Paradoxically aggressive multiple sclerosis in the face of natalizumab therapy

In the pivotal trials of natalizumab in the treatment of relapsing-remitting multiple sclerosis (AFFIRM and SENTINEL), a dramatic reduction in relapse rate, new or enlarging T2-hyperintense lesions, and mean number of gadolinium-enhancing lesions was observed. While both relapses and new MRI lesions were observed in these trials, there has been no comment on the presence of aggressive disease in the face of natalizumab treatment. I report a 31-year-old woman with relapsing remitting MS of 12 years duration who developed aggressive demyelinating disease four months after the initiation of natalizumab. The clinical worsening was accompanied by a significant increase in new large T2-hyperintense signal abnormalities and in both solid and C-shaped contrast-enhancing lesions. Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course. Neutralizing antibodies to natalizumab were not detected. She subsequently responded to combination therapy of pulsed methylprednisolone and daily glatiramer acetate.     

Natalizumab: targeting alpha4-integrins in multiple sclerosis

In 1992, it was shown that monoclonal antibodies blocking alpha(4)-integrins prevent the development of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS). As alpha(4)beta(1)-integrin was demonstrated to mediate the attachment of immune-competent cells to inflamed brain endothelium in experimental autoimmune encephalomyelitis, the therapeutic effect was attributed to the inhibition of immune cell extravasation and inflammation in the central nervous system. This novel therapeutic approach was rapidly and successfully translated into the clinic. The humanized anti-alpha(4)-integrin antibody natalizumab demonstrated an unequivocal therapeutic effect in preventing relapses and slowing down the pace of neurological deterioration in patients with relapsing-remitting MS in phase II and phase III clinical trials. The occurrence of 3 cases of progressive multifocal leukoencephalopathy in patients treated with natalizumab led to the voluntary withdrawal of the drug from the market. After a thorough safety evaluation of all patients receiving this drug in past and ongoing studies for MS and Crohn's disease, natalizumab again obtained approval in the US and the European Community. A treatment targeting leukocyte trafficking in MS has now re-entered the clinic. Further thorough evaluation is necessary for a better understanding of the risk-benefit balance of this new treatment option for relapsing MS. In this review, we discuss the basic mechanism of action, key clinical results of clinical trials and the emerging indication of natalizumab in MS.     

Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy

To measure the prevalence of JCV-specific antibodies in a French cohort of MS patients treated with natalizumab and to identify risk factor(s) of JCV seropositivity. Progressive multifocal leukoencephalopathy (PML) risk may be stratified by anti-JCV antibody status, duration of natalizumab therapy (≥24?months) and prior exposure to immunosuppressive (IS) drugs. No data are available in France on the prevalence of anti-JCV antibodies and distribution of PML risk factors in patients treated with natalizumab. Sera of 361 patients under natalizumab therapy in two MS centers were analyzed using a previously validated ELISA test. We studied different characteristics: demographic, ethnic, radiological, clinical, prior use of immunomodulatory (IM) or IS drugs and natalizumab exposure duration. The JCV seropositivity rate was 51?% for the whole cohort. Mean natalizumab exposure duration was 27.27?months?±?15.57 (mean?±?SD), and prior use of IS drugs was observed in 15.24?% of patients. Twenty-three patients (6.4?%) presented the three PML risk factors. By multivariate analysis, presence of anti-JCV antibodies was significantly linked to age, North African origin and natalizumab exposure duration. Anti-JCV antibody prevalence was similar to previously published data. Anti-JCV antibody status was linked to age. We also suggested that anti-JCV antibody status could be linked to natalizumab exposure duration and ethnic characteristics.     

