Reduced risk of mortality associated with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment and Registry (PSOLAR): A nested case-control analysis.

BACKGROUND: The effects of systemic therapy on mortality risk among patients with psoriasis are not fully understood. OBJECTIVE: To evaluate the impact of systemic treatment on mortality risk in patients enrolled in the Psoriasis Longitudinal Assessment and Registry. METHODS: Nested case-control analyses were performed to estimate mortality risk. Cases were defined as patients who died while participating in the Psoriasis Longitudinal Assessment and Registry. Cases were matched (1:4) with controls by age, race, sex, and geographic region. Evaluated treatments included methotrexate, ustekinumab, and tumor necrosis factor α inhibitors. Exposure was defined as at least 1 dose of treatment within 3 months before death and was stratified by duration of therapy. RESULTS: Among 12,090 patients, 341 deaths occurred, matched to 1364 controls. Biologic treatment within the preceding 3 months was protective against mortality versus no exposure: odds ratio (OR) for exposure of less than 1 year, 0.08 (95% confidence interval [CI], 0.03-0.23); OR for exposure of 1 year or longer, 0.09 (95% CI, 0.06-0.13). Methotrexate was protective against mortality only with exposure for 1 year or longer (OR, 0.08; 95% CI, 0.02-0.28). LIMITATIONS: Observational studies are subject to unmeasured confounding. CONCLUSIONS: Biologic therapy was associated with reduced mortality risk in patients with moderate to severe psoriasis, regardless of treatment duration; methotrexate reduced risk only with exposure for 1 year or longer.

Biological treatment for psoriasis and the risk of herpes zoster: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Purpose: To describe the risk of herpes zoster (HZ) in patients with psoriasis and its relation to non-biologic systemic therapies or biologic treatment. Materials and methods: Psoriasis Longitudinal Assessment and Registry (PSOLAR) is an international, prospective, registry that follows adult patients with psoriasis eligible to receive non-biologic systemic therapies or biologic therapies. Mutually exclusive therapy cohorts were defined. HZ incident rates were calculated for each therapy cohort and rates between cohorts were compared using hazard ratios (HR) adjusted for potential confounders, in new users and prevalent-exposure patients. Results: A total of 55 HZ events were identified in 10,469 patients in PSOLAR. The adjusted hazard ratio in the overall study population (new user and prevalent-exposed patients) was 2.22 (95% CI: 0.82-5.97; p = .116) for tumor necrosis factor-α (TNF) inhibitors, 2.73 (0.98-7.58; p = .054) for ustekinumab, and 1.04 (0.20-5.41; p = .966) for methotrexate versus reference (combined phototherapy, systemic steroids, topical therapy, and immunomodulators other than methotrexate). Conclusions: Exposure to ustekinumab, TNF-α inhibitors, and methotrexate was not associated with a statistically significant increased risk of HZ. However, HRs were elevated for ustekinumab and TNF-α inhibitors; a larger number of HZ events would be needed to assess the presence or absence of risk.

Evaluation of Risk of Major Adverse Cardiovascular Events With Biologic Therapy in Patients With Psoriasis.

