-up scans from 93 patients (fingolimod, 48; natalizumab, 45) were investigated. Mean follow-up time was 1.9 years. We determined the number of new white matter lesions as well as thalamic, cortical, and whole-brain atrophy. After scaling for time of the interscan interval, measures were analyzed by group comparisons and, to account for demographic and clinical characteristics, by multiple regression models and a binary logistic regression model. Compared to natalizumab, fingolimod treatment went along with more new white matter lesions (median [interquartile range, IQR] 0.0 [0.0; 0.7] vs. 0.0 [0.0; 0.0] /year; p < 0.01) whereas whole-brain atrophy was lower (median [IQR] 0.2 [0.0; 0.5] vs. 0.5 [0.2; 1.0] %/year; p = 0.01). These significant differences were confirmed by multiple regression models and the binary logistic regression model. In conclusion, our observation is compatible with stronger neuroprotective properties of fingolimod compared to natalizumab.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01118-2.