Ongoing Disease Activity Research Articles

Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity

BackgroundRituximab (RTX) and other anti-CD20 therapies are increasingly used as disease modifying treatments (DMTs) in MS. However, data on reasons to interrupt treatment, alternative DMTs after anti-CD20 therapy and potential rebound disease activity are limited. The objective here was therefore to determine the rate and cause of RTX treatment interruptions and responses to subsequent DMTs in a large single centre cohort addressing also the hypothesis that there would not be rebound activity after discontinuation of RTX, regardless of reason for discontinuation and irrespective of subsequent treatments. MethodsA retrospective observational study of all relapsing-remitting MS (RRMS) patients having received at least one dose of RTX at the Karolinska University Hospital from 2009 to 2018 and having either stopped treatment or had more than one year since last RTX infusion, as identified in the Swedish MS registry with additional data derived from clinical charts. ResultsAs of February 2018, we identified 808 patients ever treated with RTX out of 1513 RRMS patients with current or previous DMT, 92 (11%) had terminated RTX; 27 (29%) stopped RTX due to pregnancy, 26 (28%) due to adverse events, 23 (25%) for other reasons, 9 (10%) due to stable disease and the remaining 7 (8%) due to lack of effect. The cohort of 92 patients was followed until April 2019, when 34 had restarted RTX, 27 switched DMT, 24 remained without DMT and 7 were lost to follow up. Of the 7 patients terminating RTX due to lack of effect, 4 started ofatumumab, 2 had autologous hematopoietic stem cell transplantation and 1 was lost to follow up. In all of the 92 patients, after initial RTX discontinuation, only 3 patients had relapses and 4 had new T2 lesions (one of which had both). Gadolinium was administered in 78% of follow up magnetic resonance imaging (MRI) with no enhancing lesions found (mean MRI follow up from RTX discontinuation 29 months, range 7–92 months, n = =77). ConclusionFindings are consistent with a low rate of RTX interruptions, with pregnancy and adverse events as most frequent reasons. A small proportion of patients switched due to breakthrough disease in context of incomplete B-lymphocyte depletion. Signs of ongoing disease activity in the remaining group was low regardless of whether a new DMT was started. These findings are consistent with a long acting effect of RTX in RRMS and absence of rebound disease activity phenomena upon stopping therapy.

Persistent Basal Cell Hyperplasia Is Associated With Clinical and Endoscopic Findings in Patients With Histologically Inactive Eosinophilic Esophagitis

Although eosinophil count is the standard used to monitor disease activity in patients with eosinophilic esophagitis (EoE), there are often disparities between patient-reported symptoms and eosinophil counts. We examined the prevalence of epithelial alterations, namely basal cell hyperplasia (BCH) and spongiosis, among patients with inactive EoE (eosinophil counts below 15 following therapy) and aimed to determine whether maintenance of these changes in epithelial morphology are associated with persistent clinical findings. Esophageal biopsies of 243 patients (mean age, 16.9 years) undergoing routine endoscopy at the University of Pennsylvania were evaluated for epithelial BCH and spongiosis. Univariable analysis was used to calculate the association between epithelial changes and symptoms as well as endoscopic findings and peak eosinophil count. We validated our findings using data from a cohort of patients at the University of North Carolina. The discovery and validation cohorts each included patients with inactive EoE, based on histologic factors, but ongoing BCH and spongiosis. Ongoing BCH, but not spongiosis, in patients with inactive EoE was associated with symptoms (odds ratio, 2.14; 95% CI, 1.03-4.42; P = .041) and endoscopic findings (odds ratio, 7.10; 95% CI, 3.12-16.18; P < .001). In patients with EoE, the presence of BCH might indicate ongoing disease activity, independent of eosinophil count. This might account for the persistent symptoms in patients who are considered to be in remission based on histologic factors.

