Deucravacitinib in Moderate to Severe Psoriasis: Clinical and Quality-of-Life Outcomes in a Phase 2 Trial.

INTRODUCTION: Deucravacitinib is an oral, selective tyrosine kinase 2 inhibitor that demonstrated therapeutic benefit in a Phase 2 clinical trial of adults with moderate to severe plaque psoriasis. This analysis was designed to evaluate the effect of deucravacitinib on additional clinical and quality-of-life (QoL) outcomes and assess the relationship between these outcomes in adults with psoriasis. METHODS: Post-hoc analysis of a 12-week Phase 2 trial was conducted for the three most efficacious dosage groups (3 mg twice daily, 6 mg twice daily, 12 mg once daily) and placebo. Investigator assessments for efficacy included Psoriasis Area and Severity Index (PASI), body surface area (BSA) involvement, and static Physician's Global Assessment; QoL was assessed using the Dermatology Life Quality Index (DLQI). Treatment responses and their associations were evaluated over time. RESULTS: Deucravacitinib elicited improvement versus placebo as early as Week 4 for most efficacy measures (including changes in absolute PASI and BSA), with efficacy trends observed from Week 2 to Week 12. Improvements in QoL, assessed by achievement of a DLQI overall score of 0/1 (no effect at all on patient's life), followed a pattern similar to deucravacitinib-related clinical outcomes over 12 weeks. Overall, patients with greater improvements in psoriasis-related clinical signs and symptoms also reported greater improvement in QoL. However, complete skin clearance was not required for achieving DLQI 0/1. CONCLUSION: Deucravacitinib treatment produced early response and similar trends in improvements across multiple efficacy assessments and QoL in moderate to severe plaque psoriasis. Deucravacitinib has the potential to become a promising new oral therapy for this condition. TRIAL REGISTRATION: ClinicalTrials.gov identifier; NCT02931838.

Psoriasis is a skin disease that affects up to 2% of the population. In psoriasis, red, scaly lesions develop on the skin driven by an aberrant immune response. Psoriasis impacts not only physical and mental health but also quality of life (QoL). Deucravacitinib is being investigated as a treatment for psoriasis. We performed a Phase 2 dose-ranging, placebo-controlled, 12-week study of deucravacitinib in adults with moderate to severe psoriasis. Patients in the USA, Australia, Canada, Germany, Japan, Latvia, Mexico, and Poland participated. The study showed that oral treatment with deucravacitinib was effective using a disease severity score (percentage of patients with ≥ 75% reduction from baseline in Psoriasis Area and Severity Index score) at Week 12­placebo 7% and deucravacitinib 67%­75% for the three highest dosages­and was generally well tolerated. We further analyzed the association between efficacy and a QoL measure, the Dermatology Life Quality Index (DLQI), in patients who received placebo or the most effective dosages of deucravacitinib (≥ 3 mg twice daily). Deucravacitinib was effective at the three dosage levels tested. Skin improvement occurred early during treatment and was mirrored by improvements in DLQI score during the 12 weeks of treatment. Although some patients did not have complete clearance of their psoriasis, a large percentage of those patients still achieved considerable improvement in QoL as measured by achieving a DLQI score of 0/1 (i.e., no effect at all on the patient's QoL).

Erythema Ab Igne and Malignant Transformation to Squamous Cell Carcinoma.

Erythema ab igne (EAI) is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn. It is most commonly reported on the lower extremities and back, and it presents with persistent areas of reticular erythema associated with hyperpigmentation, epidermal atrophy, and telangiectases. Erythema ab igne traditionally is associated with chronic exposure to open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters. Histologic features of squamous atypia with basal layer crowding and loss of maturation throughout the epidermis can be seen in later stages of EAI. Therefore, although EAI is predominantly a chronic pigmentary disorder, a percentage of patients might be at increased risk for cutaneous malignant transformation, including squamous cell carcinoma (SCC).

Tildrakizumab efficacy, drug survival, and safety are comparable in patients with psoriasis with and without metabolic syndrome: Long-term results from 2 phase 3 randomized controlled studies (reSURFACE 1 and reSURFACE 2).

