On the Interdisciplinary Treatment and Management of Patients with Immune-Mediated Inflammatory Diseases. A Study on Patients' Personal Experiences and Perspectives.

Purpose: Immune-mediated inflammatory diseases (eg, axial spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and hidradenitis suppurativa) are common diseases that exert an extensive effect on the health-related quality of life, particularly when multiple concomitant conditions are present. Previous reports indicate that the traditional siloed approach to care can lead to a lack of patient centricity and inefficient disease management. In this article, we aimed to evaluate an interdisciplinary program for the treatment of immune-mediated inflammatory diseases compared to routine clinical practice. Patients and Methods: This was a mixed-method study, combining qualitative and quantitative data. Patients with co-occurrence of ≥2 immune-mediated inflammatory diseases treated in an interdisciplinary clinic (n = 48) or traditional usual care (n = 17) answered open-ended questions about their care experiences. Two independent coders blinded to patients' treatment group coded three aspects of the narratives provided by the patients' responses: Themes, Emotional valence, and Personal growth (ie, redemption). Themes were analyzed descriptively to explore possible differences between patients assigned to the interdisciplinary clinic and patients assigned to the usual care setting. Group differences in patients' emotional experiences were assessed, and we examined potential group differences in positive personal growth. Results: Our findings indicate that an interdisciplinary combined clinic approach provides benefits for patients with multiple inflammatory diseases towards the usual setup. Patients experienced benefits on a number of specific quality-of-life themes including acceptance, optimism, disease understanding, personal growth, and better disease control. The narratives of the patients in the interdisciplinary group were significantly more emotionally positive and included more positive personal growth compared to the usual care group. Conclusion: The findings indicate a patient-reported benefit, especially from the holistic approach and cross-specialty combined consultations in an interdisciplinary clinic compared to usual specialized healthcare, which was underscored by narratives highlighting an overall improved quality of life.

Secukinumab and Dead Sea Climatotherapy Impact Resolved Psoriasis Skin Differently Potentially Affecting Disease Memory.

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory.

The Epidemiology of Hospital-Treated Alopecia Areata in Denmark, 1995-2016.

INTRODUCTION: Alopecia areata (AA) is an autoimmune skin disease presenting as nonscarring hair loss. Information on the epidemiology of AA, especially the occurrence of AA and its subtypes within the general population, is scarce. The study aimed to estimate the incidence rates and prevalence of hospital-treated AA and its subtypes in Denmark and to examine the demographic and clinical characteristics of patients with AA, including comorbidities and use of prescription medications. METHODS: This was a cohort study based on data from administrative and health registers in Denmark in 1995-2016. The study included individuals who were (1) registered with a hospital inpatient or hospital-based outpatient clinic diagnosis of AA between 1995 and 2016 in the Danish National Patient Registry covering encounters at all Danish hospitals, (2) alive and resided in Denmark anytime between 1995 and 2016, (3) aged ≥ 12 years, and (4) resided uninterrupted in Denmark during the 12 months before the first AA diagnosis during the study period. RESULTS: During the study period, 2778 individuals with an incident hospital-based diagnosis of AA were identified; 63.1% were female and 28.7% of the patients were aged ≥ 50 years. Over the study period, the overall incidence rate for any hospital-treated AA per 100,000 person-years was 2.62 (95% confidence interval [CI], 2.53-2.72), and the overall prevalence in 2016 was 71.7 (95% CI 69.4-74.1) per 100,000 persons. Both incidence rate and prevalence increased over time. Prevalence of most hospital-treated comorbidities or history of medication use was below 10% and was similar in the alopecia totalis (AT)/alopecia universalis (AU) and non-AT/AU subtypes of AA. CONCLUSION: This cohort study reported incidence rates and prevalence over time and characteristics of individuals with hospital-treated AA in Denmark, which are in agreement with those previously reported in this population.

ERAP1 and ERAP2 Gene Variants as Potential Clinical Biomarkers of Anti-IL-17A Response in Psoriasis Vulgaris.

