Secukinumab in adult patients with lichen planus: Efficacy and safety results from the randomised, placebo-controlled, proof-of-concept PRELUDE study.

BACKGROUND: Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden; representing a population with a clear unmet need for new treatments. OBJECTIVES: To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP), inadequately controlled by topical corticosteroids. METHODS: PRELUDE was a, randomised, double-blind, placebo-controlled, Phase 2 proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomised to eithersecukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W), or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤2 at Week 16. RESULTS: Overall, 111 patients were randomised (n=37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the 3 cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤2 response at Week 16 with SECQ4W vs. placebo in the MLP (37.5% [95% credibility interval (Crl): 20.3-57.2] vs. 23.1% [95% Crl: 6.5-49.2]) and LPP cohorts (37.5% [95% Crl: 20.2-57.3] vs. 30.8% [95% Crl: 10.8-57.6]). In the LPP cohort, a sustained response for IGA ≤2 from Week 16 to Week 32 was achieved with SECQ4W (Week 16: 37.5%; Week 32: 45.8%), and a substantial improvement was observed in IGA ≤2 response in patients of this cohort switching from placebo (Week 16: 30.8%) to SECQ2W after Week 16 (Week 32: 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals. CONCLUSIONS: PRELUDE is the first randomised controlled basket trial evaluating interleukin-17A inhibition with secukinumab across 3 subtypes of LP. Secukinumab was well-tolerated and safe, showing different response rates across the 3 subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of interleukin-17A across LP subtypes. The novel IGA score showed significant correlation with patient as well as physician reported outcome measurements. TRIAL REGISTRATION NUMBER: NCT04300296.

Safety of IL-23 p19 Inhibitors for the Treatment of Patients With Moderate-to-Severe Plaque Psoriasis: A Narrative Review.

The approved biologics targeting interleukin (IL)-23 p19 for the treatment of moderate-to-severe plaque psoriasis, including guselkumab, tildrakizumab, and risankizumab, have generally favorable safety profiles. The aim of the current review is to describe in detail the safety of these selective inhibitors. A literature search was performed using PubMed from inception to 1 November 2022, to identify clinical trials and real-world evidence publications using the keywords "guselkumab," "tildrakizumab," and "risankizumab." Overall, the most common adverse events (AEs) associated with IL-23 p19 inhibitors in clinical trials were nasopharyngitis, headache, and upper respiratory tract infections. Rates of serious AEs and AEs of interest, including serious infections, nonmelanoma skin cancer (NMSC), malignancies excluding NMSC, major adverse cardiovascular events, and serious hypersensitivity reactions, were not increased with long-term use in clinical trials. Selectively targeting IL-23 p19 was also not associated with elevated risk of opportunistic infections, tuberculosis reactivation, oral candidiasis, or inflammatory bowel disease. Results from real-world studies were similar, supporting the safe long-term use of these biologics in a wider population of patients with psoriasis, including older patients, patients for whom multiple biologics failed, and those with comorbidities such as obesity, metabolic syndrome, cardiovascular disease, dyslipidemia, diabetes, hypertension, and psoriatic arthritis. This review is limited by the lack of direct comparisons among therapeutic agents due to differences among study designs and safety data reporting methods. In conclusion, the favorable safety profiles of IL-23 p19 inhibitors support their long-term use in the management of patients with moderate-to-severe psoriasis.

Narrative Review of the Emerging Therapeutic Role of Brodalumab in Difficult-to-Treat Psoriasis.

