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.

Under pressure: a day in the life of front-line nurses.

7.10am: In office to finish previous day's paperwork.

A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis.

OBJECTIVE: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS. METHODS: Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses. RESULTS: Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04). CONCLUSION: We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.

Paraneoplastic sensorimotor neuropathy associated with regression of small cell lung carcinoma.

An elderly female smoker presented with nausea and anorexia. Imaging and histopathology were consistent with a diagnosis of small cell lung cancer (SCLC). She subsequently developed a progressive sensorimotor neuropathy with high titres of anti-Hu antibodies. Development of the neuropathy was associated with marked regression in the lung neoplasm. Repeat investigation with radioimaging and bronchoscopy showed no evidence of neoplasia. Paraneoplastic sensorimotor neuropathies are commonly associated with SCLC particularly in the presence of anti-Hu antibodies. Regression of SCLC with anti-Hu antibodies has only been reported twice previously. The authors believe this case supports the theory that anti-Hu antibodies confer anti-tumour activity causing tumour regression.

An investigation of susceptibility loci in benign, aggressive and primary progressive multiple sclerosis in Northern Irish population.

OBJECTIVE: To investigate the possibility that susceptibility loci in multiple sclerosis (MS) have a role in determining the disease outcome in Northern Ireland population. BACKGROUND: The Genetic Analysis of Multiple Sclerosis in Europeans (GAMES) initiative and follow-up refined analysis identified 15 candidate susceptibility loci within the Northern Irish population for MS. We aimed to investigate the 12 most significant markers for their role in disease outcome. METHODS: Cases with probable or definite MS (Poser criteria) were classified as benign onset (Kurtzke Expanded Disability Status Scale [EDSS]or=6.0 by 10 years), or primary progressive MS. All cases were Caucasian of Northern Irish origin. DNA was extracted from venous blood, microsatellite markers were amplified using polymerase chain reaction and typed using fluorescent fragment analysis. Allele frequencies were compared statistically using a chi-squared test with allowance for multiple comparisons (critical P<0.0042); significant markers were further analyzed by CLUMP (critical P<0.0014). RESULTS: Two microsatellite markers were significant: D3S1278 (Chr 3q13, P<0.001) and tumor necrosis factor (TNF)-alpha (Chr 6p21, P<0.001). A further three markers were significant in our preliminary analysis suggesting a trend toward impact on disease outcome; D4S432 (Chr 4p16, P=0.001), D2S347 (Chr 2q14, P=0.003), and D19S903 (Chr 19p13, P=0.003). CONCLUSIONS: This is the first study to suggest a role for TNF-alpha in the disease outcome in MS. Larger replication studies need to be performed to assess the role of markers D4S432, D2S347, and D19S903.

Factors in the rising prevalence of multiple sclerosis in the north-east of Ireland.

BACKGROUND: Northern Ireland is recognized as an area of high risk for multiple sclerosis. The original study of Allison and Millar in 1951 found a prevalence of 51/100,000 and mean annual incidence of 2.74/100,000/year. Subsequent studies in 1961, 1986, and 1996 suggested rising prevalence--80, 138, and 168.2/100,000, respectively. METHODS: In 2004, we surveyed the North-East of Northern Ireland (population 160,446, area 2030 km(2)) using multiple sources of case ascertainment, all satisfying the Poser criteria for definite or probable multiple sclerosis (MS) or the McDonald criteria. RESULTS: From a provisional list of 469 cases, 370 (123 males, 247 females) were identified. The prevalence was 230.6 per 100,000 (95% CI 207.0-255.4) with significantly higher prevalence in females (300.8/100,000) than males (157.0/100,000). Direct standardization to the 1961 Northern Ireland population reduced the overall prevalence rate to 200.5/100,000 (95% CI 193.2-208.0), in females to 270.2/100,000 (95% CI 258.8-282.4) and in males to 131.1/100,000 (95% CI 122.8-139.9). In 1996, incidence had risen to 9.3/100,000/year (14 cases in population of 151,000) with a higher incidence in females (10.3/100,000/year) than males (8.3/100,000/year). CONCLUSIONS: Northern Ireland continues to have a rising prevalence of MS. The increase in incidence suggests a true increase in the disease.

