Correction to: Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs.

In the original publication of this article, the following correction should be noted in Table 5.

Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs.

INTRODUCTION: Theoretical risks of biologic agents remain under study. OBJECTIVE: The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials. METHODS: Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]). RESULTS: Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications. CONCLUSIONS: Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.

Longitudinal Study of the Psoriasis-Associated Skin Microbiome during Therapy with Ustekinumab in a Randomized Phase 3b Clinical Trial.

Plaque psoriasis, a chronic inflammatory disease primarily affecting the skin, is thought to have a multifactorial etiology, including innate immune system dysregulation, environmental triggers, and genetic susceptibility. We sought to further understand the role of skin microbiota in psoriasis pathogenesis, as well as their response to therapy. We systematically analyzed dynamic microbiota colonizing psoriasis lesions and adjacent nonlesional skin in 114 patients prior to and during ustekinumab treatment in a phase 3b clinical trial. By sequencing the bacterial 16S ribosomal RNA gene from skin swab samples obtained at six anatomical sites, we identified minor, site-specific differences in microbial diversity and composition between pretreatment lesional and nonlesional skin. During therapy, microbial communities within lesional and nonlesional skin diverged, and body-site dispersion increased, reflecting microbial skin site-specificity. Microbiota demonstrated greater pretreatment heterogeneity in psoriatic lesions than in nonlesional skin, and variance increased as treatment progressed. Microbiota colonizing recurrent lesions did not overlap with pretreatment lesional microbiota, suggesting colonization patterns varied between initial and recurrent psoriatic lesions. While plaque psoriasis does not appear to be associated with specific microbes and/or microbial diversity, this large dataset provides insight into microbial variation associated with (i) disease in different body locations, (ii) initial versus recurrent lesions, and (iii) anti-IL12/23 therapy.

Demography, baseline disease characteristics, and treatment history of psoriasis patients with self-reported psoriatic arthritis enrolled in the PSOLAR registry.

BACKGROUND: To evaluate demographics, family history, and previous medication use at enrollment in a subset of psoriasis patients with self-reported psoriatic arthritis (PsA) enrolled in Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is an international, prospective, longitudinal, disease-based registry that collects data in patients receiving, or are eligible to receive, systemic or biologic treatments for psoriasis. Baseline demographic, disease characteristics, medical history, and prior medication use at enrollment were evaluated in PSOLAR psoriasis patients self-reporting PsA (n = 4315); a subset of which had their diagnosis of PsA established by a healthcare provider (HCP; n = 1719); patients with psoriasis only (n = 7775); and the overall PSOLAR population (n = 12,090). RESULTS: At enrollment, demographic characteristics were distinct between psoriasis patients self-reporting PsA and psoriasis only patients. Of the patients with psoriasis self-reporting PsA, 44.4% had cardiovascular disease (CVD), 26.3% had psychiatric illness, and 3.2% had inflammatory bowel disease (IBD), with each more prevalent than among patients with psoriasis only (p < 0.001). Overall, 17.5% of psoriasis patients self-reporting PsA had a family history of PsA, 29.8% had used systemic steroids, 39.5% had used nonsteroidal anti-inflammatory drugs, and 83.5% had used biologics. CONCLUSIONS: Demographics, family history, and previous medication use were generally comparable between "PsA established by a HCP" patients and psoriasis patients self-reporting PsA in the PSOLAR registry, but there were statistical differences compared with the psoriasis only group regarding the prevalence of certain comorbidities (CVD, psychiatric illness, and IBD). These analyses provide important data regarding characteristics of psoriasis patients with self-reported PsA in PSOLAR. TRIAL REGISTRATION: NCT00508547.

Patient Preference for Dosing Frequency Based on Prior Biologic Experience.

