The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout.

OBJECTIVES: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. METHODS: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. RESULTS: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. CONCLUSIONS: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. CLINICAL TRIAL REGISTRATION: NCT03905512.

Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial.

BACKGROUNDSystemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs.METHODSWe randomized 15 participants with early diffuse cutaneous SSc to tofacitinib 5 mg twice a day or matching placebo in a phase I/II double-blind, placebo-controlled trial. The primary outcome measure was safety and tolerability at or before week 24. To understand the changes in gene expression associated with tofacitinib treatment in each skin cell population, we compared single-cell gene expression in punch skin biopsies obtained at baseline and 6 weeks following the initiation of treatment.RESULTSTofacitinib was well tolerated; no participants experienced grade 3 or higher adverse events before or at week 24. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicated IFN-activated gene expression. Tofacitinib inhibited IFN-regulated gene expression in SFRP2/DPP4 fibroblasts (progenitors of myofibroblasts) and in MYOC/CCL19, representing adventitial fibroblasts (P < 0.05), as well as in the basal and keratinized layers of the epidermis. Gene expression in macrophages and DCs indicated inhibition of STAT3 by tofacitinib (P < 0.05). No clinically meaningful inhibition of T cells and endothelial cells in the skin tissue was observed.CONCLUSIONThese results indicate that mesenchymal and epithelial cells of a target organ in SSc, not the infiltrating lymphocytes, may be the primary focus for therapeutic effects of a Janus kinase inhibitor.TRIAL REGISTRATIONClinicalTrials.gov NCT03274076.FUNDINGPfizer, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01 AR070470, NIH/NIAMS K24 AR063120, Taubman Medical Research Institute and NIH P30 AR075043, and NIH/NIAMS K01 AR072129.

Reducing Immunogenicity of Pegloticase With Concomitant Use of Mycophenolate Mofetil in Patients With Refractory Gout: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase. METHODS: Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24-week durability of serum urate level ≤6 mg/dl. Fisher's exact test and Wilcoxon's 2-sample test were used for analyses, along with Kaplan-Meier estimates and log rank tests. RESULTS: A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF-treated patients versus 30% of placebo-treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%). CONCLUSION: Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout.

A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares.

OBJECTIVE: To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares. METHODS: Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient- and physician-assessed global response. RESULTS: One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient-assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction. CONCLUSION: Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.

Systemic Urate Deposition: An Unrecognized Complication of Gout?

Gout, an inflammatory arthritis, affects over nine million people in the US with increasing prevalence. Some medical societies do not recommend treating gout unless it is recurrent. While soft tissue urate deposits (tophi), resultant bone erosions, and joint inflammation are frequently recognized in gout, urate crystal deposits in other sites have been thought to be rare. Recent diagnostic testing, such as dual energy computed tomography (DECT), has led to the recognition that urate deposits are not uncommon in other tissues including the vasculature. To understand the potential risks for untreated gout, we reviewed the literature on extra-articular urate deposition documented by autopsy, histopathology, surgery, and radiology, including the heart, blood vessels, kidney, spine, eye, skin, and gastrointestinal system. These studies extend the significance of gout beyond the rheumatologist and emphasize the need for physicians to follow the American College of Rheumatology guidelines to treat subjects with gout to a goal of achieving serum urate <6 mg/dl. Given the growing body of literature on extraarticular urate deposition, further studies and clinical trials are needed to determine the clinical consequences of systemic urate deposition, including if reducing cardiac and vascular urate deposits may provide a survival benefit for this at-risk population.

2020 American College of Rheumatology Guideline for the Management of Gout

To provide guidance for the management of gout, including indications for and optimal use of urate- lowering therapy (ULT), treatment of gout ares, and lifestyle and other medication recommendation Fifty- seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta- analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the nal recommendations and grade their strength as strong or conditional.Results. Forty- two recommendations (including 16 strong recommendations) were generated. Strong recommen-dations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout ares; allopurinol as the preferred rst- line ULT, including for those with moderate- to- severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat- to- target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinammatory prophylaxis therapy for a duration of at least 3­6 months was strongly recommended. For management of gout ares, colchicine, nonsteroidal antiinammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended.Conclusion. Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

2020 American College of Rheumatology Guideline for the Management of Gout.

OBJECTIVE: To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS: Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS: Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. CONCLUSION: Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

2020 American College of Rheumatology Guideline for the Management of Gout.

OBJECTIVE: To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS: Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS: Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. CONCLUSION: Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

Pigmented Malignant Lesion of Central Arch Gingiva of Mandible.