A systematic review of oral methotrexate for multiple sclerosis.

Oral methotrexate is a potent immunosuppressant, which could have a beneficial effect on relapse rates and delay disease progression in multiple sclerosis (MS). We performed a systematic review of all randomized controlled trials of oral methotrexate for MS. Of the two randomized controlled trials identified, one was excluded due to its allocation concealment and definition of a relapse and time to sustained disease progression. The other trial studied 60 participants with progressive MS only. This trial reported a non-significant reduction in sustained Expanded Disability Status Scale (EDSS) progression and number of relapses in favour of methotrexate therapy. There were no data on relapse rate and no difference in time to first relapse. Minor side-effects were reported in both methotrexate (87.1%) and placebo groups (89.7%), but there were no major side-effects. Further trials are required in both relapsing-remitting and progressive groups to establish the role of oral methotrexate in MS.

A primary care-based needs assessment of people with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a common cause of chronic progressive neurological disability where reduction in quality of life is an important feature. Many GPs have MS patients with a range of disabilities. Little is known about the supply of medical and community services and how this compares with demand. AIM: We aim to describe a community based sample of MS patients and investigate how disease characteristics, benefits, services accessed and perceived needs relate to sense of wellbeing. DESIGN: Cross-sectional survey. SETTING: Participants were recruited from a representative network of 30 GP practices across Northern Ireland. METHOD: MS patients answered a professionally administered questionnaire and agreed to their medical records being examined. Information was collected about their medical condition, sociodemographic characteristics, receipt of benefits and services, perceived needs and sense of wellbeing. RESULTS: Of the 149 participants, 23% were mildly affected (Kurtzke's Expanded Disability Status Scale [EDSS] 0-4.5), 41% were moderately disabled (EDSS 5.0-6.5) and 36% were severely disabled (EDSS 7.0-9.5). Disability was related to employment, receipt of benefits and services. Physiotherapy was a commonly perceived need. Other perceived needs differed between the moderately and severely disabled groups. Scores relating to wellbeing were related to disability and perceived needs. CONCLUSIONS: The relationship between use of medical and community services and disability is important for planning service provision. We have shown that perceived needs are related to wellbeing. In a progressive illness these developing needs could be anticipated.

Methotrexate for multiple sclerosis.

BACKGROUND: Methotrexate is a potent immunosuppressant which in theory could reduce relapse rates and delay disease progression in multiple sclerosis (MS). Subsequently, clinical trials of methotrexate have been conducted in people with MS. OBJECTIVES: To identify and summarise the evidence that methotrexate is beneficial and safe for people with MS. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (searched December 2003), the Cochrane Central Register of Controlled Trails (The Cochrane Library Issue 4, 2003), MEDLINE (Pub Med) (January 1966 to June 2001), EMBASE (January 1988 to June 2001), and reference lists of articles. We also contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials of methotrexate for the prevention of relapses and disease progression in MS. DATA COLLECTION AND ANALYSIS: Two reviewers (OG, GM, ) independently selected articles for inclusion, assessed the trials' quality and extracted the data. Authors of one trial were contacted to obtaining missing information. MAIN RESULTS: One trial involving 60 participants with chronic progressive multiple sclerosis was included. The trial showed a non-significant reduction in sustained EDSS progression and number of relapses in favour of methotrexate therapy. There was no difference in time to first relapse and no data on relapse rate. Minor side-effects were reported frequently in both methotrexate (87.1%) and placebo groups (89.7%), but there were no major side-effects. REVIEWERS' CONCLUSIONS: In progressive MS, the single included trial reveals a non-significant trend in reduction of sustained EDSS progression and number of relapses in favour of methotrexate. A trial of methotrexate in relapsing remitting MS showed non-significant trends in favour of methotrexate but was excluded on methodological grounds. Before drawing further conclusions regarding the efficacy of methotrexate in MS, further trials are required.

Intravenous immunoglobulins for multiple sclerosis.