Psoriatic involvement in areas of the body such as nails, palms and soles (palmoplantar), and scalp is associated with dramatically negative effects on quality of life relative to involvement elsewhere in the body. Although numerous evidence-based studies demonstrate the efficacy of biologics for overall skin clearance in moderate-to-severe plaque psoriasis (including tumor necrosis factor α [TNFα] inhibitors and interleukin [IL]-17A, IL-12/IL-23, IL-23, IL-17F, and IL-17A/F inhibitors), large, randomized, placebo-controlled clinical studies of psoriasis with nail, palmoplantar, and scalp involvement are needed to better inform decision-making in clinical practice. Moreover, biologic failure caused by drug ineffectiveness is a common occurrence in patients who do not respond, lose response, or are intolerant to treatment. Brodalumab is a fully human IL-17 receptor A antagonist that demonstrates high rates of skin clearance among the latest generation of biologic therapies for treatment of moderate-to-severe psoriasis. This review summarizes current literature on the efficacy of brodalumab and other therapies in difficult-to-treat psoriasis including psoriasis in difficult-to-treat locations (such as psoriasis with nail, palmoplantar, or scalp involvement) and psoriasis in patients whose disease did not respond to other biologics.

Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis.

BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).

Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes.

IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.

Nicolau syndrome and localized panniculitis: a report of dual diagnoses with an emphasis on morphea profunda-like changes following injection with glatiramer acetate.

Glatiramer acetate, given as a 40 mg subcutaneous injection thrice weekly, was recently approved by the FDA based on data suggesting better compliance and a more favorable side effect profile compared to lower dose, daily dosing. The most commonly reported adverse events are transient injection site reactions involving redness and pain at the site; however, more pronounced panniculitis and lipoatrophy have also been reported. Here, we present the case of a 51-year-old female treated with higher dose glatiramer acetate who presented with a cutaneous injection site reaction consistent with Nicolau syndrome. The excised specimen revealed typical glatiramer acetate-associated panniculitis, alongside subcutaneous sclerosis. This case shows the spectrum of cutaneous complications possible with glatiramer acetate injections, the finding of sclerosis being relatively infrequently reported. Given the relatively short duration of trials leading to FDA approval of thrice weekly dosing of glatiramer acetate, clinicians should perform careful clinical and histopathological evaluation and reporting of patients who experience injection site reactions.

Unique Cutaneous Reaction to Second- and Third-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.

BACKGROUND: Recently developed tyrosine kinase inhibitors (TKIs) offer first-line alternatives to patients with chronic myeloid leukemia. While these medications are generally well tolerated, cutaneous reactions occur frequently and can present a management challenge. We describe a newly recognized skin reaction to dasatinib and nilotinib and extend it to the newer agent ponatinib. OBSERVATIONS: Nine patients developed varying degrees of a clinically and histopathologically lichenoid exanthem comprised of erythematous, predominately follicular papules with scale and alopecia. The pattern is reminiscent of the scarring and nonscarring alopecia of follicular lichen planus/lichen planopilaris (LPP) with keratosis pilaris-like LPP--the rare Graham-Little-Piccardi-Lassueur syndrome. Importantly, the accompanying pruritus can be severe enough to result in discontinuation of therapy. CONCLUSIONS: Clinicians should be aware of this unusual eruption to the newer TKIs and the potential therapeutic challenges. Understanding these eruptions may also suggest potential mechanisms in the idiopathic forms of follicular lichen planus.

Triple antibiotic combination therapy may improve but not resolve granuloma annulare.

Granuloma annulare is a fairly common entity yet lacks reliable treatment options especially when multiple lesions or dissemination exists. A recent case series suggests that a regimen of three oral antibiotics may prove to be an effective treatment. Our objective is to evaluate the efficacy of once monthly triple antibiotic therapy for granuloma annulare. We conducted an open-label prospective study of subjects with at least five lesions of granuloma annulare who received once monthly rifampin, ofloxacin, and minocycline for 6 months. Improvement was measured with a novel objective Granuloma Annulare Severity Index (GASI) scoring system. Twenty-one subjects enrolled. Ten subjects (48%) achieved at least a 50% reduction in their GASI, including three subjects (14%) who reached 75% improvement and one subject (5%) whose skin cleared. Six subjects (29%) had no change or worsening of their granuloma annulare. Median GASI scores decreased significantly by 15 points (p < 0.01), although the clinical significance of this result is unclear. As this was a small open-label study without a control group, we cannot determine if the results simply reflect the natural course of the disease. The GASI is not a validated assessment tool. Once monthly triple antibiotic use may improve but not clear granuloma annulare over 6 months. Randomized trials may be warranted to further assess this therapy.

