Multiple Sclerosis: Elovaara I

Elovaara I, Apostolski S, van Doorn P, Gilhus NE, Hietaharju A, Honkaniemi J, van Schaik IN, Scolding N, Soelberg Sørensen P, Udd B, Anonymous00010. · Department of Neurology and Rehabilitation, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland. · Eur J Neurol. · Pubmed #18796075 No free full text.

Abstract: Despite high-dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune-mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence-based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (good practice point) [corrected],stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

Elovaara I, Kuusisto H. · Tampereen yliopisto, lääketieteen laitos. · Duodecim. · Pubmed #14655534 No free full text.

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Elovaara I, Pirttilä T. · TAYS:n neurologian ja kuntoutustoimen yksikkö 33520 Tampere. · Duodecim. · Pubmed #12001474 No free full text.

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Wu X, Kuusisto H, Dastidar P, Huhtala H, Nikkari ST, Ukkonen M, Höyhtyä M, Elovaara I. · Neuroimmunology Unit, Medical School, University of Tampere, Tampere, Finland. · Acta Neurol Scand. · Pubmed #17587254 No free full text.

Abstract: OBJECTIVE: To study the effect of weekly injected subcutaneous interferon (IFN)-beta-1a 22 microg on the extent of brain lesions on magnetic resonance imaging (MRI) and the level of serum matrix metalloproteinase (MMP)-9 in patients with secondary progressive multiple sclerosis (SPMS). SUBJECTS AND METHODS: All the 28 Finnish patients participating in the Nordic multicentre trial on the clinical efficacy of weekly IFN-beta-1a (Rebif) 22 microg in SPMS were studied neurologically and by volumetric MRI during a 3-year follow-up. The levels of MMP-9 in serum were measured over the 3-year study. RESULTS: There was no obvious effect on the number of contrast medium-enhancing lesions, the volume of T1 or T2 lesions or level of serum MMP-9, nor was any effect detected on the relapse rate and the Expanded Disability Status Scale (EDSS). Brain atrophy progression was not affected by the treatment. CONCLUSION: The lack of effect on MRI, clinical outcomes or the levels of MMP-9 indicates that subcutaneous administration of low-dose low-frequency IFN-beta-1a is insufficient in controlling either the inflammatory constitutes or the neurodegenerative changes of advanced SPMS.

Elovaara I, Kuusisto H, Paalavuo R, Särkijärvi S, Lehtimäki T, Huhtala H, Vilpo J. · Neuroimmunology Unit, Medical School, University of Tampere, Tampere, Finland. · Acta Neurol Scand. · Pubmed #16441245 No free full text.

Abstract: OBJECTIVES: Therapy of acute exacerbations of multiple sclerosis (MS) with high-dose intravenous methylprednisolone (IVMP) has shortened the recovery period after relapses, but the mechanisms responsible for the beneficial effects of IVMP in attacks have not been clearly established. Our purpose was to analyze the effect of IVMP on the expression of chemokine receptor 5 (CCR5) protein in blood in acute MS exacerbation. MATERIALS AND METHODS: Blood samples were collected from 10 patients with an acute MS exacerbation and the levels of CCR5 on CD4(+) and CD8(+) T cells and CD14(+) monocytes were analyzed by using flow cytometry before IVMP, 24 h, 1 and 3 weeks after commencement of treatment. RESULTS: During the 3-week period the percentages of CCR5-expressing CD4(+) T cells and CD8(+) T cells tended to decrease (P = 0.09 and 0.05, respectively), but the effect did not reach statistical significance. No marked changes were found in the percentage of CCR5-expressing CD14(+) cells. CONCLUSIONS: A tendency to a reduction of CCR5-expressing CD4(+) and CD8(+) blood cells induced by IVMP suggests inhibition of their potential to transmigrate into the central nervous system, which is consistent with the short-term beneficial effect of IVMP in acute exacerbation of MS.