BACKGROUND: Psoriasis is associated with increased risk of major adverse cardiovascular events (MACE). OBJECTIVES: Compare MACE risk with biologics vs topical/phototherapy use. METHODS: Psoriasis Longitudinal Assessment Registry (PSOLAR) is an international psoriasis registry of patients eligible to receive biologic/systemic treatments prospectively. MACE is defined as myocardial infarction, stroke, or cardiovascular death. Biologic cohorts, including tumor necrosis factor-alpha (TNF-α) inhibitors (ie, adalimumab, etanercept, and infliximab) and ustekinumab, combined and by class, were compared with a topical/phototherapy cohort. Incidence rates of MACE per 100-patient-years (100PY) with 95% confidence intervals (95% CI) are reported. Multivariate analyses were performed to evaluate the effect of treatment on the risk of MACE adjusting for confounders. RESULTS: Analyses included 7550 patients: 6767 in the combined biologics cohort (3949 and 2818 in the TNF-α inhibitors and ustekinumab cohorts, respectively) and 783 in the topical/phototherapy cohort. Mean duration of exposure was approximately 2.8 years (combined biologics) and 4.1 years (topical/phototherapy). A total of 52 MACE were reported; MACE incidence rates were 0.22/100PY (95% CI: 0.16, 0.30) for the combined biologics cohort (TNF-α inhibitors [0.20/100PY (0.12, 0.31)] and ustekinumab [0.24/100PY (0.15, 0.37]) and 0.34/100PY (0.17, 0.61) for the topical/phototherapy cohort. For the combined biologics (hazard ratio=0.92; 95% CI [0.426, 1.988]), TNF-α inhibitor (0.85 [0.373, 1.928]), and ustekinumab (1.03[0.440, 2.402]) cohorts, treatment was not associated with increased risk of MACE versus the topical/phototherapy cohort. CONCLUSION: Based on data accumulated to date in PSOLAR, treatment with biologics did not have an impact on the risk of MACE in patients with moderate-to-severe psoriasis.

J Drugs Dermatol. 2017;16 (10):1002-1013.

Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry.

BACKGROUND: The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood. OBJECTIVE: Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: Nested case-control analyses were performed among patients with no history of malignancy. Cases were defined as first malignancy (other than nonmelanoma skin cancer) in the Psoriasis Longitudinal Assessment and Registry, and controls were matched by age, sex, geographic region, and time on registry. Study therapies included methotrexate, ustekinumab, and tumor necrosis factor-α (TNF-α) inhibitors. Exposure was defined as 1 or more doses of study therapy within 12 months of malignancy onset and further stratified by duration of therapy. Multivariate conditional logistic regression, adjusted for potential confounders, was used to estimate odds ratios of malignancies associated with therapy. RESULTS: Among 12,090 patients, 252 malignancy cases were identified and 1008 controls were matched. Treatment with methotrexate or ustekinumab for more than 0 months to less than 3 months, 3 months to less than 12 months, or 12 months or longer was not associated with increased malignancy risk versus no exposure. Longer-term (≥12 months) (odds ratio, 1.54; 95% confidence interval, 1.10-2.15; P = .01), but not shorter-term treatment, with a TNF-α inhibitor was associated with increased malignancy risk. LIMITATIONS: Cases and controls could belong to 1 or more therapy categories. CONCLUSIONS: Long-term (≥12 months) treatment with a TNF-α inhibitor, but not methotrexate and ustekinumab, may increase risk for malignancy in patients with psoriasis.

Comparative effectiveness of biologic agents for the treatment of psoriasis in a real-world setting: Results from a large, prospective, observational study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]).

BACKGROUND: Comparing effectiveness of biologics in real-world settings will help inform treatment decisions. OBJECTIVES: We sought to compare therapeutic responses among patients initiating infliximab, adalimumab, or etanercept versus ustekinumab during the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: Proportions of patients achieving a Physician Global Assessment score of clear (0)/minimal (1) and mean decrease in percentage of body surface area with psoriasis were evaluated at 6 and 12 months. Adjusted logistic regression (Physician Global Assessment score 0/1) and analysis of covariance (percentage of body surface area with psoriasis) were performed to determine treatment factors associated with effectiveness. RESULTS: Of 2541 new users on registry, 2076 had efficacy data: ustekinumab (n = 1041), infliximab (n = 116), adalimumab (n = 662), and etanercept (n = 257). Patients receiving tumor necrosis factor-alpha(-α) inhibitors were significantly less likely to achieve Physician Global Assessment score 0/1 versus ustekinumab (infliximab [odds ratio {OR} 0.396, P < .0001], adalimumab [OR 0.686, P = .0012], etanercept [OR 0.554, P = .0003] at 6 months and infliximab [OR 0.449, P = .0040] at 12 months). Mean decrease in percentage of body surface area with psoriasis was significantly greater for ustekinumab versus adalimumab (point estimate 1.833, P = .0020) and etanercept (point estimate 3.419, P < .0001) at 6 months and versus infliximab (point estimate 3.945, P = .0005) and etanercept (point estimate 2.778, P = .0007) at 12 months. LIMITATIONS: Treatment selection bias and limited data for doing adjustments are limitations. CONCLUSIONS: In PSOLAR, effectiveness of ustekinumab was significantly better versus all 3 tumor necrosis factor-α inhibitors studied for the majority of comparisons at 6 and 12 months.