BACKGROUND: Data for the effect of metabolic syndrome (MetS) on the efficacy and safety of biologic agents for psoriasis treatment are limited. OBJECTIVE: To evaluate long-term tildrakizumab efficacy, drug survival, and safety in patients with psoriasis by baseline MetS status. METHODS: Post hoc analyses of up to 3 years of efficacy data and 5 years of safety data from the phase 3, double-blind, randomized controlled reSURFACE 1 and 2 trial (NCT01722331 and NCT01729754) base and extension studies were conducted for patients receiving continuous tildrakizumab 100 or 200 mg. RESULTS: Of 338 (n = 124/214 in reSURFACE 1/2) and 307 (n = 147/160 in reSURFACE 1/2) patients continuously receiving tildrakizumab 100 and 200 mg, respectively, throughout the studies, 26/44 (21%/21%) and 34/30 (23%/19%) met MetS criteria. Proportions of patients who achieved a 75% improvement in the Psoriasis Area and Severity Index (PASI) in reSURFACE 1/2 were generally comparable among those with versus without MetS at week 52 (tildrakizumab 100 mg, 85%/86% vs 86%/94%; tildrakizumab 200 mg, 76%/87% vs 76%/87%) and through week 148. Results were similar for responders with 90% and 100% improvement in the PASI. Tildrakizumab's safety profile did not vary by MetS status. LIMITATIONS: Small sample size and post hoc analysis limit interpretation. CONCLUSION: Long-term tildrakizumab efficacy and safety were comparable between patients with and without MetS.

The Effect of Tildrakizumab on Cardiometabolic Risk Factors in Psoriasis by Metabolic Syndrome Status: Post Hoc Analysis of Two Phase 3 Trials (ReSURFACE 1 and ReSURFACE 2).

Background: Metabolic syndrome (MetS) is the most prevalent comorbidity in psoriasis and increases the risk of cardiovascular disease, diabetes, and mortality. Assessment of impacts of biologic therapies on cardiometabolic risk factors are relatively limited. This study evaluated the effect of tildrakizumab on cardiometabolic risk factors in patients with moderate to severe plaque psoriasis and stratified by MetS status. Methods: In this post hoc analysis of reSURFACE 1/2, tildrakizumab 100 and 200 mg were continuously administered to patients with moderate to severe plaque psoriasis at weeks 0 and 4, and every 12 weeks thereafter. Mean and mean percent changes from baseline were assessed for fasting serum glucose, low/high-density lipoprotein-cholesterol, total cholesterol, triglyceride levels, body weight, and blood pressure at week 64/52 for reSURFACE 1 and 2, respectively, in patients with and without MetS. Results: A total of 369 patients in reSURFACE 1 and 2 received continuous tildrakizumab 100 mg and 330 received tildrakizumab 200 mg; 21.4% and 20.3% in reSURFACE 1 and 2, respectively, had MetS. At week 64/52, mean changes in cardiometabolic risk factors from baseline did not significantly differ regardless of MetS status. Numerically larger mean decreases in fasting glucose, triglycerides, and systolic blood pressure following tildrakizumab 100 mg and in systolic and diastolic blood pressure following tildrakizumab 200 mg were observed in patients with MetS relative to those without MetS. Conclusions: Changes in cardiometabolic disease risk factors following tildrakizumab treatment were limited. Risk factors were not increased in patients with MetS vs without MetS. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5337.

IL-17 inhibitors for psoriasis.

The role of the Th17/interleukin (IL)-23 pathway has been well elucidated in psoriasis. The IL-17 family includes 6 cytokines: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. Two monoclonal antibodies targeting IL-17A (secukinumab, ixekizumab) and one antibody against the IL-17 receptor (brodalumab) have been approved for the treatment of moderate-to-severe plaque psoriasis. Clinical efficacy, safety, and tolerability of each agent is reviewed.

Histiocytoid Sweet syndrome successfully treated with etanercept.

We report the first case of a 34-year-old woman with histiocytoid Sweet syndrome (HSS) that was successfully treated with etanercept. HSS is a rare histological variant of acute febrile neutrophilic dermatosis that was described by Requena et al in 2005. It is distinguished by dermal infiltration by mononuclear cells with a histiocytic morphology. To date there are three reported cases of the use of etanercept in the treatment of classic febrile neutrophilic dermatosis but none targeting this disease variant. Our patient presented with a 6-month history of scattered erythematous papules on the neck, trunk, and upper and lower limbs bilaterally. Clinical findings and histopathological evaluation were highly suggestive of HSS. After 32 months of refractory disease activity, our patient was initiated on a regimen of etanercept 1 mg/kg subcutaneously twice weekly and topical desoximetasone 0.05% ointment twice daily as required. To date, our patient has achieved 37 months of remission.

The Evolving Landscape of Psoriasis Treatment.