Wu X, Dastidar P, Kuusisto H, Ukkonen M, Huhtala H, Elovaara I. · Neuroimmunology Unit, Medical School, University of Tampere, Tampere, Finland. · Acta Neurol Scand. · Pubmed #16146494 No free full text.

Abstract: OBJECTIVE: To examine neurological and magnetic resonance imaging (MRI) changes following discontinuation of interferon (IFN)-beta-1a treatment in secondary progressive multiple sclerosis (SPMS). METHODS: The study involved 21 SPMS patients who received subcutaneous (s.c.) IFN-beta-1a 44 microg three times weekly (t.i.w.) for 12 months and were thereafter followed up without treatment for a further 12 months. The number of relapses, disability on the Expanded Disability Status Scale (EDSS) and MRI were recorded at baseline, at 12 months of IFN-beta-1a 44 microg t.i.w. and 1 year after discontinuation of treatment. RESULTS: During the 12-month treatment EDSS score and volumes of brain T2- and T1-weighted lesions remained without significant progression, but at 12 months after treatment discontinuation both EDSS score and the volumes of cerebral lesions increased significantly. Cerebrospinal fluid fraction increased significantly both during the treatment and during follow-up. CONCLUSIONS: Discontinuation of IFN-beta-1a 44 microg t.i.w. in SPMS may be associated with an increase in neurological disability and brain lesions on MRI.

Vallittu AM, Peltoniemi J, Elovaara I, Kuusisto H, Färkkilä M, Multanen J, Erälinna JP. · Department of Virology, University of Turku, Turku, Finland. · Acta Neurol Scand. · Pubmed #16146492 No free full text.

Abstract: OBJECTIVES: Glatiramer acetate (GA) is routinely used in multiple sclerosis (MS) patients who cannot tolerate or fail to respond to beta-interferon (IFN-beta). The aim of this study was to assess the efficacy and tolerability of GA in these patients. METHODS: Fifteen relapsing-remitting MS patients who had discontinued IFN-beta therapy due to side effects were included in this open, 1-year prospective study. Neurologic examinations and laboratory assessments were performed every 3 months. The induction of MxA protein production was also evaluated. RESULTS: Eleven of fifteen patients (73%) tolerated GA well whereas four patients (27%) discontinued treatment due to side effects. The relapse rate reduced from 1.86 per year to 0.91 per year. Neither laboratory abnormalities nor MxA protein induction was found. CONCLUSION: GA can be considered as a good treatment alternative to IFN-beta-intolerant MS patients. However, some patients were not able to use available immunomodulative treatments, which emphasizes the need for new therapeutic options. The lack of MxA protein induction confirms the different mechanisms of action of GA and IFN-beta.

Andersen O, Elovaara I, Färkkilä M, Hansen HJ, Mellgren SI, Myhr KM, Sandberg-Wollheim M, Soelberg Sørensen P. · Institute of Clinical Neuroscience, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden. · J Neurol Neurosurg Psychiatry. · Pubmed #15090564 links to  free full text

Abstract: OBJECTIVE: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with secondary progressive MS. METHODS: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. RESULTS: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. CONCLUSIONS: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose-response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

Elovaara I, Ukkonen M, Leppäkynnäs M, Lehtimäki T, Luomala M, Peltola J, Dastidar P. · Department of Neurology, Tampere University Hospital, Finland. · Arch Neurol. · Pubmed #10768630 links to  free full text