BACKGROUND: Interleukin-17A (IL-17A) is a proinflammatory cytokine, playing an essential role in the development of psoriasis. Although treatment with anti-IL-17A monoclonal antibodies has demonstrated high efficacy in psoriasis patients, not all patients respond equally well, highlighting the need for biomarkers to predict treatment response. Specific single nucleotide polymorphisms (SNPs) in the endoplasmatic reticulum aminopeptidase (ERAP) 1 and 2 genes have been associated with psoriasis and other immune-mediated diseases. OBJECTIVES: We aimed to investigate the association between the ERAP1 and ERAP2 genotypes and response to secukinumab treatment in psoriasis patients. METHODS: A total of 75 patients with plaque psoriasis were included. All patients were genotyped for the ERAP1 rs27524, rs27044, rs30187, rs2287987, and rs26653 SNPs, the ERAP2 rs2248374 SNP, and human leukocyte antigen-C*06:02 (HLA-C*06:02) status. RESULTS: Our results demonstrated that individuals with specific ERAP1 and ERAP2 genotypes had a considerably lower response rate to secukinumab treatment. Patients with the ERAP2 rs2248374 G/G genotype had a more than 6-fold increased risk of treatment failure compared with patients with the rs2248374 A/G or -A/A genotypes. Stratifying for HLA-C*06:02 status, the ERAP2 G/G genotype pointed towards an increased risk of treatment failure among HLA-C*06:02-positive patients, although this was not statistically significant. CONCLUSION: Taken together, this unique study breaks new ground by identifying distinct ERAP1 and ERAP2 gene variants that may serve as potential biomarkers for predicting the treatment response to secukinumab in psoriasis patients. Notable, out data extends existing knowledge by linking specific ERAP1 and ERAP2 gene variants to treatment outcome.

Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans.

Psoriatic arthritis mutilans (PAM) is the rarest and most severe form of psoriatic arthritis, characterized by erosions of the small joints and osteolysis leading to joint disruption. Despite its severity, the underlying mechanisms are unknown, and no susceptibility genes have hitherto been identified. We aimed to investigate the genetic basis of PAM by performing massive parallel sequencing in sixty-one patients from the PAM Nordic cohort. We found rare variants in the NADPH oxidase 4 (NOX4) in four patients. In silico predictions show that the identified variants are potentially damaging. NOXs are the only enzymes producing reactive oxygen species (ROS). NOX4 is specifically involved in the differentiation of osteoclasts, the cells implicated in bone resorption. Functional follow-up studies using cell culture, zebrafish models, and measurement of ROS in patients uncovered that these NOX4 variants increase ROS levels both in vitro and in vivo. We propose NOX4 as the first candidate susceptibility gene for PAM. Our study links high levels of ROS caused by NOX4 variants to the development of PAM, offering a potential therapeutic target.

Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome.

ABSTRACT: Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus-specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial.

Importance: Hidradenitis suppurativa is a painful immune-mediated disorder with limited treatment options; hence, a need exists for new treatments. Objective: To evaluate the feasibility of heat shock protein 90 inhibition by RGRN-305 as a novel mechanism of action in treating moderate to severe hidradenitis suppurativa. Design, Setting, and Participants: This was a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial conducted between September 22, 2021, and August 29, 2022, at the Department of Dermatology, Aarhus University Hospital in Denmark. The study included a 1- to 30-day screening period, a 16-week treatment period, and a 4-week follow-up period. Eligibility criteria included age 18 years or older and moderate to severe hidradenitis suppurativa with 6 or more inflammatory nodules or abscesses in at least 2 distinct anatomic regions. Of 19 patients screened, 15 patients were enrolled in the study. Intention-to-treat analysis was performed. Interventions: Patients were randomly assigned (2:1) to receive oral RGRN-305, 250-mg tablet, or matching placebo once daily for 16 weeks. Main Outcomes and Measures: The primary efficacy end point was the percentage of patients achieving Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) at week 16. Secondary efficacy end points included HiSCR-75 or HiSCR-90, Hidradenitis Suppurativa Physician's Global Assessment, Dermatology Life Quality Index scores, and a pain numeric rating scale. Safety was assessed by adverse events, physical examinations, clinical laboratory measurements, and electrocardiograms. Results: A total of 15 patients were enrolled, completed the study, and were included in all analyses (10 [67%] female; median age, 29 [IQR, 23-41] years). The primary end point HiSCR-50 at week 16 was achieved by a higher percentage in the RGRN-305 group (60% [6 of 10]) than in the placebo group (20% [1 of 5]). Improvements were also observed across all secondary end points at week 16, including higher rates of the harder-to-reach HiSCR levels; 50% (5 of 10) achieved HiSCR-75 and 30% (3 of 10) achieved HiSCR-90, whereas none of the placebo-treated patients achieved HiSCR-75 or HiSCR-90. RGRN-305 was well tolerated, with no deaths or serious adverse events, and treatment-emergent adverse events were similarly frequent between the RGRN-305 and placebo groups. Conclusions and Relevance: The findings of this trial suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials. Trial Registration: ClinicalTrials.gov Identifier: NCT05286567.

Transcriptomic Analysis of Hidradenitis Suppurativa: A Unique Molecular Signature with Broad Immune Activation.

