Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages.

BACKGROUND: We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-ß) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs' recommended dosages. METHODS: We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-ß and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis. RESULTS: We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs. CONCLUSIONS: Meta-analyses confirmed that IFN-ß and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear 'winner' across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness. REVIEW REGISTRATION: PROSPERO CRD42016043278 .

Adverse events in women and children who have received intrapartum antibiotic prophylaxis treatment: a systematic review.

BACKGROUND: Adverse events from intrapartum antibiotic prophylaxis (IAP) are poorly documented yet essential to inform clinical practice for neonatal group B Streptococcus (GBS) disease prevention. In this systematic review, we appraised and synthesised the evidence on the adverse events of IAP in the mother and/or her child. METHODS: We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane, and Science Citation Index from date of inception until October 16th 2016. Reference lists of included studies and relevant systematic reviews were hand-searched. We included primary studies in English that reported any adverse events from intrapartum antibiotics for any prophylactic purpose compared to controls. The search was not restricted to prophylaxis for GBS but excluded women with symptoms of infection or undergoing caesarean section. Two reviewers assessed the methodological quality of studies, using the Cochrane Risk of Bias tool, and the Risk of Bias Assessment Tool for Nonrandomised Studies. Results were synthesised narratively and displayed in text and tables. RESULTS: From 2364 unique records, 30 studies were included. Despite a wide range of adverse events reported in 17 observational studies and 13 randomised controlled trials (RCTs), the evidence was inconsistent and at high risk of bias. Only one RCT investigated the long-term effects of IAP reporting potentially serious outcomes such as cerebral palsy; however, it had limited applicability and unclear biological plausibility. Seven observational studies showed that IAP for maternal GBS colonisation alters the infant microbiome. However, study populations were not followed through to clinical outcomes, therefore clinical significance is unknown. There was also observational evidence for increased antimicrobial resistance, however studies were at high or unclear risk of bias. CONCLUSIONS: The evidence base to determine the frequency of adverse events from intrapartum antibiotic prophylaxis for neonatal GBS disease prevention is limited. As RCTs may not be possible, large, better quality, and longitudinal observational studies across countries with widespread IAP could fill this gap. TRIAL REGISTRATION: CRD42016037195 .

Efficacy and safety of widely used treatments for macular oedema secondary to retinal vein occlusion: a systematic review.

BACKGROUND: Macular oedema secondary to retinal vein occlusion (RVO) can cause vision loss due to blockage of the central retinal vein (CRVO) or a branch retinal vein (BRVO). This systematic review assessed the efficacies of widely used treatments for macular oedema secondary to RVO and the feasibility of conducting indirect comparisons between these therapies. METHODS: A systematic review was undertaken in November 2010, including a literature search for trials in medical databases and relevant websites. Abstracts, conference presentations and unpublished studies were considered. Studies were data-extracted and quality assessed by two independent researchers. Outcome measures included the mean change in best corrected visual acuity (BCVA) from baseline in the study eye and/or number of patients gaining at least 10 letters from baseline to 6 months or the nearest equivalent time point. RESULTS: Fourteen unique randomized controlled trials (RCTs) were identified. Ranibizumab 0.5 mg produced greater improvements in BCVA at 6 months than sham in BRVO (mean difference 11.0 letters, 95% confidence interval [CI] 7.83, 14.17) and CRVO (mean difference 14.10 letters, 95% CI 10.51, 17.69) in two double-blind sham-controlled RCTs. Pooled data from two double-blind, sham-controlled RCTs showed that improvements in BCVA were also significantly better for dexamethasone intravitreal (IVT) implant 0.7 mg compared with sham in patients with BRVO or CRVO (mean difference 2.5 letters, 95% CI 0.7, 4.3); the difference was significant for BRVO alone, but not CRVO alone. A significantly greater proportion of patients with BRVO gained ≥15 letters with laser therapy vs. no treatment at 36 months in a large prospective RCT (odds ratio 3.16, 95% CI 1.25, 8.00), whereas no difference was observed at 9 months in a smaller study. Three studies reported no benefit for laser therapy in CRVO. No indirect comparisons with ranibizumab were feasible due to differences in study design and baseline characteristics. CONCLUSIONS: Data from RCTs for ranibizumab and dexamethasone IVT demonstrate that both new agents constitute significant improvements over the previously widely accepted standard of care (laser therapy) for the treatment of BRVO and CRVO. However, head-to-head studies are needed to assess the relative efficacies of licensed therapies for RVO.