Abstract: OBJECTIVES: To determine levels of adhesion molecules in blood and cerebrospinal fluid (CSF) samples from patients with different subtypes and activities of multiple sclerosis (MS) and to assess the effect of intravenous methylprednisolone sodium succinate treatment on the levels of soluble adhesion molecules. DESIGN: The expressions of very late activation antigen 4 (VLA-4), lymphocyte function associated antigen 1 (LFA-1), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) were determined immunocytochemically, and levels of soluble VCAM-1, ICAM-1, and E-selectin, by means of enzyme immunoassay technique. The volumes of T2- and T1-weighted MS plaques and brain atrophy were determined by means of the semiautomatic magnetic resonance imaging (MRI) segmentation technique. SETTING: A university hospital in Finland. PATIENTS: One hundred subjects (71 patients with MS and 29 healthy control subjects). The subtypes of MS were relapsing-remitting (RRMS [n = 26]), secondary progressive (SPMS [n = 20]), and primary progressive (PPMS [n = 25]). RESULTS: In patients with RRMS and SPMS, the expressions of VLA-4 and LFA-1 on immune cells from blood were at least 1.5- to 3-fold higher than in controls (RRMS, P = .002 and P<.001, respectively; SPMS, P = .03 and P =.001, respectively). In RRMS, LFA-1 and ICAM-1 expression in blood was more up-regulated than in SPMS (P = .03 and P = .01, respectively). The expressions of adhesion molecules on CSF lymphocytes in RRMS and SPMS were of similar magnitude, but the proportions of CSF VLA-4- and LFA-1-expressing lymphocytes were 3- to 4-fold higher than in controls (P = .04 and P = .008, respectively). The levels of serum soluble VCAM-1 were higher in SPMS than in RRMS (P = .005) or PPMS (P = .04). Intravenous methylprednisolone treatment of patients with RRMS in exacerbation caused a significant reduction in the serum levels of soluble VCAM-1 and E-selectin (P<.001). In SPMS, the volumes of T2-weighted plaques correlated with the serum level of soluble ICAM-1 (r = 0.64; P = .03). CONCLUSIONS: Up-regulated adhesion molecules in blood and CSF indicate sustained potential for inflammation in the CNS throughout the clinical spectrum of MS. Therapies interfering with cell adhesion may be of key importance in suppressing MS.

Dastidar P, Heinonen T, Lehtimäki T, Ukkonen M, Peltola J, Erilä T, Laasonen E, Elovaara I. · Department of Diagnostic Radiology, Tampere University Hospital, Finland. · J Neurol Sci. · Pubmed #10426145 No free full text.

Abstract: The objectives of the present study was to correlate the segmented magnetic resonance imaging (MRI) volumes of intracranial cerebrospinal fluid (CSF) spaces (expressing the extent of brain atrophy) and cerebral plaques with the neurological disability in secondary progressive multiple sclerosis (MS). Earlier studies have mainly correlated MS plaques and neurological disability measured by expanded disability status scale (EDSS). The data on the association between brain atrophy and EDSS or regional functional scoring scale (RFSS) are very limited. We measured the volumes of intracranial CSF spaces in 28 patients with secondary progressive MS using MRI, and semiautomatic segmentation software. The volumes of T1-weighted hypointense and T2-weighted hyperintense MS plaques were also measured. In multiple regression analysis, increasing volumes of total (P=0.006) and relative (P=0.005) intracranial CSF spaces were significantly associated with worsening neurological disability as expressed by EDSS. No associations were found between these intracranial CSF space volumes and total RFSS scores. The mean volume of T2-weighted plaques showed a tendency to associate with total RFSS score (r=0.40, P=0.03), but no correlations were detected between T1- or T2-weighted plaque volumes and EDSS. The application of a new segmentation technique in quantifying intracranial cerebrospinal fluid spaces allowed an exact and sensitive way of assessing brain atrophy. The associations between brain atrophy and neurological disability expressed by EDSS suggests that the effect of MS therapies should be evaluated by measurement of brain atrophy.

Narkilahti S, Hovatta O, Elovaara I. · Tampereen yliopisto, TAYS, Sekä Solu- ja kudosteknologiakeskus Regea, Biokatu, Tampere. · Duodecim. · Pubmed #19517865 No free full text.

Abstract: In multiple sclerosis, inflammatory autoimmune response, degeneration of the central nervous system and axonal damage eventually lead to disability. The inflammatory reaction can be controlled with current medication, whereas the neuronal and myelin damage is practically uncontrollable. Cell therapies may provide a new means to prevent nerve cell destruction and promote the regeneration of brain tissue. Bone marrow stem cell transplantation has been used as an immune response modifying therapy in severe MS. Experimental evidence of corrective and protective effects on tissues by preneuronal cells differentiated from fetal and embryonal human stem cells has been obtained in an animal model.

