Ixekizumab for the treatment of pediatric patients with moderate to severe plaque psoriasis.

Introduction: Ixekizumab (IXE), a high affinity humanized monoclonal antibody that selectively targets interleukin-17A, is approved in the United States (US) and the European Union (EU) for pediatric patients with moderate to severe plaque psoriasis. This review summarizes ixekizumab use in the phase 3, randomized, double-blind, placebo-controlled study in pediatric patients with moderate to severe plaque psoriasis and provides some clinical pearls we have learned after using the drug in the pediatric population for the past 3 years.Areas covered: Review of IXORA-PEDS trial data, general literature review pertaining to the systemic treatment of pediatric psoriasis as well as our clinical experience with IXEExpert opinion: IXE is the only IL17 antagonist for pediatric psoriasis and is a welcome addition to our armamentarium.

Cannabidiol primer for healthcare professionals.

Emerging research and clinical data are demonstrating potential benefits of cannabidiol for multiple medical conditions. This article gives healthcare providers information on cannabidiol and the endocannabinoid system as a foundation on which to build their medical knowledge as the risks and benefits of CBD in various diseases are further evaluated over time.

Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).

BACKGROUND: Plaque psoriasis affects children and adults, but treatment options for paediatric psoriasis are limited. OBJECTIVES: To evaluate the efficacy and safety of ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, for moderate-to-severe paediatric psoriasis. METHODS: In a randomized, double-blind, placebo-controlled, phase III study (IXORA-PEDS), patients aged 6 to < 18 years with moderate-to-severe plaque psoriasis were randomized 2 : 1 to weight-based dosing of IXE every 4 weeks (IXE Q4W, n = 115) or placebo (n = 56) through week 12, followed by open-label IXE Q4W. Coprimary endpoints were the proportions of patients at week 12 achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and those achieving a static Physician's Global Assessment score of 0 or 1 (sPGA 0,1). RESULTS: IXE was superior (P < 0·001) to placebo for both coprimary endpoints of PASI 75 (IXE Q4W, 89%; placebo, 25%) and sPGA (0,1) (IXE Q4W, 81%; placebo, 11%). IXE was also superior for all gated secondary endpoints, including PASI 75 and sPGA (0,1) at week 4, improvement in itch, and complete skin clearance. IXE Q4W provided significant (P < 0·001) improvements vs. placebo in quality of life and clearance of scalp and genital psoriasis. Responses at week 12 were sustained or further improved through week 48. Through week 12, 45% (placebo) and 56% (IXE) of patients reported treatment-emergent adverse events. One serious adverse event was reported (IXE), one patient discontinued due to an adverse event (placebo) and no deaths were reported. CONCLUSIONS: IXE was superior to placebo in the treatment of moderate-to-severe paediatric psoriasis, and the safety profile was generally consistent with that observed in adults. What is already known about this topic? Paediatric psoriasis affects approximately 1% of children and can negatively impact health-related quality of life. Treatment options for paediatric psoriasis are typically limited to off-label treatments and approved systemic biologics. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for moderate-to-severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate-to-severe paediatric psoriasis. What does this study add? Ixekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health-related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate-to-severe plaque psoriasis. The safety profile of ixekizumab was generally consistent with that seen in adults. Ixekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin-17A antagonist) for the treatment of moderate-to-severe paediatric psoriasis. Plain language summary available online.

Safety of selective IL-23p19 inhibitors for the treatment of psoriasis.

Psoriasis is a chronic disease that requires long-term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)-23. This article reviews published data on the safety of these IL-23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo- and active-controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk-benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL-23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL-23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long-term extension studies and patient registries will further establish the safety profile of IL-23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.

Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis.

BACKGROUND: Genital psoriasis (GenPs) is a common, debilitating and difficult-to-treat manifestation of plaque psoriasis. However, few controlled, interventional studies of GenPs exist. OBJECTIVES: To determine the efficacy of ixekizumab vs. placebo in patients with moderate-to-severe GenPs with ≥ 1% involved body surface area (BSA). METHODS: Patients with moderate-to-severe GenPs, defined as a baseline static Physician's Global Assessment of Genitalia (sPGA-G) score of ≥ 3, with BSA ≥ 1% were randomized 1 : 1 to receive placebo (n = 74) or the recommended dosing of ixekizumab (n = 75). Major outcomes included the percentage of patients achieving 0 or 1 scores on the sPGA-G (primary end point), overall sPGA, GenPs Sexual Frequency Questionnaire (GenPs-SFQ) item 2, and ≥ 3-point improvement from baseline on the GenPs itch numerical rating scale. RESULTS: At week 12, ixekizumab was superior to placebo for sPGA-G 0/1 (73% vs. 8%, P < 0·001), overall sPGA 0/1 (73% vs. 3%, P < 0·001), GenPs-SFQ item 2 score of 0 or 1 (78% vs. 21%, P < 0·001) and genital itch (60% vs. 8%, P < 0·001). No candidiasis was reported, no deaths occurred and one (1%) serious adverse event was reported in a patient receiving placebo. CONCLUSIONS: Ixekizumab was superior to placebo for the treatment of moderate-to-severe GenPs with BSA ≥ 1%. The safety profile of ixekizumab was consistent with previous studies in moderate-to-severe plaque psoriasis.