BACKGROUND: From animal experiments, there is evidence to suggest that intravenous immunoglobulins can reverse some of the disease process of central nervous system demyelination. Subsequently, clinical trials of intravenous immunoglobulins have been conducted in people with multiple sclerosis (MS). OBJECTIVES: To identify and summarise the evidence that intravenous immunoglobulins are safe and beneficial for people with MS. SEARCH STRATEGY: We searched the Cochrane Multiple Sclerosis Group trials Register( January 2003) The Cochrane Central Register of Controlled Trials (The Cochrane Library issue 4, 2002), MEDLINE (January 1966 to April 2001), EMBASE (January 1988 to April 2001) and reference lists of articles. We also contacted relevant pharmaceutical companies and authors of identified trials. SELECTION CRITERIA: Randomised controlled trials of intravenous immunoglobulins for the secondary prevention of relapses and disease progression in MS. DATA COLLECTION AND ANALYSIS: 913 titles and abstracts were obtained from the literature search, and we eventually identified 10 clinical trials. All reviewers agreed on the final dataset for entry into RevMan 4.1, and summarised the results. Study authors were contacted for additional information but no response was obtained. MAIN RESULTS: Of 913 potential studies, 10 trials were identified with a total of 918 participants, four of which are in progress or awaiting publication. The remaining six trials were suitable for consideration by this review (344 participants). Only two trials met our protocol's inclusion criteria. The four remaining trials were excluded as they did not use outcome measures specified in our review (2 trials, 122 participants), or were of insufficient methodological quality (2 trials, 34 participants). From the two included trials (168 participants) there was a reduction in relapse rate and increased time to first relapse during treatment with intravenous immunoglobulins, but reliable disease progression outcomes were not reported, nor were magnetic resonance imaging (MRI) data available to support clinical information. There may be as many as 574 participants in ongoing or yet to be published trials. REVIEWER'S CONCLUSIONS: There is some evidence to support use of intravenous immunoglobulins as a preventative treatment for relapses in relapsing remitting MS, but further studies should be performed using MRI and disease progression endpoints. It may be possible to draw more robust conclusions when ongoing or recently completed trials make their data available for review. Two rigorously conducted trials with a total of 122 participants did not demonstrate a positive clinical benefit, but were excluded from this review as they employed outcome measures not specified in our protocol. Immunoglobulins were well tolerated with a less than 5% risk of adverse events in participants in included trials.

Primary isolated brainstem injury producing internuclear ophthalmoplegia.

Abstract Brainstem injuries are classically associated with a grave prognosis. We present a case of a male with primary isolated brainstem injury who had a right internuclear ophthalmoplegia who made a complete recovery. A review of literature suggests that the mortality from such injuries is about 6% and most make a good functional recovery.

Acceptability of female condom use among women exchanging street sex in New York City.

Greater access to alternative female-initiated barrier methods, such as the female condom, is needed among women exchanging street sex. This study describes knowledge of and experience with the female condom among 101 women exchanging sex for money and drugs on the streets of New York City, and examines the acceptability of female condom use as an alternative barrier method for HIV/STD prevention among this population. Female condom use among this sample of sex workers was found to be related to having a regular sexual partner, living with someone who is a drug or alcohol abuser, not being homeless, using alcohol or intravenous heroin, having heard of the device, and having discussed the device with other women or with a regular sexual partner. Despite decreased acceptability post-use, most sex workers indicated an intention for future female condom use.

PIP: This study describes the knowledge and experience of the female condom among 101 women exchanging sex for money and drugs on the streets of New York City, and examines the acceptability of female condom use as an alternative barrier method for HIV and sexually transmitted disease (STD) prevention among this population. Samples included were African American, never married, and with an average age of 35.9 years. The result shows that women who were single and never married were more likely to use the female condom than those who were married, separated, divorced, or widowed. Moreover, those who lived with someone having drug or alcohol problems were more likely to use female condoms than their counterparts than those who were homeless, women with a place to live were more likely to use female condoms. These suggest that the female condom may be feasible alternative barrier method for STD and HIV prevention among women engaging in commercial sex work. Despite decreased acceptability post-use, most sex workers indicated an intention for future female condom use.

Student-initiated revision in child health.

Most teaching of child health in Cardiff takes place in block attachments of 8 weeks. There is an introductory seminar of 2 days followed by a 6-week clinical attachment in a district general hospital in Wales, and then a revision period of one week designed to help students formalize and structure their basic knowledge and to clarify aspects of child health which they may have had difficulty in understanding. The revision programme has to take into account: the short time available, the small number of teaching staff, the most relevant basic knowledge and active participation by the student. This paper describes how this week has been improved through the use of student-initiated revision (SIR). The students' appraisal of this revision and in particular SIR is presented.