Primary oral malignant melanoma (OMM) is a rare malignant lesion with a relatively poor prognosis. The clinical presentation may be nodular, macular, or mixed type, with or without pigmentation. The pigmented lesions in the oral cavity may be either melanocytic or non-melanocytic and neoplastic or non-neoplastic lesions. For all the pigmented lesions of the oral cavity, clinicians must consider OMM as a differential diagnosis. Hence, a histopathological examination is required. Herein, we report a case of pigmented growth over the central arch and gingival mucosa, which turned out to be an OMM.

Performance of Anti-Topoisomerase I Antibody Testing by Multiple-Bead, Enzyme-Linked Immunosorbent Assay and Immunodiffusion in a University Setting.

BACKGROUND/OBJECTIVE: The criterion standard for anti-topoisomerase I antibody (anti-topo I antibody) testing in systemic sclerosis (SSc) uses immunodiffusion (ID) techniques, but enzyme-linked immunosorbent assay (ELISA) and multiple-bead technology are often used in current settings to save time and cost. Our aim was to assess the performance of the multiple-bead assay, ELISA, and ID testing methods. METHODS: We conducted a retrospective study of patients at the University of Michigan whose extractable nuclear antigen 10 autoantibody panel tested positive for the anti-topo I antibody by multiple-bead technology during a 1-year period. All samples positive by multiple-bead assay were sent to the RDL Laboratories and reflexed for ELISA, and all anti-topo I antibodies positive by ELISA were further tested by ID. Clinical data were reviewed by a rheumatologist and assessed for presence of SSc. Data were analyzed via frequency tables. RESULTS: Approximately 9500 extractable nuclear antigen 10 panels were ordered by physicians at the University of Michigan. Of these, 129 patients were positive for the anti-topo I antibody by multiple-bead assay, 51 were positive by multiple-bead assay and ELISA, and 21 were positive by multiple-bead assay, ELISA, and ID. We found that 26.4% of patients positive by multiple-bead assay, 47.1% positive by multiple-bead assay and ELISA, and 95.2% positive by multiple-bead assay, ELISA, and ID had SSc. CONCLUSIONS: Multiple-bead assays have a high rate of false-positive results for the anti-topo I antibody in patients without clinical evidence of SSc. A stepwise approach of confirmation of positive multiple-bead assay results using both ELISA and ID improves the predictive value of antibody testing for the diagnosis of SSc.

Development and Pilot Testing of MyGoutCare: A Novel Web-Based Platform to Educate Patients With Gout.

BACKGROUND: Management guidelines have identified unmet educational needs in gout patients. Our objective was to develop and pilot test MyGoutCare (MGC©)-a web-based, interactive educational resource for gout patients, tailored to improve knowledge. METHODS: The website was developed with input from patients and experts. A health informatics expert tailored content areas so the patient could walk through a journey to learn various aspects of gout. During the pilot study, patients completed baseline demographics and a 10-item validated gout knowledge questionnaire. After reviewing the website, patients completed a post-survey within 2 weeks of their physician visit. Data were analyzed using paired t-tests and effect size (ES) was calculated for the changed scores. RESULTS: Gout patients and experts agreed on these content areas-triggers of flares, comorbidities, pharmacologic and non-pharmacologic treatment, healthy gout diet, and lifestyle choices. In the pilot study, 50 patients (mean age of 54 years, mean disease duration of 9.5 years, and mean 3-5 flares/year) were recruited. Their post-survey scores (0-10) on knowledge questions improved significantly when compared to pre-survey scores with mean (SD) of 1.95 (1.76) p < 0.0001, ES = 0.95. Patients identified actionable changes moving forward after reviewing the website-decision to continue lifelong urate-lowering therapy, complying with periodic monitoring of serum urate, and making dietary changes. CONCLUSIONS: Web-based platforms that offer patient-focused materials can serve as a practical tool to address ongoing educational needs of gout patients. Additional studies are needed to evaluate if the website can improve patient-physician communication and lead to better long-term outcomes.

Evaluation of Proposed Criteria for Remission and Evidence-Based Development of Criteria for Complete Response in Patients With Chronic Refractory Gout.

OBJECTIVE: The objective of this study is to assess criteria for gout remission and to use the results to inform criteria for a complete response (CR). METHODS: A post hoc analysis of two clinical trials was undertaken to determine the frequency with which subjects with chronic refractory gout who were treated with pegloticase met remission criteria. Mixed modeling was then employed to identify the components that best correlated with time to maximum benefit. RESULTS: Of the 56 subjects treated with biweekly pegloticase for whom adequate data were collected, 48.2% met the remission criteria. When subjects with persistent lowering of urate levels were examined separately, 27 of 32 (84.4%) met the criteria for remission. In contrast, even when the requirement for lowering of serum urate levels was waived, only 2 of 24 (8.3%) subjects without persistent lowering of urate levels and 0 of 43 subjects receiving placebo met criteria. Mixed modeling indicated that in addition to urate levels, assessment of tophi, swollen joints, and tender joints and patient global assessment best correlated with time to maximum benefit. Using these criteria of CR, 23 of the responders (71.9%) met the criteria. All patients who achieved a CR maintained it for a mean duration of 507.4 days. Finally, 64% of persistent responders to monthly pegloticase also met criteria for CR. CONCLUSION: These results have validated the proposed remission criteria for gout and have helped define criteria for CR in individuals with chronic gout treated with pegloticase. This composite CR index can serve as an evidence-based target to inform the design and end points of future clinical trials.

Gout.

Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition. Gout typically presents as an acute, self-limiting inflammatory monoarthritis that affects the joints of the lower limb. Elevated serum urate level (hyperuricaemia) is the major risk factor for MSU crystal deposition and development of gout. Although traditionally considered a disorder of purine metabolism, altered urate transport, both in the gut and the kidneys, has a key role in the pathogenesis of hyperuricaemia. Anti-inflammatory agents, such corticosteroids, NSAIDs and colchicine, are widely used for the treatment of gout flare; recognition of the importance of NLRP3 inflammasome activation and bioactive IL-1ß release in initiation of the gout flare has led to the development of anti-IL-1ß biological therapy for gout flares. Sustained reduction in serum urate levels using urate-lowering therapy is vital in the long-term management of gout, which aims to dissolve MSU crystals, suppress gout flares and resolve tophi. Allopurinol is the first-line urate-lowering therapy and should be started at a low dose, with gradual dose escalation. Low-dose anti-inflammatory therapies can reduce gout flares during initiation of urate-lowering therapy. Models of care, such as nurse-led strategies that focus on patient engagement and education, substantially improve clinical outcomes and now represent best practice for gout management.

Comparison of Frictional Resistance in Conventional Brackets with Different Stainless Steel Wires.

AIM: The aim of the study was to evaluate and compare static and kinetic friction of round (0.018") and rectangular (0.019 × 0.025") stainless steel (SS) wires of different brands with conventional preadjusted edgewise brackets. MATERIALS AND METHODS: Maxillary canine and two bicuspids of 0.022 × 0.028" slot sized MBT prescription (Gemini, 3M Unitek, Monrovia, California) brackets were chosen. The wires selected were 0.018" SS (3M Unitek); 0.018" Australian wire (AJ Wilcock, UK), and 0.019 × 0.025" SS (3M Unitek). The testing was done on Instron 3382. A total of 30 test combinations with three wires were repeated 10 times. The static and kinetic friction was recorded in Newton. The kinetic friction was also recorded in Newton at 3, 5, 7, and 9 mm of movement. One-way analysis of variance (ANOVA) and descriptive statistics were used for comparing the friction. To test the level of significance, multiple comparisons were used within wire in bracket by using post hoc test. RESULTS: Static friction was found to be greater than kinetic in all wires; 0.018" SS (3M) wire exhibited minimum static and kinetic friction; while 0.019 × 0.025" SS (3M) exhibited maximum static friction. Kinetic friction was similar in both 0.018" AJ Wilcock and 0.019 × 0.025" SS but greater than 0.018" SS (3M). CONCLUSION: Least static and kinetic friction was exhibited by 0.018" SS (3M). Kinetic friction was similar in both 0.018" AJ Wilcock and 0.019 × 0.025" SS. CLINICAL SIGNIFICANCE: The study concluded that 0.018" SS (3M) is better for individual canine retraction than the other wires used in the study because it has the least frictional resistance; 0.019 × 0.025" SS (3M) is a better wire for canine retraction than 0.018" AJ Wilcock as we can have a three-dimensional control over tooth movement. When torque control is not a prime requisite, then 0.018" SS (3M) can be used for retraction of incisors instead of 0.018" AJ Wilcock in severely proclined incisor cases.

Y-box binding protein-1 and STAT3 independently regulate ATP-binding cassette transporters in the chemoresistance of gastric cancer cells.