Clinical failure of natalizumab in multiple sclerosis: Specific causes and strategy

BackgroundNatalizumab is a very effective treatment of multiple sclerosis (MS). Failure is rare and should lead to consider some specific etiologies. The purpose of our study was to describe causes of subacute neurological events under natalizumab.MethodsObservational single-center retrospective study in the MS expert center of Lyon, France. Inclusion criteria: any patient with definite MS who received at least three infusions of natalizumab between April 2007 and February 2017. Clinical data were extracted from the Lyon EDMUS/OFSEP database. Events of interest: occurrence of a subacute neurological deficit, characterized by new clinical symptoms. We excluded pseudo-relapses and progression.FindingsA subacute neurological deficit occurred in 35 cases, for 607 patients treated with natalizumab. Ten patients presented natalizumab antibodies, nine had progressive multifocal leukoencephalopathy (PML), five presented an isolated subacute neurological deficit and two had AQP4 antibodies. No myelin oligodendrocyte glycoprotein (MOG) antibodies were found.InterpretationThe occurrence of an acute or subacute neurological deficit with natalizumab is rarely a MS relapse and should lead systematically to explore some important alternate etiologies, eliminating PML first.     

Drug insight: using monoclonal antibodies to treat multiple sclerosis

Multiple sclerosis (MS) is an immunopathological, presumably autoimmune, disease of the CNS. Several immunomodulatory treatments, including various preparations of interferon-beta, glatiramer acetate and mitoxantrone, have been approved for MS therapy. Because these agents are only partially effective, the search for better therapies continues. Therapeutic monoclonal antibodies (mAbs), a class of biotechnological agents, allow the precise targeting of molecules involved in pathological processes. Therapeutic mAbs have shown much promise in the treatment of many disorders, including inflammatory and putative autoimmune diseases such as MS. These agents have intrinsic limitations, however, such as induction of neutralizing 'anti-antibodies', systemic inflammatory reactions and severe adverse effects, some of which remain to be explained. Most notably, natalizumab (Tysabri), a mAb against alpha4 integrin, was very effective in suppressing MS activity, but had to be withdrawn from the market because several treated patients developed progressive multifocal leukoencephalopathy. This article reviews the state of development of various therapeutic mAbs for MS treatment.     

Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis

Progressive multifocal leukoencephalopathy (PML) is an uncommon and often fatal demyelinating disease of human central nervous system, which is caused by reactivation of the polyomavirus JC (JCV). PML generally occurs in patients with profound immunosuppression such as AIDS patients. Recently, a number of PML cases have been associated with administration of natalizumab for treatment of multiple sclerosis (MS) patients. Diagnosis and management of PML became a major concern after its occurrence in multiple sclerosis patients treated with natalizumab. Diagnosis of PML usually rests on neuroimaging in the appropriate clinical context and is further confirmed by cerebrospinal fluid polymerase chain reaction (PCR) for JCV DNA. Treatment with antiretroviral therapies in HIV-seropositive patients or discontinuing natalizumab in MS patients with PML may lead to the development of immune reconstitution inflammatory syndrome (IRIS) which presents with deterioration of the previous symptoms and may lead to death. In patients under treatment with monoclonal antibodies in routine practice, or new ones in ongoing clinical trials, differentiating PML from new MS lesions on brain MRI is critical for both the neurologists and neuroradiologists. In this review, we discuss the clinical features, neuroimaging manifestations of PML, IRIS and neuroimaging clues to differentiate new MS lesions from PML. In addition, various neuroimaging features of PML on the non-conventional MR techniques such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS) are discussed.     

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.     

The effects of natalizumab on the innate and adaptive immune system in the central nervous system

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Natalizumab ((R)Tysabri) is a humanized recombinant monoclonal antibody that binds to the alpha (alpha)(4) chain of the alpha(4) beta (beta)(1) integrin (very late activation antigen 4; VLA-4), and alpha(4)beta(7) integrin. Recently, two patients with MS and one patient with Crohn's disease who were treated with natalizumab in the setting of clinical trials developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyoma virus JC. We recently showed that natalizumab decreases the numbers of CD4(+) and CD8(+) T lymphocytes, CD19(+) B cells, and CD138(+) plasma cells in the cerebrospinal fluid (CSF) of patients with MS on natalizumab therapy. In addition, we demonstrated that the cell numbers in CSF remained unchanged even 6 months after cessation of natalizumab treatment.     