Safety Surveillance for Ustekinumab and Other Psoriasis Treatments From the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

BACKGROUND: Safety surveillance is needed for biologic therapies for psoriasis. OBJECTIVE: To assess the risk of adverse events of special interest (AEoSIs) with ustekinumab and other psoriasis treatments in a real-world setting using 2014 Psoriasis Longitudinal Assessment and Registry (PSOLAR) data. AEoSIs included malignancy (excluding nonmelanoma skin cancer), major adverse cardiovascular events (MACE), serious infection, and all-cause mortality. METHODS: Cumulative rates of AEoSIs/100 patient-years (PY) are reported for ustekinumab, infliximab, other biologics (mostly adalimumab/etanercept), and non-biologics based on pre-specified analyses using attribution rules biased against ustekinumab. Risk factors for AEoSIs, including treatments, were determined using multivariate statistical analysis. RESULTS: A total of 12,093 patients (40,388 PY) were enrolled in PSOLAR. Overall incidence rates were 0.68/100PY for malignancy, 0.33/100PY for MACE, 1.60/100PY for serious infection, and 0.46/100PY for mortality. Unadjusted rates of serious infection for infliximab (2.91/100PY) and other biologics (1.91/100PY) were numerically higher compared with ustekinumab (0.93/100PY). Exposure to the combined group of biologics other than ustekinumab was significantly associated with serious infection (hazard ratio=1.96, P<.001). None of the biologics was associated with increased risk of malignancy, MACE, or mortality. LIMITATIONS: Observational data have inherent biases. CONCLUSION: Analysis of 2014 PSOLAR data identified no increased risk of malignancy, MACE, serious infection, or mortality with ustekinumab.

Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis: Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

IMPORTANCE: The efficacy of treatment for psoriasis must be balanced against potential adverse events. OBJECTIVE: To determine the effect of treatment on the risk of serious infections in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, longitudinal, disease-based registry (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) at dermatology centers. Participants were adult patients with psoriasis who were receiving or were eligible to receive conventional systemic or biologic agents. The registry opened on June 20, 2007, and data included herein were collected through August 23, 2013. EXPOSURES: Patients were prescribed psoriasis therapies as in standard clinical practice. Patients will be followed for up to 8 years. Data were collected and serious adverse events (including serious infections) were assessed at regular intervals. MAIN OUTCOMES AND MEASURES: Cohort characteristics are described based on evaluation at entry into the registry. The cumulative incidence rates of serious infections are reported across treatment cohorts, including ustekinumab, infliximab, adalimumab, etanercept, and nonbiologics (with or without methotrexate). A multivariate analysis using a Cox proportional hazards regression model was used to identify predictors of the time to the first serious infection using the nonmethotrexate/nonbiologics cohort as the reference. RESULTS: Data were analyzed from 11,466 patients with psoriasis (22,311 patient-years). Differences in patient characteristics were found between the biologics and nonmethotrexate/nonbiologics cohorts (eg, age, sex, body mass index, and disease characteristics), as well as among the individual biologic groups (eg, a higher prevalence of psoriatic arthritis in the infliximab cohort). The cumulative incidence rate of serious infections was 1.45 per 100 patient-years (n = 323) across treatment cohorts, and the rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient-years in the ustekinumab, etanercept, adalimumab, and infliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient-years in the nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts, respectively. The most commonly reported types of serious infections across the registry were pneumonia and cellulitis. Increasing age, diabetes mellitus, smoking, significant infection history, infliximab exposure, and adalimumab exposure were each associated with an increased risk of serious infection. CONCLUSIONS AND RELEVANCE: Results from PSOLAR suggest a higher risk of serious infections with adalimumab and infliximab compared with nonmethotrexate and nonbiologic therapies. No increased risk was observed with ustekinumab or etanercept. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00508547.

