Investigations in the Hungarian Multiple Sclerosis Patient Population: New Data on the Genetic Background and Validation of the Fatigue Impact Scale

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The disease is heterogeneous, which results in different clinical manifestations. In the majority of MS patients, the disease begins with a relapsing course (relapsing-remitting form, RRMS), characterized by relapses and remissions, and followed by a progressive phase (secondary progressive MS, SPMS). In a smaller subset of patients, the relapsing phase is not observed and the disease progresses from the beginning (primary progressive form, PPMS). The appearance of the disease is determined by a combination of exogenous factors and the genetic background. Two of the genes whose potential association emerged from the analyses published previously by our MS Workgroup were selected for further analysis: • Tumour necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of infectious and autoimmune disorders, including MS. The human TNF gene maps to chromosome 6p21.3 in the highly polymorphic MHC region. The chromosome location suggests that TNF α single nucleotide polymorphisms (SNPs) may be involved in influencing the disease course during MHC-associated diseases such as MS. • Apolipoprotein E (ApoE), an important glycoprotein in the transport, uptake and redistribution of cholesterol, is necessary in nerve tissue repair. The APOE gene (APOE) is involved in neurodegenerative diseases, the best-known association being that between the APOE ε4 allele and Alzheimer’s disease. Our primary aims were a multicentre assessment of the possible influence of the TNF-α -376 polymorphism and of the APOE gene on the susceptibility to PPMS in Hungary. Polymerase chain reaction and restriction fragment length polymorphism were carried out on 45 PPMS patients, 45 age and sex-matched RRMS patients and 45 healthy controls (HCs). In our study, the GG genotype and the guanine allele (G) in the TNF-α gene at position -376 were detected significantly more often in the PPMS group than in the HC group. As regards the APOE gene, the number of PPMS patients without the ε2 allele was found to be notably high, whilst the ε2 allele was overrepresented in the RRMS group. A markedly high frequency of the ε4 allele was found in the PPMS group and a very low frequency in the HC group. As concerns the clinical parameters, significant differences were observed between the RRMS and PPMS groups. Differences were also detected regarding the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) scores when the patients were grouped according to the presence or absence of the ε2 allele. All of the observed differences in the clinical parameters disappeared when the patients were further stratified according to the type of MS. Our findings suggest that the G allele at position -376 of the TNF-α gene may be one of the factors responsible for progression in PPMS, and that the presence of the ε2 and ε4 alleles may play a role in the development of the disease. However, when any type of the disease has already developed, the alleles show no association with the clinical parameters. In addition to the genetic investigations, as a secondary aim we intended to better understand fatigue a very important feature of MS. Fatigue is one of the most frequent complaints of patients with MS. The Fatigue Impact Scale (FIS), one of the 30 available fatigue questionnaires, is commonly applied because it evaluates multidimensional aspects of fatigue. An objective questionnaire for evaluation of the impact of fatigue in Hungarian MS patients has not yet been approved. On the basis of our previous experience with the adaptation and validation process of the Multiple Sclerosis Quality of Life Instrument, we set out to test the validity, test-retest reliability and internal consistency of the Hungarian version of the FIS. One hundred and eleven MS patients and 85 HCs completed the FIS and the Beck Depression Inventory (BDI), a large majority of them on 2 occasions, 3 months apart. The total FIS score and subscale scores differed statistically between the MS patients and the HCs in both FIS sessions. In the test-retest reliability assessment, the ICCs were statistically high in both the MS and HC groups. Cronbach’s alpha values were also notably high. Consequently, our results indicate that the FIS can be regarded as a valid and reliable scale with which to improve our understanding of the impact of fatigue on the health-related quality of life in MS patients without severe disability

Validation of the Fatigue Impact Scale in Hungarian patients with multiple sclerosis

PURPOSE: Fatigue is one of the most frequent complaints of patients with multiple sclerosis (MS). The Fatigue Impact Scale (FIS), one of the 30 available fatigue questionnaires, is commonly applied because it evaluates multidimensional aspects of fatigue. The main purposes of this study were to test the validity, test-retest reliability, and internal consistency of the Hungarian version of the FIS. METHODS: One hundred and eleven MS patients and 85 healthy control (HC) subjects completed the FIS and the Beck Depression Inventory, a large majority of them on two occasions, 3 months apart. RESULTS: The total FIS score and subscale scores differed statistically between the MS patients and the HC subjects in both FIS sessions. In the test-retest reliability assessment, statistically, the intraclass correlation coefficients were high in both the MS and HC groups. Cronbach's alpha values were also notably high. CONCLUSIONS: The results of this study indicate that the FIS can be regarded as a valid and reliable scale with which to improve our understanding of the impact of fatigue on the health-related quality of life in MS patients without severe disability

APOE epsilon status in Hungarian patients with primary progressive multiple sclerosis

PRINCIPLES: Apolipoprotein E (ApoE), an important glycoprotein in the transport, uptake and redistribution of cholesterol, is necessary in nerve tissue repair. The APOE gene (APOE) is involved in neurodegenerative diseases, the best-known association being that between the APOE epsilon4 allele and Alzheimer's disease. Multiple sclerosis (MS) is a chronic inflammatory neurological disease. The aim of this study was to assess (multicentre assessment) the possible influence of the APOE gene on the susceptibility of primary progressive MS (PPMS) in Hungary. METHODS: Polymerase chain reaction and restriction fragment length polymorphism were carried out on DNA isolated from 135 volunteers. RESULTS: The number of PPMS patients without the epsilon2 allele was found to be remarkably high, whilst the epsilon2 allele was overrepresented in the RRMS group. A markedly high frequency of the epsilon4 allele was found in the PPMS group and a very low frequency in the HC group. With regards to the clinical parameters, significant differences were observed between the RRMS and PPMS groups. Differences were also detected regarding the EDSS and MSSS scores when the patients were grouped by the presence or absence of the epsilon2 allele. All of the observed differences in the clinical parameters disappeared when the patients were further stratified by the type of MS. CONCLUSIONS: Our findings suggest that the presence of the epsilon2 and epsilon4 alleles may play a role in the development of the disease. However, if any type of the disease has already developed the alleles show no association with the clinical parameters