多发性硬化治疗措施的临床证据评价

目的 评价不同治疗方案对多发性硬化的疗效及不良反应,从循证医学角度为制定最佳治疗方案提供依据.方法 以多发性硬化、免疫调节、治疗等词组作为检索词,分别检索MEDLINE、Cochrane图书馆、万方数据知识服务平台学术期刊库和中国知网中国期刊全文数据库并辅助手工检索,获取有关糖皮质激素、血浆置换、静脉注射免疫球蛋白、干扰素-β、醋酸格拉默、米托恩醌、那他珠单抗及芬戈莫德等治疗药物或方法的系统评价、随机对照临床试验、临床对照试验及病例观察研究,采用Jadad量表对文献质量进行评价.结果 经筛选共纳入与多发性硬化治疗有关的系统评价6篇、随机对照临床试验7篇、临床对照试验2篇、病例观察研究2篇.其中15篇评为高质量文献,评分分别为4分(5篇)、5分(6篇)和7分(4篇);2篇为低质量文献,评分3分.根据对各种治疗方法的疗效及安全性评价显示:(1)糖皮质激素为多发性硬化急性复发时的首选治疗药物,病情不能缓解的患者应以血浆置换或静脉注射免疫球蛋白作为替代治疗.(2)干扰素-β、醋酸格拉默可以作为多发性硬化缓解期治疗的一线药物,若无效可以米托恩醌、那他珠单抗作为二线治疗药物.(3)芬戈莫德作为多发性硬化缓解期治疗的口服药物,有利于提高患者的依从性.结论 借助循证医学的方法可为多发性硬化患者的治疗提供最佳临床证据.     

Headache and Chiari malformation in young age: clinical aspects and differential diagnosis

To evaluate the efficacy and safety of natalizumab in patients with active relapsing–remitting multiple sclerosis (MS). We included 285 MS patients receiving natalizumab. Clinical, neuroradiological and safety data were registered every 6 months. Neutralizing antibodies (NABs) were tested after 6 months of treatment. After 1 year, the annualized relapse rate decreased to 0.26, with a significant reduction compared to the previous year (2.13). At 24 months the proportion of “relapse free” patients was 78% while that of “MRI free” patients was 69%. Considering clinical and MRI cumulative activity, “disease free” patients were 63% at 24 months. A total of 18 patients showed NABs positivity. We reported 34 cases of treatment interruptions. In conclusion, our data confirm the remarkable efficacy of natalizumab in a group of patients with higher disease activity than that of pivotal studies.     

Natalizumab im klinischen Alltag

BACKGROUND: Since June 2006 natalizumab has been available for use as monotherapy in relapsing-remitting MS with high disease activity. The AFFIRM study showed the occurrence of persisting and neutralising antinatalizumab antibodies (nAb) in 6% of the patients. We present data revealing the number of nAb-positive patients assessed in our independent laboratory. Additionally we provide retrospective clinical data on the efficacy of natalizumab as escalating immunotherapy. PATIENTS AND METHODS: Blood samples of patients treated with natalizumab in Germany were tested for nAb using an enzyme-linked immunosorbent assay. If nAb were detectable at a single time point, the according patients were categorised as transiently positive. They were diagnosed as persistently positive if they had nAb at two or more time points which were at least 6 weeks apart. The treating neurologists sending the serum samples were asked to provide clinical data of their patients. RESULTS: Forty-seven of 593 samples (9.1%) were nAb-positive, 19 of them (3.7%) persistently positive and two (0.3%) transiently. Twenty-six patients (5%) were not retested for nAb, as we did not receive material for confirmatory analysis. Infusion-related adverse events were reported for 53 patients (10.3%). Averages of 2.6 relapses per year were reported previous to natalizumab therapy and 0.3 per year during natalizumab therapy. CONCLUSION: During natalizumab therapy, testing for nAb should be strongly considered for further therapy decisions and in cases of suspected allergic reaction. Basically the obtained data compare with those of the AFFIRM study. Natalizumab is applied as escalating therapy in MS according to the recommendations of the MSTKG, and it seems to match the expectations in open-label use.     

