Secukinumab versus guselkumab in the complete resolution of ustekinumab-resistant psoriatic plaques: The ARROW study.

Interleukin (IL)-23-independent IL-17A production has been suggested to be involved in persistent manifestations of psoriatic disease, including anti-IL-12/23-refractory psoriatic plaques; this study aimed to test this hypothesis by investigating the clinical and molecular effects of direct IL-17A (with secukinumab) versus selective IL-23 inhibition (with guselkumab) in patients with anti-IL-12/23 (ustekinumab)-refractory psoriatic plaques. A 16-week, randomized, open-label, parallel-group, Phase IIa study (ARROW, NCT03553823) was conducted in patients with ≥1 active psoriatic plaque (total clinical score [TCS] ≥6) at screening despite treatment with ustekinumab, and a Psoriasis Area and Severity Index (PASI) score 1-10. Patients were randomized 1:1 to receive secukinumab 300 mg (n = 20) or guselkumab 100 mg (n = 20). Biopsies from one refractory ('target plaque') were obtained at baseline and Week 16. The primary endpoint was the proportion of patients whose ustekinumab-refractory target plaque achieved clear/almost clear status (TCS 0-2) at Week 16. Transcriptomic and histological analyses were conducted on target plaques to determine the molecular effects of direct IL-17A versus selective IL-23 inhibition. At Week 16, target plaque clear/almost clear status was achieved in 60.0% of patients treated with secukinumab versus 40.0% of patients treated with guselkumab (p = 0.1715). Molecular analyses identified that secukinumab modulated a greater proportion of psoriasis disease transcriptome genes (72.1% vs. 48.0%) and resulted in more histological responders (72.2% vs. 53.3%) compared with guselkumab. Secukinumab demonstrated a greater clinical and molecular effect on ustekinumab-refractory psoriatic plaques versus guselkumab. These results are consistent with the hypothesis that IL-23-independent IL-17 mechanisms may be relevant to the inflammation driving refractory manifestations of psoriasis.

Inhibition of IL-13: A New Pathway for Atopic Dermatitis [Formula: see text].

Dupilumab, a monoclonal antibody against the common receptor of interleukin (IL)-4 and IL-13, was the first biologic therapy approved in Canada for treatment of moderate-to-severe atopic dermatitis (AD). While it is considered safe and effective, dupilumab is not universally effective and 8%-38% of patients develop conjunctivitis, while some patients develop head and neck dermatitis. Thus, new therapeutic options are warranted. While both IL-4 and IL-13 play important roles in the pathogenesis of AD, it has been recently demonstrated that IL-13 is the primary upregulated cytokine in AD skin biopsy samples. A placebo-controlled phase 2b clinical trial evaluating the efficacy and safety of lebrikizumab, an IL-13 inhibitor, in AD demonstrated that, at 16 weeks, Eczema Area and Severity Index (EASI) 75 and Investigator's Global Assessment (IGA) 0/1 were achieved by 60.6% and 44.6% of patients taking lebrikizumab at its highest dose (vs 24.3% and 15.3% of patients taking placebo, respectively). Moreover, treatment with lebrikizumab was associated with rapid improvement of pruritus and low rates of conjunctivitis (1.4%-3.8%). Another IL-13 monoclonal antibody, tralokinumab, was evaluated for safety and efficacy in moderate-to-severe AD. By week 12, among adults receiving 300 mg tralokinumab, 42.5% achieved EASI-75 and 26.7% achieved IGA 0/1 score (vs 15.5% and 11.8% in the placebo group, respectively). Both lebrikizumab and tralokinumab demonstrated acceptable safety profiles in AD (and non-AD) trials with adverse events often being comparable between treatment and control groups. Thus, IL-13 inhibitors may provide a safe and effective treatment alternative for patients with moderate-to-severe AD.

A Patient Charter for Chronic Urticaria.