Sorensen PS, Mellgren SI, Svenningsson A, Elovaara I, Frederiksen JL, Beiske AG, Myhr KM, Søgaard LV, Olsen IC, Sandberg-Wollheim M. · Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · Lancet Neurol. · Pubmed #19409854 No free full text.

Abstract: BACKGROUND: Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce the yearly relapse rate in patients with relapsing-remitting multiple sclerosis. METHODS: NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) was a randomised, placebo-controlled trial done in 29 neurology departments in Denmark, Norway, Sweden, and Finland. We enrolled outpatients with relapsing-remitting multiple sclerosis who had had at least one relapse within the previous 12 months despite subcutaneous interferon beta-1a treatment (44 microg three times per week). We randomly allocated patients by computer to add-on therapy of either 200 mg methylprednisolone or matching placebo, both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary outcome measure was mean yearly relapse rate. Primary analyses were by intention to treat. This trial is registered, number ISRCTN16202527. FINDINGS: 66 patients were assigned to interferon beta and oral methylprednisolone and 64 were assigned to interferon beta and placebo. A high proportion of patients withdrew from the study before week 96 (26% [17 of 66] on methylprednisolone vs 17% [11 of 64] on placebo). The mean yearly relapse rate was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; p<0.0001). Sleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks. INTERPRETATION: Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis leads to a significant reduction in relapse rate. However, because of the small number of patients and the high dropout rate, these findings need to be corroborated in larger cohorts.

Kallio SP, Jakkula E, Purcell S, Suvela M, Koivisto K, Tienari PJ, Elovaara I, Pirttilä T, Reunanen M, Bronnikov D, Viander M, Meri S, Hillert J, Lundmark F, Harbo HF, Lorentzen AR, De Jager PL, Daly MJ, Hafler DA, Palotie A, Peltonen L, Saarela J. · Finnish Institute for Molecular Medicine, Biomedicum, Helsinki, Finland. · Hum Mol Genet. · Pubmed #19221116 No free full text.

Abstract: Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.

Pigard N, Elovaara I, Kuusisto H, Paalavuo R, Dastidar P, Zimmermann K, Schwarz HP, Reipert B. · BMT-Research GmbH, Vienna, Austria. · J Neuroimmunol. · Pubmed #19217671 No free full text.

Abstract: The objective of this study was to identify genes that are differentially expressed in peripheral T cells of patients with MS exacerbation receiving treatment with IVIG. Using microarray analysis, we identified 360 genes that were at least two-fold up- or down-regulated. The expression of four representative genes (PTGER4, CXCL5, IL11 and CASP2) was confirmed by quantitative PCR. Four of the differentially expressed genes encode chemokines (CXCL3, CXCL5, CCL13 and XCL2) that are involved in directing leukocyte migration. We suggest that the modulation of chemokine expression in peripheral T cells contributes to the beneficial activity of IVIG in patients with MS exacerbation.

Bonetti A, Koivisto K, Pirttilä T, Elovaara I, Reunanen M, Laaksonen M, Ruutiainen J, Peltonen L, Rantamäki T, Tienari PJ. · Molecular Neuroscience Programme, Biomedicum-Helsinki, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland. · J Neuroimmunol. · Pubmed #19195718 No free full text.

Abstract: A possible role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility has been suggested. We tested association of sixteen 19q13 markers with MS in 459 families. Nominally significant associations were tested in an independent set of 323 families as well as in the pooled set of 782 families. We were not able to confirm previously suggested associations with APOE, GIPR, ZNF45, ILT6 and D19S585. In the screening dataset nominally significant associations were found with D19S867 and with APOE haplotype (p=0.007 in both), but these were not replicated in the independent dataset nor in the pooled analysis of 757 families. Thus, we were not able to detect any statistically significant allelic associations. Re-sequencing based approaches may be required for elucidating the role chromosome 19q13 with MS.