BACKGROUND: There is limited research exploring patient preferences regarding dosing frequency of biologic treatment of psoriasis. METHODS: Patients with moderate-to-severe plaque psoriasis identified in a healthcare claims database completed a survey regarding experience with psoriasis treatments and preferred dosing frequency. Survey questions regarding preferences were posed in two ways: (1) by likelihood of choosing once per week or 2 weeks, or 12 weeks; and (2) by choosing one option among once every 1-2 or 3-4 weeks or 1-2 or 2-3 months. Data were analyzed by prior biologic history (biologic-experienced vs biologic-naïve, and with one or two specific biologics). RESULTS: Overall, 426 patients completed the survey: 163 biologic-naïve patients and 263 biologic-experienced patients (159 had some experience with etanercept, 105 with adalimumab, and 49 with ustekinumab). Among patients who indicated experience with one or two biologics, data were available for 219 (30 with three biologics and 14 did not specify which biologic experience). The majority of biologic-naïve (68.8%) and overall biologic-experienced (69.4%) patients indicated that they were very likely to choose the least frequent dosing option of once every 12 weeks (Table 1). In contrast, fewer biologic-naïve (9.1% and 16.7%) and biologic-experienced (22.5% and 25.3%) patients indicated that they were very likely to choose the 1-week and 2-week dosing interval options, respectively. In each cohort grouped by experience with specific biologics, among those with no experience with ustekinumab, the most chosen option was 1-2 weeks. The most frequently chosen option was every 2-3 months, among patients with any experience with ustekinumab, regardless of their experience with other biologics. CONCLUSIONS: The least frequent dosing interval was preferred among biologic naïve patients and patients who had any experience with ustekinumab. Dosing interval may influence the shared decision-making process for psoriasis treatment with biologics.

J Drugs Dermatol. 2017;16(3):220-226.

A multicenter, non-interventional study to evaluate patient-reported experiences of living with psoriasis.

BACKGROUND: Moderate to severe plaque psoriasis (with or without psoriatic arthritis) places significant burden on patients' lives. OBJECTIVE: Explore and document patients' experiences of living with psoriasis, including symptoms, treatments, impact on daily lives and patient-reported functioning. METHODS: In a US-based, non-interventional study, narrative interviews were conducted at baseline and again within 16 weeks. In interviews, patients with moderate to severe psoriasis indicated symptoms, ranked symptoms according to level of bother and indicated areas of their lives affected by psoriasis. Transcripts of interviews were coded for themes. Measurements of psoriasis severity including BSA, PGA and PASI were recorded. RESULTS: Symptoms reported most frequently included flaking/scaling (non-scalp areas), itching/scratching and rash, while the most bothersome symptoms were itching/scratching, flaking/scaling (non-scalp areas) and skin pain. Frequently reported impact areas were social and emotional. CONCLUSION: Broad-reaching interviews with patients with psoriasis show that these patients suffer in many aspects of their lives and in ways not indicated by typical psoriasis severity measures. Patients with psoriatic arthritis reported symptoms and disease-related complications at higher rates than those without arthritis. Physicians' explorations of the effect of psoriasis on patients' life events could aid in managing these patients.

Patient-reported treatment satisfaction and choice of dosing frequency with biologic treatment for moderate to severe plaque psoriasis.

BACKGROUND: Moderate to severe plaque psoriasis has a serious effect on health-related quality of life. Patients treated with biologic medications place importance on satisfaction and treatment frequency options. We assessed patient-reported treatment satisfaction and dosing frequency choice with biologics. METHODS: We used a health care claims database to identify patients with moderate to severe plaque psoriasis. Participants completed the Treatment Satisfaction Questionnaire for Medication. Results were compared between patients experienced with biologics (adalimumab, etanercept, or ustekinumab) or not (cyclosporine or methotrexate). Participants were asked for their choices of dosing options of once every 1-2 weeks, 3-4 weeks, 1-2 months, or 2-3 months. Participants were also asked for their choices of dosing options of every 1, 2, 3, and so on up to every 12+ weeks. RESULTS: A total of 426 patients completed the survey (263 biologic-experienced and 163 biologic-naïve patients). Patient satisfaction with psoriasis treatment was significantly higher in the biologic-experienced cohort. The most frequently chosen option (38.8% of all participating patients) was every 2-3 months; 37.3% chose once every 1-2 weeks. Significant differences were found in the percentage of biologic-naïve patients choosing 2-3-month (49.7%) over 1-2-week (20.9%) dosing (P<0.001). Among biologic-experienced patients, the difference between the percentage of patients choosing the 2-3-month (35.7%) and 1-2-week (41.8%) options was not significant (P=0.264). The two most often week-specific intervals chosen by biologic-naïve patients were 12+ weeks (42.3%) and 4 weeks (15.6%). The biologic-experienced patients most often chose 12+ weeks (31.2%) and 1 week (25.9%). CONCLUSION: Patients using biologics reported satisfaction with their treatment, which may positively affect outcomes. Longer dosing intervals were chosen most frequently among all patients combined. Reports of patient satisfaction with prior treatments and choices regarding dosing frequency, among all other considerations, should be evaluated in determining an appropriate biologic medication for psoriasis.