Impact of ixekizumab treatment on skin-related personal relationship difficulties in moderate-to-severe psoriasis patients: 12-week results from two Phase 3 trials.

BACKGROUND: Psoriasis symptoms may decrease quality of life for patients. Skin-related personal relationship difficulties in psoriasis patients are common, under-reported and poorly understood. OBJECTIVE: To assess the effect of ixekizumab (IXE) treatment on skin-related personal relationship difficulties in patients with moderate-to-severe psoriasis. METHODS: Pooled data (N = 2570) on skin-related relationship problems were obtained from two large phase 3 trials (UNCOVER-2 and UNCOVER-3) in patients with moderate-to-severe plaque psoriasis randomized to subcutaneous placebo (PBO, N = 361), etanercept (ETN; 50 mg twice weekly, N = 740), or 80 mg IXE as one injection every 4 (IXEQ4W, N = 733) or 2 weeks (IXEQ2W, N = 736) for 12 weeks, following a 160-mg initial dose. The Dermatology Life Quality Index (DLQI) Personal Relationships Domain (PRD) (Items 8 and 9) was used to assess how much the skin caused any personal relationship difficulties at weeks 0, 2, 4 and 12. Improvement was compared for IXE vs PBO and ETN using logistic models. Factors associated with improvement were assessed using multiple linear regressions. DLQI Item 9, assessing sexual difficulties, was also analysed separately. RESULTS: PRD scores (mean ± standard deviation) at baseline were similar across all treatment groups (PBO: 1.8 ± 1.9; ETN: 1.7 ± 1.8; IXEQ4W: 1.6 ± 1.8; IXEQ2W: 1.7 ± 1.8). Treatment with IXE rapidly and significantly improved the mean PRD score compared to PBO and ETN (P < 0.001 at all time points). Baseline PRD score was the strongest negative predictor of improvement. IXE enabled significantly more patients with moderate-to-severe plaque psoriasis to reduce their skin-related sexual difficulties at Week 12 compared to PBO (P < 0.001) or ETN (P < 0.001). CONCLUSION: Ixekizumab improves patient-reported skin-related PRD difficulties in patients with moderate-to-severe psoriasis.

A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: The interleukin-17 cytokine family plays a central role in psoriasis pathogenesis. OBJECTIVES: To evaluate the efficacy and safety of brodalumab, a human anti-interleukin-17 receptor antibody, in treating patients with moderate-to-severe plaque psoriasis. METHODS: In this phase III, double-blind, placebo-controlled study (NCT01708590; AMAGINE-1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12-week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re-treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12. RESULTS: There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable. CONCLUSIONS: Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate-to-severe plaque psoriasis.

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2).

BACKGROUND: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis. OBJECTIVES: ESTEEM 2 evaluated the efficacy and safety of apremilast 30 mg twice daily for moderate-to-severe plaque psoriasis. METHODS: This phase III, double-blind, placebo-controlled trial randomized adults to apremilast or placebo (2 : 1). At week 16, placebo patients switched to apremilast. At week 32, apremilast patients achieving ≥ 50% reduction in Psoriasis Area and Severity Index (PASI 50) were rerandomized (1 : 1) to continue apremilast or receive placebo. Upon loss of 50% of PASI improvement obtained at week 32, patients rerandomized to placebo resumed apremilast. RESULTS: The modified intention-to-treat population (full analysis set) included 137 placebo and 274 apremilast patients. At week 16, significantly more apremilast patients achieved PASI 75 (28·8%), PASI 50 (55·5%) and static Physician's Global Assessment score of 0 or 1 (20·4%) vs. placebo (5·8%, 19·7%, 4·4%, respectively; P < 0·001). Most patients rerandomized to apremilast at week 32 had a PASI 50 response at week 52 (80%). Patients treated with apremilast showed significant improvements in quality of life (as assessed by the Dermatology Life Quality Index) and pruritus at week 16 compared with placebo (P < 0·001). The exposure-adjusted incidence of adverse events did not increase with continued apremilast treatment for up to 52 weeks. The most common adverse events were nausea, diarrhoea, nasopharyngitis and upper respiratory tract infection. CONCLUSIONS: Apremilast was effective in the treatment of moderate-to-severe plaque psoriasis over 52 weeks.

