Multipel skleros (MS) är en kronisk sjukdom som drabbar det centrala nervsystemet, CNS. Sjukdomen karakteriseras av återkommande och periodvisa inflammationer som orsakar demyelinisering och påföljande skada på underliggande axon som finns i hjärna, synnerv och ryggmärg. Vid demyelinisering så försämras ledningen av elektriska impulser vilket leder till störande effekt på fysisk, mental, sensorisk och känslomässig aktivitet i kroppen. I Sverige är incidensen ca 5 fall per 100 000 invånare per år och prevalensen ca 190 fall per 100 000 invånare. Det finns därmed ca 17 500 personer som är drabbade av MS i Sverige. Kvinnor drabbas dubbelt så ofta som män av MS och de flesta som insjuknar gör det i åldrarna 20–45 år. Det finns ingen behandling som botar sjukdomen och symptomen som uppstår vid MS behandlas symptomatiskt. Patienter med MS får också immunomodulerande behandling som interferon beta, fingolimod, glatirameracetat, dimetylfumarat, teriflunomid, natalizumab och alemtuzumab för att få kontroll över den inflammatoriska aktiviteten och därmed minska risken för bestående funktionsnedsättning. Akuta skov av MS behandlas med metylprednisolon och där det ej gett effekt kan plasmaferes övervägas. Syftet med det här arbetet var att jämföra behandlingarna natalizumab och alemtuzumab vid skovvis förlöpande MS. Arbetet är ett litteraturarbete där sökningar gjordes i sökbasen PubMed med sökorden ”Alemtuzumab multiple sclerosis”, ”Natalizumab multiple sclerosis” och ”Natalizumab Alemtuzumab multiple sclerosis”. Det fanns inga kliniska studier där natalizumab och alemtuzumab jämfördes. Sex studier valdes ut, tre där alemtuzumab utvärderas och tre där natalizumab utvärderas. Resultatet visade att natalizumab var något mer effektivt avseende minskning i poäng på expanded disability status scale (EDSS) och resultat på magnetisk resonanstomografi (MRI). Alemtuzumab var däremot mer effektivt avseende sjukdomsprogression. Skovfrekvens och skovfria patienter var svårt att jämföra då definitionen på skov skiljde sig mellan studierna. Biverkningsmässigt var natalizumab mer fördelaktigt då det visade färre andel patienter med allvarliga biverkningar och inte samma typ av allvarliga biverkningar. En klinisk studie där de båda läkemedlen jämförs med varandra med samma effektmått och definition på effektmått skulle vara önskvärt.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by lesions formed due to demyelination. MS is a complex disease thought to be triggered by environmental factors in genetically predisposed individuals. The strongest associated susceptibility allele is HLA-DRB1*1501. Environmental factors include smoking, latitude and previous infection of Epstein-Barr virus (EBV), a common herpes virus. There is no cure for MS, but several inhibitor and symptomatic drugs. Tysabri® (natalizumab) is the most effective drug, but it may lead to progressive multifocal leukoencephalopathy (PML), a rare but often fatal disease caused by reactivation of JC virus. The aim of this thesis was to replicate previous findings from a genome-wide association study and to find host genetic factors influencing JCV seropositivity and EBNA1 IgG titers in Swedish MS patients and healthy controls. Samples from the EIMS and IMSE studies were genotyped by TaqMan® OpenArray™ PCR, an end-point SNP genotyping analysis. 1143 cases and 556 healthy controls were genotyped. Due to poor call rates, genotype data from an Immunochip study was added. A total of 3408 samples (1664 cases and 1744 controls) were analyzed. EBNA1 IgG antibodies were previously measured as a detection of EBV infection and increased MS risk, and JCV IgG antibodies were measured to find patients potentially at risk for PML. One significant result was found, gene 105 (p = 0.01674, OR 0.68, CI 95% 0.49-0.93), with a protective effect in MS. More significant results might have been found with better loading of the plate, or with a different genotyping method.