Sporulation genes in members of the low G+C Gram-type-positive phylogenetic branch ( Firmicutes).

Endospore formation is a specific property found within bacteria belonging to the Gram-type-positive low G+C mol% branch ( Firmicutes) of a phylogenetic tree based on 16S rRNA genes. Within the Gram-type-positive bacteria, endospore-formers and species without observed spore formation are widely intermingled. In the present study, a previously reported experimental method (PCR and Southern hybridization assays) and analysis of genome sequences from 52 bacteria and archaea representing sporulating, non-spore-forming, and asporogenic species were used to distinguish non-spore-forming (void of the majority of sporulation-specific genes) from asporogenic (contain the majority of sporulation-specific genes) bacteria. Several sporulating species lacked sequences similar to those of Bacillus subtilis sporulation genes. For some of the genes thought to be sporulation specific, sequences with weak similarity were identified in non-spore-forming bacteria outside of the Gram-type-positive phylogenetic branch and in archaea, rendering these genes unsuitable for the intended classification into sporulating, asporogenic, and non-spore-forming species. The obtained results raise questions regarding the evolution of sporulation among the Firmicutes.

Detection of lateral gene transfer events in the prokaryotic tRNA synthetases by the ratios of evolutionary distances method.

The availability of large numbers of genomic sequences has demonstrated the importance of lateral gene transfer (LGT) in prokaryotic evolution. However, considerable uncertainty remains concerning the frequency of LGT compared to other evolutionary processes. To examine LGTs in ancient lineages of prokaryotes a method was developed that utilizes the ratios of evolutionary distances (RED) to distinguish between alternative evolutionary histories. The advantages of this approach are that the variability inherent in comparing protein sequences is transparent, the direction of LGT and the relative rates of evolution are readily identified, and it is possible to detect other types of evolutionary events. This method was standardized using 35 genes encoding ribosomal proteins that were believed to share a vertical evolution. Using RED-T, an original computer program designed to implement the RED method, the evolution of the genes encoding the 20 aminoacyl-tRNA synthetases was examined. Although LGTs were common in the evolution of the aminoacyl-tRNA synthetases, they were not sufficient to obscure the organismal phylogeny. Moreover, much of the apparent complexity of the gene tree was consistent with the formation of the paralogs in the ancestors to the modern lineages followed by more recent loss of one paralog or the other.

RED-T: utilizing the Ratios of Evolutionary Distances for determination of alternative phylogenetic events.

SUMMARY: RED-T is a Java application for phylogenetic analysis based on a unique method, RED, that utilizes the ratios of evolutionary distances E(d) to distinguish between alternative evolutionary histories. RED-T allows the user to examine if any given experimental gene shares the same evolutionary history as the designated control gene(s). Moreover, the tool detects any differences in evolutionary history and allows the user to examine comparisons of E(d) for a likely explanation. Lateral gene transfer, which may have a significant influence in organismal evolution is one mechanism that could explain the findings of these RED-T analyses. AVAILABILITY: The application is available online at http://www.arches.uga.edu/~whitman/RED.