Non-Melanoma Skin Cancer Risk Among Patients in the Psoriasis Longitudinal Assessment and Registry (PSOLAR)

To the Editor: Patients with psoriasis are at increased risk of developing non melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).1,2 The risk is especially elevated among those who previously received systemic treatment or phototherapy.2 Systemic treatments, including biologic therapies and methotrexate (MTX), are effective in managing immune-mediated diseases; however, they may increase susceptibility to NMSC due to immunosuppression or other factors.3

Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR).

BACKGROUND: Patients with psoriasis are at an increased risk for depression. However, the impact of treatment on this risk is unclear. OBJECTIVE: Evaluate the incidence and impact of treatment on depression among patients with moderate-to-severe psoriasis. METHODS: We defined a study population within the Psoriasis Longitudinal Assessment and Registry and measured the incidence of depressive symptoms (Hospital Anxiety and Depression Scale-Depression score ≥8) and adverse events (AEs) of depression within cohorts receiving biologics, conventional systemic therapies, or phototherapy. Patients were evaluated at approximately 6-month intervals. Multivariate modeling determined the impact of treatment on risk. RESULTS: The incidence rates of depressive symptoms were 3.01 per 100 patient-years (PYs) (95% confidence interval [CI], 2.73-3.32), 5.85 per 100 PYs (95% CI, 4.29-7.97), and 5.70 per 100 PYs (95% CI, 4.58-7.10) for biologics, phototherapy, and conventional therapy, respectively. Compared with conventional therapy, biologics reduced the risk for depressive symptoms (hazard ratio, 0.76; 95% CI, 0.59-0.98), whereas phototherapy did not (hazard ratio, 1.05; 95% CI, 0.71-1.54). The incidence rates for AEs of depression were 0.21 per 100 PYs (95% CI, 0.15-0.31) for biologics, 0.55 per 100 PYs (95% CI, 0.21-1.47) for phototherapy, and 0.14 per 100 PYs (95% CI, 0.03-0.55) for conventional therapy; the fact that there were too few events (37 AEs) precluded modeling. LIMITATIONS: Incomplete capture of depression and confounders in the patients on registry. CONCLUSION: Compared with conventional therapy, biologics appear to be associated with a lower incidence of depressive symptoms among patients with psoriasis.

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.

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.

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.

WITHDRAWN: Experience with ustekinumab in patients with psoriasis enrolled in a large, multicenter, prospective, disease-based registry (Psoriasis Longitudinal Assessment and Registry [PSOLAR]).

The above-referenced article has been voluntarily withdrawn by the authors in order to present more updated data in a subsequent manuscript. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

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.

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.

Considerations for the US health-system pharmacist in a world of biosimilars.

As numerous biosimilar products are forecast to enter the US market in the coming years, health-system pharmacists will be faced with novel challenges while incorporating them into clinical practice. The current regulatory approval framework and guidance from the US Food and Drug Administration do not address many real-world scenarios that pharmacists will encounter. We provide an overview of the evolving healthcare landscape shaped by the entry of multiple biosimilars, including for a given reference product, and their impact on the health-system pharmacist with respect to formulary assessment, implementation, and education of various health-system stakeholders, including patients.

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.

A descriptive analysis of real-world treatment patterns of innovator (Remicade®) and biosimilar infliximab in an infliximab-naïve Turkish population.

PURPOSE: Biosimilar IFX (CT-P13) received marketing approval in Turkey for treatment of rheumatologic diseases, including ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Population data on real-world treatment patterns of CT-P13 following marketing approval in European countries are largely unreported. This study examined the prescribing and medication utilization patterns of innovator infliximab (IFX) and CT-P13 in Turkey for patients with RA or IBD naïve to either IFX. MATERIALS AND METHODS: Adult patients with ≥1 diagnosis claim for RA or IBD and ≥1 claim for IFX or CT-P13 were identified in the Turkish Ministry of Health database during the following identification periods: 1 Oct 2014-30 May 2015 (RA) and 1 Oct 2014-31 Dec 2015 (IBD). Continuous medical and pharmacy coverage for ≥12 months before and after the date of the first dose (index) IFX or CT-P13 was also required. Separate analyses were done for each population. RESULTS: Seven hundred and seventy nine adult RA and 581 IBD patients met the selection criteria. The majority of RA (74%; n=575) and IBD patients (87%; n=504) were initiated on IFX. The average study observation period was 16 months for the RA and 12 months for the IBD population. Over the observation periods, discontinuation among RA patients occurred in 42% of IFX and 63% of CT-P13 while discontinuation in the IBD cohort occurred in 38% of IFX; and 62% of CT-P13. CONCLUSION: In this population-based study, more IFX-naïve RA and IBD patients were initially treated with IFX than CT-P13. Discontinuation and switching were observed more often and earlier among patients treated with CT-P13 regardless of disease state. Further studies are needed to understand the reasons for these observed differences.