Fatty infiltration in the liver in medium chain acyl CoA dehydrogenase deficiency.

Fatty infiltration of the liver at postmortem examination has been recommended as a criterion for selection of infants who have died suddenly and unexpectedly for further biochemical investigation for disorders of fatty acid oxidation. We describe a boy with medium chain acyl CoA dehydrogenase deficiency who died four months after diagnosis and in whom only minimal hepatic fatty infiltration was found.

Epidural versus general anaesthesia for elective caesarean section. Effect on Apgar score and acid-base status of the newborn.

Elective Caesarean section deliveries over a 5-year period were studied to compare the effect of epidural block with general anaesthesia on the condition of the infant at birth. The Apgar score and umbilical arterial acid-base status were used as determinants of the latter. Epidural block was used in 139 (22.8%) mothers while 471 (77.2%) were performed under general anaesthesia. No babies in the epidural group were severely depressed (Apgar less than 4), compared with 6.2% in the general anaesthesia group. Only 4.3% of the epidural sections were moderately depressed (Apgar 4-6), compared with 15.4% of the others. These differences remained highly significant when infants of less than 2500 g were excluded, and when matched groups were compared. Mean umbilical arterial pH was similar within the two groups (pH 7.28), and was not consistent with asphyxia in almost 90% of the depressed infants. The findings suggest that general anaesthesia, rather than asphyxia or aortocaval compression, is responsible for most of the depressed infants born by elective Caesarean section. This may involve over 20% of babies delivered in this manner, so greater use of epidural block for elective Caesarean section is recommended. Further investigations are required to improve results with general anaesthesia.

Plasma zinc concentration and catch up growth in preterm infants.

Changes in plasma zinc concentration during the period of catch up growth were examined in 44 preterm infants. Blood samples were collected at birth, 6, 12 and 24 weeks. Plasma zinc concentration showed a mean of 13.6 mumol/l at birth and dropped to 9.8 mumol/l at 6 weeks and rose to 11.3 and 15.4 mumol/l at 12 and 24 weeks respectively. Plasma zinc concentrations showed significant correlation with weight velocity at 12 weeks. Male infants had significantly lower plasma zinc concentrations than females at 12 weeks. Infants of gestational age more than 32 weeks had lower plasma zinc concentrations at 12 and 24 weeks than those of earlier gestations. At the same time males were growing faster than females and also infants of gestational ages more than 32 weeks were growing faster than those born at earlier gestations. These observations, together with the finding that the decline in zinc occurred during the phase of rapid growth, suggest that growth is the predominant modulator of plasma zinc concentration.

Catch up growth in preterm infants.

Seventy-one surviving infants were followed up from birth to 24 weeks of postnatal age. Their mean gestational age was 32 weeks with a range of 26-36 weeks and a standard deviation of 2.1 weeks. Their mean birth weight was 1,805 kg with a range of 0.675-2.5 kg and a standard deviation of 0.408 kg. Their weights, lengths and head circumferences were measured at birth, 6, 12 and 24 weeks. Curves for the mean weight, length and head circumference were produced and superimposed on the available intrauterine and extrauterine growth charts. The growth curves of the preterm infants did not show the flattening noted in the intrauterine curves towards term. The curve of the mean weight of the preterm infants started at the 50th centile for Gairdner & Pearson (1971) at birth to drop below that shortly after birth. At 40 weeks of postconceptional age the mean weight curve of preterm infants crossed the 50th centile and continued above it to reach the 90th centile at 60 weeks. The curves of mean length and head circumference started below the 50th centile at birth and crossed it at 40 weeks and continued above it to approach the 90th centile at 60 weeks. Growth velocity was calculated as a relative gradient using the straight line equation (y = a + bx), where y is the weight, length or head circumference, and x is the independent variable and here it is the group mean of the parameter at the corresponding ages. Catch up growth is taken as a relative gradient significantly greater than one. The first 24 weeks of postnatal life are defined as a period of catch up growth with the first 8 weeks as an interval of maximum head velocity.