Hidradenitis suppurativa is a chronic inflammatory skin disease with limited treatment options. The poorly understood pathogenesis hinders the development of effective treatments; therefore, a pressing need exists to further elucidate the molecular mechanisms in hidradenitis suppurativa. This study investigated the underlying inflammatory pathways and cell types in hidradenitis suppurativa using transcriptomic approaches with RNA sequencing of lesional and non-lesional skin biopsies from hidradenitis suppurativa, which was jointly analyzed with previously published transcriptomic data from atopic dermatitis and psoriasis patients. The differential expression and pathway enrichment analyses demonstrated the activation of multiple inflammatory processes, including the innate and adaptive immune systems, implicated in the hidradenitis suppurativa pathogenesis. In agreement, hidradenitis suppurativa exhibited a unique and heterogeneous cell type signature involving lymphoid and myeloid cells such as B cells and macrophages. Furthermore, hidradenitis suppurativa displayed increased expression of TH1/2/17 signatures with no predominant TH signatures unlike psoriasis (TH1/17) and atopic dermatitis (TH2). In summary, our study provides molecular insights into the pathomechanisms in hidradenitis suppurativa, revealing a strong and widespread immune activation, which may benefit from treatment strategies offering a broad immunomodulation of various key inflammatory pathways. Our data not only corroborate previously reported findings but also enhance our understanding of the immune dysregulation in hidradenitis suppurativa, uncovering novel and potential therapeutic targets.

Investigation of plaque psoriasis relapse after secukinumab withdrawal in patients from two Phase 3 studies.

BACKGROUND: Secukinumab is effective against a range of psoriatic manifestations. Investigating psoriasis (PsO) relapse following secukinumab discontinuation could provide insights into long-term PsO remission. OBJECTIVE: To examine PsO relapse rates upon treatment discontinuation following one year of secukinumab treatment. METHODS: This study (NCT01544595) is an extension of the Phase 3 ERASURE/FIXTURE studies in patients with moderate-to-severe plaque PsO. After one year of secukinumab 300 mg or 150 mg treatment, Week 52 PASI75 responders were randomly assigned to receive placebo. Upon relapse, patients receiving placebo were switched to their previous secukinumab dose. The study primary outcome was non-relapse rate after secukinumab withdrawal. RESULTS: Following the last dose of secukinumab 300 mg, 21% and 10% of patients who switched to placebo did not relapse at one and two years after discontinuation, respectively. Patients who received secukinumab 150 mg for one year showed a lower proportion of non-relapse following treatment discontinuation (14% and 6%) at one and two years, respectively). Non-relapsing patients maintained low mean PASI (2.8) at one year drug-free versus baseline (20.9); 1.7 at two years drug-free versus baseline (19.2). Disease duration (P=0.017) and severity (P=0.022) were significantly associated with time-to-relapse in patients initially treated with secukinumab 300 mg; patients with shorter disease duration and lower baseline PASI remained relapse-free for longer. CONCLUSIONS: Following discontinuation of secukinumab, a proportion of patients stayed relapse-free. Further, patients with shorter disease duration remained relapse-free for longer, suggesting that earlier treatment with secukinumab may result in long-term clinical control of moderate-to-severe PsO.

Calcipotriol and Betamethasone Dipropionate Cream Based on PAD Technology for the Treatment of Plaque Psoriasis: A Narrative Review.

Topical treatment plays a crucial role in psoriasis management, with non-adherence being a major barrier to treatment success. The fixed-dose combination of calcipotriol (CAL) and betamethasone dipropionate (BDP) represents the first-line choice in topical psoriasis treatment. A CAL/BDP cream based on polyaphron dispersion (PAD) Technology has emerged as a novel formulation for a more convenient topical treatment of psoriasis. This article aims to summarize the most relevant published evidence about CAL/BDP PAD-cream and its underlying PAD Technology. The PAD Technology enables CAL and BDP stability in an aqueous cream through a multimolecular shell structure, as well as it increases the penetration of both active ingredients into the epidermis and dermis. This technology also demonstrated to increase the cosmetic acceptability and to provide the desirable sensory properties for a topical psoriasis treatment. Two phase III clinical trials have been conducted so far with CAL/BDP PAD-cream. Findings from both trials revealed high efficacy with a fast onset of action, a favourable safety and tolerability profile and convenience for CAL/BDP PAD-cream compared to CAL/BDP gel. In the trial including patients with psoriasis affecting the scalp (MC2-01-C7), results support the use of CAL/BDP PAD-cream in scalp psoriasis. An anchored matching-adjusted indirect comparison (MAIC) was conducted to compare CAL/BDP PAD-cream and CAL/BDP foam, as both products had been previously compared to CAL/BDP gel. CAL/BDP PAD-cream and CAL/BDP foam showed equivalent efficacy and quality of life at their recommended treatment duration, whereas greater treatment satisfaction for CAL/BDP PAD-cream was found after one week of treatment. Overall, the high patient acceptability and treatment satisfaction observed with CAL/BDP PAD-cream in clinical trials may lead to improved adherence and hence higher efficacy in clinical practice.