The process of discovering new drugs for plaque psoriasis has revealed much about the multisystemic nature of the disease. Current and emerging biologic agents may reliably achieve a Psoriasis Area and Severity Index (PASI 75) up to 90. Initially, clinicians select therapies based on the severity of the psoriasis. Although mild disease can be treated with topical agents, for patients with moderate to severe disease, concurrent therapy with oral systemic agents, biologics, and/ or phototherapy needs to be considered. In some instances, clinicians may need to combine medications to provide patients with rapid relief of symptoms. Semin Cutan Med Surg 37(supp2):S39-S43.

Treating to Target-A Realistic Goal in Psoriasis?

For many patients, the new biologic therapies for psoriasis can improve Psoriasis Area and Severity Index (PASI) scores in a relatively short time. But when results are less than optimal, patients often become frustrated. By providing effective medical treatment using a treat-to-target strategy, clinicians can relieve symptoms and halt disease progression. Although body surface area (BSA) and PASI scores are appropriate for analyzing results of clinical trials, clinicians need to use more patient-centered assessments of patients' progress such as the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Inventory (PSI), as well as other validated patientreported outcomes, which can enable them to set realistic and achievable goals for individual patients. Semin Cutan Med Surg 37(supp2):S44-S47.

Common and Not-So-Common Comorbidities of Psoriasis.

Plaque psoriasis is increasingly recognized as a multisystemic disease whose most common comorbidities include psoriatic arthritis, cardiovascular disease, metabolic syndrome, overweight/obesity, inflammatory bowel disease, and depression. The presence of such comorbidities affects the therapeutic choices for clinicians. Patients often visit dermatologists more frequently than they do other clinicians, so it is incumbent upon dermatologists to recognize and address early signs of psoriatic comorbidities to prevent further deterioration and improve their patients' quality of life. Semin Cutan Med Surg 37(supp2):S48-S51.

Practical Strategies for Optimizing Management of Psoriasis.

Approximately 30% of patients with moderate plaque psoriasis and 20% of those with severe psoriasis have inadequate disease control with their current therapeutic regimens. Among the factors that affect treatment efficacy are drug selection and lack of patient adherence to treatment, which is often due to patient frustration that psoriasis is a chronic, multisystemic, and incurable disease. By forming a strong therapeutic alliance with patients and by asking them about their expectations for treatment, clinicians have a better chance of providing patients with more effective and durable relief from their psoriasis symptoms. Semin Cutan Med Surg 37(supp2):S52-S55.

Pharmacotherapeutic approaches for treating psoriasis in difficult-to-treat areas.

INTRODUCTION: Despite great therapeutic advancements in psoriasis, four notable difficult-to-treat areas including the scalp, nails, intertriginous (including genitals), and palmoplantar regions, pose a challenge to both physicians and patients. Localized disease of these specific body regions inflicts a significant burden on patients' quality of life and requires an adequate selection of treatments. AREAS COVERED: This manuscript discusses appropriate therapies and important treatment considerations for these difficult-to-treat areas based on the available clinical data from the literature. EXPERT OPINION: Clinical trials assessing therapies for the difficult-to-treat areas have been inadequate. With the first biological clinical trial for genital psoriasis pending publication, it is with hope that other biological agents will be evaluated for region-specific psoriasis. A greater understanding of the genetic and immunologic aspects of regional psoriasis, as well as identification of unique biomarkers, will further guide management decisions. For example, the recent discovery of the IL-36 receptor gene for generalized pustular psoriasis may prove valuable for other forms of psoriasis. Ultimately, identification of the most beneficial treatments for each psoriasis subtype and difficult-to-treat area will provide patients with maximal quality of life.

Spectrum of orocutaneous disease associations: Immune-mediated conditions.

There are a number of diseases that manifest both on the skin and the oral mucosa, and therefore the importance for dermatologists in clinical practice to be aware of these associations is paramount. In the following continuing medical education series, we outline orocutaneous disease associations with both immunologic and inflammatory etiologies.

Spectrum of orocutaneous disease associations: Genodermatoses and inflammatory conditions.

The oral cavity and cutaneous organ systems share a close embryologic origin. Therefore, there are numerous dermatologic conditions presenting with concomitant oral findings of which the dermatologist must be aware. The second article in this continuing medical education series reviews inflammatory orocutaneous conditions and a number of genodermatoses. It is essential for dermatologists to be familiar with oral cavity manifestations associated with dermatologic diseases for prompt diagnosis, management, and appropriate referral to stomatology and dentistry.

Evaluation and management of an unusual congenital nevus.

Abnormal findings on routine skin exams are common and can be a source of unnecessary medical workup if a clinician is unfamiliar with the finding. Sebaceous nevi are rare skin lesions that are most often benign but may be associated with a multiorgan syndrome or local skin cancer. Dermatologists and primary care physicians may encounter these on routine exams and thus must be comfortable with diagnosis and management. We present the clinical characteristics of a benign sebaceous nevus to help aid in diagnosis of these lesions and outline suggestions for appropriate management options.

From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis.

BACKGROUND: An urgent need exists in the United States to establish treatment goals in psoriasis. OBJECTIVE: We aim to establish defined treatment targets toward which clinicians and patients with psoriasis can strive to inform treatment decisions, reduce disease burden, and improve outcomes in practice. METHODS: The National Psoriasis Foundation conducted a consensus-building study among psoriasis experts using the Delphi method. The process consisted of: (1) literature review, (2) pre-Delphi question selection and input from general dermatologists and patients, and (3) 4 Delphi rounds. RESULTS: A total of 25 psoriasis experts participated in the Delphi process. The most preferred instrument was body surface area (BSA). The most preferred time for evaluating patient response after starting new therapies was at 3 months. The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline. The target response at 3 months postinitiation was BSA 1% or less. During the maintenance period, evaluation every 6 months was most preferred. The target response at every 6 months maintenance evaluation is BSA 1% or less. LIMITATIONS: Although BSA is feasible in practice, it does not encompass health-related quality of life, costs, and risks of side effects. CONCLUSION: With defined treatment targets, clinicians and patients can regularly evaluate treatment responses and perform benefit-risk assessments of therapeutic options individualized to the patient.

Efficacy of Tofacitinib for the Treatment of Moderate-to-Severe Chronic Plaque Psoriasis in Patient Subgroups from Two Randomised Phase 3 Trials.

BACKGROUND: Tofacitinib is a Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. We report efficacy of tofacitinib in patient subgroups based on pooled data from two Phase 3 trials (NCT01276639, NCT01309737).
OBJECTIVES: To assess consistency of treatment effects of tofacitinib versus placebo in subgroups defined by baseline characteristics, and to ascertain whether baseline characteristics are of value in optimizing tofacitinib use.
METHODS: Pooled data from the two trials were used to evaluate ≥75% reduction in PASI from baseline (PASI75 response) in subgroups defined by age, age at psoriasis onset, gender, race, geographical region, weight, body mass index, diabetes, metabolic syndrome, tobacco/alcohol use, psoriatic arthritis, disease activity, and prior therapy.
RESULTS: Week 16 PASI75 response rates (N=1843) were 43%, 59% and 9% with tofacitinib 5 and 10mg twice daily (BID) and placebo, respectively (each P<0.0001 versus placebo). Tofacitinib 5 and 10mg BID were effective regardless of baseline characteristics. Across subgroups, tofacitinib generally produced greater response rates with the 10 versus 5mg BID dosage. Lower absolute response rates were seen in heavier patients and patients with prior biologic experience.
CONCLUSIONS: Both tofacitinib dosages demonstrated consistent efficacy versus placebo across subgroups. Lower response rates were seen in heavier patients and those with prior biologic experience. Tofacitinib 10mg BID resulted in a substantial proportion of responders regardless of baseline characteristics.

J Drugs Dermatol. 2016;15(5):568-580.

Psoriasis: the future.

The umbrella term psoriasis is now understood to incorporate several distinct phenotypes or endotypes along the disease spectrum that in turn will dictate different therapies. A stratified medicine approach to psoriasis using this clinical information coupled with pharmacogenomic and immunologic data will become more widely acceptable in the future. Comorbidities associated with psoriasis, such as diabetes, depression, and Crohn disease, and the debate about the interdependence of psoriasis and cardiovascular disease will also dictate future research and holistic and management plans for this complex disease.

The spectrum of oculocutaneous disease: Part I. Infectious, inflammatory, and genetic causes of oculocutaneous disease.

Many skin diseases are associated with ocular findings, emphasizing the need for dermatologists to be fully aware of their presence, and as a result, avoid overlooking conditions with potentially major ocular complications, including blindness. We review important oculocutaneous disease associations with recommendations for the management of the ocular complications and appropriate referral to our ophthalmology colleagues. Part I of this 2-part review focuses on the infectious, inflammatory, and genetic relationships.