Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

A population-based epidemiological study of neuromyelitis optica spectrum disorder in Hungary.

BACKGROUND AND PURPOSE: The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO Diagnosis (IPND) criteria. METHODS: A retrospective population-based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re-evaluation from multiple sources. Crude and sex- and serostatus-specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person-years) from 2006 to 2015 were estimated and age-adjusted rates were determined. RESULTS: Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 [95% confidence interval (CI) 1.52-2.28] per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person-years provided an incidence rate of 1.32 (95% CI 1.08-1.61) per 1 000 000 person-years. Age-adjusted prevalence was 1.87 (95% CI 1.56-2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98-1.46) per 1 000 000 person-years. CONCLUSIONS: In this first report of a large population-based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations.

Antibody response against gastrointestinal antigens in demyelinating diseases of the central nervous system.

BACKGROUND: Antibodies against gastrointestinal antigens may indicate altered microbiota and immune responses in the gut. Recent experimental data suggest a connection between gastrointestinal immune responses and CNS autoimmunity. METHODS: Antibodies against gliadin, tissue transglutaminase (tTG), intrinsic factor (IF), parietal cells (PC) and Saccharomyces cerevisiae (ASCA) were screened in the sera of 45 patients with AQP4-seropositive neuromyelitis optica (NMO) and NMO spectrum diseases (NMO/NMO-SD), 17 patients with AQP4-seronegative NMO, 85 patients with clinically definite multiple sclerosis (MS), and 48 healthy controls (HC). RESULTS: Thirty-seven percentages of patients with AQP4-seropositive NMO/NMO-SD and 28% of patients with MS had at least one particular antibody in contrast to 8% of HC (P < 0.01, respectively). Antibodies were most common (46%) in AQP4-seropositive myelitis (P = 0.01 versus HS, P = 0.05 versus MS). Anti-gliadin and ASCA were more frequent in the AQP4-seropositive NMO-spectrum compared to controls (P = 0.01 and P < 0.05, respectively). CONCLUSION: Antibody responses against gastrointestinal antigens are common in MS and AQP4-seropositive NMO/NMO-SD, especially in longitudinally extensive myelitis.

High anti-EBNA-1 IgG levels are associated with early-onset myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acethylcholine receptor (AchR) of the neuromuscular junction in the majority of patients. METHODS: Here, we examined IgG antibodies against the type 1 nuclear antigen of Epstein-Barr virus (EBNA-1) in the sera of 158 patients with MG compared to 184 healthy controls. RESULTS: Although serum concentration in the sera was not different, high anti-EBNA-1 IgG titers (above 90th percentile of the normal values) were more common in the patients (26.6 vs. 16.3%, P=0.024). In addition, high EBNA-1 IgG levels occurred more frequently amongst the 94 patients with early-onset myasthenia gravis (EOMG, 30.8%) as compared to the 64 patients with late-onset disease (LOMG, 14.1%) (P=0.021). Using multiple logistic regression, high serum concentration of the anti-EBNA-1 IgG antibodies was significantly associated with EOMG (OR: 3.17, P=0.027), even after adjustment for sex, presence/absence of anti-AchR antibodies and presence/absence of anti-Titin antibodies. Out of 39 patients with EOMG, who underwent thymectomy, 18 patients (46%) had thymoma, 6 had thymic hyperplasia (15%), and 15 patients had thymic atrophy (39%); there was no difference comparing EBNA-1 antibody titers in the sera. As no correlation was found between the titers of anti-AchR, anti-Titin, and EBNA-1 antibodies, a dysregulated heterogeneous B-cell response was unlikely to be responsible for the elevated levels of EBV-associated antibody in patients. CONCLUSIONS: In summary, our data suggest that high levels of EBNA-1 antibodies are more common in MG compared to healthy controls and are especially associated with EOMG.

Long-term effects of combined immunosuppressive treatment on myasthenic crisis.