Multipel skleros (MS) är en kronisk immunologisk sjukdom som slår på centrala nervsystemet (CNS) och kan leda till minskad neurologisk funktion. I Sverige finns 17 500 personer som fått en MS-diagnos. Den vanligaste åldern för insjuknande är 20-40 år och sjukdomen är dubbelt så vanlig bland kvinnor som bland män. Om patienterna inte får behandling finns risk för kraftiga funktionsnedsättningar. Syftet med detta arbete var att undersöka effekten och säkerheten med det perorala läkemedlet fingolimod jämfört med intravenös behandling med natalizumab vid MS. Arbetet utformades som en litteraturstudie där sökningar gjordes i PubMed genom Linnéuniversitetets bibliotek. De sökord som användes var "multiple sclerosis AND drug therapy AND fingolimod" samt "multiple sclerosis AND drug therapy AND natalizumab". Sökningarna ledde till att 7 studier granskades. Studierna visade att både fingolimod och natalizumab ger bättre effekt än placebo och de har dessutom bra säkerhet. Det var dock inga stora skillnader mellan de två substanserna. Vad gällde risken för progredierande funktionsnedsättning och risken för allvarliga biverkningar tycktes fingolimod vara något mera fördelaktigt, medan natalizumab hade en liten fördel vad gällde antalet gadoliniumförstärkta lesioner. Då man i några av fingolimodstudierna inte använde sig av intention-to-treat (ITT) och dubbelblindning kan läkemedlets effekter i dessa studier framstå som bättre än vad de är och de små förbättringar i effekter som sågs i resultaten blir osäkra. För att säkert kunna säga om det är någon skillnad i effekt och säkerhet mellan preparaten vore det önskvärt med nya dubbelblindade långtidsstudier av fingolimod där ITT använts vid analysen. Det vore också intressant med en randomiserad klinisk prövning som jämför fingolimod med natalizumab. De resultat som framförallt bör studeras är skovfrekvens, risk för ökande funktionsnedsättning och risk för allvarliga biverkningar, då dessa parametrar borde vara av störst värde för patienterna.

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A Esclerose Múltipla (EM) é uma doença autoimune caracterizada por um processo neuroinflamatório com degeneração axonal progressiva. O medicamento Natalizumab (Biogen Idec, NC, USA) representa hoje um dos tratamentos mais promissores para EM. Entretanto, pacientes sob esse tratamento possuem maiores chances de desenvolver Leucoencefalopatia Multifocal Progressiva (LEMP), em decorrência de uma possível reativação do poliomavírus JC (VJC). Além do VJC, o poliomavírus BK (VBK) pode representar uma preocupação adicional para tais pacientes, uma vez que também apresenta capacidade de causar encefalopatias. Apesar do Natalizumab ser uma ótima ferramenta contra a EM, o fato de interagir de alguma maneira com os poliomavírus, em especial o VJC, impede que seja utilizado em larga escala. Dessa forma,o objetivo desse trabalho foi investigar os padrões de excreção e reativação dos VJC e VBK em pacientes com EM durante o tratamento com Natalizumab e comparar aos padrões observados em pacientes que se encontram sob outros tratamentos. Amostras seriadas de sangue e urina foram coletadas e submetidas a testes de biologia molecular para detecção do vírus e caracterização molecular. Foram analisados 97 pacientes em diferentes tempos de acompanhamento. Não foi observada presença de poliomavírus no sangue de nenhum dos indivíduos analisados. Entretanto, 36% excretavam poliomavírus na urina em pelo menos uma das coletas, sendo que 21,7% excretavam VJC, 9,3% excretavam VBK e 5,1% excretavam ambos os poliomavírus. Não foi observada diferença entre as taxas de excreção urinária de poliomavírus entre pacientes que tratavam com Natalizumab (38,9%) e pacientes que sob outros tratamentos (34,5%), sendo que para o Grupo Controle (GC); 21,3%, 8,2% e 4,9% excretavam VJC, VBK e ambos os vírus, respectivamente e para o grupo Grupo Natalizumab (GN) 22,2%, 11,1% e 5,6% excretavam VJC, VBK e ambos os vírus, respectivamente. As análises moleculares da Região Regulatória do VJC revelaram sequências de característica arquetípica. A reconstrução filogenética de sequências do gene VP1 do VJC revelou predominância do genótipo 3 e do genótipo 1 para o VBK. Não foi observada diferença estatística da carga viral do VJC e do VBK entre os dois grupos. Foi detectada uma mutação (E29G) na VP1 de uma paciente que apresentou alta carga viral do VJC. Do grupo GN, 14 apresentaram anticorpos para VJC, sendo que desses 58% apresentou excreção de VJC, 42% não apresentou excreção urinária, interessantemente uma paciente não apresentou anticorpos contra o VJC, mas apresentou excreção de VJC. Pode-se concluir principalmente que a detecção de anticorpos, concomitantemente com a investigação molecular do VJC poderá contribuir para uma melhor determinação da estratificação do risco de desenvolvimento de LEMP em indivíduos com EM sob tratamento com Natalizumab. / Multiple sclerosis (MS) is an autoimmune disease characterized by neuronal inflamatory process with progressive axonal degeneration. The drug Natalizumab (Biogen Idec, NC, USA) is today one of the most promising treatments for MS. However, patients undergoing this treatment have higher chances of developing progressive multifocal leukoencephalopathy (PML), due to a possible reactivation of the polyomavirus JC (VJC). Besides VJC, the BK polyomavirus (VBK) may represent an additional concern for such patients, since it also has ability to cause encephalopathies. Despite Natalizumab be a great tool against MS, the fact that drug some way may interact with polyomavirus, especially VJC, prevents it from being used on a large scale. Thus, aim of this study was to investigate the patterns of excretion and reactivation of VJC and VBK in MS patients during treatment with Natalizumab and compare the patterns observed in patients who are under other treatments. Serial blood samples and urine were collected and submitted to molecular biology tests for virus detection and molecular characterization. Ninety seven patients were analyzed at different follow-up times. There was no polyomavirus DNA in the blood of none subjects analyzed. However, 36% of patients excreted polyomavirus in the urine in at least one of the samples, of those 21.7%, 9.3% and 5.1% excreted VJC, VBK and both polyomavirus, respectively. No difference was observed between the rates of urinary excretion of polyomavirus patients treated with Natalizumab (38.9%) and patients treated with other drugs (34.5%), for the Control Group (GC); 21,3%, 8,2% and 4,9 shed VJC, VBK and both viruses, respectevely and for the Natalizumab Group (GN) 22,2%, 11,1% and 5,6% shed VJC, VBK and both viruses, respectvely. Molecular analysis of the Regulatory Region of VJC revealed sequences similar to the archetype form of VJC. A phylogenetic reconstruction of the VP1 gene sequences revealed VJC predominance of genotype 3 and genotype 1 for VBK. There was no statistical difference in the viral load VJC and VBK between the two groups. It was detected a mutation (E29G) in VP1 of a patient who had a high viral load VJC, however the mutation disappeared after a few months of monitoring. Fourteen patients of GN had antibodies to VJC, and of these 58% had excretion VJC, 42% showed no urinary excretion, interestingly one patient had no antibodies against VJC but showed excretion of VJC. It can be concluded that mostly anti-VJC antibodies detection, concurrently with the VJC molecular research may contribute to a better determination of risk stratification for development of PML in patients with MS undergoing treatment with Natalizumab.

