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Background In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy. Methods Patients receiving combined lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study (“200CONT”, “400CONT”), whereas those receiving only febuxostat 80 mg were randomized to lesinurad 200 or 400 mg with febuxostat (“200CROSS”, “400CROSS”). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of lesinurad exposure, 800 days). Results Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT ( n  = 64), 200CROSS ( n  = 33), 400CONT ( n  = 65), and 400CROSS ( n  = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged lesinurad exposure in the extension study. Conclusions Patients receiving lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study. Trial registration ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.

Background Provisional gout remission criteria including five domains (serum urate, tophus, flares, pain due to gout, and patient global assessment) have been proposed. The aim of this study was to test the concurrent validity of the provisional gout remission criteria by comparing the criteria with dual-energy CT (DECT) findings. Methods Patients with gout on allopurinol ≥ 300 mg daily were prospectively recruited into a multicenter DECT study. Participants attended a standardized study visit which recorded gout flare frequency in the preceding 12 months, physical examination for tophus, serum urate, and patient questionnaires. DECT scans of both hands/wrists, feet/ankles/Achilles, and knees were analyzed by two DECT radiologists. The relationship between the DECT urate crystal volume and deposition with individual domains as well as the provisional remission criteria set was analyzed. Results The provisional remission criteria were fulfilled in 23 (15.1%) participants. DECT urate crystal deposition was observed less frequently in those fulfilling the provisional remission criteria (44%), compared with those not fulfilling the criteria (73.6%, odds ratio 0.28, P  = 0.004). The median (range) DECT urate crystal volume was 0.00 (0.00–0.46) cm 3 for those fulfilling the remission criteria, compared with 0.08 (0.00–19.53) cm 3 for those not fulfilling the criteria ( P  = 0.002). In multivariate regression analysis, the serum urate and tophus domains were most strongly associated with DECT urate crystal deposition. Conclusions In people with gout established on allopurinol, a state of remission as defined by the provisional remission criteria is associated with less DECT urate crystal deposition. While this study provides support for the validity of the provisional gout remission criteria, it also demonstrates that some crystal deposition may be present in people achieving these criteria.

This study assesses the efficacy and exposure–response relationship of omega-3-carboxylic acids (OM-3 CA) in models of crystal-based inflammation. Human THP-1 macrophages and primary peripheral blood mononuclear cells exposed to multiple inflammatory crystal types were used to determine the anti-inflammatory potential of omega-3 (OM-3) fatty acids in vitro . Anti-inflammatory effects of OM-3 CA in vivo were tested in rat monosodium urate (MSU) crystal air pouch and rat knee intra-articular MSU injection models. Acute treatment with the OM-3 fatty acid docosahexaenoic acid suppressed MSU-, cholesterol crystal-, and calcium pyrophosphate crystal-mediated interleukin-1β (IL-1β) production in vitro . In vivo , OM-3 CA dose-dependently reduced crystal-mediated cell migration, exudate volume, and levels of IL-1β and prostaglandin E 2 . Following intra-articular injection of MSU, treatment with OM-3-CA (1 mL/kg) and indomethacin (1 mg/kg) resulted in similar mean reductions in pain (23% and 41%, respectively) and swelling (58% and 50%, respectively), compared with controls. Additionally, in complex formulations of OM-3 fatty acids, high levels of palmitic acid could reduce the in vivo effect on crystal-mediated IL-1β elevation. OM-3 CA has a broadly efficacious anti-inflammatory effect with a strong exposure–response relationship that could be beneficial in prevention and treatment of crystal arthritis, with potential applications in other IL-1β-mediated diseases.

Rheumatoid arthritis is a common disease, and it produces substantial morbidity as well as an increase in mortality. 1 – 4 Although the causes of rheumatoid arthritis are not fully understood, laboratory and clinical evidence suggests that proinflammatory cytokines, particularly tumor necrosis factor (TNF), have an important role in its pathogenesis. 5 , 6 TNF induces the release of matrix metalloproteases from neutrophils, fibroblasts, and chondrocytes 7 – 9 ; induces the expression of endothelial adhesion molecules involved in the migration of leukocytes to extravascular sites of inflammation 10 ; and stimulates the release of other proinflammatory cytokines. 11 , 12 TNF concentrations are increased in the synovial fluid . . .

ObjectivesDetermine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.MethodsPatients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data.ResultsPatients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively.ConclusionLesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.Trial registration numberNCT01493531.

