Faculty Bibliography

BACKGROUND: Treatment satisfaction among patients with moderate-to-severe psoriasis has not been studied and compared across treatments using a validated instrument. OBJECTIVES: To assess patient-reported satisfaction with systemic and phototherapy treatments for moderate-to-severe psoriasis in clinical practice and to correlate satisfaction with disease severity and quality-of-life measures. METHODS: This was a cross-sectional study of 1182 patients with moderate-to-severe psoriasis in the Dermatology Clinical Effectiveness Research Network in the U.S.A. Patients receiving either topical therapies only; monotherapy with oral systemic therapies, biologics or narrowband ultraviolet B phototherapy; or combination therapy with biologics and methotrexate completed the Treatment Satisfaction Questionnaire for Medication version II. RESULTS: Median unadjusted overall satisfaction scores were highest for patients receiving biologic monotherapies, biologic-methotrexate combinations, or phototherapy (83.3); scores were lowest for those receiving topical therapies only or acitretin (66.7). In fully adjusted models, compared with patients receiving methotrexate monotherapy, those receiving adalimumab, etanercept, ustekinumab, phototherapy or adalimumab with methotrexate had significantly higher median overall satisfaction scores by 7.2-8.3 points, while those receiving topical therapies only had significantly lower overall satisfaction by 8.9 points. Adjusted convenience scores were lowest for patients receiving topical therapies only or infliximab. Modest but significant correlations were found between the overall satisfaction subscale and both the Psoriasis Area and Severity Index (rho = -0.36, P < 0.001) and the Dermatology Life Quality Index (rho = -0.47, P < 0.001). CONCLUSIONS: Discernible differences were found in treatment satisfaction among therapies, particularly regarding treatment effectiveness and convenience. Further application of treatment satisfaction measures may inform treatment decisions and guideline development.

BACKGROUND: Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. METHODS: A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m(2) loading, 250 mg/m(2) maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS: Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV(max)) for those treated initially with everolimus was -24% (2% to -54%), and with cetuximab was -5% (-23 to 36%). The K(trans) measured by DCE-MRI did not decrease, regardless of run-in drug. CONCLUSIONS: Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population.

BACKGROUND: There are conflicting reports in the literature of the mortality risk among patients with psoriatic arthritis (PsA). The objective of this study was to examine the risk of mortality in patients with PsA compared with matched controls, patients with psoriasis and those with rheumatoid arthritis (RA). METHODS: A longitudinal cohort study was performed in a large UK medical record database, The Health Improvement Network, among patients with PsA, rheumatoid arthritis (RA) or psoriasis with data from 1994 to 2010. Unexposed controls were matched on practice and start date within the practice for each patient with PsA. Cox proportional hazards models were used to calculate the relative hazards for death. RESULTS: Patients with PsA (N=8706), RA (N=41 752), psoriasis (N=138 424) and unexposed controls (N=82 258) were identified; 1 442 357 person-years were observed during which 21 825 deaths occurred. Compared with population controls, patients with PsA did not have an increased risk of mortality after adjusting for age and sex (disease-modifying antirheumatic drug (DMARD) users: HR 0.94, 95% CI 0.80 to 1.10; DMARD non-users: HR 1.06, 95% CI 0.94 to 1.19) whereas patients with RA had increased mortality (DMARD users: HR 1.59, 95% CI 1.52 to 1.66; DMARD non-users: HR 1.54, 95% CI 1.47 to 1.60). Patients with psoriasis who had not been prescribed a DMARD had a small increased risk of mortality (HR 1.08, 95% CI 1.04 to 1.12) while those who had been prescribed a DMARD, indicating severe psoriasis, were at increased risk (HR 1.75, 95% CI 1.56 to 1.95). CONCLUSIONS: Patients with RA and psoriasis have increased mortality compared with the general population but patients with PsA do not have a significantly increased risk of mortality.

Sezary syndrome (SS) cells express cell surface molecules also found on normal activated CD4 T cells. In an effort to find a more specific surface marker for malignant SS cells, a microarray analysis of gene expression was performed. Results showed significantly increased levels of mRNA for CD164, a sialomucin found on human CD34+ hematopoietic stem cells, and FCRL3, a molecule present on a subset of human natural T regulatory cells. Both markers were increased in CD4 T cells from SS patients compared with healthy donors (HD). Flow cytometry studies confirmed the increased expression of CD164 and FCRL3 primarily on CD4+CD26- T cells of SS patients. Importantly, a statistically significant correlation was found between an elevated percentage of CD4+CD164+ T cells and an elevated percentage of CD4+CD26- T cells in all tested SS patients but not in patients with mycosis fungoides and atopic dermatitis or HD. FCRL3 expression was significantly increased only in patients with high tumor burden. CD4+CD164+ cells displayed cerebriform morphology and their loss correlated with clinical improvement in treated patients. Our results suggest that CD164 can serve as a marker for diagnosis and for monitoring progression of cutaneous T-cell lymphoma (CTCL)/SS and that FCRL3 expression correlates with a high circulating tumor burden.

Early rehospitalization after kidney transplantation (KT) is common and may predict future adverse outcomes. Previous studies using claims data have been limited in identifying preventable rehospitalizations. We assembled a cohort of 753 adults at our institution undergoing KT from January 1, 2003 to December 31, 2007. Two physicians independently reviewed medical records of 237 patients (32%) with early rehospitalization and identified (1) primary reason for and (2) preventability of rehospitalization. Mortality and graft failure were ascertained through linkage to the Scientific Registry of Transplant Recipients. Leading reasons for rehospitalization included surgical complications (15%), rejection (14%), volume shifts (11%) and systemic and surgical wound infections (11% and 2.5%). Reviewer agreement on primary reason (85% of cases) was strong (kappa = 0.78). Only 19 rehospitalizations (8%) met preventability criteria. Using logistic regression, weekend discharge (odds ratio [OR] 1.59, p = 0.01), waitlist time (OR 1.10, p = 0.04) and longer initial length of stay (OR 1.42, p = 0.03) were associated with early rehospitalization. Using Cox regression, early rehospitalization was associated with mortality (hazard ratio [HR] 1.55; p = 0.03) but not graft loss (HR 1.33; p = 0.09). Early rehospitalization has diverse causes and presents challenges as a quality metric after KT. These results should be validated prospectively at multiple centers to identify vulnerable patients and modifiable processes-of-care.

PURPOSE: This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA). EXPERIMENTAL DESIGN: Twenty-two patients with chemotherapy-naive advanced PDA were treated with 1,000 mg/m(2) gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle. RESULTS: CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P = 0.007). CONCLUSIONS: CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.