50. Vascular BehÇet’s disease in a 20-year-old man presenting with an abdominal aortic aneurysm

IntroductionBehçet’s Disease (BD) is a complex, multisystem auto-inflammatory disorder. The most frequent manifestations are oral aphthous ulcers, genital ulcers and uveitis. Vascular involvement is less common but one of the major causes of mortality and morbidity. This case highlights the need to consider BD, especially in young, male, patients with arterial abnormalities and the challenges of treatment.Case descriptionA 20-year-old man with a Moroccan father, presented to A&E with abdominal pain, constipation and night sweats, following recurrent admissions with lower abdominal and back pain. On this occasion he was noted to have a CRP of 160 mg/L and a subsequent CT scan of the abdomen showed a 4 cm pseudo-aneurysm arising from the right lateral infrarenal abdominal aorta which was initially repaired with open surgery and a vein graft. This subsequently leaked and so he had further surgery and an EVAR procedure. On further questioning it was noted that he had had frequent mouth ulcers for seven years and also episodes of epididymo-orchitis and folliculitis and the possibility of BD was considered. He was seen in the Birmingham Behçet’s Centre of Excellence and started azathioprine together with oral prednisolone. Six months later he required embolization of a left renal artery pseudoaneurysm and stent-grafting of the same artery. Given these new changes he was commenced on IV cyclophosphamide.Despite six pulses of cyclophosphamide and high doses of prednisolone he continued to have a raised CRP and so was switched to tocilizumab infusions. His inflammatory markers initially improved, but after about two years he attended for an infusion and complained of worsening abdominal pain. At that point it was noted that his inflammatory markers had been intermittently raised over the preceding few months. There had been a few breaks in treatment due to possible infections and non-attendance. A further CT scan was performed that showed disease progression at the distal site of the graft with small new aneurysms. After an MDT discussion it was decided to switch him to infliximab. He has now been on infliximab for over six months and his inflammatory markers have, reassuringly, remained low. DiscussionArterial involvement in BD is relatively uncommon, presenting variably with stenosis, thrombotic occlusions and aneurysms, as the vasculitic process can affect perivascular and endovascular tissues. Aneurysms are typically seen a number of years after the initial diagnosis and are believed to be due to an obliterative endarteritis with inflammation causing destruction of elastic and muscle cells in the media. The aneurysms tend to be more saccular, and the abdominal aorta is more frequently involved than the thoracic aorta or pulmonary artery. In this case the initial surgical procedure was performed prior to the diagnosis of BD, so it was not possible to give something such as cyclophosphamide prior to surgical intervention which would be advised. The EULAR guidelines recommend cyclophosphamide and corticosteroids as first line in treatment in arterial involvement. However, no further guidance is given regarding subsequent immunosuppression if needed. In this case the decision to start tocilizumab was made based on successful use in other patients with vascular Behçet’s disease.Subsequently infliximab was chosen as it has been used more widely in BD including in patients with vascular BD. Biochemically and symptomatically the patient has been well since infliximab was started, but we are currently awaiting a repeat CT scan. This case has also proved challenging as the patient has struggled with the diagnosis and need for frequent hospital appointments. He has had some help from the psychologist available through the Behçet’s service but has continued to DNA appointments and turn up for infusions at times that suit him. We are hopeful that a longer period of stability will also be beneficial from that point of view. Key learning pointsVascular is less common than other features of BD but can sometimes be a presenting feature and is a major cause of mortality and morbidity. Unlike the international study group (ISG) criteria for Behçet’s disease the international criteria for Behçet’s disease (ICBD) do include vascular lesions. The possibility of BD needs to be considered, especially in patients presenting with potential vascular involvement. For both aortic and peripheral artery aneurysms the 2018 update of the EULAR guidelines recommend medical treatment with cyclophosphamide and corticosteroids before surgical intervention. If there is ongoing arterial disease activity despite cyclophosphamide anti-TNF and IL6 inhibition can be considered and have shown some success. Endovascular surgery is increasingly being preferred to open surgery, although there is a risk of further aneurysm formation, particularly at graft peripheries. Conflicts of interestThe authors have declared no conflicts of interest.

12. Dramatic improvement of chronic pleural effusion with abatacept treatment in longstanding rheumatoid arthritis, after chest sepsis during treatment with anti-TNF-α

Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disorder, with various pulmonary manifestations, including parenchymal disease (interstitial lung disease), inflammation of the pleura (thickening and effusions), and inflammation of the airways and pulmonary vasculature (vasculitis and pulmonary hypertension). These changes may reflect chronic immune activation, increased susceptibility to infection, or direct toxicity from disease modifying or biological therapy. This case report describes a 69-year-old male with longstanding seropositive rheumatoid arthritis who developed severe pneumonia during adalimumab treatment, with subsequent persistent right basal pleural effusion. Treatment with abatacept has resulted in remission with significant decrease in size of the pleural effusion.

Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years

Blood sample-based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed. To evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set. Single-center, ongoing, prospective observational cohort study of 607 patients with MS from the longitudinal EPIC (Expression, Proteomics, Imaging, Clinical) study at the University of California, San Francisco from July 1, 2004, through August 31, 2017. Clinical evaluations and sample collection were performed annually for 5 years, then at different time points for up to 12 years, with a median follow-up duration of 10 (interquartile range, 7-11) years. Serum NFL levels were measured using a sensitive single molecule array platform and compared with clinical and magnetic resonance imaging variables with the use of univariable and multivariable analyses. The main outcomes were disability progression defined as clinically significant worsening on the Expanded Disability Status Scale (EDSS) score and brain fraction atrophy. Mean (SD) age of the 607 study participants at study entry was 42.5 (9.8) years; 423 (69.7%) were women; and all participants were of non-Hispanic European descent. Of 3911 samples sequentially collected, 3904 passed quality control for quantification of sNFL. Baseline sNFL levels showed significant associations with EDSS score (β, 1.080; 95% CI, 1.047-1.114; P < .001), MS subtype (β, 1.478; 95% CI, 1.279-1.707; P < .001), and treatment status (β, 1.120; 95% CI, 1.007-1.245; P = .04). A significant interaction between EDSS worsening and change in levels of sNFL over time was found (β, 1.015; 95% CI, 1.007-1.023; P < .001). Baseline sNFL levels alone were associated with approximately 11.6% of the variance in brain fraction atrophy at year 10. In a multivariable analysis that considered sex, age, and disease duration, baseline sNFL levels were associated with 18.0% of the variance in brain fraction atrophy at year 10. After 5 years' follow-up, active treatment was associated with lower levels of sNFL, with high-potency treatments associated with the greater decreases in sNFL levels compared with platform therapies (high-potency vs untreated: β, 0.946; 95% CI, 0.915-0.976; P < .001; high-potency vs platform: β, 0.972; 95% CI, 0.948-0.998; P = .04). This study found that statistically significant associations of sNFL with relevant clinical and neuroimaging outcomes in MS were confirmed and extended, supporting the potential of sNFL as an objective surrogate of ongoing MS disease activity. In this data set of patients with MS who received early treatment, the prognostic power of sNFL for relapse activity and long-term disability progression was limited. Further prospective studies are necessary to assess the assay's utility for decision-making in individual patients.

Optimal response to dimethyl fumarate is mediated by a reduction of Th1-like Th17 cells after 3months of treatment.

AimDimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples.MethodsA longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed.ResultsThe beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells.ConclusionThe optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response.

Neurofilament-Light Chain Levels Are Predictive of On-going Disease Activity in Radiologically Isolated Syndrome (S37.003)

Neurofilament-Light Chain Levels Are Predictive of On-going Disease Activity in Radiologically Isolated Syndrome (S37.003)

Therapy with cladribine is efficient and safe in patients previously treated with natalizumab.

Background:The humanized anti-α4 integrin monoclonal antibody natalizumab has proven to be very effective in patients with highly active relapsing-remitting multiple sclerosis (MS), but harbors the risk of progressive multifocal leukoencephalopathy (PML). Recently, new therapeutic options have become available for patients with high risk of developing PML while on natalizumab treatment. One of these new therapeutics is the oral synthetic purine analogue cladribine. In order to determine whether therapy with cladribine is effective and safe in patients with MS who previously had been treated with natalizumab, we analyzed clinical, radiological, and laboratory data of 17 patients whose disease modifying treatment (DMT) was switched from natalizumab to cladribine.Methods:A total of 17 patients with prior natalizumab treatment were switched to a DMT with cladribine because of a John Cunningham virus (JCV) antibody index above 1.5 (N = 13), ongoing disease activity (N = 6), magnetic resonance imaging (MRI) disease activity (N = 4), or patients preference (N = 2). A chart review and follow up of those patients was performed. In addition to MRI and laboratory data, clinical data regarding MS relapses and disease progression or possible adverse events were analyzed.Results:The median duration of cladribine treatment between February 2018 and April 2019 amounted to 9.7 months (range: 1.5–15 months). None of our 17 patients presented with a clinical relapse. Only two patients showed a new T2 lesion on brain MRI, but without any signs of PML. As expected, reduction of lymphocyte count was frequent in cladribine-treated patients, but only four patients exhibited lymphopenia grade 2 (500–800/µl).Conclusions:In our cohort the switch from natalizumab to cladribine treatment was effective and safe. So far, no serious adverse events other than lymphopenia have been observed, especially no cases of PML.