Modulating T cell responses for the treatment of psoriasis: a focus on efalizumab.

An improved understanding regarding the pathophysiology of psoriasis, coupled with advances in molecular research, has prompted the development of targeted biologic treatments for patients with plaque psoriasis. T lymphocytes play an important role in initiating the immune system and the inflammatory responses that result in the development and maintenance of psoriatic plaques. Efalizumab (anti-CD11a, Raptiva; Genentech, Inc.) is a mAb that targets the T cell adhesion molecule, leukocyte function-associated antigen-1 (LFA-1). By binding to CD11a - the alpha-subunit of LFA-1 - LFA-1 is prevented from binding with its ligand, intercellular adhesion molecule-1 (ICAM-1). This inhibits various T cell processes believed to be important in the pathogenesis of psoriasis, including T cell activation, T cell adhesion to endothelial cells and T cell migration. Clinical trials demonstrate that efalizumab, given subcutaneously once-weekly, provides clinical benefit, including improved quality of life, in patients with moderate-to-severe plaque psoriasis. Efalizumab is associated with an early onset of action, with improvement noted as early as 14 days. Studies with extended treatment suggest that continuing efalizumab therapy is more beneficial in maintaining and improving responses. Relapse of psoriasis is usually seen within 60 - 70 days after discontinuation of therapy, and rebound in approximately 5% of patients (i.e., flare to > 125% of baseline) is noted. Efalizumab is associated with acute adverse events during the first and second injections, which decrease in incidence with each subsequent injection. Data indicate that efalizumab can be safely administered for extended periods of time. Given the efficacy, early onset of clinical benefit, the safety profile and the convenience of once-weekly subcutaneous home dosing, efalizumab offers an interesting new therapeutic option for the treatment of psoriasis and the potential for improved and potentially safer long-term, continuous 'maintenance' therapy.

Update on botulinum toxin for facial aesthetics.

The use of botulinum toxin has revolutionized the treatment of facial lines with an incomparable safety record over the past 14 years. The most common used injection sites are shown in Fig. 9. With the recent FDA approval for Botox in the treatment of glabellar lines, its use will likely increase dramatically. It is essential that practitioners have a detailed and specific knowledge of the facial and neck musculature to be injected to minimize untoward side effects, especially in the early days of new users' learning curve. The specifics of the dilutions and units per amount used for the various different commercial forms of botulinum toxin types A and B need to be understood fully and standardized together with the potential for antigenicity with the higher protein load of type B. In addition, specific indications for the use of botulinum toxin as adjunctive therapy for specific facial surgical procedures (i.e., blepharoplasty, surgical brow lift, and laser resurfacing) will become better understood. [figure: see text] Finally, even though the anatomy of the facial musculature is well described, individual differences in men and women, in different population groups, and in tissue qualities, such as turgor and elasticity [87], are important factors to be considered before undertaking botulinum toxin injections. It is likely that the use of specific measuring devices, such as digital imaging, will further help define the use of botulinum toxin for different muscle groups and facial aesthetic indications.

Cyclosporine and tacrolimus in dermatology.

Immune modulators are being used with increasing frequency in dermatology. This article reviews two such agents, cyclosporine and tacrolimus. Discussion emphasizes the pharmacology, side effects, and uses of these two drugs in dermatologic disorders.

Emerging new therapies for cutaneous T-cell lymphoma.

Improved therapy for CTCL will depend on a better understanding of the pathogenesis of this disease at a molecular level. It is clear that the T cells in MF and CTCL do not undergo normal programmed cell death and have prolonged lifespans. Skin flora or other antigens may stimulate the initial proliferation, offering another approach to change the course of the disease. There has been tremendous interest in biological response modifiers, and the first targeted fusion toxin to activated T cells has been approved for CTCL. New retinoids with increased selectivity and decreased side effects are being tested for this disease. In summary, the treatment of CTCL should continue to improve and should be focused on strategies that preserve the immune function in these patients.