In this 12-week, phase 2 trial, an anti–interleukin-17–receptor antibody was effective in treating moderate-to-severe psoriasis. Adverse events included neutropenia. Larger trials of longer duration are needed to assess the risk of infections. Psoriasis is a chronic T-cell–mediated autoimmune disease 1 that affects 2 to 3% of the U.S. population 2 , 3 and 0.6 to 6.5% of the European population. 4 Emerging data identify a subset of helper T cells, Th17, that preferentially produce interleukin-17 and play a major role in orchestrating inflammation in psoriasis. 5 – 7 Levels of interleukin-17 are elevated in the lesional skin and blood of patients with psoriasis 5 , 8 – 10 and correlate with disease severity. 11 The interleukin-17 cytokine family consists of six cytokines (interleukins 17A to 17F) and five receptors (interleukins 17RA to 17RE). 12 The interleukin 17A, 17F, and 17A/F heterodimer ligands share . . .

ObjectiveDual-energy CT (DECT) detects and quantifies monosodium urate (MSU) crystal deposition with high precision. This DECT study assessed crystal deposition in patients with gout treated with stable-dose allopurinol, and investigated potential clinical determinants for crystal deposition.MethodsPatients with gout treated with allopurinol ≥300 mg daily for at least 3 months were prospectively recruited from the USA and New Zealand, using monitored enrolment to include approximately 25% patients with palpable tophi and approximately 50% with serum urate (sUA) levels <6.0 mg/dL (<357µmol/L). MSU crystal deposition was measured in the hands/wrists, feet/ankles/Achilles and knees bilaterally. The presence and total volume of crystals were assessed by DECT and analysed according to sUA levels and gout characteristics.ResultsAmong 152 patients receiving allopurinol ≥300 mg/day for 5.1 years on average, 69.1% had crystal deposition on DECT, with a median total crystal volume of 0.16 cm3 (range: 0.01–19.53 cm3). The prevalence of crystal deposition ranged from 46.9% among patients with sUA <6.0 mg/dL and no palpable tophi to 90.0% among those with sUA ≥6.0 mg/dL and tophi. Total volume of crystal deposition was positively associated with sUA ≥6.0 mg/dL, gout flares within the past 3 months and tophi. Total volume of crystal deposition correlated positively with Patient Global Impression of Disease Activity scores.ConclusionA substantial proportion of patients without palpable tophi have MSU crystal deposition, despite receiving allopurinol doses ≥300 mg/day for a considerable duration. Patients with higher sUA and clinical features of severe disease have a higher frequency and greater volume of MSU crystal deposition.

Abstract Background Nutrition is a vital component in the management of IBD and can be an effective primary therapy for many patients. Certain types of diets, including the Western diet, have been speculated to be associated with increased IBD risk or exacerbations. There are currently no specific dietary recommendations for IBD risk reduction. However, online resources may offer nutritional guidance to patients seeking information. This study evaluated specific nutritional and dietary treatment information for IBD on the Internet. Methods Google search engine was used to query “nutrition and inflammatory bowel disease” to obtain the first 100 websites. Websites that were non-accessible, duplicates, videos without transcripts, or evaluated animal models were excluded. Websites were categorized as informational or academic/professional. Websites were reviewed for discussion of specific nutritional treatments, acknowledgement of areas of uncertainty and references. Statistical analysis was performed using a two-tailed Fisher’s Exact Test with a significance value set at p <0.05. Results 89 (50 informational, 39 academic) met the inclusion criteria. No websites were commercial or personal. 49 (55%) websites discussed nutrition as a treatment modality. Enteral nutrition was discussed in 38 (77.6%), probiotics in 22 (44.9%), parenteral nutrition in 21 (42.9%), elimination diet in 19 (38.8%), and low FODMAP diet in 15 (30.6%). Academic resources discussed specific nutritional therapy more often than informational resources (82.1% and 45.0%, respectively; p=0.003) (Figure 1). Academic resources acknowledged areas of uncertainty more frequently than informational resources (64.1% and 30.0%, respectively; p=0.024). Academic resources cited references significantly more often than informational resources (80.9% and 10.6%, respectively; p<0.0001). Diets Discussed in Online Resources Discussion This study shows that the most commonly discussed nutritional therapy was enteral feedings (77.6%), followed by probiotics (44.9%), parenteral feeding (42.9%), elimination diet (38.8%), and the low FODMAP diet (30.6%). Academic websites discussed dietary options significantly more than informational websites. These results suggest that there is a paucity in consumer-oriented literature regarding nutrition in IBD. Academic websites are the primary online resources for information about nutrition in IBD, discuss areas of uncertainty, and offer references. As patients with IBD are increasingly utilizing the Internet for recommendations regarding disease management, it is important that both academic and informational online IBD resources provide comprehensive nutritional information to enhance patient education. Reference Cosnes J. Smoking, physical activity, nutrition and lifestyle: environmental factors and their impact on IBD. Digestive diseases. 2010;28(3):411–7.

