Factors influencing daily treatment choices in multiple sclerosis: practice guidelines, biomarkers and burden of disease.

At two meetings of a Central European board of multiple sclerosis (MS) experts in 2018 and 2019 factors influencing daily treatment choices in MS, especially practice guidelines, biomarkers and burden of disease, were discussed. The heterogeneity of MS and the complexity of the available treatment options call for informed treatment choices. However, evidence from clinical trials is generally lacking, particularly regarding sequencing, switches and escalation of drugs. Also, there is a need to identify patients who require highly efficacious treatment from the onset of their disease to prevent deterioration. The recently published European Committee for the Treatment and Research in Multiple Sclerosis/European Academy of Neurology clinical practice guidelines on pharmacological management of MS cover aspects such as treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and are based on expert consensus statements. However, the recommendations constitute an excellent framework that should be adapted to local regulations, MS center capacities and infrastructure. Further, available and emerging biomarkers for treatment guidance were discussed. Magnetic resonance imaging parameters are deemed most reliable at present, even though complex assessment including clinical evaluation and laboratory parameters besides imaging is necessary in clinical routine. Neurofilament-light chain levels appear to represent the current most promising non-imaging biomarker. Other immunological data, including issues of immunosenescence, will play an increasingly important role for future treatment algorithms. Cognitive impairment has been recognized as a major contribution to MS disease burden. Regular evaluation of cognitive function is recommended in MS patients, although no specific disease-modifying treatment has been defined to date. Finally, systematic documentation of real-life data is recognized as a great opportunity to tackle unresolved daily routine challenges, such as use of sequential therapies, but requires joint efforts across clinics, governments and pharmaceutical companies.

MMP-2 -1575G/A polymorphism modifies the onset of optic neuritis as a first presenting symptom in MS?

Previous studies show altered activities of matrix metalloproteinase (MMP)-2 and MMP-9 in serum and cerebrospinal fluid of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients. Optic neuritis (ON) is a common symptom of both disorders. Here we investigated the impacts of MMP-2 -1575G/A and MMP-9 -1562 C/T gene polymorphisms on disease phenotype in 100 MS patients with ON as a first symptom and 376 MS patients with other initial symptomatology. The MMP-2 -1575G/A polymorphism led to a 5-year-earlier age of disease onset in MS patients with ON as a first symptom (p=0.009).

The role of TPA I/D and PAI-1 4G/5G polymorphisms in multiple sclerosis.

BACKGROUND: Previous studies have shown impaired fibrinolysis in multiple sclerosis (MS) and implicated extracellular proteolytic enzymes as important factors in demyelinating neuroinflammatory disorders. Tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) are key molecules in both fibrinolysis and extracellular proteolysis. In the present study, an association of the TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS was analyzed within the Genomic Network for Multiple Sclerosis (GENoMS). METHODS: The GENoMS includes four populations (Croatian, Slovenian, Serbian, and Bosnian and Herzegovinian) sharing the same geographic location and a similar ethnic background. A total of 885 patients and 656 ethnically matched healthy blood donors with no history of MS in their families were genotyped using PCR-RFLP. RESULTS: TPA DD homozygosity was protective (OR = 0.79, 95% CI 0.63-0.99, P = 0.037) and PAI 5G5G was a risk factor for MS (OR = 1.30, 95% CI 1.01-1.66, P = 0.038). A significant effect of the genotype/carrier combination was detected in 5G5G/I carriers (OR = 1.39 95% CI 1.06-1.82, P = 0.017). CONCLUSIONS: We found a significantly harmful effect of the combination of the PAI-1 5G/5G genotype and TPA I allele on MS susceptibility, which indicates the importance of gene-gene interactions in complex diseases such as MS.

How does fingolimod (gilenya(®)) fit in the treatment algorithm for highly active relapsing-remitting multiple sclerosis?

Multiple sclerosis (MS) is a neurological disorder characterized by inflammatory demyelination and neurodegeneration in the central nervous system. Until recently, disease-modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta-interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya(®)) is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS) for adult patients with high disease activity despite basic treatment (beta-interferon) and for treatment-naïve patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from ten Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients.

Recommendations for the use of prolonged-release fampridine in patients with multiple sclerosis (MS).

Prolonged-release fampridine (fampridine PR) is a potassium channel blocker that improves conductivity of signal on demyelinated axons in central nervous system. Fampridine PR has been approved to improve speed of walking in patients with multiple sclerosis. This statement provides a brief summary of data on fampridine PR and recommendations on practical use of the medication in clinical practice, prediction, and evaluation of response to treatment and patient management.

Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group.

Fingolimod is the first oral treatment of multiple sclerosis. It is the first-in-class sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phophate receptors on lymphocytes and via downregulation of the receptor prevents lymphocyte egress from lymphoid tissues into the circulation. This mechanism reduces the infiltration of potentially auto-aggressive lymphocytes into the central nervous system. Two large phase III studies with fingolimod have shown superior efficacy of the drug in two dosages compared to placebo and to weekly intramuscular injections of Interferon beta-1a. Among possible side effects of the drug is a transient bradycardia after the first dose of fingolimod including possible AV blockade and therefore monitoring of pulse rate and blood pressure for 6 h following the first application is needed. During treatment, attention has to be given to specific infections, elevated liver enzymes, and ophthalmologic changes. Recommendations on the use of fingolimod including safety aspects are given in this article.

Influence of sports climbing and yoga on spasticity, cognitive function, mood and fatigue in patients with multiple sclerosis.