Persistence of Staphylococcus aureus colonization among individuals with immune-mediated inflammatory diseases treated with TNF-α inhibitor therapy.

OBJECTIVE: We investigated the relationship between Staphylococcus aureus colonization and the use of immunosuppressive therapies in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: We prospectively enrolled IMID patients from the rheumatology and dermatology departments of Oregon Health & Science University. At enrolment, we surveyed patients for S. aureus infection risk factors and those using immune-modulating therapies, and evaluated their colonization status with bilateral nares and inguinal fold cultures. Patients were asked to follow up 6-12 months later for reassessment of colonization status by repeat culture. S. aureus isolates were tested for the presence of methicillin resistance by PCR. RESULTS: We enrolled a total of 548 IMID patients. At enrolment, 219 (40.0%) patients were colonized with S. aureus, of which 27 (12.3%) were methicillin-resistant S. aureus (MRSA). Baseline colonization rates were similar between TNF-α inhibitor users and non-users (40.5% and 39.4%, P = 0.79), but were significantly higher for psoriasis patients compared with those with RA (43.5% and 31.8%, P = 0.02). A total of 384 patients were available for follow-up. Patients who were colonized at enrolment were more likely to be colonized at follow-up if they were treated with TNF-α inhibitors during the study as compared to patients without TNF-α inhibitor exposure [odds ratio (OR) = 2.2 (95% CI 1.1, 4.2), P = 0.02]. CONCLUSION: Patients with psoriasis are more likely to be colonized with S. aureus than patients with RA. Patients who are colonized with S. aureus are more likely to remain colonized if exposed to TNF-α inhibitors.

Chronic ulcerative herpes simplex virus infection of the vulva.

Herpes simplex virus infections in HIV-infected individuals can be clinically unusual and difficult to treat due to underlying problems with cell-mediated immunity and the occurrence of antiviral resistance. Additionally, partial or incomplete restoration of immune function may result in chronic ulcerations that require rotational treatments. In this report, we describe the case of a 38-year-old HIV-positive woman who developed the ulcerative form of chronic herpes simplex infection despite highly active antiretroviral therapy and valacyclovir prophylaxis. Repeated intravenous courses of foscarnet and topical cidofovir finally controlled her erosions as her cell-mediated immunity was slowly restored. This case highlights the challenges that still exist in diagnosing and managing this rare presentation of herpes simplex virus.

A double-blind, randomized, bilateral comparison of skin irritancy following application of the combination acne products clindamycin/tretinoin and benzoyl peroxide/adapalene.

BACKGROUND: The use of topical medications for acne vulgaris is often limited by their irritant properties. Newer combination preparations are available and offer convenience, but irritant potential may still be a hindrance, perhaps more so with the combination of 2 agents. Few studies have compared these formulations directly for tolerability. OBJECTIVE: We sought to compare the tolerability of 2 combination topical acne products, clindamycin 1.2%-tretinoin 0.025% (CLIN/RA) gel and benzoyl peroxide 2.5%-adapalene 0.1% (BPO/ADA) gel. METHODS: CLIN/RA and BPO/ADA were applied daily to opposite sides of a subject's face for 21 days in a double-blinded fashion. Investigators' Global Assessments and study subject self-assessments of burning/stinging, itching, erythema, and dryness/scaling were collected. Transepidermal water loss (TEWL) was also measured as an objective measure of skin irritation. A mixed model analysis and repeated-measures analysis of variance were used to compare outcomes for both acne formulations. RESULTS: CLIN/RA produced significantly less burning/stinging than BPO/ADA (P<.001) as well as significantly less pruritus than BPO/ ADA (P<.001). BPO/ADA caused significantly more TEWL than CLIN/RA (P=.005). There was no significant difference in the amount of erythema or the amount of dryness/scaling caused by either formulation. CONCLUSION: CLIN/RA produced significantly less skin irritancy and TEWL than BPO/ADA.