Kemppinen A, Suvela M, Tienari PJ, Elovaara I, Koivisto K, Pirttilä T, Reunanen M, Rautakorpi I, Hillert J, Lundmark F, Oturai A, Ryder L, Harbo HF, Celius EG, Palotie A, Daly M, Peltonen L, Saarela J. · Department of Molecular Medicine, National Public Health Institute and Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland. · Eur J Hum Genet. · Pubmed #19142207 No free full text.

Abstract: Single-nucleotide polymorphisms (SNPs) in the 3' region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS.

Sulonen AM, Kallio SP, Ellonen P, Suvela M, Elovaara I, Koivisto K, Pirttilä T, Reunanen M, Tienari PJ, Palotie A, Peltonen L, Saarela J. · Finnish Institute for Molecular Medicine, FIMM, and National Public Health Institute, Biomedicum, Helsinki, Finland. · J Neuroimmunol. · Pubmed #19019460 links to  free full text

Abstract: Loss-of-function mutations of DAP12 and TREM2 cause a recessively inherited disease PLOSL, manifesting in brain white matter. The genes of the DAP12-TREM2 signaling receptor are located on 19q13.12 and 6p21.1, to which linkage has been observed also in families affected by another immune-mediated demyelinating disease, MS. We have tested if allelic variation in DAP12 or TREM2 predisposes also to MS by monitoring carrier frequency of the Finnish PLOSL mutation in Finnish MS cases and by studying DAP12 and TREM2 in MS by linkage and association. To conclude, the DAP12-TREM2 complex unlikely has a role in genetic susceptibility of MS.

Rinta S, Kuusisto H, Raunio M, Paalavuo R, Levula M, Lehtimäki T, Elovaara I. · Neuroimmunology Unit, Department of Neurology, Finn-Medi 3, Biokatu 10, 33014 University of Tampere, Finland. · J Neuroimmunol. · Pubmed #18963025 No free full text.

Abstract: A failure in apoptosis of lymphocytes may lead to harmful immunoreactivity in MS. We analyzed apoptosis-related molecules including TRAIL, sFas, sFasL and MIF in the blood of 117 MS patients and controls to answer whether these molecules may be used in the evaluation of disease activity and immunomodulatory effect of IFN-beta. Increased levels of sTRAIL, sFasL and MIF were found in sera of untreated patients with MS relapse indicating their association with MS disease activity. IFN-beta treated patients in remission had increased TRAIL mRNA, sTRAIL, sFaL and MIF that most likely reflect bioactivity of IFN-beta.

Kuusisto H, Kaprio J, Kinnunen E, Luukkaala T, Koskenvuo M, Elovaara I. · Department of Neurology and Rehabilitation, Tampere University Hospital, Tampere, Finland. · Eur J Neurol. · Pubmed #18727671 No free full text.

Abstract: OBJECTIVES: To evaluate the changes in the multiple sclerosis (MS) concordance in twins, and the contribution of genetic and environmental factors to the aetiology of MS in Finland. BACKGROUND: Both genes and the environment contribute to the development of MS. A well-conducted twin study is an excellent means to assess the relative contribution of heritability and environmental factors. METHODS: Multiple sclerosis concordance was assessed for 10 Monozygotic and 14 dizygotic twin pairs using pairwise and probandwise concordance rates. The tetrachoric correlations in liability to disease for twin pairs were computed and a polygenic multifactorial model was used to estimate heritability. RESULTS: The pairwise concordance for MZ twins was 30% and for the DZ twins 14.3%, compared with 30% for MZ and 0% for DZ 20 years ago. The corresponding probandwise concordance rates were 46.2% and 25%. The genetic variance (heritability) was 15.3% (95% Cl 0.0-77.6), the common environmental variance 73.7% (95% Cl 14.1-93.9) and the unique environmental variance 11.1% (95% Cl 2.3-30.0). CONCLUSIONS: As the concordance of MS in DZ twins has increased during the past two decades and the heritability estimate is low, it seems that the reported increase in MS incidence in Finland is mainly caused by environmental factors.