BACKGROUND AND PURPOSE: We studied the long-term crisis-preventing effect of combined prednisolone-azathioprine (PR-AZA) treatment in myasthenia gravis (MG). METHODS: Case-control study with a median follow-up of 64 months in the treated group, and 80 months in the non-treated group. Sixty-nine patients with episodes of myasthenic crisis (MC) were treated and followed prospectively in 1990-2004. Twenty-seven patients had MC between 1990 and 1996, and were not treated with immunosuppressants on long-term. Long-term PR-AZA treatment was introduced in another 42 patients, who developed MC in 1997-2004. The difference in the frequency of repeated MCs between the treated and the non-treated group during long-term follow-up was investigated. As secondary end-points, we analyzed the number of admittances to the ICU; the number of mechanical ventilation episodes; the duration of ICU treatment; the characteristics of the applied treatment; and the functional outcome of the patients 1 month after the onset of the crisis. RESULTS: Recurrent MCs occurred in 74% of the non-treated and 19% of the treated group (P < 0.001). The number of ICU admissions (P = 0.005) and mechanical ventilation events (P = 0.002) were also reduced. The highly significant MC preventing effect of PR-AZA was evident after 6 months. CONCLUSIONS: After the initial 6 months of therapy, PR-AZA is effective in preventing MC.

Epidemiology of familial multiple sclerosis in Hungary.

The prevalence of familial aggregation of multiple sclerosis (MS) is estimated between 5 and 10%. Studies emphasize the effect of genetic factors over the environment of the patients in the development of the disease. We investigated familial accumulation of MS in the cases of 1500 patients in five Hungarian MS centers. According to our data, the risk of familial MS in Hungary is lower than in other countries for which literature data are accessible. The literature does not contain any data for the prevalence of familial MS in Hungary and middle-eastern Europe.

Safety of long-term combined immunosuppressive treatment in myasthenia gravis--analysis of adverse effects of 163 patients.

The aim of this study was to evaluate the long-term adverse effect (AE) profile of azathioprine (AZA) plus methylprednisolone combined immunosuppressive treatment in myasthenia gravis (MG) in a larger patient cohort. A prospective, open, observational study was conducted on 163 MG patients treated with combined immunosuppressive medication for a mean duration of 35.5 months (range 9-79 months). During the treatment course, AEs occurred in 61.4% of patients; 18% of these patients developed both steroid- and AZA-related AE, 15% had purely AZA-related AE and 67% had steroid-associated AEs. Severe AEs were encountered in only 6.7% of patients in whom treatment had to be discontinued. The clinical severity of MG at the start of the immunosuppressive treatment was positively correlated with the frequency and severity of AEs during the treatment, and patients with severe MG were found to be at higher risk of developing AEs during the combined immunosuppressive treatment. Combined immunosuppressive treatment of MG patients is well tolerated, and severe AEs requiring treatment cessation are rare. The incidence of steroid-related AEs is high during long-time therapy which underlines the importance of its combination with AZA. The probability of developing AEs seems to correlate with the severity of MG at the beginning of the treatment.

alpha-Tocopherol/lipid ratio in blood is decreased in patients with Leber's hereditary optic neuropathy and asymptomatic carriers of the 11778 mtDNA mutation.

OBJECTIVES: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease characterised by acute or subacute bilateral visual loss in young patients. The primary aetiological event is a mutation in the mitochondrial genome (mtDNA) affecting in most cases mtDNA-encoded subunits of the respiratory chain NADH: coenzyme Q oxidoreductase (complex I). The impaired function of complex I leads to a decline in mitochondrial energy production and enhances free radical generation. METHODS: The concentrations of some non-enzymatic antioxidants (alpha-tocopherol, beta-carotene, lycopene, glutathione, free sulphydryl groups) and the lipid peroxides in the blood of patients with LHON, carriers with homoplasmic DNA mutation at 11 778, and controls were investigated using high performance liquid chromatography and spectrophotometric methods to assess the function of their antioxidant defence systems. RESULTS: The alpha-tocopherol/cholesterol+ triglyceride ratio was significantly reduced (p<0.05) both in the patients and asymptomatic carriers. The concentrations of the other antioxidants and the lipid peroxides were not different from those of control subjects. CONCLUSION: The low concentration of plasma alpha-tocopherol most probably reflects the consumption of the antioxidant by the affected tissues. Furthermore, it suggests that alpha-tocopherol may be the primary scavenger molecule against the free radicals induced by complex I deficiency.