OBJECTIVES: Spasticity, cognitive impairment, depression and fatigue significantly reduce the quality of life in multiple sclerosis (MS) patients. To find out whether nonpharmalogical treatment approaches can reduce these symptoms we investigated effects of sports climbing (SC) and yoga on spasticity, cognitive impairment, mood change and fatigue in MS patients. Sports climbing (SC) and yoga are aerobic physical activities comprised a series of stretching techniques, implementation of which demands body control and planning of complex movements. MATERIALS AND METHODS: 20 subjects with relapsing-remitting or progressive MS, 26-50 years of age, with EDSS2 were enrolled in a randomized prospective study. The participants were randomly divided into SC and yoga group. We evaluated spasticity, cognitive function, mood and fatigue before and after both programs, that lasted 10 weeks, with standardized assessment methods. RESULTS: There were no significant improvements in spasticity after SC and yoga. In the SC group we found a 25% reduction (p=0.046) in EDSSpyr. There were no differences in executive function after the completion of both programs. There was a 17% increase in selective attention performance after yoga (p=0.005). SC reduced fatigue for 32.5% (p=0.015), while yoga had no effect. We found no significant impact of SC and yoga on mood. CONCLUSIONS: Yoga and SC might improve some of the MS symptoms and should be considered in the future as possible complementary treatments.

Clinical, magnetic resonance imaging, cerebrospinal fluid and electrophysiological characteristics of the earliest multiple sclerosis.

OBJECTIVES: The vast majority of clinically isolated syndrome (CIS) patients with at least two silent brain MRI lesions progress to multiple sclerosis (MS) as early as after 2 years meaning that they actually have MS, the earliest MS. Effective therapy with interferon beta preparations in patients with the earliest MS demands early and accurate diagnosis of the disease. PATIENTS AND METHODS: In order to find the differentiating clinical and paraclinical characteristics of patients with the earliest MS we compared clinical, MRI, CSF and evoked potential findings in patients with the earliest MS and patients with relapsing-remitting (RR) MS. Retrospective analysis included 149 patients (103 women), among them 40 patients with the earliest MS and 95 patients with RR MS. RESULTS: Patients with the earliest MS had more often predominant afferent symptoms (p=0.023) but less often predominant cerebellar (p=0.033) and efferent symptoms (p=0.012) than patients with RR MS. They were less likely to fulfill the Barkhof brain MRI criteria (p=0.050) and had less often prolonged latencies of visual evoked potentials (VEP) (p=0.006) than patients with RR MS. On the other hand they were more likely to have elevated CSF cells (p=0.010) than patients with RR MS and had as often present CSF oligoclonal bands (p=0.112). CONCLUSION: The differentiating characteristics of patients with the earliest MS are predominance of afferent symptoms, less brain MRI dissemination and more frequently normal VEP, but on the other hand abnormal CSF findings with elevated CSF cells and positive oligoclonal bands.

PAI and TPA gene polymorphisms in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system. It manifests as acute focal inflammatory demyelination and axonal loss with limited remyelination and results in the chronic multifocal sclerotic plaques. Previously published data showed impaired fibrinolysis in MS. Tissue plasminogen activator t-PA is a serine protease that catalyses the activation of plasmin, which mediates the effects of fibrinolytic system. Alu insertion/deletion (I/D) genetic polymorphism in TPA gene in MS patients has not been analysed previously. The major inhibitor of t-PA is plasminogen activator inhibitor-1 (PAI-1). Its gene expression is modulated by functional genetic polymorphism in the promoter (4G/5G). In the present study, an association of two genetic polymorphisms with MS, its progression and subtype were analysed. TPA DD/PAI-1 4G4G genotype combination has reached a borderline significance for reduced risk for MS (OR = 0.543, 95% CI 0.301-0.978, P = 0.04), suggesting a gene-gene interaction. The explanation for this interaction may be a complex interplay between these two pleiotropic proteins within the brain tissue and in plasma.

No association of CCR5delta32 gene mutation with multiple sclerosis in Croatian and Slovenian patients.

Several studies investigating the role of the CCR5delta32 mutation in multiple sclerosis (MS) have reported varied, often contradictory results. Therefore in the present study we have analysed whether the CCR5delta32 mutation is associated with the risk of/or disease process in Croatian and Slovene MS patients. Three hundred and twenty-five MS patients and 356 healthy controls were genotyped by the polymerase chain reaction method. Our results showed no significant differences in the distribution of CCR5delta32 mutations between MS and control subjects, indicating that this mutation does not influence susceptibility to MS. Furthermore, we did not observe that CCR5delta32 carrier-status could modulate age of disease onset or progression of the disease. It is therefore our conclusion that the present study indicates that the CCR5delta32 mutation is neither protective of, nor a risk factor, for MS development.

Mutations in the hemochromatosis gene (HFE) and multiple sclerosis.

In the present study we have investigated whether HFE gene polymorphism may play a role in the disease process of Croatian and Slovenian MS patients and their potential genetic susceptibility to MS. We genotyped 314 MS patients and 400 healthy controls for the C282Y and H63D mutations by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) analysis. Our results showed no significant differences in the distribution of the two mutations between MS patients and controls, suggesting that HFE polymorphisms do not contribute to the susceptibility to MS. Also, there was no significant correlation between HFE polymorphism and the disease progression index. However, we observed that MS patients carrying the mutant C282Y allele exhibited earlier onset of disease symptom relative to other genotypes, but it warrants further study in a larger series of MS patients.