Y-box binding protein-1 (YB-1) facilitates cancer chemoresistance through the upregulation of ATP-binding cassette (ABC) transporters associated with multidrug resistance, which is one of the primary obstacles in cancer treatment. Since aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is also implicated in chemoresistance in numerous human malignancies, the interaction between YB-1 and JAK/STAT signaling was explored underlying the chemoresistance of NUGC3 gastric cancer cells. It was demonstrated that YB-1 translocated into the nuclei of NUGC3 cells exposed to doxorubicin hydrochloride, suggesting its important role in chemoresistance. Consistently, knockdown of YB-1 significantly decreased the chemoresistance of cells to doxorubicin hydrochloride and epirubicin hydrochloride, as evidenced by a decrease in cell viability. Notably, JAK inhibitor AG490 treatment further decreased the cell viability caused by YB-1 inhibition and doxorubicin hydrochloride. It was also observed that YB-1 transcriptionally regulated the ABCC3 transporter, whereas STAT3 modulated ABCC2 transporter levels. These findings suggest that YB-1 and STAT3 act together to facilitate chemoresistance via modulating the expression of different ABC transporters in NUGC3 cells. Notably, siYB-1 did not exhibit any significant effect on STAT3 expression. Similarly, siSTAT3 failed to alter YB-1 expression, suggesting that the two may not regulate each other in a mutual manner. However, double knockdown of YB-1 and STAT3 led to a synergistic inhibition of cell invasion in NUGC3 cells. Nonetheless, the combined treatment of YB-1 antagonists with STAT3 inhibitors may serve as an effective therapy in gastric cancer.

GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling.

Dysregulated JAK/STAT signaling has been implicated in breast cancer metastasis, which is associated with high relapse risks. However, mechanisms underlying JAK/STAT signaling-mediated breast tumorigenesis are poorly understood. Here, we showed that GRAMD1B expression is upregulated on IL-6 but downregulated upon treatment with the JAK2 inhibitor AG490 in the breast cancer MDA-MB-231 cells. Notably, Gramd1b knockdown caused morphological changes of the cells, characterized by the formation of membrane ruffling and protrusions, implicating its role in cell migration. Consistently, GRAMD1B inhibition significantly enhanced cell migration, with an increase in the levels of the Rho family of GTPases. We also found that Gramd1b knockdown-mediated pro-migratory phenotype is associated with JAK2/STAT3 and Akt activation, and that JAK2 or Akt inhibition efficiently suppresses the phenotype. Interestingly, AG490 dose-dependently increased p-Akt levels, and our epistasis analysis suggested that the effect of JAK/STAT inhibition on p-Akt is via the regulation of GRAMD1B expression. Taken together, our results suggest that GRAMD1B is a key signaling molecule that functions to inhibit cell migration in breast cancer by negating both JAK/STAT and Akt signaling, providing the foundation for its development as a novel biomarker in breast cancer.

Development of the American College of Rheumatology Electronic Clinical Quality Measures for Gout.

OBJECTIVE: Electronic clinical quality measures (eCQMs) are increasingly used by health registries and third parties to evaluate and improve the quality of health care. To complete these eCQMs, data are extracted from electronic health records (EHRs). The treatment of gout has been an area identified with gaps in quality of care. On behalf of the American College of Rheumatology (ACR), we sought to develop and test eCQMs to evaluate gout care. METHODS: Drawing from the 2012 ACR gout guidelines, a working group developed candidate gout process measures that were evaluated by an interdisciplinary panel of health care stakeholders, the ACR Quality Measures Subcommittee (QMS), and ultimately the ACR Board of Directors for formal validity testing. For each of the selected gout eCQMs, 3 clinical sites using different EHR systems tested the scientific feasibility and validity of the measures. Measures appropriate for accountability were presented for national endorsement. RESULTS: Of the 10 proposed eCQMs, 4 were endorsed by the ACR QMS, 3 were incorporated into the ACR's Rheumatology Informatics System for Effectiveness (RISE) Registry, and 2 were endorsed by the National Quality Forum. The 3 eCQMs incorporated into RISE (evaluating indications for urate-lowering therapy [ULT]), monitoring serum urate, and treat-to-target outcome) demonstrated high validity and reliability. Proportions of patients passing these 3 eCQMs in RISE and at the 3 clinical testing sites ranged between 32% and 58%, indicating significant room for improvement in care. CONCLUSION: Three eCQMs have been validated and implemented into RISE. Two of these measures (evaluating indications for ULT and monitoring serum urate) are available for use in federal quality reporting programs. Performance on these measures suggests there is significant room for improvement in the management of gout.