Toxocarosis in humans: how much of a problem is it in the UK?

Toxocara canis (from dogs) is recognised as a potential cause of human toxocarosis, but Toxocara cati (from cats) and other species (eg, Toxascaris leonina found in foxes) are also possible causes. Most colonisation with Toxocara species does not lead to symptomatic infection in well-cared for adult animals; young and debilitated animals are at greater risk. Humans can acquire infection from infected animals, for example, via soil contaminated with faeces; however, most human infections are asymptomatic, with symptomatic infection being very rare in the UK. The risk of human infection is reduced by measures such as hand washing and responsible disposal of dog faeces. Some organisations recommend regular prophylactic treatment of pet dogs and cats. However, there are concerns that some parasiticides are contaminating the environment. As an example of a One-Health problem there is a potential conflict between the needs of animal health, human health and the health of the wider ecosystem. Also, considering that only about 5% of non-juvenile household dogs shed Toxocara eggs at a given time, it has been questioned whether it is worthwhile to invest in frequent blind treatments. British veterinary organisations have suggested less frequent treatment may be more appropriate and should be based on individual risk assessment and faecal examinations for worms rather than blanket regular prophylactic treatment, which could reduce the impact of parasiticides on the environment without greatly increasing the risks to animal or human health.

Small interfering RNA (siRNA)-based therapeutics.

In early studies in simple organisms and mammalian cell lines, small interfering RNA (siRNA) molecules were found to allow experimental cleavage of intracellular messenger RNA (mRNA; the transcription product of a cell gene), reducing the levels of the proteins that would otherwise be formed by the action of the mRNA, thereby 'silencing' a specific gene. Researchers subsequently assessed the effects of this class of molecule in patients with various genetic conditions (eg, hereditary amyloidosis) that could benefit from reductions in the excessive quantities of harmful proteins (eg, amyloid). Due to the hydrophilic (non-fat-soluble) nature of the molecules, they have been formulated as lipid nanoparticles to aid transport into cells or conjugated to molecules with an ability to target certain cells in the body (eg, hepatocytes) to aid specificity of action. Their intracellular effects may last up to several months before they are broken down and inactivated. As they need to be composed of an exact complementary sequence to be able to cleave the target mRNA, they are thought to have few unwanted effects apart from infusion or injection site reactions. Several siRNA medicines have been licensed and many other products are in development for genetic hepatic, cardiovascular and ocular conditions.

Systematic review on the use of biologics in adult-onset still's disease.

This systematic review (SR) describes the efficacy and safety of biologic disease modifying anti-rheumatic drugs (bDMARDs) for patients with adult-onset Still's disease (AOSD). Three randomised controlled trials (RCTs), one retrospective case series of multiple interventions, and 17 case series of single interventions met the inclusion criteria for this SR. Comparisons of biologic therapy in AOSD were only available against conventional DMARDs in one RCT and against placebo in two RCTs. There was a lack of common assessment criteria, meaning treatment efficacy across studies could not be compared. Uncontrolled retrospective case series suggested that bDMARDs have an effect for patients with AOSD, but these studies did not provide comparative data to show whether bDMARDs were more effective than other interventions or, whether any bDMARD was more effective than another bDMARD. However, there was evidence that bDMARDs could reduce steroid dose. Safety data from all included studies showed that bDMARDs appear to be a safe alternative to conventional DMARDs. This SR has highlighted the need for larger comparative studies in AOSD and has shown the need to standardize the definition of therapeutic response in AOSD. This would allow comparisons between studies in order to gain clarity on which bDMARDs may be more effective treatments for AOSD.