Kristjansdottir G, Sandling JK, Bonetti A, Roos IM, Milani L, Wang C, Gustafsdottir SM, Sigurdsson S, Lundmark A, Tienari PJ, Koivisto K, Elovaara I, Pirttilä T, Reunanen M, Peltonen L, Saarela J, Hillert J, Olsson T, Landegren U, Alcina A, Fernández O, Leyva L, Guerrero M, Lucas M, Izquierdo G, Matesanz F, Syvänen AC. · Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · J Med Genet. · Pubmed #18285424 links to  free full text

Abstract: BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

Airas L, Saraste M, Rinta S, Elovaara I, Huang YH, Wiendl H, Anonymous00012. · MediCity Research Laboratory, University of Turku, Turku, Finland. · Clin Exp Immunol. · Pubmed #18062798 links to  free full text

Abstract: Multiple sclerosis (MS) ameliorates typically during pregnancy but after the delivery the relapse rate often increases. Our study was conducted to understand the immunoregulatory mechanisms accompanying this phenomenon. MS patients were followed-up prospectively during pregnancy and 6 months postpartum, with immunological characterization of the peripheral blood. Groups of age- and parity-matched healthy pregnant women, and age- and sex-matched non-pregnant women and non-pregnant MS patients were studied as controls. In our patient cohort, the annualized relapse rate was 1.0 +/- 1.0 relapses/woman/year (mean +/- standard deviation) during the year before pregnancy, but dropped to 0.2 +/- 0.9 during the third trimester (P = 0.02). After the delivery the relapse rate increased again to 1.4 +/- 1.9 (1-3 months postpartum versus third trimester P = 0.003). While percentages of peripheral blood CD3, CD4, CD8 and CD19 immune cell subsets were unchanged over the observation period, reduced disease activity during the last trimester was associated with a significant increase in the percentage of circulating CD56(bright) natural killer (NK) cells. Simultaneously, the proportion of circulating CD56(dim) NK cells was clearly reduced. No alteration was noted in CD4+ CD25(high) forkhead box P3+ regulatory T cells. Production of interferon-gamma by peripheral blood lymphocytes was down-regulated significantly during pregnancy in comparison to the postpartum period, resulting in an increased T helper type 2 (Th2) : Th1 ratio during pregnancy. In conclusion, pregnant state in MS patients is characterized by an increase in the percentage of CD56(bright) NK cells and by enhanced Th2 type cytokine secretion. Our findings suggest a potential role for CD56(bright) regulatory NK cells in the control of autoimmune inflammation during pregnancy in MS.

Kuusisto H, Hyöty H, Kares S, Kinnunen E, Elovaara I. · Department of Neurology, University Hospital of Tampere, Tampere, Finland. · Mult Scler. · Pubmed #17893113 No free full text.

Abstract: OBJECTIVE: To investigate the possible association of human herpes virus 6- (HHV6) infection and multiple sclerosis (MS). BACKGROUND: Despite intensive investigations of genetic and environmental factors, the etiopathogenesis of MS remains unknown. HHV6 is a possible candidate in that it is neurotropic, able to induce demyelination and become latent and be reactivated. We had access to The Finnish National Twin Cohort, which provided a unique opportunity to study the association between HHV6 and MS in genetically homogenous patients. METHODS: Thirty-four serum samples from 17 MS twin pairs and 12 cerebrospinal fluid (CSF) samples from six MS twin pairs were tested by PCR specific for HHV6. Immunoglobulin (Ig) G and M response against HHV6 in serum and CSF were analysed using ELISA method. The samples were collected during a remission of the disease. RESULTS: No HHV6 DNA was found in any serum (n=34) or CSF (n=12) samples. Eighty-eight percent of the twins with MS and 86% of the healthy twin siblings were positive for IgG in serum. One twin with MS was also positive for IgM in serum, whereas none of the healthy twins was IgM positive. All CSF samples were negative for IgG and IgM in both groups. CONCLUSIONS: During a clinical remission of MS the detection of antibodies against HHV6 in CSF and HHV6 DNA in serum, CSF supernatant or CSF leukocytes is unlikely. However, the results do not exclude a possibility of HHV6 reactivation during MS exacerbation or acute HHV6 infection being one of the triggering agents in development of MS long before its clinical manifestation.

