Prospective Cohort Study

BackgroundB cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. MethodsIn two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disabilit...

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Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

A systematic review shows no performance benefit of machine learning over logistic regression for clinical prediction models

Pre–B cell colony-enhancing factor (PBEF) is a highly conserved 52-kDa protein, originally identified as a growth factor for early stage B cells. We show here that PBEF is also upregulated in neutrophils by IL-1β and functions as a novel inhibitor of apoptosis in response to a variety of inflammatory stimuli. Induction of PBEF occurs 5–10 hours after LPS exposure. Prevention of PBEF translation with an antisense oligonucleotide completely abrogates the inhibitory effects of LPS, IL-1, GM-CSF, IL-8, and TNF-α on neutrophil apoptosis. Immunoreactive PBEF is detectable in culture supernatants from LPS-stimulated neutrophils, and a recombinant PBEF fusion protein inhibits neutrophil apoptosis. PBEF is also expressed in neutrophils from critically ill patients with sepsis in whom rates of apoptosis are profoundly delayed. Expression occurs at higher levels than those seen in experimental inflammation, and a PBEF antisense oligonucleotide significantly restores the normal kinetics of apoptosis in septic polymorphonuclear neutrophils. Inhibition of apoptosis by PBEF is associated with reduced activity of caspases-8 and -3, but not caspase-9. These data identify PBEF as a novel inflammatory cytokine that plays a requisite role in the delayed neutrophil apoptosis of clinical and experimental sepsis.

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Pre–B cell colony–enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis

Routine practice fails to incorporate research evidence in a timely and reliable fashion. Many quality improvement (QI) efforts aim to close these gaps between clinical re- search and practice. However, in sharp contrast to the paradigm of evidence-based medi- cine, these efforts often proceed on the basis of intuition and anecdotal accounts of suc- cessful strategies for changing provider behavior or achieving organizational change. We review problems with current approaches to QI research and outline the steps required to make QI efforts based as much on evidence as the practices they seek to implement. C onsider t he f ollowing s cenario: A patient comes to see a physi- cian. The patient obviously suffers from a serious chronic illness. Various diagnostic tests show gross abnormalities. Some sort of treatment is neces- sary. The physician consults several colleagues, one of whom reports success in the treatment of a patient with a similar chronic illness using oval red capsules with the number "250" stamped on them. The physician rummages through the clinic's medication room and finds some red pills, although they are square tablets with the number "100" stamped on them. He instructs the patient to take this medica- tion once daily and report back to him. At the next visit, the patient reports most of the same symptoms, except that mornings tend to be better than they used to. A little disappointed at this equivocal improvement, the doctor nonetheless publishes his results, as he knows there are other clinicians out there with sick pa- tients and they may benefit from knowing that "red pills improve morning symp- toms in patients with chronic illnesses," as his article title reads. Moreover, it may not matter if they come in tablet or capsule form. The article receives considerable attention. Many decide that the problem of sick patients is so urgent that there is no time to conduct further studies:

Evidence-Based Quality Improvement: The State Of The

Importance With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown. Objective To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI). Design, Setting, and Participants Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset). Main Outcomes and Measures NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes. Results A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years. Conclusions and Relevance NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.

https://jamanetwork.com/journals/jamaneurology/articlepdf/2048956/noi140092.pdf

Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort

Personalized treatment is ideal for multiple sclerosis (MS) owing to the heterogeneity of clinical features, but current knowledge gaps, including validation of biomarkers and treatment algorithms, limit practical implementation. The contemporary approach to personalized MS therapy depends on evidence-based prognostication, an initial treatment choice and evaluation of early treatment responses to identify the need to switch therapy. Prognostication is directed by baseline clinical, environmental and demographic factors, MRI measures and biomarkers that correlate with long-term disability measures. The initial treatment choice should be a shared decision between the patient and physician. In addition to prognosis, this choice must account for patient-related factors, including comorbidities, pregnancy planning, preferences of the patients and their comfort with risk, and drug-related factors, including safety, cost and implications for treatment sequencing. Treatment response has traditionally been assessed on the basis of relapse rate, MRI lesions and disability progression. Larger longitudinal data sets have enabled development of composite outcome measures and more stringent standards for disease control. Biomarkers, including neurofilament light chain, have potential as early surrogate markers of prognosis and treatment response but require further validation. Overall, attainment of personalized treatment for MS is complex but will be refined as new data become available. Personalized multiple sclerosis therapy depends on evidence-based prognostication, an initial treatment choice and evaluation of early treatment responses to identify the need to switch therapy. In this Review, Rotstein and Montalban discuss the factors that need to be taken into account to make personalized treatment decisions.

Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis.

Objective 
To explore the value of machine learning methods for predicting multiple sclerosis disease course.


Methods 
1693 CLIMB study patients were classified as increased EDSS≥1.5 (worsening) or not (non-worsening) at up to five years after baseline visit. Support vector machines (SVM) were used to build the classifier, and compared to logistic regression (LR) using demographic, clinical and MRI data obtained at years one and two to predict EDSS at five years follow-up.


Results 
Baseline data alone provided little predictive value. Clinical observation for one year improved overall SVM sensitivity to 62% and specificity to 65% in predicting worsening cases. The addition of one year MRI data improved sensitivity to 71% and specificity to 68%. Use of non-uniform misclassification costs in the SVM model, weighting towards increased sensitivity, improved predictions (up to 86%). Sensitivity, specificity, and overall accuracy improved minimally with additional follow-up data. Predictions improved within specific groups defined by baseline EDSS. LR performed more poorly than SVM in most cases. Race, family history of MS, and brain parenchymal fraction, ranked highly as predictors of the non-worsening group. Brain T2 lesion volume ranked highly as predictive of the worsening group.


Interpretation 
SVM incorporating short-term clinical and brain MRI data, class imbalance corrective measures, and classification costs may be a promising means to predict MS disease course, and for selection of patients suitable for more aggressive treatment regimens.

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Exploration of machine learning techniques in predicting multiple sclerosis disease course.

—Neutrophil-mediated inflammation is terminated through the programmed cell death or apoptosis of the neutrophil, a process that can be inhibited by soluble mediators released during an inflammatory response. It has been reported, however, that the phagocytosis of intact bacteria can acceler

Phagocytosis of Candida albicans induces apoptosis of human neutrophils.

Objective We sought to better understand the reasons for increasing prevalence of multiple sclerosis (MS) by studying prevalence in relation to incidence, mortality rates, sex ratio, and geographic distribution of cases. Methods We identified MS cases from 1996 to 2013 in Ontario, Canada, by applying a validated algorithm to health administrative data. We calculated age- and sex-standardized prevalence and incidence rates for the province and by census division. Incidence and prevalence sex ratios for women to men were computed. Results The prevalence of MS increased by 69% from 1.57 (95% confidence interval [CI]: 1.54–1.59) per 1,000 in 1996 (n = 12,155) to 2.65 (95% CI: 2.62–2.68) in 2013 (n = 28,192). Incidence remained relatively stable except for a spike in 2010, followed by a subsequent decline in 2011–2013, particularly among young people and men. Mortality decreased by 33% from 26.7 (95% CI: 23.5–30.3) per 1,000 to 18.0 (95% CI: 16.4–19.8) per 1,000. The incidence sex ratio was stable from 1996 to 2009, then declined in 2010, with partial rebound by 2013. MS prevalence and incidence showed no consistent association with latitude. Conclusion In this large, population-based MS cohort, we found stable incidence and increasing prevalence of MS; the latter largely reflected declining mortality. A spike in incidence in 2010 among younger patients and men at a time of widespread media coverage of MS suggests that these groups may be vulnerable to delayed diagnosis. We did not find a latitudinal gradient; however, most Ontarians live between the 42nd and 46th parallels, reducing our ability to detect an effect of latitude.

Dalia Rotstein

Papers

Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort

Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis.

Exploration of machine learning techniques in predicting multiple sclerosis disease course.

Phagocytosis of Candida albicans induces apoptosis of human neutrophils.

Temporal trends in multiple sclerosis prevalence and incidence in a large population.