New Disease-Modifying Therapies and New Challenges for MS

The availability of the second-generation therapies for relapsing multiple sclerosis (MS), natalizumab and fingolimod, provides new treatment options for MS but also presents new challenges. Both natalizumab and fingolimod appear to be more effective than the interferon beta products and glatiramer acetate, but both have more safety problems than do the first-generation therapies. Treatment with natalizumab is associated with a significant risk of patients developing progressive multifocal leukoencephalopathy (PML), which the JC virus causes. We now are able to risk stratify MS patients into high- and low-risk groups for developing PML on the basis of the presence or absence of antibodies to the JC virus, history of prior use of immunosuppressants, and duration of therapy with natalizumab. Fingolimod appears to be associated with a risk of asystole and sudden death. It may also increase the risk of serious herpes infections and paradoxical activation of MS. More information is needed about these serious side effects from fingolimod to allow us to use it safely in patients.     

Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab

Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering natalizumab therapy. Recommendations for clinical management of patients with MS and use of natalizumab are provided based on the presence of these three risk factors. The identification of risk factors that increase the likelihood of PML in natalizumab-treated patients can facilitate benefit-risk discussions between health care professionals and patients. Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.     

Pulse monthly steroids during an elective interruption of natalizumab: a post-marketing study

Background and purpose: Temporary discontinuation of natalizumab is sometimes considered as the observed risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS). However, interruption of natalizumab may result in a re‐start of disease activity. Methods: In this prospective post‐marketing study, 23 patients with MS treated with natalizumab elected a trial of treatment interruption (90–150 days) because of safety concerns on the risk of developing PML. To reduce the risk of disease activity return, patients received monthly intravenous (i.v.) steroid pulses before natalizumab re‐start. Results: Despite the steroid coverage, seven patients (30.4%) had an active scan during the natalizumab interruption period; of these, four also had a concomitant clinical exacerbation. Conclusions: Our findings suggest that i.v. steroids are not currently recommendable as drug coverage during a scheduled treatment interruption period.     

An open-label safety and drug interaction study of natalizumab (Antegren) in combination with interferon-beta (Avonex) in patients with multiple sclerosis

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) interferon beta-1a 30 microg (IFNbeta-1a; Avonex). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNbeta-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNbeta-1a activity, beta2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNbeta-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated. The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNbeta-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNbeta-1a. The presence of antibodies to IFNbeta-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNbeta-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.     

Treating multiple sclerosis in the natalizumab era: risks, benefits, clinical decision making, and a comparison between North American and European Union practices

Multiple sclerosis (MS) is the most common cause of nontraumatic severe neurological disability in young adults. If left untreated, most individuals with MS will accumulate significant physical and/or cognitive disability as the consequence of demyelination and axonal injury. Treatment has focused on disease-modifying therapies (DMTs) and questions remain about timing and indications for their use. Natalizumab is a humanized monoclonal antibody directed against alpha4-integrin that prevents migration of leukocytes into the brain parenchyma. The clinical and radiological efficacy of natalizumab has been shown in several randomized trials; however, adverse events associated with natalizumab have limited its use as a first-line agent. In this review we compare current recommendations for the use of first-line DMTs, adverse events associated with MS therapies, and differences between the practices in North American and the European Union.     

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.     