Paavilainen T, Kurki T, Parkkola R, Färkkilä M, Salonen O, Dastidar P, Elovaara I, Airas L. · Medical Imaging Centre of Southwest Finland, Turku University Hospital, Turku, Finland. · Eur J Neurol. · Pubmed #17727663 No free full text.

Abstract: Post-partum relapses are a frequent phenomenon in multiple sclerosis (MS). The purpose of this study was to evaluate the timing and extent of new or growing T2-lesions after delivery in a cohort of Finnish MS patients. In addition to serial magnetic resonance imaging (MRI), the patients were followed up clinically with determination of relapse rate and expanded disability status scale. The annualized relapse rate was decreased during the last trimester of pregnancy [mean 0.14, standard deviation (SD) 0.14] when compared with the time before pregnancy (mean 0.64, SD 0.14; P = 0.04) and to time post-partum (mean 1.50, SD 0.45; P = 0.0002). New or enlarging lesions were detected in the post-partum images in 14 of 28 patients. Gadolinium-enhancing lesions in post-partum MRI were present in eight of 13 patients. There was a significant increase in the number of T2-lesions (P = 0.0009), in the total volume of MS-lesions measured from fluid-attenuated inversion recovery images (P = 0.0126) and in the number of diffusion weighted imaging hyperintense lesions (P = 0.0098) in the post-partum images. The clinical results support the earlier findings of decreased disease activity in late pregnancy. The clinical and MRI findings indicate that post-partum activation is an early and common phenomenon amongst mothers with MS.

Ukkonen M, Wu K, Reipert B, Dastidar P, Elovaara I. · Department of Neurology, Tampere University Hospital, Tampere, Finland. · Mult Scler. · Pubmed #17613596 No free full text.

Abstract: OBJECTIVE: We evaluated the utility of adhesion molecule (AM) and cytokine/chemokine expressions in blood and cerebrospinal fluid (CSF) as markers of disease activity in primary progressive multiple sclerosis (PPMS). METHODS: The expressions of AMs and the levels of 17 cytokines in patients with PPMS (n = 25) were compared with those in secondary progressive MS (SPMS) (n = 18) and controls (n =11) and correlated with the volumes of focal and atrophic changes on MRI. RESULTS: The expressions of very late activation antigen 4 (VLA-4), lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) in blood and CSF were higher in PPMS than in controls. Comparison between PPMS and SPMS showed higher levels of ICAM-1 in blood and CSF in PPMS, while the level of the vascular adhesion molecule (VCAM-1) was higher only in blood. There was no difference in the levels of cytokines in serum or CSF between PPMS and SPMS or controls, but evidence suggesting intrathecal synthesis of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) was found in PPMS. The expressions of CSF VLA-4 in PPMS correlated with the total volume of cerebral lesions and the number of diffuse brain lesions in MRI, while the amount of LFA-1 in CSF correlated with the number of spinal T2 lesions. The level of serum MIP-1beta correlated with the T2 lesion load and EDSS score in PPMS. CONCLUSIONS: The upregulated expressions of AMs in blood and CSF and evidence for intrathecal synthesis of MCP-1 and IL-8 in PPMS indicate the importance of inflammatory changes in the pathogenesis of PPMS.

Beiske AG, Naess H, Aarseth JH, Andersen O, Elovaara I, Farkkila M, Hansen HJ, Mellgren SI, Sandberg-Wollheim M, Sorensen PS, Myhr KM, Anonymous00298. · Department of Neurology, University Hospital of Akershus, Lørenskog, Norway. · Mult Scler. · Pubmed #17439908 No free full text.

Abstract: Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-beta1a (IFN-beta1a), 22 mug subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-beta1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS.