Clinical Significance of the Immunohistochemical Expression of Histone Deacetylases (HDACs)-2, -4, and -5 in Ovarian Adenocarcinomas.

BACKGROUND: Histone deacetylases (HDACs) are implicated in carcinogenesis, and HDAC inhibitors (HDACis) are explored as a therapeutic tool in several tumors. The aim of this study was to evaluate the clinical significance of HDAC-2, -4, and -5 expression in epithelial ovarian carcinoma (EOC). METHODS: HDAC-2, -4, and -5 immunohistochemical expression was examined in 92 EOC tissue specimens and was correlated with clinicopathological characteristics. RESULTS: HDAC-2 was the most frequently (94.4%) expressed isoform, being marginally higher in serous tumors compared with other types (p = 0.08). HDAC-5 was the less frequently expressed (28.1%), being positively associated with HDAC-4. HDAC-4 positivity was associated with lower FIGO-stage (p = 0.045) and T-category (p = 0.043) and the absence of lymph node (p = 0.05) or distant metastasis (p = 0.09) in serous carcinomas. HDAC-2 positivity was correlated with the absence of lymph node metastasis in serous tumors (p = 0.045). On the contrary, HDAC-5 nuclear positivity was correlated with lymph node metastasis in the entire cohort (p = 0.048). HDAC-4 positivity was marginally associated with favorable prognosis in serous carcinomas in univariate survival analysis (p = 0.086), but this correlation was not significant in multivariate analysis. CONCLUSIONS: These findings suggest a differential expression among HDAC-2, -4, and -5 in ovarian adenocarcinomas in terms of immunolocalization, positivity rate, and associations with clinicopathological parameters, providing evidence for a potential role in the pathobiology of EOC.

Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis.

BACKGROUND: Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. OBJECTIVE: To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. METHODS: This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged ≥ 18 and < 90 years from an integrated health care delivery system. Patients were newly initiated on adalimumab (ADA), etanercept (ETN), or infliximab (IFX) as index biologic therapy between July 1, 2006, and February 28, 2014. Outlier status was defined as a patient having received at least 1 dose < 90% or > 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. RESULTS: This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (≈75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low-dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). CONCLUSIONS: Approximately 1 in 10 study patients with RA was identified as a biologic-dosing outlier. Dosing outliers did not appear to have better clinical outcomes compared with nonoutliers. Before initiating outlier biologic dosing, health care providers may better serve their RA patients by prescribing alternate DMARD therapy. DISCLOSURES: This study was sponsored by Janssen Scientific Affairs. It is the policy of Janssen Scientific Affairs to publish all sponsored studies unless they are exploratory studies or are determined a priori for internal use only (e.g., to inform business decisions). Meyer is an employee of Janssen Scientific Affairs and a stockholder in Johnson and Johnson, its parent company. Delate and Jenkins have nothing to disclose. Study concept and design were contributed by Delate and Meyer. Delate took the lead in data collection, along with Jenkins. All authors participated in data analysis. The manuscript was written primarily by Delate, along with Meyers and Jenkins, and was revised by Meyer, along with Delate and Jenkins.

Assessment of Rheumatoid Arthritis Quality Process Measures and Associated Costs.

The objective was to examine the relationship between health care costs and quality in rheumatoid arthritis (RA). Administrative claims were used to calculate 8 process measures for the treatment of RA. Associated health care costs were calculated for members who achieved or did not achieve each of the measures. Medical, pharmacy, and laboratory claims for RA patients (International Classification of Diseases, Ninth Revision, Clinical Modification 714.x) were extracted from the Optum Clinformatics Datamart database for 2011. Individuals were predominately female and in their mid-fifties. Measure achievement ranged from 55.9% to 80.8%. The mean cost of care for members meeting the measure was $18,644; members who did not meet the measures had a mean cost of $14,973. Primary cost drivers were pharmacy and office expenses, accounting for 42.4% and 26.3% of total costs, respectively. Regression analyses revealed statistically significant associations between biologic usage, which was more prevalent in groups attaining measures, and total expenditure across all measures (Ps < 0.001). Pharmacy costs were similar between both groups. Individuals meeting the measures had a higher proportion of costs accounted for by office visits; those not meeting the measures had a higher proportion of costs from inpatient and outpatient visits. These findings suggest that increased quality may lead to lower inpatient and outpatient hospital costs. Yet, the overall cost of RA care is likely to remain high because of intensive pharmacotherapy regimens.