Elevated Levels of Urinary Extracellular Vesicle Fibroblast-Specific Protein 1 in Patients with Active Crescentic Glomerulonephritis

Background/Aims: Extracellular vesicles (EVs), including exosomes, are present in various bodily fluids, including urine. We and others previously reported that cells expressing fibroblast-specific protein 1 (FSP1) accumulate within damaged glomeruli, and that urinary FSP1, as well as urinary soluble CD163, could potentially serve as a biomarker of ongoing glomerular injury. Methods: To test that idea, we collected urine samples from 37 patients with glomerular disease; purified the urinary EVs; characterized them using Nanosight, western blotting, and immunoelectron microscopy; and determined FSP1 and soluble CD163 levels using enzyme-linked immunosorbent assays. Results: Deemed to be mainly exosomes based on their size distribution, the EVs in urine contained FSP1, and a portion of the FSP1-positive vesicles was also positive for podocalyxin. FSP1 levels in urinary EVs were (1) positively correlated with rates of biopsy-proven cellular crescent formation (r = 0.562, p < 0.001) and total crescent formation (r = 0.448, p = 0.005) among total glomeruli; (2) significantly higher in patients with cellular crescents affecting 20% or more of their glomeruli than in those with fewer affected glomeruli (p = 0.003); and (3) significantly decreased after glucocorticoid and immunosuppressant therapy (p < 0.05). A positive correlation between FSP1 levels in urinary EVs and urinary soluble CD163 levels was confirmed (r = 0.367, p < 0.05). Conclusion: These data suggest that a portion of urinary FSP1 is secreted as EVs originating from podocytes, and that FSP1 levels reflect active and ongoing glomerular injury and disease activity, such as cellular crescent formation.

Diagnostic and Therapeutic Long-term Management of Eosinophilic Esophagitis- Current Concepts and Perspectives for Steroid Use.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus, which requires short- and long-term treatment. In addition, patients under long-term treatment for any chronic condition should have a structured follow-up. The mainstays in EoE treatment are drugs (such as swallowed topical corticosteroids [STC] and proton pump inhibitors), dietary exclusions, and endoscopic dilations. STC are the most widely used treatment and have proven efficacy in inducing clinical, endoscopic and histological remission in active EoE. However, data regarding maintaining disease remission and long-term management are limited. Ongoing disease activity and relapses despite STC treatment are frequently observed. This sheds light on the urgent need for adequate maintenance strategies, which have not been well defined. In terms of follow-up concepts, to date neither guidelines nor consensus recommendations have been published. To summarize the current knowledge on long-term diagnostic and therapeutic STC management of EoE, we conducted a literature search using PubMed and Embase applying the following key search items: Eosinophilic esophagitis, eosinophils, esophagus, swallowed topical corticosteroids, fluticasone, budesonide, long-term, treatment, therapy, and follow-up. In addition, we present empirically developed long-term management concepts applied at two large EoE centers, with a special focus on STC treatments. Finally, we highlight areas of future research and perspectives regarding the long-term management of EoE.

Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation

Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce. To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ. We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation. 195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12-4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04-57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26-4.60; p = 0.004). The odds ratio for disability progression after 12months was 4.84 (95% CI 1.74-13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time). Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ.

Technology-enabled specialty pharmacy utilization of the routine assessment of patient index data 3 (RAPID3) to monitor and enhance outcomes of rheumatoid arthritis (RA) patients – a retrospective review

Background: Rheumatoid arthritis is a chronic progressive autoimmune disease affecting 1.5 million people in the United States. Uncontrolled disease can lead to irreversible joint damage, deformity, and disability. Current practice guidelines by the American College of Rheumatology (ACR) recommend frequent monitoring of disease activity and treatment to a goal of remission or low severity. However, clinicians’ adherence to this treatment strategy is low. With monthly patient contact, specialty pharmacies are well positioned to facilitate patient outcomes tracking. The RAPID3 is a validated quality measure instrument endorsed by the ACR to monitor patient disease activity. TherigySTM is a therapy management software utilized by pharmacies to deliver and document specialty therapy management. The availability of RAPID3 implemented in TherigySTM® demonstrates the opportunity for pharmacies to optimize patient care.Objectives: To observe the potential of technology-enabled delivery and utilization of RAPID3 to RA patients by specialty pharmacies to augment patient care and better comply with guidelines.Methods:• TherigySTM® generated RAPID3 initial and auto-triggered follow-up assessments based on the previous score per guideline recommendations.• TherigySTM® prompted engagement of patients by pharmacists to conduct RAPID3 surveys.• Captured aggregated data for 944 unique patients managed between 12/1/17 and 8/5/18 by selected specialty pharmacies using TherigySTM® with more than 50 completed RAPID3 assessments.• RAPID3 score calculated to non-simplified scale of 0–30. • Potential trends and metrics were identified with data captured.Results: 85% of follow-up RAPID3 assessments scheduled via TherigySTM® were completed on time. Initial RA disease activity assessments were able to be stratified: 47% high, 28% moderate, 15% low and 10% Remission. Ongoing disease activity changes were trackable and monitored by pharmacists over the course of therapy (55% of observed patients had no change, 31% improved and 14% worsened). 265 patients with moderate to high disease activity completed follow-up RAPID3 assessments. The average patient received 1–2 follow-up assessments during the observation period.Conclusions: Technology-enabled clinical support has the potential to improve compliance with practice guidelines. Pharmacies using validated instruments such as the RAPID3 delivered via TherigySTM® can expand their role in monitoring and enhancing outcomes. In a multi-disciplinary setting, pharmacy can efficiently share outcomes data with providers and make appropriate recommendations.

Antibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers.

Lupus nephritis (LN) is one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), considered as the major predictor of poor prognosis. An early diagnosis of LN is a real challenge in the management of SLE and has an important implication in guiding treatments. In clinical practice, conventional parameters still lack sensitivity and specificity for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. One of the possible mechanisms of induction of autoantibodies in SLE is a defect in apoptotic cells clearance and subsequent release of intracellular autoantigens. Autoantibodies against soluble protective molecules involved in the uptake of dying cells, including complement proteins and pentraxins, have been described. In this review, we present the main autoantibodies found in LN, with a focus on the antibodies against these protective molecules. We also discuss their pathogenic role and conclude with their potential interest as serological biomarkers in LN.

The Association of Diet and Exercise With Body Composition in Pediatric Crohn's Disease.

In pediatric Crohn's disease, fat mass improves over time with treatment, but lean mass deficits persist. This observational study of the associations of physical activity and dietary intake with lean mass and muscle strength in children with Crohn's disease was ancillary to a previously reported randomized clinical trial of an intervention to improve bone health. In this study, 138 participants were followed at baseline and at 6, 12, and 24 months with evaluation of lean and fat mass using DXA, muscle strength (peak torque), Crohn's characteristics, dietary intake, time in moderate to vigorous physical activity (MVPA), and serum insulin-like growth factor-1 (IGF-1) and tumor necrosis factor-alpha (TNF-α). Race- and sex-specific Z-scores for leg lean mass and whole body fat mass were generated. Quasi least square regression evaluated determinants of changes in body composition and muscle strength. Leg lean mass and muscle strength were positively associated with time in MVPA (P < 0.05) and negatively associated with increasing clinical disease activity (P < 0.05). Both leg lean mass and strength were positively associated with IGF-1 Z-score (P ≤ 0.03) but negatively associated with serum TNF-α (P ≤ 0.04). Neither lean mass nor muscle strength was associated with caloric or protein intake. Persistence of lean mass deficits was related to ongoing Crohn's disease activity but improved with greater time spent in moderate to vigorous physical activity. Future trials are needed to evaluate the efficacy of physical activity in improving lean mass in pediatric Crohn's disease.