Analysis of real-world treatment patterns in a matched rheumatology population that continued innovator infliximab therapy or switched to biosimilar infliximab.

PURPOSE: This study compared treatment patterns of Turkish patients with a diagnosis of rheumatoid arthritis (RA) who were treated with innovator Remicade® (infliximab [IFX]) and either continued IFX or switched to CT-P13. MATERIALS AND METHODS: Adult RA patients with ≥1 IFX claim were identified from the Turkish Ministry of Health database. Eligible patients initiated and continued IFX treatment (continuers cohort [CC]) or initiated IFX and switched to CT-P13 (switchers cohort [SC]) during the study period. The initial IFX claim date was defined as the index date. The switch/reference date was defined as the CT-P13 switch date for the SC or a random IFX date during the period of CT-P13 availability for the CC. Cohorts were matched by age, sex, and number of IFX prescriptions during baseline. Patient demographics, discontinuation, and switching were summarized. The baseline period was defined as the period from the index date to the switch/reference date. The follow-up period ranged from the switch/reference date to the end of data availability. RESULTS: After matching, 697 patients were selected: 605 patients for the CC and 92 patients for the SC. Mean IFX duration for the baseline period was 422 days in the CC and 438 days in the SC. Median time on any infused tumor necrosis factor (TNF) antagonist therapy was 1,080 days in the CC and 540 days in the SC during the study period. During the follow-up period, discontinuation was lower in the CC (CC=33.9% vs SC=87.5%; P<0.001). The mean time to discontinuation was longer in the CC (CC=276 days vs SC=132 days; P<0.001). A switch to another biologic medication during the follow-up period was observed in 19.0% of patients in the CC (n=115) and 81.5% of patients in the SC (n=75; P<0.001). CONCLUSION: Treatment patterns differed between patients prescribed IFX and CT-P13. In Turkey, RA patients maintained on IFX had greater treatment persistence (ie, fewer and later discontinuations) than those who initiated IFX and switched to CT-P13.

Ensuring Product Quality, Consistency and Patient Supply over Time for a Large-Volume Biologic: Experience with Remicade®.

Biologics are produced from living organisms in complex, multi-stage manufacturing processes and contain inherent variability, which must be understood and controlled during manufacturing to avoid unexpected changes in key quality attributes that may contribute to clinically meaningful differences. The process must also meet large commercial demand, while simultaneously being able to accommodate change without sacrificing product consistency. The four key components of successful biologics manufacturing are (1) a stable, well-defined proprietary cell line; (2) a good manufacturing practice (GMP)-compliant supply chain with a process control strategy defining acceptable levels of variability for target product/process attributes and capable of managing complex material flows; (3) a tightly controlled procedure for implementation of proposed process changes that ensures product consistency; and (4) built-in redundancy and flexibility providing the ability to adapt rapidly to unexpected developments. This report describes the requirements for the manufacturing and distribution of biologics, using Remicade® (infliximab, Janssen Biotech, Horsham, PA, USA) as an example of best practices. Since Remicade's first marketing approval in 1998, Janssen has manufactured > 150 million vials used to treat > 2.6 million patients around the world for a variety of inflammatory diseases. Remicade displays a highly consistent quality attribute profile and meets all product/process specifications across multiple manufacturing sites and process scales. Janssen's experience with Remicade demonstrates that deep product knowledge, extensive manufacturing experience, diligent product/process monitoring and a sustained commitment to compliance and research are required to ensure quality, consistency and uninterrupted patient supply for large-volume biologics over the long term.