Chronic urticaria (CU) is the recurring development of wheals (aka "hives" or "welts"), angioedema, or both for more than 6 weeks. Wheals and angioedema occur with no definite triggers in chronic spontaneous urticaria, and in response to known and definite physical triggers in chronic inducible urticaria. Approximately 1.4% of individuals globally will have CU during their lifetime. The itching and physical discomfort associated with CU have a profound impact on daily activities, sexual function, work or school performance, and sleep, causing significant impairment in a patient's physical and mental quality of life. CU also places a financial burden on patients and healthcare systems. Patients should feel empowered to self-advocate to receive the best care. The voice of the patient in navigating the journey of CU diagnosis and management may improve patient-provider communication, thereby improving diagnosis and outcomes. A collaboration of patients, providers, advocacy organizations, and pharmaceutical representatives have created a patient charter to define the realistic and achievable principles of care that patients with CU should expect to receive. Principle (1): I deserve an accurate and timely diagnosis of my CU; Principle (2): I deserve access to specialty care for my CU; Principle (3): I deserve access to innovative treatments that reduce the burden of CU on my daily life; Principle (4): I deserve to be free of unnecessary treatment-related side-effects during the management of my CU; and Principle (5): I expect a holistic treatment approach to address all the components of my life impacted by CU. The stated principles may serve as a guide for healthcare providers who care for patients with CU and translate into better patient-physician communication. In addition, we urge policymakers and authors of CU treatment guidelines to consider these principles in their decision-making to ensure the goals of the patient are achievable.

Immune response to pneumococcus and tetanus toxoid in patients with moderate-to-severe psoriasis following long-term ustekinumab use.

BACKGROUND: Little is known about the impact of long-term use of immunosuppressive agents on immune response. OBJECTIVES: Assess the impact of continuous maintenance ustekinumab treatment on patients' ability to mount immune responses to pneumococcal (T-cell-independent) and tetanus toxoid (T-cell-dependent) vaccines. PATIENTS AND METHODS: Ustekinumab-treated patients with moderate-to-severe psoriasis treated in the long-term extension of the Phase 3 PHOENIX 2 trial (n=60) were compared with control psoriasis patients not receiving systemic therapy (n=56). Patients were vaccinated with both 23-valent pneumococcal and tetanus toxoid vaccines. Serum samples collected pre-vaccination and 4 weeks post-vaccination were assessed for antibody responses. RESULTS: No differences in the ability of ustekinumab-treated patients to respond to pneumococcal or tetanus toxoid vaccinations were observed compared with controls. A ≥2-fold increase in antibody levels in ≥7 of 14 serotypes of the pneumococcal vaccine was observed in ustekinumab-treated (96.6%) and untreated control (92.6%) patients following vaccination. Ustekinumab-treated patients achieved a ≥4-fold increase (84.7%) in anti-tetanus antibody vs. 77.8% in the control group. No differences were detected in ex-vivo responses to anti-CD3/CD28 or tetanus toxoid between ustekinumab-treated and control groups. CONCLUSION: Long-term treatment (≥3 years) with ustekinumab does not compromise the immune response to T-cell-dependent/-independent vaccines in patients with moderate-to-severe psoriasis.

Influence of the quantity of sunscreen applied on the ability to protect against ultraviolet-induced polymorphous light eruption.

BACKGROUND/PURPOSE: Despite the fact that most people apply less sunscreen than the 2 mg/cm(2) required to measure sun protection factor (SPF), there is a lack of clinical data on the protection afforded from lower applied quantities. The aim of this study was to compare the ability of sunscreens to protect against UV-induced polymorphous light eruption (PLE) when applied at 2 mg/cm(2) and 1 mg/cm(2) . METHODS: Two SPF 45 sunscreens (one with a high level and one with a low level of UVA protection) were applied at 2 mg/cm(2) and 1 mg/cm(2) to four randomized 6 × 6 cm areas on the upper thorax of 15 female patients with a typical history of PLE. The areas were exposed daily to increasing UVA-UVB radiation until a PLE reaction was detected or a maximum of five consecutive days. RESULTS: The proportion of patients who developed a PLE reaction with the high UVA-protection sunscreen was significantly lower (0%) than with the low UVA-protection sunscreen (73%) when both sunscreens were applied at 2 mg/cm(2) (P = 0.004). At 1 mg/cm(2) , 33% and 80% of patients presented a PLE reaction with the high and low UVA-protection sunscreen, respectively (P = 0.064). CONCLUSION: A high SPF and high UVA-protection broad spectrum sunscreen was able to protect the majority of patients from the development of UV-induced PLE reaction even at 1 mg/cm(2) .

Photodynamic therapy with methylaminolevulinate 80 mg/g without occlusion improves acne vulgaris.

BACKGROUND: Photodynamic therapy (PDT) with methylaminolevulinate (MAL) under occlusion is effective for the treatment of acne vulgaris but is associated with significant phototoxic side effects. OBJECTIVE: To evaluate the safety and efficacy of topical MAL with or without occlusion followed by red light exposure in patients with facial acne vulgaris. PATIENTS/METHODS: Forty-four patients with facial acne vulgaris were randomized to receive four MAL applications (80 mg/g) at two-week intervals with occlusion on either the right or left side followed 90 minutes later by either 25 or 37 J/cm2 of red light. RESULTS: At 18 weeks after the first MAL-PDT treatment, the percentage of inflammatory lesions was reduced by a median of 31.7, 59.4, 58.1 and 55.8 percent for patients randomized to 25 J/cm2 without occlusion, 25 J/cm2 with occlusion, 37 J/cm2 without occlusion and 37 J/cm2 with occlusion respectively. MAL-PDT was, in general, well tolerated and only two patients discontinued their participation due to adverse events. CONCLUSION: PDT with MAL at 80 mg/g without occlusion reduces the number of inflammatory lesions in patients with facial acne vulgaris.

Protection afforded by sunscreens containing inorganic sunscreening agents against blue light sensitivity induced by aminolevulinic acid.

BACKGROUND: Application of aminolevulinic acid (ALA) for photodynamic therapy induces significant sensitivity to visible light. OBJECTIVE: To determine whether sunscreens containing inorganic agents are effective against sensitivity to blue light induced by ALA application. METHODS & MATERIALS: Twenty subjects received application of ALA on the arm. Thirty minutes before blue light exposure, two sun protection factor 50 inorganic-based sunscreens containing iron oxide 3.2% and 0.2% were applied on separate areas where ALA was applied; a third area received no sunscreen. Small areas of skin were exposed to increasing fluences of blue light 3 or 18 hours later, and the minimal phototoxic dose (MPD) was noted. RESULTS: Three hours after ALA application MPD was 29.2 and 22.6 J/cm(2) for skin protected with sunscreen containing iron oxide 3.2% and 0.2%, respectively, and 10.6 J/cm(2) for unprotected skin (p=.003 and .0497 respectively). At 18 hours after ALA application, MPD for sunscreen containing iron oxide 3.2% was 5.78, compared with 0.33 for unprotected skin (p<.001) with a blue light protection factor of 21. CONCLUSION: The sunscreen containing iron oxide 3.2% afforded significant protection against blue light sensitivity induced by ALA application.

Palmoplantar pustular psoriasis (PPPP) is characterized by activation of the IL-17A pathway.

BACKGROUND: Palmoplantar pustular psoriasis (PPPP) is a variant of psoriasis, which has significant negative impact on quality of life. The cellular and molecular inflammatory pathways involved in PPPP have not been well studied. OBJECTIVE: Study the expression of cytokines and chemokines involved in the IL-17/IL-23 axis in palmoplantar pustular psoriasis and other difficult to treat psoriasis areas (palms, scalp, elbows and lower legs). METHODS: Skin biopsies were performed on a total of 80 patients with PPPP, non-pustular palmoplantar psoriasis (NPPPP), or psoriasis located on elbows, knees and scalp as well as 10 healthy subjects. RT-PCR, immunohistochemistry and flow cytometry on cells extracted from skin biopsies were used to compare PPPP to other forms of psoriasis. RESULTS: There was a significant (p<0.05) increase in the expression of IL-1ß, IL-6, LL-37, IL-19, IL-17A, CXCL1 and CXCL2 in PPPP as compared to NPPPP. However, there was no significant difference in expression of IL-23 in PPPP as compared to NPPPP and other forms of psoriasis. The proportion of IL-22+ but not IL-17A+ mast cells was higher in PPPP as compared to NPPPP (p<0.05). CONCLUSION: These results suggest that the IL-17A pathway may play a more important role in PPPP than in NPPPP.

Open-label exploratory study of acitretin for the treatment of severe chronic hand dermatitis.

INTRODUCTION: Acitretin is a retinoid approved for the treatment of psoriasis that has good efficacy for palmoplantar psoriasis. The safety and efficacy of acitretin in severe chronic hand dermatitis (CHD) is unknown. METHODS: A total of nine patients with severe CHD were enrolled and treated with acitretin 10 mg once daily which could be increased to 30 mg daily if well-tolerated. Patients were treated for up to 24 or 12 weeks if the physician global assessment (PGA) was clear or almost clear at that time. CHD severity was evaluated using a 5-grade PGA scale and the modified total lesion symptom score (mTLSS). RESULTS: The proportion of patients achieving PGA of clear or almost clear was 33.3% (95% CI: 9-69%) and the proportion achieving PGA of clear, almost clear or mild was 44% (95% CI: 15-77%). The mTLSS decreased by 45% (-6.3 ± 4.7; p = 0.02). Three patients did not complete the study: one due to an increase in facial dermatitis, one due to lack of efficacy and one who withdrew consent. CONCLUSIONS: This pilot study suggests that acitretin could improve severe CHD. Further studies are needed to better assess the efficacy and safety of acitretin in patients with severe CHD.

Drug eruptions: approaching the diagnosis of drug-induced skin diseases.

Adverse drug reactions are a major problem in drug therapy, and cutaneous drug reactions account for a large proportion of all adverse drug reactions. Cutaneous drug reactions are also a challenging diagnostic problem since they can mimic a large variety of skin diseases, including viral exanthema, collagen vascular disease, neoplasia, bacterial infection, psoriasis, and autoimmune blistering disease, among others. Furthermore, determining that a particular medication caused an eruption is often difficult when the patient is taking multiple drugs. In this review, we will describe and illustrate a thoughtful, comprehensive, and clinical approach to the diagnosis and management of adverse cutaneous drug reactions. A morphologic approach to drug eruption includes those that are classified as maculopapular, urticarial, blistering or pustular with or without systemic manifestations. Exanthematous drug eruptions, drug hypersensitivity syndrome, urticaria and angioedema, serum sickness-like reactions, fixed drug eruptions, drug-induced autoimmune blistering diseases, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced acne, acute generalized exanthematous pustulosis, lichenoid drug eruptions and photosensitivity eruptions will be discussed.

Effect of adalimumab on sleep parameters in patients with psoriasis and obstructive sleep apnea: a randomized controlled trial.

INTRODUCTION: Obstructive sleep apnea (OSA) is frequently seen in patients with psoriasis vulgaris. The effect of adalimumab, a TNF-α antagonist, on OSA is unknown. METHODS: Patients with at least 5% of their body surface area covered with psoriasis and a sleep apnea defined as an apnea/hypopnea index (AHI) of at least 15 were recruited. They were randomized to either adalimumab 80 mg followed by adalimumab 40 mg every other week for 7 weeks or placebo. Patients were evaluated by polysomnography at baseline and day 56. The objective of this trial was to study the efficacy of adalimumab on sleep parameters in patients with psoriasis and OSA. The primary end point of this double-blind study was the change in AHI between baseline and day 56. RESULTS: A total of 20 patients who were randomized completed the trial. There was no significant difference (p = 0.485) (95% CI = -21.07-42.73) at day 56 in the change from baseline in AHI between groups. CONCLUSIONS: Adalimumab used for 8 weeks at 40 mg every other week for the treatment of psoriasis did not improve OSA in this 20-patient study.

