Sharon Rose

Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial

Background: Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. Objective: Evaluate interleukin 22 blockade in adults with moderate‐to‐severe atopic dermatitis (AD). Methods: We performed a randomized, double‐blind, placebo‐controlled trial with intravenous fezakinumab monotherapy every 2 weeks for 10 weeks, with follow‐up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. Results: At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 ± 2.7 in the fezakinumab arm and 8.0 ± 3.1 in the placebo arm (P = .134). In the severe AD patient subset (with a baseline SCORAD of ≥50), SCORAD decline was significantly stronger in the drug‐treated patients than placebo‐treated patients at 12 weeks (21.6 ± 3.8 vs 9.6 ± 4.2, P = .029) and 20 weeks (27.4 ± 3.9 vs 11.5 ± 5.1, P = .010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug‐treated than placebo‐treated patients (12.4% ± 2.4 vs 6.2% ± 2.7; P = .009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug‐treated than placebo‐treated patients (0.7 ± 0.2 vs 0.3 ± 0.1; P = .034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. Limitations: The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. Conclusion: Fezakinumab was well‐tolerated, with sustained clinical improvements after last drug dosing.

Use of 308 nm excimer laser for the treatment of chronic hand and foot eczema

Chronic hand and foot eczema (CHFE), a prevalent debilitating disorder affecting approximately 15% of the population, presents a socioeconomic and psychosocial burden for patients and often follows a chronic course, refractory to conventional therapies. Thus, a large need exists for more effective therapeutics; the excimer laser (308 nm) is effective for some inflammatory skin diseases, but its efficacy has not been evaluated for CHFE.

Ustekinumab as therapy for psoriasis in a 2‐year‐old girl

Editor Psoriasis is a chronic, inflammatory disease that affects approximately 2% of the population. Though psoriasis is usually diagnosed between the ages of 15 and 25, 8% of cases manifest before adolescence and 2% during infancy. Unfortunately, psoriasis causes significant physical and psychological burden in children, sometimes resulting in isolation and depression. Despite the therapeutic developments for adults, systemic treatments that are widely used for adult psoriasis are not yet available for children. It is imperative that we evaluate systemic therapies for the paediatric population impacted by severe and refractory psoriasis. A 2-year-old girl presented to our clinic with biopsy-proven psoriasis (Fig. 1a) that began when she was 6-months-old. Topical corticosteroids and calcineurin inhibitors, narrow-band UVB (NB-UVB) phototherapy, and excimer laser treatments provided minimal benefit. A recent clinical trial demonstrated the efficacy and safety of half-standard dosage (22.5 mg) of ustekinumab in psoriatic adolescents. Therefore, we decided to administer 20 mg ustekinumab to our patient at weeks 0, 4, and then every 12 weeks. Our patient demonstrated rapid improvements in Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA) involvement after only 4 weeks of ustekinumab treatment. Within 16 weeks, she achieved PASI-90, improving from PASI 26.4 at baseline to 1.6 (Fig. 1b). BSA improved from 34% at baseline to 25% at 4 weeks, 3% at 16 weeks and <1% in 24 weeks. One year later, our patient is completely clear of psoriasis (Fig. 1c). No adverse events, including increased infection rate or abnormal laboratory parameters, have been noted. Systemic therapies including phototherapy and systemic immunomodulators can be considered in adults and children with psoriasis. Unfortunately, in children, the long-term carcinogenic and photoageing effects of phototherapy are unknown, and adherence to frequent treatments is difficult. Traditional systemic medications, such as acitretin, methotrexate and cyclosporine, are not FDA-approved for paediatric psoriasis but their use has been reported. However, these therapies are limited by their side effects including end-organ toxicity. Novel treatment modalities with biological agents and small molecules are emerging as attractive therapeutic alternatives. These treatments target specific components of the inflammatory cascade involved in disease pathogenesis. Additionally, they offer convenient dose scheduling, less laboratory monitoring and a better safety profile. Of all biologics, TNF-a inhibitors, particularly etanercept, have accumulated the most data in paediatric psoriasis; however, black-box warnings of associated increased malignancy rates in children deter widespread use. Ustekinumab is an alternative biologic, wherein a human monoclonal antibody binds the shared p40 subunit of interleukin (IL)-12 and IL-23. These interleukins have been implicated in mediating inflammatory processes, with increased levels measured in psoriatic lesions compared to normal skin. Remarkably, ustekinumab has been demonstrated to be superior to etanercept with patients showing greater clinical response, less injection-site reactions and quicker onset of action, with less frequent dosing.

Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab

Background: IL‐22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL‐22 antagonism have not been defined in human subjects. Objective: We sought to evaluate the cellular and molecular effects of IL‐22 blockade in tissues from patients with moderate‐to‐severe AD. Methods: We assessed lesional and nonlesional skin from 59 patients with moderate‐to‐severe AD treated with anti–IL‐22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. Results: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10−5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10−19), respectively. Because IL‐22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL‐22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL‐22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL‐22–high drug‐treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL‐22–high placebo‐treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL‐22–low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100As, were restricted to the IL‐22–high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T‐cell and dendritic cell activation and differentiation. Conclusions: This is the first report showing a profound effect of IL‐22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL‐22 baseline expression, suggest a central role for IL‐22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.

Skin Diseases Associated with Biologic Therapies

Biologics have become the mainstay of many dermatological and systemic diseases in our current practice. While safety and efficacy of these drugs has been proven extensively in clinical trials, these drugs possess the potential for cutaneous as well as systemic toxicity owing to their immunosuppressive effects. This book chapter focuses on the adverse cutaneous reactions observed with biologics, specifically tumor necrosis factor-alpha inhibitors. These side effects can include but are not limited to injection site reactions, hypersensitivity reactions, psoriasiform eruptions, eczema, vasculitis, and lupus-like reactions.

The Annual Economic Burden of Psoriasis

Psoriasis is a chronic disease that affects approximately 2.2% of the U.S. population. The annual economic burden of this disease, both on an individual and national level, has not been clearly defined. Two recently published articles estimated the annual cost to be

Acitretin for the Treatment of Psoriasis: A Case Report of Long-Lasting Alopecia:

35.2 billion (2013

Iconography : Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial

US) and

Iconography : Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab

112-

Supplementary material : Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab

135 billion (2013