Treatment of relapsing-remitting multiple sclerosis 96 patients with IFN-beta 1b: Results of a 6-year follow-up

The first pharmacon with proved efficacy for the treatment of patients with the relapsing-remitting or relapsing-progressive form of multiple sclerosis (MS) was interferon-beta 1b (IFN-beta 1b). In 1996, we started treating 34 relapsing-remitting (RRMS) and 2 relapsing-progressive MS (RPMS) patients with IFN-beta 1b. Of these 36 patients, 28 received continuous medication for 6 years. The primary end point of the study was the effect of 6 years of continuous IFN-beta 1b treatment on the annual relapse rate, the secondary end point was the change in the progression index during the 6 years, and the tertiary end point was the alteration in the expanded disability status scale (EDSS) score of the patients. Finally, we give the reasons for the dropouts. The relapse rate decreased by 80.62% (p < 0.001), the mean EDSS score increased significantly, by approximately 0.5 points, to 2.21 +/- 1.48 (p = 0.016), and the reduction in the mean progression index was 67.19% (p < 0.001). This increase of < 0.5 point in the EDSS score is appreciably different from the 3- point deterioration expected after 6 years for the natural course of the disease. The significant improvement in the progression index clearly demonstrates that 6 years of IFN-beta 1b therapy slowed the progression of the disease, thereby improving the quality of life of these MS patients

Factors influencing the health-related quality of life in Hungarian multiple sclerosis patients

Background: The 'Multiple Sclerosis Quality of Life Instrument' (MSQOL-54) was recently validated in Hungarian, on more than 400 multiple sclerosis (MS) patients. The aim of the present study was to examine the impact on their overall quality of life (QoL) of the demographic and clinical data on these patients, and their scores on different QoL scales. Methods: The Hungarian version of MSQOL-54 was given to patients at the outpatient units at the Department of Neurology, University of Szeged, and two other Hungarian MS centres. Additional data, including the EDSS scores of the patients, and relevant clinical and demographic data, were also collected. Results: The questionnaire scales relating to social function, general health, mental health and satisfaction with the sexual function mostly determined the overall QoL ratings. 62.1% of the patients indicated at least one comorbid condition. Depressed patients had a significantly worse quality of life (p<0.0001). Conclusions: MSQOL-54 is a useful tool for the recognition of possibly treatable factors influencing the QoL, but not assessed by the EDSS. Quality of life data have emerged on more than 400 patients, i.e. a considerable proportion of the Hungarian MS patient population. (C) 2010 Elsevier B.V. All rights reserved

Tumour necrosis factor alpha gene (TNF-alpha)-376 polymorphism in Hungarian patients with primary progressive multiple sclerosis

Tumour necrosis factor alpha (TNF-alpha) is associated with clinical activity in relapsing-remitting multiple sclerosis (RRMS) and the development of progressive disease. Our aim was to investigate the TNF-alpha -376 polymorphism in primary progressive MS (PPMS) patients. Polymerase chain reaction and restriction fragment length polymorphism were carried out on 45 PPMS patients, 45 age and sex-matched RRMS patients and 45 healthy controls (HC). The GG genotype and the guanine allele (G) were detected significantly more often in the PPMS group as compared with the HC group (p=0.027; p=0.032). The G allele may be one of the factors responsible for progression in PPMS

Real-World Evidence for Favourable Quality-of-Life Outcomes in Hungarian Patients with Relapsing-Remitting Multiple Sclerosis Treated for Two Years with Oral Teriflunomide: Results of the Teri-REAL Study

Relapsing-remitting multiple sclerosis (RRMS) is a degenerative, inflammatory disease of the central nervous system in which symptoms and disability progression vary significantly among patients. Teri-REAL was a prospective, real-world observational study that examined quality-of-life (QoL) and treatment outcomes in a Hungarian cohort of RRMS patients treated with once-daily oral teriflunomide. QoL was assessed at baseline, 12, and 24 months with the Multiple Sclerosis Quality of Life-54 (MSQoL-54) questionnaire. Other measurements included disease progression (Patient Determined Disease Steps [PDDS]), clinical efficacy (relapses), fatigue (Fatigue Impact Scale [FIS]), depression (Beck Depression Inventory [BDI]), cognition (Brief International Cognitive Assessment in MS [BICAMS]), persistence and safety. 212 patients were enrolled (69.1% female, 50.5% treatment naïve), with 146 (69%) completing the study. Statistically significant improvements in subscales of the MSQoL-54 versus baseline were found at Month 12 and Month 24. Significant improvements were also observed for individual components of the BICAMS score at 24 months, while PDDS, FIS and BDI scores remained stable. The mean annualised relapse rate was 0.08 ± 0.32. There were 93 safety events, most of which were mild to moderate. Improved QoL and cognitive outcomes in teriflunomide-treated patients over 2 years offer a unique perspective to this real-world study