The Effectiveness and Acceptability of Comprehensive and Multicomponent School Health Services: A Systematic Review.

PURPOSE: Comprehensive school-based health services were reviewed as part of preparing World Health Organization guidelines. METHODS: Six databases were searched for controlled trials with schoolchildren aged 5-19 years, involving school-linked health services incorporating 4 of 7 health areas. RESULTS: Seventeen quasi-experimental studies conducted in high-income countries found school health services associated with reductions in suicide planning (male: 7.1% vs. 7.7%, p < .01), hospitalization (relative risks 3.403, 95% confidence interval [CI] 1.536 to 8.473, p < .05), emergency department visits (odds ratio .85, 95% CI .75 to .95, p = .006), school absence (odds ratio .78, 95% CI .69 to .87, p < .0001), carrying weapons (male: 16.1% vs. 25.1%, p < .01), fighting (male: 32.6% vs. 43.1%, p < .01), sexual activity (53.5% vs. 60.5%, p < .05), drinking alcohol (60.1% vs. 70.5%, p < .001), using drugs (28.0% vs. 38.3%, p < .001), and physical activity (female: 57.4% vs. 50.4%, p < .01). They can be cost-saving, were also associated with smoking and less contraceptive use, and had no effect on depression prevalence. Acceptability/satisfaction was good. The certainty of evidence was low to moderate. Heterogeneity was high for some outcomes. CONCLUSIONS: Results suggest moderate desirable and trivial undesirable effects of school health services in high-income countries. This article compiles evidence on effectiveness, cost-effectiveness, and acceptability into one review, enabling decision-makers to consider all essential factors.

Systematic review of the impact of appropriate versus inappropriate initial antibiotic therapy on outcomes of patients with severe bacterial infections.

We investigated the impact of appropriate versus inappropriate initial antimicrobial therapy on the clinical outcomes of patients with severe bacterial infections as part of a systematic review and meta-analyses assessing the impact of delay in appropriate antimicrobial therapy. Literature searches of MEDLINE and Embase, conducted on 24 July 2018, identified studies published after 2007 reporting the impact of delay in appropriate antibiotic therapy for hospitalised adult patients with bacterial infections. Results were statistically pooled for outcomes including mortality, hospital length of stay (LOS) and treatment failure. Subgroup analyses were explored by site of infection where data permitted. Inclusion criteria were met by 145 studies, of which 114 reported data on the impact of appropriate versus inappropriate initial therapy. In the pooled analysis, rates of mortality were significantly in favour of appropriate therapy [odds ratio (OR) = 0.44, 95% CI 0.38-0.50]. Across eight studies, LOS was shorter with appropriate therapy compared with inappropriate therapy [mean difference (MD) -2.54 days (95% CI -5.30 to 0.23)], but not significantly so. The incidence of treatment failure was significantly lower in patients who received appropriate therapy compared with patients who received inappropriate therapy (six studies: OR = 0.33, 95% CI 0.16-0.66) as was mean hospital costs (four studies: MD -7.38 thousand US$ or Euros, 95% CI -14.14 to -0.62). Initiation of appropriate versus inappropriate antibiotics can reduce mortality, reduce treatment failure and decrease LOS, highlighting the importance of broad­spectrum empirical therapy and rapid diagnostics for early identification of the causative pathogen. [Study registration: PROSPERO: CRD42018104669].

A Systematic Review of the Effect of Delayed Appropriate Antibiotic Treatment on the Outcomes of Patients With Severe Bacterial Infections.