Efficacy of natalizumab in multiple sclerosis patients with high disease activity: a Danish nationwide study

Introduction:  Previous studies of natalizumab (Tysabri®) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity.
Patients and Methods:  We analyzed data from 234 consecutive, natalizumab-treated patients, followed for at least 3 months. Three groups of patients were eligible for natalizumab therapy: patients with two or more documented relapses or sustained increase of 2 EDSS points on disease modifying therapy (DMT) in the previous year; patients switching from mitoxantrone; and patients with very active MS as de novo therapy.
Results:  During a median observation time of 11.3 months (range 3.0–21.5) the annualized relapse rate decreased to 0.68 from a pre-treatment rate of 2.53 (73% reduction). We assessed the annualized relapse rate in three subgroups: (i) 0.83 in 14 (6.0%) de novo treated patients; (ii) 0.71 in 175 (74.8%) patients with ≥2 relapses or sustained increase in EDSS of ≥2 points on a first-line DMT; and (iii) 0.56 in 45 (19.2%) patients switching from mitoxantrone. Nine anaphylactoid reactions, two severe, were reported. Out of 215 patients 7 (3%) were persistently positive for antibodies to natalizumab.
Conclusions:  Tysabri appears to be effective in MS patients with high disease activity, but the relapse rate was higher than in the pivotal study after the first treatment year. This is likely to reflect differences in disease activity before the initiation of natalizumab treatment.     

CD49d expression as a promising biomarker to monitor natalizumab efficacy

Natalizumab (Tysabri?), a monoclonal antibody against the α4-integrin of VLA-4 (CD49d) antigen of leukocytes, is highly effective in multiple sclerosis (MS). The most common reason for treatment failure is the development of neutralizing antibodies (NAbs). According to health authorities Nabs testing is recommended in case of relapse or repeated infusion reactions. However NAbs may develop in clinically asymptomatic patients. In this study we investigated if CD49d expression could serve as a biomarker of natalizumab bioavailability and treatment response. In a cohort of 49 natalizumab treated relapsing-remitting MS, followed over 2 years, CD49d expression was determined on peripheral blood mononuclear cells (PBMCs) before each infusion and compared to NAbs and serum natalizumab levels. In a majority of patients (41/49) the CD49d expression in PBMCs was strongly inhibited (>50%) after the first infusion and maintained at low levels throughout the treatment period. In contrast, in eight patients (16%) there was an early recovery of CD49d expression to pre-treatment levels related to NABs development. While three cases experienced hypersensitivity reactions, three others were identified solely on the basis of an undiminished level of CD49d, with neither infusion reaction nor clinical worsening. These 3 patients had very high levels of NAbs and no detectable serum natalizumab. Two additional patients had early but transient recovery of CD49d expression. These patients had low levels of transient Nabs and returned to significant CD49d inhibition after few natalizumab infusions. We suggest that monitoring of CD49d expression can be used as a surrogate biomarker of natalizumab efficiency. If the CD49d expression is sustained at pre-treatment levels, patients should be tested for persistent NAbs and considered for treatment interruption.     

Age as a risk factor for early onset of natalizumab-related progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare but potentially fatal opportunistic infection that arises almost exclusively in immunocompromised patients or in those treated with monoclonal antibodies, especially natalizumab. Here, we aimed at exploring if age at treatment start affects the time to onset of natalizumab-related PML. PubMed was searched for the terms “natalizumab and progressive multifocal leukoencephalopathy” in articles published from January 2005 to March 2017. We collected information on each identified PML case, including demographic and clinical variables at natalizumab start and at PML onset. The number of natalizumab infusions until PML onset was investigated in time-to-event analyses. We identified 238 cases who developed PML after a median number of 33 natalizumab infusions (range 6 to 103). Risk factors for an earlier onset of natalizumab-related PML were prior immunosuppressant exposure (hazard ratio [HR] = 1.43, p = 0.017) and older age at treatment start (HR = 1.02, p = 0.016). In particular, patients older than 50 years had a more than doubled-increased risk for an earlier PML onset (HR = 2.11, p = 0.006). Our findings suggest that the age at natalizumab start may represent a risk factor for an earlier PML onset, thus claiming further investigations about the interplay between immunosenescence and MS treatments.