A double-blind study of tolerance and efficacy of a new urea-containing moisturizer in patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis patients almost all use moisturizers to prevent and treat their skin disease. However, the safety and efficacy of moisturizers are rarely studied in this patient population. Aims To evaluate the efficacy and tolerability of urea-containing moisturizers in subjects with atopic dermatitis. METHODS: One hundred subjects with atopic dermatitis were randomized to apply either a new 5% urea moisturizer or a commercially available 10% urea lotion twice a day for 42 days. Scoring Atopic Dermatitis severity index (SCORAD) was performed at Day 0 and Day 42. Cosmetic acceptability questionnaires, adverse events, and a 5-point tolerance evaluation were administered or performed at Day 42. RESULTS: Both study products were very well tolerated by subjects and only three subjects discontinued their participation in the study due to adverse events. Mean SCORAD significantly decreased between Day 0 and Day 42 by 19.76% and 19.23%, respectively, for subjects treated with the new 5% urea moisturizer or the 10% urea lotion (P < 0.001). There was no difference between the two products in SCORAD reduction; however, significantly more subjects preferred using the new 5% urea moisturizer as compared with the 10% urea lotion. CONCLUSIONS: Both the new 5% urea moisturizer and the 10% urea lotion improved atopic dermatitis and were very well tolerated. However, the cosmetic acceptability questionnaire showed that subjects preferred using the new 5% urea moisturizer over the 10% urea lotion.

Efficacy and tolerability of topical tacrolimus ointment for the treatment of male genital psoriasis.

BACKGROUND: Genital psoriasis is difficult to treat and has a significant psychological impact on affected patients. OBJECTIVE: To study the safety and efficacy of topical tacrolimus ointment in male patients with genital psoriasis. METHODS: This was an open-label study in 12 male patients with genital psoriasis. Patients received topical tacrolimus 0.1% ointment twice daily for 8 weeks followed by a 4-week observational period. Efficacy was assessed by a modification of the Psoriasis Area and Severity Index (PASI) scale adapted for genital psoriasis (male genital PASI). Severity was also evaluated individually for the glans, shaft of the penis, and scrotum. RESULTS: Male genital PASI decreased from a mean score of 15.8 at baseline to 1.2 at week 8 (p < .001). Psoriasis severity also improved significantly for the glans, shaft of the penis, and scrotum evaluated individually. Tacrolimus 0.1% ointment was very well tolerated, with only mild pruritus or burning sensation of limited duration reported. CONCLUSIONS: Topical tacrolimus ointment appears very efficacious and well tolerated in male patients with genital psoriasis.

Pyodermatitis-pyostomatitis vegetans: two cases and a review of the literature.

BACKGROUND: Pyodermatitis-pyostomatitis vegetans (PD-PSV) is a rare vegetating, pustular, eosinophilic, mucocutaneous dermatosis characterized by mucocutaneous lesions of the genital, axillary, and oral regions, as well as on the scalp. OBJECTIVE: We report two patients who were diagnosed with PD-PSV. The published cases of this rare disorder are reviewed. RESULTS: The first patient presented with vegetating pustular plaques of the scalp, vulva, and mouth. The second patient initially showed pustules on fingers and then on toes. Vulva and mouth were later involved. There was no gastrointestinal involvement in either case. In both cases, histology revealed eosinophilic spongiosis with eosinophilic microabscesses and pseudoepitheliomatous hyperplasia. Direct immunofluorescence was negative. CONCLUSION: Pyodermatitis-pyostomatitis vegetans is a rare disorder of unknown cause. It bears similarities to pemphigus vegetans but histology, direct immunofluorescence, and clinical history show the differences. Response to treatment is generally rapid. In several reported cases, an inflammatory gastrointestinal disorder is found in association with the mucocutaneous signs.