BACKGROUND: Patients with severe bacterial infections often experience delay in receiving appropriate treatment. Consolidated evidence of the impact of delayed appropriate treatment is needed to guide treatment and improve outcomes. RESEARCH QUESTION: What is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections? STUDY DESIGN AND METHODS: Literature searches of MEDLINE and Embase, conducted on July 24, 2018, identified studies published after 2007 reporting the impact of delayed appropriate therapy on clinical outcomes for hospitalized adult patients with bacterial infections. Where appropriate, results were pooled and analyzed with delayed therapy modeled three ways: delay vs no delay in receiving appropriate therapy; duration of delay; and inappropriate vs appropriate initial therapy. This article reports meta-analyses on the effect of delay and duration of delay. RESULTS: The eligibility criteria were met by 145 studies, of which 37 contributed data to analyses of effect of delay. Mortality was significantly lower in patients receiving appropriate therapy without delay compared with those experiencing delay (OR, 0.57; 95% CI, 0.45-0.72). Mortality was also lower in the no-delay group compared with the delay group in subgroups of studies reporting mortality at 20 to 30 days, during ICU stay, or in patients with bacteremia (OR, 0.57 [95% CI, 0.43-0.76]; OR, 0.47 [95% CI, 0.27-0.80]; and OR, 0.54 [95% CI, 0.40-0.75], respectively). No difference was found in time to appropriate therapy between those who died and those who survived (P = .09), but heterogeneity between studies was high. INTERPRETATION: Avoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections. CLINICAL TRIAL REGISTRATION: PROSPERO; No.: CRD42018104669; URL: www.crd.york.ac.uk/prospero/.

Family relationships in childhood and common psychiatric disorders in later life: systematic review of prospective studies.

BACKGROUND: Most evidence for associations between childhood adversity and adult mental illness is retrospective. AIMS: To evaluate prospective evidence of associations between poor parent-child relationships and common psychiatric disorders in later life. METHOD: Systematic review of studies published between 1970 and 2008 including: (a) more than 100 participants; (b) measures of relationships in the home during childhood; (c) at least 10 years between assessment of exposures; and (d) measures of anxiety, depression, suicide, suicidal ideation or post-traumatic stress disorder (PTSD). Analysis was by narrative synthesis. RESULTS: Twenty-three papers were identified reporting data from 16 cohorts. Abusive relationships predicted depression, anxiety and PTSD. Maternal emotional unavailability in early life predicted suicide attempts in adolescence. Results of studies investigating less severe relationship problems were suggestive but not conclusive of causal association, due partly to methodological heterogeneity. CONCLUSIONS: Given the prevalence and disabling nature of common psychiatric problems, these studies highlight the need to minimise harm associated with dysfunctional parent-child relationships.

Pembrolizumab for Previously Treated Advanced or Metastatic Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pembrolizumab is an intravenously administered monoclonal antibody licensed for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. This summary presents the perspective of Warwick Evidence, the Evidence Review Group (ERG) appointed by the National Institute of Health and Care Excellence (NICE) for the single technology appraisal of pembrolizumab for this indication. Pembrolizumab is manufactured by Merck, Sharp and Dohme (MSD). The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician's choice of docetaxel, paclitaxel or vinflunine as a second-line treatment. No indirect treatment comparison was performed. The clinical effectiveness was assessed using hazard ratios for overall survival (OS) and progression-free survival (PFS) of the intention-to-treat (ITT) population, together with the subpopulations positive for programmed cell death 1 ligand 1 (PD-L1) expression (combined positive score [CPS] ≥ 1%) and strongly positive for PD-L1 expression (CPS ≥ 10%). In the ITT population, OS improved with pembrolizumab (HR 0.73, 95% CI 0.59-0.91) while PFS outcomes showed no difference (HR 0.98, 95% CI 0.81-1.19). Pembrolizumab demonstrated a better safety profile than its combined comparators, with fewer patients experiencing adverse events (60.9 vs 90.2%). Similar results were observed in populations expressing PD-L1. MSD estimated the cost effectiveness of pembrolizumab using a de novo partitioned survival model. The model had three health states: pre-progression, post-progression and death, where OS and PFS estimates excluded patients who received vinflunine. The largest uncertainty was over the selection of the parametric models used to extrapolate OS and PFS and the time point for when to begin their extrapolation. The company preferences for extrapolation were not well supported and the ERG disagreed with their selection for OS. Utility values were also contentious, with the company preferring to use pooled time-to-death-based utilities pooled across treatment arms, whilst the ERG preferred pooled progression-based utilities. The company preferred to use data from patients receiving vinflunine when calculating the utility values, which the ERG disagreed with as this is not recommended treatment within the UK. The company assumed a lifetime treatment effect for their model; however, the lack of evidence made it difficult to confidently provide a realistic estimate of treatment effect duration. Various durations were explored (3, 5 and 10 years). The first appraisal committee meeting concluded that pembrolizumab was not cost effective, largely due to uncertainty in the OS and PFS extrapolations. The company's second submission included an additional 4 months follow-up to survival data. The company in this new submission maintained their original assumptions in their base-case analysis, changing only the choice of parametric curve for PFS. This change resulted in the OS and PFS curves intersecting at 6 years in the pembrolizumab arm, at which point PFS identically followed OS. This resulted in no patients in the post-progression health state beyond this time point, and therefore, the majority of pembrolizumab's benefit came from pre-progression survival. Given the unclear PFS benefit, the ERG found this implausible and maintained their original base-case model assumptions. Considerable uncertainty remained over the specification of the extrapolations and the duration of treatment effect. Based on a new-value proposition submitted by the company, the appraisal committee concluded that pembrolizumab had plausible potential to be cost effective. Pembrolizumab was referred for funding through the Cancer Drugs Fund, so that further data could be collected with the aim of diminishing the outstanding uncertainties pertaining to its clinical effectiveness.