Nephrogenic systemic fibrosis: incidence, associations, and effect of risk factor assessment--report of 33 cases.

PURPOSE: To describe the presentation and clinical course of patients with nephrogenic systemic fibrosis (NSF) at a large acute-care hospital, to evaluate the overall incidence of NSF, and to assess the effect of a hospital-wide policy regarding gadolinium-based contrast agent (GBCA) use on NSF incidence. MATERIALS AND METHODS: A review of all cases of NSF observed at an institution from 2003 to 2008 was conducted. This HIPAA-compliant study was approved by the institutional review board. The informed consent requirement was waived. Demographics, medical history, and associated conditions were recorded. Radiologic procedures were evaluated if they were performed within 1 year prior to NSF onset. GBCA use was assessed by checking the electronic database for each procedure. The incidence of NSF was compared before and after implementation of an institutional policy designed to assess risk of NSF prior to GBCA use. RESULTS: All 33 patients with NSF (mean age, 49 years; age range, 15-78 years) had advanced renal failure (estimated glomerular filtration rate < 15 mL/min/1.73 m(2)) when the GBCA was injected. Twenty-six patients had severe chronic or end-stage renal disease, and seven had acute renal failure. The mean interval between contrast material injection and NSF onset was 29 days +/- 25 (standard deviation) (range, 4-112 days). The overall incidence of NSF was 36.5 cases per 100,000 gadolinium-enhanced magnetic resonance (MR) examinations between 2003 and 2006 and four cases per 100,000 gadolinium-enhanced MR examinations between 2007 and 2008 after screening for NSF risk was instituted (Fisher exact test, P = .001). Five patients developed NSF in the peritransplant period, and four underwent a catheter-based radiographic procedure with administration of a GBCA. CONCLUSION: Common associations of GBCA MR imaging and NSF were acute and severe chronic renal failure and liver or renal transplantation. Screening procedures performed before MR imaging to determine which patients were at risk of developing NSF appear to reduce the incidence of this complication and further support the belief that NSF is associated with GBCA administration.

Adalimumab therapy for recalcitrant pyoderma gangrenosum.

OBJECTIVE: To describe a patient with treatment-refractory pyoderma gangrenosum and the outcome of a novel therapeutic approach. METHODS: Case report and review of the literature. RESULTS: A patient with inflammatory bowel disease developed severe pyoderma gangrenosum while receiving treatment with the chimeric anti-TNF-alpha antibody infliximab. Despite subsequent trials of numerous immunosuppressive and immunomodulatory medications, the dermatologic disease progressed. The patient's ulcers finally resolved when treatment with adalimumab, a fully humanized monoclonal antibody specific for TNF-alpha, was initiated. CONCLUSIONS: We report a novel application of the TNF-alpha inhibitor, adalimumab, in the treatment of pyoderma gangrenosum.

CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death.

The 'help' provided by CD4+ T lymphocytes during the priming of CD8+ T lymphocytes confers a key feature of immune memory: the capacity for autonomous secondary expansion following re-encounter with antigen. Once primed in the presence of CD4+ T cells, 'helped' CD8+ T cells acquire the ability to undergo a second round of clonal expansion upon restimulation in the absence of T-cell help. 'Helpless' CD8+ T cells that are primed in the absence of CD4+ T cells, in contrast, can mediate effector functions such as cytotoxicity and cytokine secretion upon restimulation, but do not undergo a second round of clonal expansion. These disparate responses have features of being 'programmed', that is, guided by signals that are transmitted to naive CD8+ T cells during priming, which encode specific fates for their clonal progeny. Here we explore the instructional programme that governs the secondary response of CD8+ T cells and find that helpless cells undergo death by activation-induced cell death upon secondary stimulation. This death is mediated by tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Regulation of Trail expression can therefore account for the role of CD4+ T cells in the generation of CD8+ T cell memory and represents a novel mechanism for controlling adaptive immune responses.