A Esclerose Múltipla (EM) é uma doença autoimune caracterizada por um processo neuroinflamatório com degeneração axonal progressiva. O medicamento Natalizumab (Biogen Idec, NC, USA) representa hoje um dos tratamentos mais promissores para EM. Entretanto, pacientes sob esse tratamento possuem maiores chances de desenvolver Leucoencefalopatia Multifocal Progressiva (LEMP), em decorrência de uma possível reativação do poliomavírus JC (VJC). Além do VJC, o poliomavírus BK (VBK) pode representar uma preocupação adicional para tais pacientes, uma vez que também apresenta capacidade de causar encefalopatias. Apesar do Natalizumab ser uma ótima ferramenta contra a EM, o fato de interagir de alguma maneira com os poliomavírus, em especial o VJC, impede que seja utilizado em larga escala. Dessa forma,o objetivo desse trabalho foi investigar os padrões de excreção e reativação dos VJC e VBK em pacientes com EM durante o tratamento com Natalizumab e comparar aos padrões observados em pacientes que se encontram sob outros tratamentos. Amostras seriadas de sangue e urina foram coletadas e submetidas a testes de biologia molecular para detecção do vírus e caracterização molecular. Foram analisados 97 pacientes em diferentes tempos de acompanhamento. Não foi observada presença de poliomavírus no sangue de nenhum dos indivíduos analisados. Entretanto, 36% excretavam poliomavírus na urina em pelo menos uma das coletas, sendo que 21,7% excretavam VJC, 9,3% excretavam VBK e 5,1% excretavam ambos os poliomavírus. Não foi observada diferença entre as taxas de excreção urinária de poliomavírus entre pacientes que tratavam com Natalizumab (38,9%) e pacientes que sob outros tratamentos (34,5%), sendo que para o Grupo Controle (GC); 21,3%, 8,2% e 4,9% excretavam VJC, VBK e ambos os vírus, respectivamente e para o grupo Grupo Natalizumab (GN) 22,2%, 11,1% e 5,6% excretavam VJC, VBK e ambos os vírus, respectivamente. As análises moleculares da Região Regulatória do VJC revelaram sequências de característica arquetípica. A reconstrução filogenética de sequências do gene VP1 do VJC revelou predominância do genótipo 3 e do genótipo 1 para o VBK. Não foi observada diferença estatística da carga viral do VJC e do VBK entre os dois grupos. Foi detectada uma mutação (E29G) na VP1 de uma paciente que apresentou alta carga viral do VJC. Do grupo GN, 14 apresentaram anticorpos para VJC, sendo que desses 58% apresentou excreção de VJC, 42% não apresentou excreção urinária, interessantemente uma paciente não apresentou anticorpos contra o VJC, mas apresentou excreção de VJC. Pode-se concluir principalmente que a detecção de anticorpos, concomitantemente com a investigação molecular do VJC poderá contribuir para uma melhor determinação da estratificação do risco de desenvolvimento de LEMP em indivíduos com EM sob tratamento com Natalizumab. / Multiple sclerosis (MS) is an autoimmune disease characterized by neuronal inflamatory process with progressive axonal degeneration. The drug Natalizumab (Biogen Idec, NC, USA) is today one of the most promising treatments for MS. However, patients undergoing this treatment have higher chances of developing progressive multifocal leukoencephalopathy (PML), due to a possible reactivation of the polyomavirus JC (VJC). Besides VJC, the BK polyomavirus (VBK) may represent an additional concern for such patients, since it also has ability to cause encephalopathies. Despite Natalizumab be a great tool against MS, the fact that drug some way may interact with polyomavirus, especially VJC, prevents it from being used on a large scale. Thus, aim of this study was to investigate the patterns of excretion and reactivation of VJC and VBK in MS patients during treatment with Natalizumab and compare the patterns observed in patients who are under other treatments. Serial blood samples and urine were collected and submitted to molecular biology tests for virus detection and molecular characterization. Ninety seven patients were analyzed at different follow-up times. There was no polyomavirus DNA in the blood of none subjects analyzed. However, 36% of patients excreted polyomavirus in the urine in at least one of the samples, of those 21.7%, 9.3% and 5.1% excreted VJC, VBK and both polyomavirus, respectively. No difference was observed between the rates of urinary excretion of polyomavirus patients treated with Natalizumab (38.9%) and patients treated with other drugs (34.5%), for the Control Group (GC); 21,3%, 8,2% and 4,9 shed VJC, VBK and both viruses, respectevely and for the Natalizumab Group (GN) 22,2%, 11,1% and 5,6% shed VJC, VBK and both viruses, respectvely. Molecular analysis of the Regulatory Region of VJC revealed sequences similar to the archetype form of VJC. A phylogenetic reconstruction of the VP1 gene sequences revealed VJC predominance of genotype 3 and genotype 1 for VBK. There was no statistical difference in the viral load VJC and VBK between the two groups. It was detected a mutation (E29G) in VP1 of a patient who had a high viral load VJC, however the mutation disappeared after a few months of monitoring. Fourteen patients of GN had antibodies to VJC, and of these 58% had excretion VJC, 42% showed no urinary excretion, interestingly one patient had no antibodies against VJC but showed excretion of VJC. It can be concluded that mostly anti-VJC antibodies detection, concurrently with the VJC molecular research may contribute to a better determination of risk stratification for development of PML in patients with MS undergoing treatment with Natalizumab.