Communication of cancer screening results by letter, telephone or in person: A mixed methods systematic review of the effect on attendee anxiety, understanding and preferences.

Attending and receiving a result from screening can be an anxious process. Using an appropriate method to deliver screening results could improve communication and reduce negative outcomes for screening attendees. Screening programmes are increasingly communicating results by letter or telephone rather than in-person. We investigated the impact of communication methods on attendees. We systematically reviewed the literature on the communication methods used to deliver results in cancer screening programmes for women, focusing on screening attendee anxiety, understanding of results and preferences for results communication. We included qualitative and quantitative research. We searched MEDLINE, PsycINFO, CINAHL, Cochrane Library and Embase. Results were analysed using framework synthesis. 10,558 papers were identified with seven studies meeting the inclusion criteria. Several key ideas emerged from the synthesis including speed, accuracy of results, visual support, ability to ask questions, privacy of results location and managing expectations. Verbal communication methods (telephone and in-person) were preferred and facilitated greater understanding than written methods, although there was considerable variability in attendee preferences. Findings for anxiety were mixed, with no clear consensus on which method of communication might minimise attendee anxiety. The low number of identified studies and generally low quality evidence suggest we do not know the most appropriate communication methods in the delivery of cancer screening results. More research is needed to directly compare methods of results communication, focusing on what impact each method may have on screening attendees.

Bacterial Load and Molecular Markers Associated With Early-onset Group B Streptococcus: A Systematic Review and Meta-analysis.

BACKGROUND: The natural history of neonatal group B Streptococcus (GBS) is poorly understood. Little is known about the bacterial factors influencing the transmission of GBS from mother to neonate, or the development of invasive early-onset GBS disease (EOGBS) in colonized neonates. We reviewed whether bacterial load and molecular markers are associated with GBS vertical transmission and progression to EOGBS. METHODS: We searched Medline, Embase, Cochrane and Web of Science from inception to October 10, 2016, for observational studies in English. We also hand-searched reference lists of relevant publications and experts cross-checked included studies. Two reviewers independently screened studies, extracted data and appraised the quality of included studies using the Quality in Prognosis Studies tool. We conducted random-effects meta-analyses where possible and narratively synthesized the evidence in text and tables. RESULTS: Seventeen studies were included from 1107 records retrieved from electronic databases and publication references. Meta-analyses of 3 studies showed that neonates colonized by serotype III had a higher risk of developing EOGBS than serotype Ia (pooled risk ratio: 1.51, 95% confidence interval: 1.12-2.03) and serotype II (risk ratio: 1.95, 95% confidence interval: 1.10-3.45). Eleven studies showed that in heavily colonized mothers, 2-3 times more neonates were colonized, and in heavily colonized neonates, up to 15 times more neonates had EOGBS, compared with light colonization. Most evidence was published before 2000 and was at risk of bias. CONCLUSIONS: Acknowledging the difficulty of natural history studies, well-controlled studies are needed to assess the predictive value of pathogen subtype and heavy load; they may be useful for better-targeted prevention.

Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation.

BACKGROUND: At the time of publication of the most recent National Institute for Health and Care Excellence (NICE) guidance [technology appraisal (TA) 32] in 2002 on beta-interferon (IFN-ß) and glatiramer acetate (GA) for multiple sclerosis, there was insufficient evidence of their clinical effectiveness and cost-effectiveness. OBJECTIVES: To undertake (1) systematic reviews of the clinical effectiveness and cost-effectiveness of IFN-ß and GA in relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome (CIS) compared with best supportive care (BSC) and each other, investigating annualised relapse rate (ARR) and time to disability progression confirmed at 3 months and 6 months and (2) cost-effectiveness assessments of disease-modifying therapies (DMTs) for CIS and RRMS compared with BSC and each other. REVIEW METHODS: Searches were undertaken in January and February 2016 in databases including The Cochrane Library, MEDLINE and the Science Citation Index. We limited some database searches to specific start dates based on previous, relevant systematic reviews. Two reviewers screened titles and abstracts with recourse to a third when needed. The Cochrane tool and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and Philips checklists were used for appraisal. Narrative synthesis and, when possible, random-effects meta-analysis and network meta-analysis (NMA) were performed. Cost-effectiveness analysis used published literature, findings from the Department of Health's risk-sharing scheme (RSS) and expert opinion. A de novo economic model was built for CIS. The base case used updated RSS data, a NHS and Personal Social Services perspective, a 50-year time horizon, 2014/15 prices and a discount rate of 3.5%. Outcomes are reported as incremental cost-effectiveness ratios (ICERs). We undertook probabilistic sensitivity analysis. RESULTS: In total, 6420 publications were identified, of which 63 relating to 35 randomised controlled trials (RCTs) were included. In total, 86% had a high risk of bias. There was very little difference between drugs in reducing moderate or severe relapse rates in RRMS. All were beneficial compared with BSC, giving a pooled rate ratio of 0.65 [95% confidence interval (CI) 0.56 to 0.76] for ARR and a hazard ratio of 0.70 (95% CI, 0.55 to 0.87) for time to disability progression confirmed at 3 months. NMA suggested that 20 mg of GA given subcutaneously had the highest probability of being the best at reducing ARR. Three separate cost-effectiveness searches identified > 2500 publications, with 26 included studies informing the narrative synthesis and model inputs. In the base case using a modified RSS the mean incremental cost was £31,900 for pooled DMTs compared with BSC and the mean incremental quality-adjusted life-years (QALYs) were 0.943, giving an ICER of £33,800 per QALY gained for people with RRMS. In probabilistic sensitivity analysis the ICER was £34,000 per QALY gained. In sensitivity analysis, using the assessment group inputs gave an ICER of £12,800 per QALY gained for pooled DMTs compared with BSC. Pegylated IFN-ß-1 (125 µg) was the most cost-effective option of the individual DMTs compared with BSC (ICER £7000 per QALY gained); GA (20 mg) was the most cost-effective treatment for CIS (ICER £16,500 per QALY gained). LIMITATIONS: Although we built a de novo model for CIS that incorporated evidence from our systematic review of clinical effectiveness, our findings relied on a population diagnosed with CIS before implementation of the revised 2010 McDonald criteria. CONCLUSIONS: DMTs were clinically effective for RRMS and CIS but cost-effective only for CIS. Both RCT evidence and RSS data are at high risk of bias. Research priorities include comparative studies with longer follow-up and systematic review and meta-synthesis of qualitative studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016043278. FUNDING: The National Institute for Health Research Health Technology Assessment programme.