Anke Salmen

Efficacy and Side Effects of Natalizumab Therapy in Patients with Multiple Sclerosis

Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08–3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.

Mode of action and clinical studies with fumarates in multiple sclerosis.

Multiple sclerosis (MS) as a chronic neuro-inflammatory and neurodegenerative disease of the central nervous system is frequently associated with severe disability and impairment in quality of life. Early disease-modifying treatment options have mainly focused on inflammatory aspects of the disease. Recently, the neurodegenerative features have received more attention in experimental models, paraclinical assessments and the evaluation of drug effects. Fumaric acid esters (FAEs) as orally available immunomodulatory and neuroprotective compounds have thus advanced to a highly interesting MS treatment option. Here, we will review the pharmaceutical history of FAEs, their immunomodulatory and putative neuroprotective mechanisms of action and clinical trial data in relapsing MS.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci. We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Serological evidence of increased susceptibility to varicella-zoster virus reactivation or reinfection in natalizumab-treated patients with multiple sclerosis.

Background: Serious adverse drug reactions of disease-modifying drugs in multiple sclerosis (MS) therapy may include enhanced susceptibility to reactivation of neurotropic herpes viruses like varicella-zoster virus (VZV) and the John Cunningham (JC) polyomavirus. Objective: Because symptomatic reactivation of these viruses are rare events, we determined the incidence of rises in anti-VZV IgG antibody levels as a potential marker for enhanced susceptibility to subclinical and symptomatic reactivation of neurotropic viruses. Methods: Anti-VZV IgG levels were measured in paired serum samples taken 6–8 months apart from natalizumab-treated MS patients, healthy blood donors and human immunodeficiency virus (HIV) infected patients. Results: The incidence of significant rises in anti-VZV IgG levels in natalizumab-treated MS patients was 4.26 per 100 person-years, which was significantly higher than in healthy blood donors. Retrospective evaluation of the available medical records of patients with rises of anti-VZV IgG levels did not reveal herpes zoster (i.e. shingles) manifestations. Conclusions: The increased incidence of significant rises of anti-VZV IgG levels in natalizumab-treated MS patients might indicate an association of natalizumab treatment of MS with an elevated risk of a subclinical VZV reactivation and/or reinfection events. Whether this is predictive of an increased risk of herpes zoster or even symptomatic reactivation of other neurotropic viruses remains to be determined in larger prospective studies.

Cardiotoxicity of Mitoxantrone Treatment in a German Cohort of 639 Multiple Sclerosis Patients

Background and Purpose The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment. Methods Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. Results None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. Conclusions The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically).

Predictors of severity and functional outcome in natalizumab-associated progressive multifocal leukoencephalopathy

Objective: Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described. Methods: We retrospectively analyzed medical records of all patients with natalizumab-PML (n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman’s rho and multivariate regression analysis. Results: In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed. Conclusion: This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings.

Lack of efficacy of mitoxantrone in primary progressive Multiple Sclerosis irrespective of pharmacogenetic factors: A multi-center, retrospective analysis

BACKGROUND Mitoxantrone is used on an off-label basis in primary progressive MS (PPMS). ABC-transporter-genotypes are associated with therapeutic response in relapsing/secondary progressive MS (RP/SPMS). OBJECTIVE To evaluate potential pharmacogenetic response markers for mitoxantrone in PPMS. METHODS 41 mitoxantrone-treated PPMS-patients, 155 mitoxantrone-treated RP/SPMS-patients and 43 PPMS-controls were retrospectively assessed for clinical therapy-response and in correlation with four single-nucleotide-polymorphisms in ABCB1- and ABCG2-genes. RESULTS 53.7% PPMS-patients were mitoxantrone-responders, in comparison to 78.1% of RP/SPMS-patients (p=0.039). There was no association between genotype and treatment response. CONCLUSION Our data discourages the use of mitoxantrone in PPMS regardless of pharmacogenetic response markers previously described in RP/SPMS.

Parkinson disease and multiple sclerosis are not associated with autoantibodies against structural proteins of the dermal-epidermal junction.

DEAR EDITOR, Bullous pemphigoid (BP), the most frequent autoimmune blistering disease, is associated with autoantibodies against two proteins of the dermal–epidermal junction (DEJ), BP180 (type XVII collagen) and BP230 [BP antigen 1 (BPAG1)]. Two peculiar clinical features of BP are the advanced age of patients, with a mean age of between 75 and 80 years at disease onset, and its association with neurological disease. Neurological diseases can be diagnosed in 30–50% of patients with BP, including cognitive impairment, stroke, epilepsy, Parkinson disease (PD) and multiple sclerosis (MS), with odds ratios (ORs) of 2 2, 1 8–3 3, 1 7–4 0, 2 16–3 50 and 10 7, respectively. In addition, patients with MS are more likely to develop BP (OR 6 7). These findings are particularly intriguing as the cutaneous target antigens of BP – BP180 and BP230 – are also expressed in the central nervous system (CNS). BP180 expression was found in the cerebellum of rats and in autopsy samples of various neuroanatomical regions of human brain. Mice with mutations in the dystonin gene encoding for various isoforms of BPAG1, including the epithelial isoform BP230, develop severe dystonia and sensory nerve degeneration. While PD is thought to be a primary neurodegenerative disorder, inflammatory responses seem to be secondary. MS is believed to be initially induced via a peripheral immune response, and further driven by immune reactions within the CNS with secondary neurodegeneration. During the process of neurodegeneration the two BP autoantigens in the CNS may have been exposed to the immune system, leading to the break of tolerance and, subsequently, to the generation of anti-BP180 and anti-BP230 antibodies, and, finally, to BP. In the present study, according to this hypothesis, we expected to detect serum autoantibodies against BP180 and BP230 more frequently in patients with PD and MS compared with ageand sex-matched controls. Alternatively, or additionally, environmental factors that increase susceptibility to the development of neurological disorders might similarly change the risk of autoimmune blistering dermatoses. We compared three ageand sex-matched groups of patients with PD (n = 75, cohort A1), other neurological diseases [n = 75, cohort A2; detailed information is given in Table S1 (see Supporting Information)] and healthy controls (n = 75, cohort A3) (Table 1). All sera from cohort A were prospectively collected and matched for age and sex. Furthermore, prospectively collected sera from consecutive patients with PD at another academic site (L€ ubeck; n = 50, cohort C), a cohort

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Genome‐wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1‐Chip. Genotype calling was performed with the Illumina Genome StudioTM Genotyping Module, followed by zCall. Single‐nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome‐wide significant associations with MS (P values < 5 × 10−8). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10−5. The effect of nine SNPs in the HLA region remained (P < 10−5) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.

Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles

Objectives: We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. Methods: HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. Results: A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (pM-H = 3 × 10−7; odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40–23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (pM-H = 6 × 10−4; ORM-H = 0.2, 95% CI = 0.08–0.50), with a PPV of 81%. Conclusions: HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration.