Electrical stimulation of the vagus nerve ameliorates inflammation and disease activity in a rat EAE model of multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patients and are associated with side effects that may limit their use. The vagus nerve (VN) provides a direct communication conduit between the CNS and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the VN (VNS) shows efficacy in ameliorating pathology in several CNS and autoimmune disorders. We therefore investigated the impact of VNS in a rat experimental autoimmune encephalomyelitis (EAE) model of MS. In this study, VNS-mediated neuroimmune modulation is demonstrated to effectively decrease EAE disease severity and duration, infiltration of neutrophils and pathogenic lymphocytes, myelin damage, blood-brain barrier disruption, fibrinogen deposition, and proinflammatory microglial activation. VNS modulates expression of genes that are implicated in MS pathogenesis, as well as those encoding myelin proteins and transcription factors regulating new myelin synthesis. Together, these data indicate that neuroimmune modulation via VNS may be a promising approach to treat MS, that not only ameliorates symptoms but potentially also promotes myelin repair (remyelination).

Safety and efficacy of ADS-5102 (amantadine) extended release capsules to improve walking in multiple sclerosis: A randomized, placebo-controlled, phase 2 trial.

BACKGROUND: Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS). OBJECTIVE: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment. METHODS: This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed. RESULTS: A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE-suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test ( p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed. CONCLUSION: ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.

Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial.

OBJECTIVES: Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. METHODS: Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. RESULTS: Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26). CONCLUSIONS: In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. TRIAL REGISTRATION NUMBER: WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.

Bacillus coagulans GBI-30, 6086 Modulates Faecalibacterium prausnitzii in Older Men and Women.

BACKGROUND: Advancing age is linked to a decrease in beneficial bacteria such as Bifidobacterium spp. and reduced aspects of innate immune function. OBJECTIVES: We investigated whether daily consumption of a probiotic [Bacillus coagulans GBI-30, 6086 (BC30); GanedenBC(30)] could improve immune function and gut function in men and women aged 65-80 y, using a double-blind, placebo-controlled crossover design. METHOD: Thirty-six volunteers were recruited and randomly assigned to receive either a placebo (microcrystalline cellulose) or the probiotic BC30 (1 × 10(9) colony-forming units/capsule). Volunteers consumed 1 treatment capsule per day for 28 d, followed by a 21-d washout period before switching to the other treatment. Blood and fecal samples were collected at the beginning and end of each treatment period. Fecal samples were used to enumerate bacterial groups and concentrations of calprotectin. Peripheral blood mononuclear cells (PBMCs) were extracted from whole blood to assess natural killer cell activity and lipopolysaccharide (LPS)-stimulated cytokine production. C-reactive protein concentrations were measured in plasma. RESULTS: Consumption of BC30 significantly increased populations of Faecalibacterium prausnitzii by 0.1 log10 cells/mL more than during consumption of the placebo (P = 0.03), whereas populations of Bacillus spp. increased significantly by 0.5 log10 cells/mL from baseline in volunteers who consumed BC30 (P = 0.007). LPS-stimulated PBMCs showed a 0.2 ng/mL increase in the anti-inflammatory cytokine IL-10 28 d after consumption of BC30 (P < 0.05), whereas the placebo did not affect IL-10, and no overall difference was found in the effect of the treatments. CONCLUSIONS: Daily consumption of BC30 by adults aged 65-80 y can increase beneficial groups of bacteria in the human gut and potentially increase production of anti-inflammatory cytokines. This study shows the potential benefits of a probiotic to improve dysbiosis via modulation of the microbiota in older persons.

Effect of prebiotics on the fecal microbiota of elderly volunteers after dietary supplementation of Bacillus coagulans GBI-30, 6086.

In advancing age, gut populations of beneficial microbes, notably Bifidobacterium spp., show a marked decline. This contributes to an environment less capable of maintaining homoeostasis. This in vitro investigation studied the possible synergistic effects of probiotic supplementation in modulating the gut microbiota enabling prebiotic therapy to in elderly persons. Single stage batch culture anaerobic fermenters were used and inoculated with fecal microbiota obtained from volunteers after taking a 28 day treatment of Bacillus coagulans GBI-30, 6086 (GanedenBC30 (BC30)) or a placebo. The response to prebiotic supplements fructooligosaccharides (FOS) and galactooligosaccharides (GOS) in the fermenters was assessed. Bacterial enumeration was carried out using fluorescent in situ hybridisation and organic acids measured by gas chromatography. Baseline populations of Faecalibacterium prausnitzii, Clostridium lituseburense and Bacillus spp. were significantly higher in those having consumed BC30 compared to the placebo. Both prebiotics increased populations of several purportedly beneficial bacterial groups in both sets of volunteers. Samples from volunteers having ingested the BC30 also increased populations of C. lituseburense, Eubacterium rectale and F. prausnitzii more so than in persons who had consumed the placebo, this also resulted in significantly higher concentrations of butyrate, acetate and propionate. This shows that consumption of BC30 and subsequent use of prebiotics resulted in elevated populations of beneficial genres of bacteria as well as organic acid production.

Variations and practice in the care of patients with rheumatoid arthritis: quality and cost of care.

INTRODUCTION: Variability in treatment is linked to lower quality of care and higher costs. Rheumatoid arthritis (RA) is a chronic inflammatory disease for which care and management may vary considerably among rheumatologists. The extent of this variability and its cost ramifications have not been widely studied. This prospective study evaluated the quality and variability in care and quantified the potential cost implications. METHODS: We used Clinical Performance and Value® vignettes to measure the quality of RA care among community-based rheumatologists. Three online Clinical Performance and Value® vignettes--representing patients likely seen in practice with mild disease activity (case A), worsening disease activity (case B), and stable disease with a complicating comorbidity (case C)--were administered to each rheumatologist. Responses were scored against evidence-based criteria. Costs were computed using current (2011) Medicare pricing. Data were analyzed using t test and fixed-effects analysis of variance. RESULTS: One hundred eight board-certified rheumatologists (72% were male; mean age, 49.1 years) completed the study. Overall quality scores averaged 61.3%. Those employed by a health system or in a multispecialty practice were more likely to score higher. Highest combined scores for diagnosis and treatment were evident with case A (61.7%) and lowest with case C (46.7%). Up to 79% of rheumatologists ordered at least 1 laboratory test that was considered unnecessary by study protocol criteria, incurring a mean excess cost of $37.85 per physician per case. Up to 26.9% rheumatologists prescribed biologic agents that were not indicated based on American College of Rheumatology treatment guidelines, resulting in additional costs of $2041 per patient per month. CONCLUSION: In this study, we observed a wide range of reported practice variability by rheumatologists in the management of RA. This included unnecessary testing and use of biologic agents that increased the costs of treatment. Opportunities for quality improvement and cost control exist in the management of RA.

Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn's Disease Patients: A Prospective Open-label Study.

BACKGROUND AND AIMS: Crohn's disease [CD] is a debilitating, inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the 'inflammatory reflex', has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD, in a 16-week, open-label, multicentre, clinical trial. METHODS: A vagus nerve stimulator was implanted in 17 biologic drug-refractory patients with moderately to severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation [4/16 receiving concomitant biologics] during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient-reported outcomes, objective measures of inflammation [endoscopic/molecular], and safety. RESULTS: There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week 16 [mean ±â€…SD: -86.2 ±â€…92.8, p = 0.003], a significant decrease in faecal calprotectin [-2923 ±â€…4104, p = 0.015], a decrease in mucosal inflammation in 11/15 patients with paired endoscopies [-2.1 ±â€…1.7, p = 0.23], and a decrease in serum tumour necrosis factor and interferon-γ [46-52%]. Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related severe adverse event: a postoperative infection requiring device explantation. CONCLUSIONS: Neuroimmune modulation via vagus nerve stimulation was generally safe and well tolerated, with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality of life.

Evaluation of the impact of age and adiposity on a multi-biomarker disease activity score before and after adjustment.

PURPOSE: We assessed the impact of adjustment of the multi-biomarker disease activity score (MBDA) for age, sex, and leptin, over the range of age and adiposity, and assessed relationships with clinical disease activity. METHODS: Patients with RA, ages 18-75 years, were recruited from clinical practices and completed whole-body DXA to quantify fat mass indices (FMI, kg/m2). FMI Z-scores were calculated based on distributions in a reference population. Descriptive statistics described relationships between age, FMI Z-score, and the original MBDA and adjusted MBDA (aMBDA). Swollen joint counts (SJC) and the clinical disease activity index (CDAI) were assessed over MBDA categories. RESULTS: There were 104 participants (50% female) with mean (SD) age of 56.1 (12.5) and body mass index (BMI) of 28.8 (6.9). Older age was associated with higher MBDA scores in men. The aMBDA was not associated with age. The original MBDA score was associated with FMI Z-score among women (Rho = 0.42, p = 0.002) but not men. The aMBDA was not associated with FMI Z-score in either women or men. The aMBDA score was lower than the original MBDA in the highest quartile of FMI in women and was higher in the lowest FMI quartiles in women and men. CDAI, SJC, and radiographic scores were similar across activity categories for the original MBDA score and aMBDA. CONCLUSIONS: The aMBDA demonstrated reduced associations with adiposity, particularly among women. The aMBDA may be less likely to overestimate disease activity in women with greater adiposity and to underestimate disease activity in men and women with lesser adiposity. Key Points • Leptin adjustment of the MBDA score reduces the influence of adiposity, particularly among women. • Leptin adjustment results in significantly higher estimated disease activity in thin men and women. • The adjusted and unadjusted score correlate similarly with clinical disease activity measures.

The Fourth Bioelectronic Medicine Summit "Technology Targeting Molecular Mechanisms": current progress, challenges, and charting the future.

There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit "Technology targeting molecular mechanisms" took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here.

Harnessing the Inflammatory Reflex for the Treatment of Inflammation-Mediated Diseases.

Treating diseases nonpharmacologically, using targeted neurostimulation instead of systemic drugs, is a hallmark of the burgeoning field of bioelectronic medicine. In this review, we provide a brief overview of the discovery and function of the prototypical neuroimmune reflex, the "inflammatory reflex." We discuss various biomarkers developed and used to translate early physiological discoveries into dosing parameters used in experimental settings, from the treatment of animal models of disease through a proof-of-concept clinical study in rheumatoid arthritis (RA). Finally, we relate how unique aspects of this form of therapy enabled the design of a next-generation implanted pulse generator using integrated electrodes, currently under evaluation in a U.S.-based clinical study for patients with drug refractory RA.

Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study.

Background The inflammatory reflex plays a role in regulating innate and adaptive immunity by modulating cellular and molecular inflammatory pathways. The vagus nerve is a major constituent of the inflammatory reflex and studies have shown that the reflex can be activated by electrical stimulation of the vagus nerve. In this first in-human pilot study, we assessed the safety and efficacy of a novel miniaturised vagus nerve stimulation (VNS) device for the treatment of multidrug-refractory rheumatoid arthritis. METHODS: Participants with moderately to severely active rheumatoid arthritis and prior insufficient response to two or more biological disease-modifying anti-rheumatic drugs or Janus kinase inhibitors with at least two different modes of action were enrolled in a two-stage study done at five clinical research sites in the USA. Stage 1 was open label; participants were implanted with a miniaturised VNS device, which was activated for 1 min once a day. In stage 2, participants were randomly assigned (1:1:1) to receive active stimulation (1 min once a day or 1 min four times a day) or sham stimulation (device implanted but not activated), with the sites and participants masked to treatment assignment. The primary outcome was incidence of treatment-emergent adverse events. Clinical efficacy was assessed as a key secondary outcome. The study was registered with ClinicalTrials.gov, NCT03437473. FINDINGS: 14 patients were enrolled between March 13 and Aug 8, 2018. Three patients received stimulation in stage 1 and, following safety review board approval, the remaining 11 patients were implanted during stage 2 and randomly assigned to receive 1 min of stimulation once daily (n=3), 1 min of stimulation four times daily (n=4), or no stimulation (n=4) for 12 weeks. There were no device-related or treatment-related serious adverse events. Surgery-related adverse events were Horner's syndrome and vocal cord paralysis (in one patient each), which resolved without clinically significant sequelae. No deaths were recorded. INTERPRETATION: VNS with a miniaturised neurostimulator was safe and well tolerated and reduced signs and symptoms of rheumatoid arthritis in patients with multidrug-refractory disease. These results support further evaluation in a larger randomised sham-controlled study. FUNDING: SetPoint Medical.

Determination of the minimally important difference (MID) in multi-biomarker disease activity (MBDA) test scores: impact of diurnal and daily biomarker variation patterns on MBDA scores.

The Multi-Biomarker Disease Activity (MBDA) score is a validated rheumatoid arthritis (RA) disease activity measure based on 12 serum biomarkers. Here, we evaluate short-term biological variability of MBDA scores to determine the magnitude of change that might be considered clinically meaningful. Twenty-eight adult seropositive RA patients with clinically stable disease and no changes in RA medications for 4 weeks prior to study were enrolled. Nine serum samples were obtained over four consecutive days (non-fasting). MBDA score variation was assessed day-to-day (daily) and within 24 h (diurnal). The standard deviation (SD) of MBDA scores was calculated by a linear mixed model including random effects for patient, day, and time of day. The minimally important difference (MID) was calculated as [Formula: see text]. A subgroup analysis was performed for patients with active RA (moderate or high MBDA score). The SD of MBDA score change in the full cohort was 4.7 in a combined daily-diurnal variation analysis, which corresponds with an MID of 11. The SD of MBDA score change in the subset of patients with active RA (moderate/high MBDA scores) was 3.6. This corresponds with an MID of 8 units in patients with active RA for whom clinicians are most likely to need guidance with respect to therapeutic decisions. Changes in MBDA score ≥ 8 represent a change in RA disease activity that clinicians can use as a benchmark for therapeutic drug efficacy and can be incorporated into a treat-to-target strategy.

Multi-biomarker disease activity score as a predictor of disease relapse in patients with rheumatoid arthritis stopping TNF inhibitor treatment.

OBJECTIVE: Successfully stopping or reducing treatment for patients with rheumatoid arthritis (RA) in low disease activity (LDA) may improve cost-effectiveness of care. We evaluated the multi-biomarker disease activity (MBDA) score as a predictor of disease relapse after discontinuation of TNF inhibitor (TNFi) treatment. METHODS: 439 RA patients who were randomized to stop TNFi treatment in the POET study were analyzed post-hoc. Three indicators of disease relapse were assessed over 12 months: 1) restarting TNFi treatment, 2) escalation of any DMARD therapy and 3) physician-reported flare. MBDA score was assessed at baseline. Associations between MBDA score and disease relapse were examined using univariate analysis and multivariate logistic regression. RESULTS: At baseline, 50.1%, 35.3% and 14.6% of patients had low (<30), moderate (30-44) or high (>44) MBDA scores. Within 12 months, 49.9% of patients had restarted TNFi medication, 59.0% had escalation of any DMARD and 57.2% had ≥1 physician-reported flare. MBDA score was associated with each indicator of relapse. At least one indicator of relapse was observed in 59.5%, 68.4% and 81.3% of patients with low, moderate or high MBDA scores, respectively (P = 0.004). Adjusted for baseline DAS28-ESR, disease duration, BMI and erosions, high MBDA scores were associated with increased risk for restarting TNFi treatment (OR = 1.85, 95% CI 1.00-3.40), DMARD escalation (OR = 1.99, 95% CI 1.01-3.94) and physician-reported flare (OR = 2.00, 95% 1.06-3.77). CONCLUSION: For RA patients with stable LDA who stopped TNFi, a high baseline MBDA score was independently predictive of disease relapse within 12 months. The MBDA score may be useful for identifying patients at risk of relapse after TNFi discontinuation.

Association of a multibiomarker disease activity score at multiple time-points with radiographic progression in rheumatoid arthritis: results from the SWEFOT trial.

OBJECTIVES: In rheumatoid arthritis (RA), predictive biomarkers for subsequent radiographic progression (RP) could improve therapeutic choices for individual patients. We previously showed that the multibiomarker disease activity (MBDA) score in patients with newly diagnosed RA identified patients at risk for RP. We evaluated the MBDA score at multiple time-points as a predictor of RP during 2 years of follow-up. METHODS: A subset of patients with RA (N=220) from the Swedish Farmacotherapy (SWEFOT) trial were analysed for MBDA score, disease activity score of 28 joints (DAS28), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at baseline (BL), month 3 and year 1, for predicting RP based on modified Sharp/van der Heijde scores at BL, year 1 and year 2. RESULTS: Patients with persistently low MBDA (<30) scores or those with a decrease from moderate (30-44) to low MBDA scores, did not develop RP during 2 years of follow-up. The highest risk for RP during 2 years of follow-up (42%) was observed among patients with persistently high (>44) MBDA scores. Among methotrexate non-responders with a high MBDA score at BL or month 3, significantly more of those who received triple therapy had RP at year 2 compared with those who received antitumour necrosis factor therapy. CONCLUSIONS: Measuring the MBDA score both before and during treatment in RA was useful for the assessment of individual patient risk for RP during 2 years of follow-up. In comparison with low CRP, ESR or DAS28, a low MBDA score at any time-point was associated with numerically lower proportions of RP. TRIAL REGISTRATION NUMBER: NCT00764725.

Modular analysis of peripheral blood gene expression in rheumatoid arthritis captures reproducible gene expression changes in tumor necrosis factor responders.

OBJECTIVE: To establish whether the analysis of whole-blood gene expression is useful in predicting or monitoring response to anti-tumor necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA). METHODS: Whole-blood RNA (using a PAXgene system to stabilize whole-blood RNA in the collection tube) was obtained at baseline and at 14 weeks from 3 independent cohorts, consisting of a combined total of 240 RA patients who were beginning therapy with anti-TNF. We used an approach to gene expression analysis that is based on modular patterns of gene expression, or modules. RESULTS: Good and moderate responders according to the European League Against Rheumatism criteria exhibited highly significant and consistent changes in multiple gene expression modules after 14 weeks of therapy, as demonstrated by hypergeometric analysis. Strikingly, nonresponders exhibited very little change in any modules, despite exposure to TNF blockade. These patterns of change were highly consistent across all 3 cohorts, indicating that immunologic changes after TNF treatment are specific to the combination of both drug exposure and responder status. In contrast, modular patterns of gene expression did not exhibit consistent differences between responders and nonresponders at baseline in the 3 study cohorts. CONCLUSION: These data provide evidence that using gene expression modules related to inflammatory disease may provide a valuable method for objective monitoring of the response of RA patients who are treated with TNF inhibitors.

The significance of HIV viral load assay precision: a review of the package insert specifications of two commercial kits.

Quantification of HIV-1 RNA levels is a vital tool in the medical management of individuals infected with HIV. The commercially available US Federal Drug Administration (FDA)-approved assays vary in their ability to accurately measure and detect significant changes in plasma viral load. A more precise assay can accurately distinguish true clinically significant biologic changes in viral plasma load from background noise, or systematic variation. These differences in precision between assays are profound at low, near-cutoff levels, but also occur throughout the dynamic range of the assays. This review examines the precision specifications, expressed as fold changes in test and retesting, across the dynamic ranges of the Bayer Versant bDNA assay, and the two available versions of the Roche Amplicor Monitor PCR assays. Highly validated data from their respective package inserts are analyzed to confirm each assay's performance throughout its dynamic range. The precision of a viral load assay is critical to patient management, and gives the clinician a clearer picture of the patient's true virologic status that is attributable to infection or treatment as opposed to systematic variation in assays.

Impact of rheumatoid arthritis disease activity test on clinical practice.

BACKGROUND: Variability exists in the assessment of disease activity in rheumatoid arthritis (RA) patients that may affect quality of care. OBJECTIVES: To measure the impact on quality of care of a Multi-Biomarker Disease Activity (MBDA) test that quantitatively assesses RA disease activity. METHODS: Board-certified rheumatologists without prior experience with the MBDA test (N = 81) were randomized into an intervention or control group as part of a longitudinal randomized-control study. All physicians were asked to care for three simulated RA patients, using Clinical Performance and Value (CPV™) vignettes, in a before and after design. CPV™ vignettes have been validated to assess the quality of clinical practice and identify variation in care. The vignettes covered all domains of a regular patient visit; scores were determined as a percentage of explicit predefined criteria completed. Three vignettes, representing typical RA cases, were administered each round. In the first round, no physician received information about the MBDA test. In the second round, only physicians in the intervention group were given educational materials about the test and hypothetical test results for each of the simulated patients. The outcome measures were the overall quality of care, disease assessment and treatment. RESULTS: The overall quality scores in the intervention group improved by 3 percent (p = 0.02) post-intervention compared with baseline, versus no change in the control group. The greatest benefit in the intervention group was to the quality of disease activity assessment and treatment decisions, which improved by 12 percent (p<0.01) compared with no significant change in the control group. The intervention was associated with more appropriate use of biologic and/or combination DMARDs in the co-morbidity case type (p<0.01). CONCLUSIONS: Based on these results, use of the MBDA test improved the assessment and treatment decisions for simulated cases of RA and may prove useful for rheumatologists in clinical practice.

Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo.

BACKGROUND: The efficacy of AQX-1125, a small-molecule SH2-containing inositol-5'-phosphatase 1 (SHIP1) activator and clinical development candidate, is investigated in rodent models of inflammation. EXPERIMENTAL APPROACH: AQX-1125 was administered orally in a mouse model of passive cutaneous anaphylaxis (PCA) and a number of rodent models of respiratory inflammation including: cigarette smoke, LPS and ovalbumin (OVA)-mediated airway inflammation. SHIP1 dependency of the AQX-1125 mechanism of action was investigated by comparing the efficacy in wild-type and SHIP1-deficient mice subjected to an intrapulmonary LPS challenge. RESULTS: AQX-1125 exerted anti-inflammatory effects in all of the models studied. AQX-1125 decreased the PCA response at all doses tested. Using bronchoalveolar lavage (BAL) cell counts as an end point, oral or aerosolized AQX-1125 dose dependently decreased the LPS-mediated pulmonary neutrophilic infiltration at 3-30 mg kg⁻¹ and 0.15-15 µg kg⁻¹ respectively. AQX-1125 suppressed the OVA-mediated airway inflammation at 0.1-10 mg kg⁻¹. In the smoke-induced airway inflammation model, AQX-1125 was tested at 30 mg kg⁻¹ and significantly reduced the neutrophil infiltration of the BAL fluid. AQX-1125 (10 mg kg⁻¹) decreased LPS-induced pulmonary neutrophilia in wild-type mice but not in SHIP1-deficient mice. CONCLUSIONS: The SHIP1 activator, AQX-1125, suppresses leukocyte accumulation and inflammatory mediator release in rodent models of pulmonary inflammation and allergy. As shown in the mouse model of LPS-induced lung inflammation, the efficacy of the compound is dependent on the presence of SHIP1. Pharmacological SHIP1 activation may have clinical potential for the treatment of pulmonary inflammatory diseases.