PETANDA BIOLOGIK TERKINI LUPUS NEFRITIS

Lupus Nephritis (LN) is one of the serious clinical manifestation of Systemic Lupus Erythematosus (SLE). Early detection and treatmentof renal activity may spare patients from renal damage. Conventional biomarkers such as urine sediment, proteinuria, creatinine, antidsDNA antibody and their complement levels are not specific and sensitive enough in detecting the ongoing disease activity in the lupuskidneys and early relapse of nephritis. Renal biopsy is the gold standard in providing information on the histopathology of LN, but isinvasive and it should take a serial of biopsies making it impractical when monitoring LN. Thus, some novel biomarkers are necessary toenhance the diagnostic accuracy and sensitivity of lupus renal disease, prognostic stratification, monitoring of treatment response anddetection of early renal flares as well. Some novel biomarkers have been studied in LN, however, validation on a large scale of patientswith different ethnic backgrounds is still needed.

The Paddington International Virtual Chromoendoscopy Score in ulcerative colitis exhibits very good inter-rater agreement after computerized module training: a multicenter study across academic and community practice (with video)

Electronic virtual chromoendoscopy (EVC) can demonstrate ongoing disease activity in ulcerative colitis (UC), even when Mayo subscores suggest healing. However, applicability of EVC technology outside the expert setting has yet to be determined. Fifteen participants across 5 centers reviewed a computerized training module outlining high-definition and EVC (iScan) colonoscopy modes. Interobserver agreement was then tested (Mayo score, Ulcerative Colitis Endoscopic Index of Severity [UCEIS], and the Paddington International Virtual Chromoendoscopy Score [PICaSSO] for UC), using a colonoscopy video library (30 cases reviewed pretraining and 30 post-training). Knowledge sustainability was retested in a second round (42 cases; 9/15 participants), 6 months after training provision. Pretraining intraclass correlation coefficients (ICC) were good for the Mayo endoscopic subscore (ICC, .775), UCEIS scoring erosions/ulcers (ICC, .770), and UCEIS overall (ICC, .786) and for mucosal (ICC, .754) and vascular components of PICaSSO (ICC, .622). For the vascular components of UCEIS, agreement was only moderate (ICC, .429) and did not enhance post-training (ICC, .417); conversely, use of PICaSSO improved post-training (mucosal ICC, .848; vascular, .746). Histologic correlation using the New York Mt. Sinai System was strong for both PICaSSO components (Spearman's ρ for mucosal: .925; vascular, .873; P< .001 for both). Moreover, accuracy in specifically discriminating quiescent from mild histologic strata was strongest for PICaSSO (area under the receiver operating characteristic curve [AUROC] for mucosal, .781; vascular, .715) compared with Mayo (AUROC, .708) and UCEIS (AUROC for UCEIS overall, .705; vascular, .562; bleeding, .645; erosions/ulcers, .696). Inter-rater reliability for PICaSSO was sustained by round 2 participants (round 1 and 2 ICC for mucosal, .873 and .869, respectively; vascular, .715 and .783, respectively), together with histologic correlation (ρ mucosal, .934; vascular, .938; P< .001 for both). PICaSSO demonstrates good interobserver agreement across all levels of experience, providing excellent correlation with histology. Given the ability to discriminate subtle endoscopic features, PICaSSO may be applied to refine stratified treatment paradigms for UC patients.

Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease with a complex clinical course characterized by inflammation, demyelination, and axonal degeneration. Diagnosis of MS most commonly includes finding lesions in at least two separate areas of the central nervous system (CNS), including the brain, spinal cord, and optic nerves. In recent years, there has been a remarkable increase in the number of available treatments for MS. An optimal treatment is usually based on a personalized approach determined by an individual patient's prognosis and treatment risks. Biomarkers that can predict disability progression, monitor ongoing disease activity, and assess treatment response are integral in making important decisions regarding MS treatment. This review describes MS biomarkers that are currently being used in clinical practice; it also reviews and consolidates published findings from clinically relevant potential MS biomarkers in recent years. The work also discusses the challenges of validating and application of biomarkers in MS clinical practice.