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.

Development of the IL-12/23 antagonist ustekinumab in psoriasis: past, present, and future perspectives--an update.

Since the original publication of the article "Development of the IL-12/23 antagonist ustekinumab in psoriasis: Past, present and future perspectives" in March 2011 (see Appendix),(1) there have been several new publications and developments of note. A number of new reports from the ustekinumab psoriasis clinical development program have been published. The analysis of efficacy and safety in the PHOENIX 1 long-term extension demonstrated that continuous stable maintenance dosing of ustekinumab was generally well tolerated and sustained durable efficacy through up to three years of treatment.(2) Pooled safety data from the phase 2 and phase 3 global trials showed that the safety profile of long-term continuous ustekinumab treatment through up to three years(3,4) and four years(5) of follow-up was favorable and comparable to what has been reported previously in the shorter-term ustekinumab psoriasis studies.(6-8) This represents the greatest exposure and longest follow-up of psoriasis patients treated with a biologic published to date. Additional phase 3 trials in Asian populations demonstrated similar high levels of efficacy and favorable safety profiles in Japanese,(9,10) Korean,(11,12) and Taiwanese(11,12) patients as those observed in trials conducted in mostly White populations in North America and Europe.(6-8) These data support the positive benefit:risk profile and consistency of response to ustekinumab over years of usage, and in multiple ethnic groups. Results from up to five years of treatment with ustekinumab in the long-term extensions of the phase 3 trials, and the efficacy, safety, and effect on quality of life in Chinese patients will be available in 2012. In addition to clinical trials of ustekinumab for the treatment of psoriasis, 24-week data from one phase 3 study of ustekinumab for the treatment of psoriatic arthritis has recently been presented(13) and another study is ongoing. A Phase 2b trial in Crohn's disease has also been presented,(14) and three phase 3 studies in Crohn's disease are currently in progress.

Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab: case report and review of the literature.

BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare, generally reversible neurologic syndrome that is diagnosed based on characteristic clinical and radiologic findings. OBSERVATIONS: We describe the first case of RPLS in a 65-year-old woman who underwent ustekinumab therapy for psoriasis. Approximately 2½ years after the patient began ustekinumab therapy, she experienced an acute onset of confusion, headache, nausea, vomiting, and seizures. Computed tomographic scans and magnetic resonance images of her head revealed characteristic findings, including white matter abnormalities consistent with edema in the absence of infarction. There was no evidence of vasospasm, thrombosis, or infection. Cerebrospinal fluid tests were negative for the JC virus. The patient improved clinically and was discharged 6 days after she presented to the emergency department. She made a full neurologic recovery, with a reversal of the radiologic findings. CONCLUSIONS: Reversible posterior leukoencephalopathy syndrome is an increasingly recognized neurologic disorder that has been reported with the use of systemic and biologic agents to treat moderate to severe psoriasis. Although the relationship between RPLS and ustekinumab therapy remains unclear, this case emphasizes the need for dermatologists to recognize the syndrome's signs and symptoms and to refer patients promptly for evaluation and appropriate treatment if the clinical features of RPLS are suspected.

Development of the IL-12/23 antagonist ustekinumab in psoriasis: past, present, and future perspectives.

The development of ustekinumab as a first-in-class anti-interleukin (IL) 12/23p40 therapeutic agent for psoriasis represents an important example of modern and rational drug design and development. Psoriasis is a chronic, systemic, immune-mediated skin disorder with considerable clinical, psychosocial, and economic burden. Ustekinumab is a human monoclonal antibody (mAb) that binds the p40 subunit common to IL-12 and IL-23, key cytokines in psoriasis pathogenesis. The therapeutic mAb was developed using human gamma-1 immunoglobulin (IgG)-expressing transgenic mice, which created a molecule with endogenous IgG(1) biologic properties and low immunogenicity. Ustekinumab was well tolerated in clinical studies and yielded rapid, significant, and sustained efficacy plus improved quality of life/work performance and reduced depression/anxiety. Its pharmacologic properties afford the most convenient dosing regimen among approved biologics, representing a significant advancement in the treatment of moderate to severe psoriasis. Ustekinumab also holds promise for other immune-mediated disorders with significant unmet need.