Background The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood–brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. Methods We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. Results In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. Conclusions Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

Background The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood–brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. Methods We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. Results In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. Conclusions Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

Van Kempen et al. described high natalizumab concentrations in their natalizumab-treated multiple sclerosis (MS) patients at time of re-dosing. Based on the literature research the authors consider a natalizumab concentration above 2 μg/mL to be sufficient for an adequate alpha-4 integrin receptor saturation of above 70%. Recently, we have demonstrated similar results using our new cell-based immunoassay to evaluate free natalizumab concentration, cell-bound natalizumab, and alpha-4 integrin receptor saturation as the key pharmacokinetic/pharmacodynamic parameters of natalizumab treatment in different in vivo settings. We investigated the effects of treatment interval extension or treatment cessation.

Background: Managing medication during pregnancy and lactation in multiple sclerosis (MS) patients needs to balance potential risks to the newborn with the substantial risks of ongoing disease activity. Objective: To evaluate the potential transfer of natalizumab (NAT) into breast milk and into the serum of newborn babies in women who continued NAT treatment during pregnancy and lactation. Methods: Serum samples of 11 mother–infant pairs and mother milk samples of a further 4 women were analyzed for free NAT using a HL60 cell-based fluorescence-activated cell sorting (FACS) assay. Two mother–baby pairs were analyzed for cell-bound NAT, very-late-antigen (VLA)-4 expression, and saturation with NAT on immune cells by FACS analysis. Results: In the majority of the mother–infant serum pairs (6/11) and in all breast milk samples, free NAT was detectable. Cell-bound NAT was measurable in both mother–baby pairs with significant higher levels in babies. VLA-4 expression seems to be higher in newborns. Saturation with NAT was comparable between newborns and mothers. Conclusion: NAT can pass placental barrier before delivery and into breast milk. Measurable NAT on neonatal lymphocytes may have functional impact. Further investigations are needed to clarify safety and risk of NAT exposure during pregnancy and lactation.