Safety observations in 12095 patients with psoriasis enrolled in an international registry (PSOLAR): experience with infliximab and other systemic and biologic therapies.

BACKGROUND: Long-term data are essential to assess the safety of biologic agents for the treatment of psoriasis. OBJECTIVE: To evaluate the incidence of adverse events of interest (AEIs), including all-cause mortality, major adverse cardiovascular events (MACE), malignancy (excluding nonmelanoma skin cancer), and serious infections (SI), in patients treated for psoriasis in clinical practice settings. METHODS: PSOLAR is a large, ongoing, observational study of patients receiving, or eligible to receive, biologic or systemic therapy for psoriasis. Cumulative incidence rates of AEIs per 100 patient-years (PY) are reported across treatment cohorts: (1) infliximab, (2) ustekinumab, (3) other biologics (eg, adalimumab and etanercept), and (4) non-biologic agents. Significant predictors of each AEI were identified using Cox proportional hazards regression methodology. RESULTS: PSOLAR is now fully enrolled at 12095 patients followed for 31818PY. The cumulative rate was 0.46/100PY for death, 0.36/100PY for MACE, 0.68/100PY for malignancy, and 1.50/100PY for SI. Increasing age was a significant predictor of all AEIs. A history of cardiovascular disease, malignancy, and significant infection was associated with a higher risk of developing MACE, malignancy, and SI, respectively. Exposure to infliximab (Hazard Ratio [HR]=3.101, P<0.001) and exposure to other biologics (HR=1.736, P<0.001) were significant predictors of SI. Use of immunomodulators (HR=1.954, P=0.005) was a significant predictor of MACE. Compared with non-biologic therapy, the use of biologic agents was not a significant predictor of death, MACE, or malignancy. CONCLUSIONS: Based on PSOLAR data through 2013, no new safety concerns were observed with infliximab for all-cause mortality, MACE, or malignancy; the data suggest that infliximab was associated with serious infections.

Volatile biomarkers from human melanoma cells.

Dogs can identify, by olfaction, melanoma on the skin of patients or melanoma samples hidden on healthy subjects, suggesting that volatile organic compounds (VOCs) from melanoma differ from those of normal skin. Studies employing gas chromatography-mass spectrometry (GC-MS) and gas sensors reported that melanoma-related VOCs differed from VOCs from normal skin sources. However, the identities of the VOCs that discriminate melanoma from normal skin were either unknown or likely derived from exogenous sources. We employed solid-phase micro-extraction, GC-MS and single-stranded DNA-coated nanotube (DNACNT) sensors to examine VOCs from melanoma and normal melanocytes. GC-MS revealed dozens of VOCs, but further analyses focused on compounds most likely of endogenous origin. Several compounds differed between cancer and normal cells, e.g., isoamyl alcohol was higher in melanoma cells than in normal melanocytes but isovaleric acid was lower in melanoma cells. These two compounds share the same precursor, viz., leucine. Melanoma cells produce dimethyldi- and trisulfide, compounds not detected in VOCs from normal melanocytes. Furthermore, analyses of the total volatile metabolome from both melanoma cells and normal melanocytes by DNACNT sensors, coupled with the GC-MS results, demonstrate clear differences between these cell systems. Consequently, monitoring of melanoma VOCs has potential as a useful screening methodology.

Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials.

BACKGROUND: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. OBJECTIVE: We sought to evaluate the impact of ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. METHODS: Rates of infections and malignancies were evaluated in cumulative safety data from 3117 ustekinumab-treated patients across 4 studies. RESULTS: During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45-mg (145.7), and ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. LIMITATIONS: Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. CONCLUSIONS: The emerging safety profile of ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years.