Abstract Background Nutrition plays an essential role in inflammatory bowel disease (IBD). Optimizing nutritional status can help prevent malnutrition, osteoporosis, and may be an effective primary therapy for many patients. Patients with IBD are increasingly turning to the Internet for information. This study evaluated the readability and quality of online resources discussing nutrition for IBD. Methods Google search engine was used to query “nutrition and inflammatory bowel disease” to access the first 100 websites. Websites that were non-accessible, duplicates, videos without transcripts or evaluated animal models were excluded. Websites were categorized as informational or academic/professional. Readability was determined using the validated Flesch-Kincaid Grade Level Calculation. The quality of the information was determined using the validated DISCERN score. Websites were reviewed for inclusion of a discussion of shared decision making between patients and physicians. Statistical analysis was performed using a two-tailed Fisher’s Exact Test and a two-sample T-test with a significance value set at p <0.05. Results 89 of 100 websites met the inclusion criteria. 50 (56.2%) websites were informational and 39 (43.8%) were academic. The average Flesch-Kincaid Grade level was 13.2, with no significant difference between informational and academic websites (13.1 and 13.4 grade levels, respectively; p=0.760). The average DISCERN score was “good” without significant difference between informational and academic websites (45.75 and 45.74, respectively; p=0.994). Academic websites had significantly more “excellent” DISCERN scores than informational websites (76% and 24%, respectively; p = 0.0054). There were no significant difference in “good” or “poor” DISCERN scores between academic and informational websites (p=0.527 and p=0.095, respectively) (Figure 1). Shared decision making between patient and physician was discussed among 33.7% of all sources, significantly more often among informational than academic sources (60% and 0%, respectively; p=0.0001). DISCERN Score of Online Nutrition Resources Discussion Patients often self-manage their symptoms using easily accessible online resources. While our study demonstrated near identical DISCERN scores between academic and informational websites, the average Flesch-Kincaid Grade Level exceeded the NIH recommended 6th grade reading level. Informational websites, however, were more likely to encourage shared decision making between physician and patient. It may be important for academic online resources to specifically emphasize communication that encourages shared decision making between IBD patients and physicians. As the use of online resources continues to increase, further efforts should focus on developing informational resources written at a grade level which is applicable to the general public.

Abstract Introduction Biologics are important options for inflammatory bowel disease (IBD) management. It has been reported that people of color (POC) with IBD are less frequently prescribed biologics compared to whites. Drug manufacturers’ websites are often designed to improve patient awareness and understanding of medical conditions and treatment. There is a paucity of information evaluating racial minorities depicted on pharmaceutical websites focused on biologic therapy. This study evaluated minority representation on websites of common biologic therapies used for IBD. Methods Websites for 4 major biologics were evaluated (Humira, Remicade, Stelara, Entyvio) for minority representation. Stock photos and videos were analyzed. Individuals were categorized based upon perceived ethnicity (person of color [POC], racially ambiguous [RA], white), gender, and role (patient, provider). Individuals were categorized independently by 3 investigators. Repeat images, incomplete facial images, inactive background role in videos, or images in which there was disagreement among all investigators were excluded. Statistical analysis was performed using two-sample t-test with significance set at p<0.05. Results In the 4 websites, there were 102 total subjects (49 photos, 53 videos). There were 89 white, 11 POC, and 2 RA subjects with 33 males (32 white, 1 POC, 0 RA) and 69 females (57 white, 10 POC, 2 RA). There were significantly less POC compared to whites in photos (14.2% vs 81.6%; p=0.0003) and videos (7.0% vs 93.0%; p=0.001). Males were less frequently represented than females in photos (33.3% vs 66.7%; p=0.0096) and videos (32.3% vs 67.7%; p=0.0238). There were no males of color in photos. Humira portrayed 10 POC, Entyvio portrayed 1 POC and none were identified on Remicade and Stelara websites. Humira included 1 white, male provider, and Remicade 1 female POC provider. Stelara and Entyvio included no providers in either photos or videos. There were no images or videos about which all 3 reviewing investigators disagreed. All websites included at least 1 image with which a single investigator disagreed. Only Humira and Vedolizumab included a video with single investigator disagreement. Discussion Biologic therapy has a significant role in IBD treatment and should be considered for all IBD patients who have the appropriate indications. Pharmaceutical websites can have a role in increasing patient understanding and acceptance of therapy. Patients may have increased acceptance of treatment based upon portrayed images. While this study revealed that males and POC were significantly less represented on biologic websites, it may reflect gender and minority group IBD prevalence. However, consideration should be given to increase minority representation on biologic websites to enhance male and POC acceptance of therapeutic options and potentially improve clinical outcomes.