An Assessment of the AGA and CCFA Quality Indicators in a Sample of Patients Diagnosed with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic relapsing disease characterized by activation of the mucosal immune system and inflammation of the gastrointestinal tract. Management of IBD places a significant burden on the health care system because of the complexity of treatment, variability in patient outcomes, and chronic nature of the disease.  OBJECTIVE: To investigate the American Gastroenterological Association (AGA) and Crohn's and Colitis Foundation of America's (CCFA) quality measurement sets in a sample of IBD patients. METHODS: Fourteen quality measures were restated for application to a claims database and calculated using Optum Clinformatics DataMart database. Selected measures were calculated over calendar year 2011. RESULTS: Performance measures ranged from 0.4% for AGA measure 9, prophylaxis for venous thromboembolism, to 66.9% for AGA measure 8, testing for Clostridium difficile. CCFA outcome measures ranged from 0.6% qualifying for CCFA O10, report of fecal incontinence, to 32.9% for CCFA O1, prednisone usage. In addition to Clostridium difficile testing, the use of appropriate corticosteroid-sparing therapy (51.1%) and testing for latent tuberculosis before initiating anti-tumor necrosis factor therapy (45.0%) were the highest achieved measures. CONCLUSIONS: This is the first examination of IBD quality measures using administrative claims. Rates of achievement across measures were variable and likely affected by the ability to calculate certain measures with claims data. Future studies should further examine measurement of IBD quality indicators in claims data to assess the validity of claims-based analyses and to ascertain whether measure attainment translates into better overall health or IBD-related outcomes.

Prescribing Patterns of Intravenous Golimumab for Rheumatoid Arthritis.

PURPOSE: The use of intravenous golimumab (GLM-IV), in combination with methotrexate, was approved by the US Food and Drug Administration in July 2013 for the treatment of moderate to severe, active rheumatoid arthritis (RA). GLM-IV is available in 50-mg vials, and the prescribing information specifies a dosing regimen of 2 mg/kg at 0 and 4 weeks and then every 8 weeks thereafter. The purpose of this study was to examine the patterns of prescribing and administration of GLM-IV, including the demographic, clinical, and utilization characteristics of patients with RA newly treated with GLM-IV. METHODS: Rheumatology practices across the continental United States were solicited for a chart-review study. Inclusion criteria were: (1) diagnosis of RA; (2) current treatment with GLM-IV; (3) age ≥18 years; and (4) lack of pregnancy (in female patients). Physicians were offered a monetary incentive for each eligible chart provided. An electronic case-report form was developed to aid in the chart data extraction and included fields for demographic characteristics, available comorbid diagnoses, prior RA treatments, and doses and dates of GLM-IV administration. FINDINGS: A total of 117 eligible patient charts from 15 rheumatologist practices were reviewed. The patient sample was predominantly female (81.2%), with a mean (SD) age of 55.4 (14.5) years. A total of 55.6% of patients had evidence of biologic treatment before receiving GLM-IV, and 53% had at least 1 comorbid condition. In total, 300 individual GLM-IV infusions from this sample were reviewed. Due to the relatively recent approval of GLM-IV use by the US Food and Drug Administration, the majority of patients in this sample (69.2%) had received only between 2 and 4 infusions at the time of the review. For infusion records with valid dose data, the mean number of administered vials was 3.6 (0.8) (total dose, 180 mg); the majority of patients received a dose consistent with the prescribed dose of 2 mg/kg. Combination therapy with methotrexate was observed in the charts of a minority of patients (27.4%). The mean interval between induction and the first follow-up infusion was 32.9 (11.4) days, with a mean maintenance interval of 56.5 (13.3) days. IMPLICATIONS: This analysis provides an early glimpse of the patterns of prescribing GLM-IV. Overall, patients appeared to have been receiving GLM-IV in accordance with Food and Drug Administration labeling; although the rate of prescribing methotrexate was low, dosages and administration intervals were within the expected ranges.

Quality process measures for rheumatoid arthritis: performance from members enrolled in a national health plan.

BACKGROUND: Health care quality problems are reflected in the underuse, overuse, and misuse of health care services. There is evidence suggesting that the quality of rheumatoid arthritis (RA) patient care is suboptimal, which has spurred the development of a number of systematic quality improvement metrics. OBJECTIVE: To investigate a quality process measurement set in a sample of commercially insured RA patients. METHODS: Medical, pharmacy, and laboratory claims for members with an RA diagnosis (ICD-9-CM 714.x) during calendar years 2008 through 2012 were extracted from the Optum Clinformatics Data Mart database. Eight process quality measures focused on RA patient response and tolerance to therapy were examined in the claims database. Measures were calculated for individual calendar years from 2009 to 2012, inclusive. RESULTS: The majority of adult RA patients received at least 1 prescription for a disease-modifying antirheumatic drug (DMARD) across the 4 measurement years: range = 78.5%-81.6%. Erythrocyte sedimentation rate and C-reactive protein testing were also evident in the majority of the sample, with 67.1%-72.2% of newly diagnosed RA patients receiving baseline testing, and 56.0%-58.7% of existing RA patients receiving annual testing. Among methotrexate users, liver function tests were performed in 74.5%-75.7% of treated patients, serum creatinine tests in 70.1%-72.6% of patients, and complete blood count tests in 74.5%-76.0% of patients. Additionally, most patients initiating a new DMARD had a claim for a baseline serum creatinine test (68.0%-70.3%) and baseline liver function test (69.3%-71.0%). CONCLUSIONS: Findings suggest that a majority of RA patients are attaining patient quality process measures, although a considerable proportion of patients (approximately 25%) may be receiving suboptimal care. Further studies are warranted to understand whether attainment of these measures translates into better outcomes.

Novel Adherence Measures for Infusible Therapeutic Agents Indicated for Rheumatoid Arthritis.

BACKGROUND: Published studies on adherence to biologic medications show that many types of calculation methods are used. However, infused biologics are not well-suited to typical measures of adherence, such as proportion of days covered. OBJECTIVE: To construct and assess 7 novel adherence measures potentially applicable to infusible biologic agents and compare outcomes for 2 infusible biologics used for the treatment of patients with rheumatoid arthritis (RA). METHODS: Adults (aged ≥18 years) diagnosed with RA (ie, 2 or more 714.x claims) who received ≥24 months of continuous medical and pharmacy eligibility and who started taking abatacept or infliximab therapy were selected from a large commercial insurer database of medical and pharmacy claims. The 7 new adherence measures included cumulative amount of time with a refill gap ≥20% (CG20) beyond the expected infusion interval, cumulative time off treatment, days of uninterrupted use (DoUU), observed versus expected refill ratio (OvERR), repeated observations of underuse (RoUU), variance in time between infusions, and time to discontinuation (TTD). Mean observed infusion intervals were calculated and served as a reference measure of adherence. RESULTS: The mean maintenance intervals approximated recommended guidelines. The mean observed infusion interval for abatacept recipients was 33 days (recommended, 28 days); it was 53 days (recommended, 56 days) for patients receiving infliximab. Three measures demonstrated a significant positive relationship to the mean observed infusion interval-CG20 (r = .258), DoUU (r = .212), and TTD (r = .081; P <.05). OvERR (r = -.072) and RoUU (r = -.189; P <.05) showed significant negative correlations. Real-world comparisons showed that adherence was significantly (P <.001) greater for the infliximab group according to most measures. CONCLUSION: New measures of adherence correlate significantly with mean maintenance intervals. Future studies should examine relationships between these adherence measures and clinically relevant end points and/or cost outcomes to determine their predictive utility. Alternative methods of reporting adherence may have greater clinical significance than traditional measures.

Prescription opioid abuse: a literature review of the clinical and economic burden in the United States.

Between 2002 and 2007, the nonmedical use of prescription pain relievers grew from 11.0 million to 12.5 million people in the United States. Societal costs attributable to prescription opioid abuse were estimated at $55.7 billion in 2007. The purpose of this study was to comprehensively review the recent clinical and economic evaluations of prescription opioid abuse. A comprehensive literature search was conducted for studies published from 2002 to 2012. Articles were included if they were original research studies in English that reported the clinical and economic burden associated with prescription opioid abuse. A total of 23 studies (183 unique citations identified, 54 articles subjected to full text review) were included in this review and analysis. Findings from the review demonstrated that rates of opioid overdose-related deaths ranged from 5528 deaths in 2002 to 14,800 in 2008. Furthermore, overdose reportedly results in 830,652 years of potential life lost before age 65. Opioid abusers were generally more likely to utilize medical services, such as emergency department, physician outpatient visits, and inpatient hospital stays, relative to non-abusers. When compared to a matched control group (non-abusers), mean annual excess health care costs for opioid abusers with private insurance ranged from $14,054 to $20,546. Similarly, the mean annual excess health care costs for opioid abusers with Medicaid ranged from $5874 to $15,183. The issue of opioid abuse has significant clinical and economic consequences for patients, health care providers, commercial and government payers, and society as a whole.

Utilization and adherence patterns of subcutaneously administered anti-tumor necrosis factor treatment among rheumatoid arthritis patients.

BACKGROUND: Adherence to therapy is a key requirement underlying achievement of clinical outcomes in randomized controlled drug registration trials. In postmarketing studies, comparison of adherence among therapies can become more complicated when drug dosing and administration schedules differ or when methods used to measure adherence are not consistently applied. OBJECTIVE: The objective of this exploratory study was to investigate a broad range of utilization and adherence outcomes associated with subcutaneous biologic treatments for rheumatoid arthritis (RA). METHODS: Adult patients (aged ≥18 years) exhibiting ≥2 claims with an RA diagnosis (code 714.x), at least 24 months of continuous medical and pharmacy eligibility, and 30-day supplies of adalimumab, etanercept, or golimumab were selected from the Optum Insight Clinformatics database. Adherence and utilization measures were calculated and compared across treatment groups. RESULTS: A total of 1532 adalimumab, 2099 etanercept, and 261 golimumab patients met inclusion criteria. Compared with both adalimumab and etanercept patients, golimumab patients were significantly more likely to have a medication possession ratio of ≥0.80 (82% vs 71% vs 62%; P < 0.001) and significantly less likely to have ≥4 late medication refills (6.9% vs 17.7% vs 26.1%; P < 0.001 for all). Etanercept patients had significantly greater refill intervals (37.7 vs 34.9 and 35.1 days) and had the lowest proportion of adherent fills (70% vs 77% and 75%) compared with both golimumab and adalimumab patients (P < 0.001 for all). Bivariate effects were reproduced in multivariate models that controlled for treatment duration. CONCLUSIONS: A number of statistically significant medication adherence differences were observed among golimumab, adalimumab, and etanercept patients in treatment for RA. Overall, golimumab patients appeared to be the most adherent group. Findings may be partially attributable to golimumab patients' likely increased disease severity, their prior experience with biologic medication, or golimumab's once-monthly dosing schedule, which requires fewer administrations than both adalimumab and etanercept.

Opioid utilization patterns among medicare patients with diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) affects a large percentage of patients with type 2 diabetes and is associated with moderate-to-severe pain. Patients with DPN bear a substantial economic burden as a result of increased overall healthcare utilization. The reported costs of treating DPN are nearly $11 billion, with elderly (aged ≥65 years) patients with type 2 diabetes accounting for 93.1% ($10.2 billion) of the total costs. OBJECTIVES: To describe the real-world utilization patterns of long-acting opioids (LAOs) and chronic short-acting opioids (SAOs) use in a sample of Medicare enrollees (aged ≥65 years) with painful DPN, and to identify potential areas for improvement in the management of elderly patients with painful DPN who are treated with opioids. METHODS: In this retrospective pharmacy claims analysis, the Chronic Opioid Medication Use Evaluation (MUE) software was used to import and analyze individual plan, retrospective pharmacy utilization claims data from the MarketScan claims databases. Patients aged ≥65 years who had painful DPN as identified by ≥2 International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for painful DPN (250.6X or 357.2) in at least 2 quarters in 2009, and who had ≥1 claims for LAO and/or chronic use of SAO (≥60 days of continuous therapy), were selected for analysis. Pharmacy claim data were extracted for 12 months, and various opioid utilization measures were reported. RESULTS: A total of 1448 unique Medicare patients with painful DPN were identified who had 11,740 claims for an LAO and/or chronic use of an SAO. Of the 1448 patients, 62% had chronic use of an SAO, and of these, 89% had no concurrent claim for LAO (minimum, 60-day overlap). The most frequently filled LAOs were fentanyl transdermal (38%), oxycodone controlled release (CR; 26%), and morphine CR/extended release (ER)/sustained release (SR; 20%). The daily average consumptions for fentanyl transdermal, oxycodone CR, and morphine CR/ER/SR were 0.3, 2.5, and 2.4, respectively. Among the study population, 15.2% of the patients filled an LAO or SAO prescription at ≥2 pharmacies. Furthermore, these elderly patients with painful DPN used greater doses of LAOs than what is recommended in the package insert, and 1.6% of patients used high doses of acetaminophen and 15.2% utilized multiple pharmacies to obtain their opioid prescriptions. Moreover, this population had prevalent concomitant use of opioids and prescribed gastrointestinal (GI) medications. CONCLUSION: Results from our retrospective pharmacy claims analysis demonstrated that elderly patients with painful DPN use doses of LAOs above those recommended in the package insert, with some patients using high doses of acetaminophen and utilizing multiple pharmacies to obtain their opioid prescriptions. In addition, this population had prevalent concomitant use of opioids and prescription GI medications. The use of software, such as the Opioid MUE, to monitor opioid drug utilization trends and examine other utilization measures can assist healthcare decision makers and payers in their utilization reviews to appropriately manage this population.