Oligoclonal bands and periventricular lesions in multiple sclerosis will not increase blood-brain barrier permeability

ObjectiveTo elucidate the etiology and clinical significance of periventricular lesions (PVLs) and oligoclonal bands (OB) in multiple sclerosis (MS). MethodsWe enrolled a total of 97 MS patients (67 OB-positive and 30 OB-negative) who were negative both for anti-aquaporin-4 (AQP4) autoantibody and anti-myelin oligodendrocyte glycoprotein (MOG) antibody. In these patients, comprehensive data including clinical, laboratory, and MRI were collected to investigate the significance of OB and PVLs. ResultsWithin the MS patients, OB-positivity and the number of PVLs were associated each other. Both of OB-positivity and PVLs did not affect clinical severity or relapse rate, though the patients with ≥3 PVLs showed faster cerebral atrophy than those with <3 PVLs. The patients with OB or ≥3 PVLs showed lower values of quotient of albumin (QAlb), a biomarker of blood-brain barrier (BBB)-permeability and possibly reflects the ongoing disease activity, and lower protein levels in cerebrospinal fluid (CSF). The causal relationship between the decreased QAlb and OB or ≥3 PVLs was not determined. ConclusionsOB and PVLs were associated each other, but they did not affect the clinical course or increased the BBB-permeability within MS patients.

Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis

Background: Patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) may show alterations of retinal layer architecture as measured by optical coherence tomography. Little is known about changes in the retinal vascular network during MS. Objective: To characterize retinal vessel structures in patients with MS and CIS and to test for associations with MS disease activity. Method: In all, 42 patients with MS or CIS and 50 healthy controls underwent retinal optical coherence tomography angiography (OCT-A) with analysis of the superficial and deep vascular plexuses and the choriocapillaries. We tested OCT-A parameters for associations with retinal layer volumes, history of optic neuritis (ON), and the retrospective disease activity. Results: Inner retinal layer volumes correlated positively with the density of both the superficial and deep vascular plexuses. Eyes of MS/CIS patients with a history of ON revealed reduced vessel densities of the superficial and deep vascular plexuses as compared to healthy controls. Higher choriocapillary vessel densities were associated with ongoing inflammatory disease activity during 24 months prior to OCT-A examination in MS and CIS patients. Conclusion: Optic neuritis is associated with rarefaction of the superficial and deep retinal vessels. Alterations of the choriocapillaries might be linked to disease activity in MS.

An epidemiological study on the course of disease and therapeutic considerations in relapsing-remitting multiple sclerosis patients receiving injectable first-line disease-modifying therapies in Germany (EPIDEM).

Background:In relapsing–remitting multiple sclerosis (RRMS), ‘no evidence of disease activity’ (NEDA) is regarded as a key treatment goal. The increasing number of treatments allows for individualized treatment optimization in patients with suboptimal response to first-line disease-modifying therapies (DMTs). Therefore, monitoring of clinical and subclinical disease activity on DMTs has been recognized as an important component of long-term patient management.Methods:EPIDEM was a multicenter non-interventional retrospective study in a large cohort of RRMS patients receiving injectable DMTs for at least 2 years in outpatient centers throughout Germany. It documented measures and ratings of disease activity on DMTs to characterize the factors that made the treating neurologists consider to switch therapy towards potentially more effective or better-tolerated drugs.Results:The cohort included predominantly female patients with a mean age of 45 years and a mean disease duration of 9.6 years, who had been continuously treated with an injectable DMT for a median duration of 54 months. Overall, 34.0% of the patients had experienced ⩾1 relapse on any DMT in the previous 2 years; 21.0% exhibited magnetic resonance imaging (MRI) activity, and the Kurtzke Expanded Disability Status Scale (EDSS) score increased by at least 0.5 points in 20.1%. Overall, 50.3% of the patients with EDSS progression and 70.6% of the patients with relapses were assessed as clinically stable by the neurologists. A change of treatment was considered in a fraction of patients with disease activity: in 22.8% of those with relapse activity, in 37.8% of those with MRI activity and in 20.1% of those with EDSS progression.Conclusion:The results of EPIDEM underline the importance of standardized evaluation and documentation of ongoing disease activity and disability deterioration. Judged from the present data, the current paradigm of low tolerance for disease activity and recommendations for early treatment optimization have not been turned fully into action as yet. More widespread implementation of current guideline recommendations may allow patients to more benefit from the growing panel of effective treatment options.