Characterization CSMD1 in a large set of primary lung, head and neck, breast and skin cancer tissues.

The Cub and Sushi Multiple Domains-1 (CSMD1) is a tumor suppressor gene on 8p23.2, where allelic loss is both frequent and associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). To understand the extent of CSMD1 aberrations in vivo, we characterized 184 primary tumors from the head and neck, lung, breast and skin for gene copy number and analyzed expression in our HNSCCs and lung squamous cell carcinomas (SCCs). We detected loss of CSMD1 in a large proportion of HNSCCs (50%), lung (46%) and breast cancers (55%), and to a lesser extent in cutaneous SCCs (29%) and basal cell carcinomas (BCCs, 17%) using array-based comparative genomic hybridization (aCGH). Studying the region more closely with quantitative real-time PCR (qPCR), the loss of CSMD1 increased to 80% in HNSCCs and 93% in lung SCCs. CSMD1 expression was decreased in tumors compared to adjacent benign tissue (65%, 13/20) and was likely due to gene loss in 45% of cases (9/20). We also identified truncated transcripts lacking exons due to DNA copy number loss (30%, 5/17) or aberrant splicing (24%, 4/17). We show loss of CSMD1 in primary HNSCC tissues, and document for the first time that CSMD1 is lost in breast, lung and cutaneous SCCs. We also show that deletions of CSMD1 and aberrant splicing contribute to altered CSMD1 function in vivo.

Clinical and in vitro resistance to bexarotene in adult T-cell leukemia: loss of RXR-alpha receptor.

The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)-alpha2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor (RXR) subunits, RXR-alpha and RXR-beta, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-alpha and RXR-beta by resistant cells. We assessed RXR-alpha and RXR-beta expression by Western blot analysis and found that resistant cells had significantly decreased RXR-alpha expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-alpha receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.

Multiple eccrine poromas in the setting of total body irradiation and immunosuppression.

Eccrine poromas are benign, adnexal tumors that most often occur as a solitary lesion on the palm or sole. The occurrence of multiple eccrine poromas is extremely rare. In this report, we describe the development of several eccrine poromas in an acral distribution in a 42-year-old man. Before the appearance of these tumors, the patient had received total body irradiation and allogeneic bone marrow transplantation for treatment of acute lymphocytic leukemia. As a complication of the bone marrow transplant, the patient developed chronic graft-versus-host disease, which was treated with immunosuppressive therapy. We discuss this patient and review the available literature regarding multiple eccrine poromas.

Familial basaloid follicular hamartoma: lesional characterization and review of the literature.

Basaloid follicular hamartoma (BFH) is a rare cutaneous lesion associated with the acquisition of small papules that remain stable for many years. Basaloid follicular hamartoma lesions can present sporadically or as part of an inherited syndrome. Occasionally, biopsies of BFH lesions are interpreted as basal cell carcinoma (BCC), which necessitates complete removal of the lesion. In this report, we characterize a case of a familial BFH syndrome and discuss the clinical, histologic, and molecular features of BFH lesions that help to distinguish it from BCC. The BFH lesions in our patients remained stable for many years. Histologically, BFH lesions exhibit fewer mitoses and decreased single cell necrosis when compared with BCC. Immunohistochemical staining for the proliferation markers proliferating cell nuclear antigen and Ki-67 demonstrated less staining in BFH than in BCC. In addition, levels of PTCH (patched) mRNA were increased relative to unremarkable epidermis in familial BFH lesions but to a lesser degree and in a different pattern than that seen in BCC. In summary, familial BFH can be distinguished from BCC based on clinical, histologic, and molecular features and is associated with deregulation of the PTCH pathway. Basaloid follicular hamartoma may represent an indolent lesion within the spectrum of basaloid epithelial neoplasms associated with deregulation of the PTCH signaling pathway. We discuss this case in parallel with a growing body of literature that supports the nosologic designation of BFH.