Lyme neuroborreliosis presenting with urinary retention and spastic paraparesis.

Progressive myelopathy, urinary retention and gait problems are rare presenting features of Lyme neuroborreliosis. A 30-year-old man had 11 months of urinary retention and 3 months of spastic paraparesis. MR scans of the brain and the spinal cord showed leptomeningeal thickening with contrast enhancement. Cerebrospinal fluid showed mononuclear pleocytosis, decreased glucose, increased protein and chemokine ligand 13, with intrathecal Borrelia-specific IgM and IgG antibodies. He received 14 days of intravenous ceftriaxone followed by 14 days of oral doxycycline. Despite improvement at 6 months, he still had severe gait problems. Urinary retention in otherwise healthy people needs investigation, and Lyme neuroborreliosis is a rare cause.

PsoBarrier EU study: a Multicentre, Cross-sectional Survey Investigating the Quality of Psoriasis Care in Four European Countries.

Enhanced treatment options for psoriasis and growing use of guidelines increased the potential to better quality of psoriasis care in Europe. The aim of the PsoBarrier EU study is to compare the quality and processes of psoriasis care in four European countries with different healthcare systems, based on validated quality indicators. This cross-sectional survey was conducted in dermatology centres in Denmark, Germany, Poland and Spain on 1,304 patients, using standardized patient and physician questionnaires. Measured by quality of psoriasis care indicators, patients in Poland had the most critical outcomes, such as the highest disease severity (Psoriasis Area and Severity Index; PASI) and lowest health-related quality of life (Dermatology Life Quality Index; DLQI). This indicates differences in psoriasis care, with Polish participants experiencing more severe psoriasis and its consequences. Differences in the healthcare systems, which create barriers to accessing treatments, could explain variations in quality of care.

Treatment Preferences in Young Adults with Moderate to Severe Psoriasis: A Qualitative Study from the Nordic Countries.

INTRODUCTION: The purpose of this study is to explore treatment preferences and identify patient characteristics in young bio-naive adults with moderate to severe psoriasis in the Nordic countries (Norway, Finland, Sweden, and Denmark). METHODS: Patients were 18-45 years old and bio-naive but referred for biologic treatment of moderate to severe psoriasis. Patients were included at eight Nordic dermatology clinics. Patients with significant comorbidity or psoriatic arthritis were excluded. The Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) were assessed along with basic patient information. A semistructured interview guide was used in individual qualitative interviews, asking patients about their treatment preferences and reasons, disease journey, and disease management. The interviews were analyzed using thematic content analysis. Twenty-four patients sufficed to reach saturation in this qualitative study. RESULTS: The patient sample characteristics represented a qualitative variation in age, sex, symptoms, duration of disease, and country. We included a total of 12 male and 12 female patients. The mean age was 34 years (range 18-45 years), the mean age at diagnosis was 20 years (range 6-34 years), the mean ± standard deviation (SD) time since diagnosis was 13 ± 8 years, PASI was 9.5 ± 4.7, and DLQI was 15.2 ± 6.4. Interviews suggested that both the burden of disease as well as the burden of treatment influenced patient preferences regarding treatment attributes, hence getting alleviation from symptoms did not alone influence patient preferences. Time, effort, and inconvenience related to psoriasis treatments also influenced patient preferences. CONCLUSIONS: This first in-depth, qualitative study in young bio-naive adults with psoriasis suggests that patient preferences are focusing not only on symptom relief but also on alleviating the burden of psoriasis treatment. Understanding the reasons for patient preferences and the perspectives of young adults is needed to guide individual shared decision-making in psoriasis management.

Not much research has been done on understanding the disease burden and treatment needs of young adults suffering from psoriasis. This is an interview study with young adults from Nordic countries suffering from moderate to severe psoriasis with an active lifestyle. The adult patients were all referred for biologic treatment of psoriasis but had not yet started treatment when they were interviewed. The aim was to explore treatment preferences in this group.The study showed that treatment goals depended upon both alleviation of symptoms and obtaining a low treatment burden. The most influential symptoms were scaling, itching, and visible plaques. The most important treatment burden features were efficacy, durability, speed of response, safety, and convenience. Understanding the reasons behind these different treatment preferences is essential to help shared-decision psoriasis management that matches individual needs.

Calcipotriene and Betamethasone Dipropionate PAD-Cream Demonstrates Greater Treatment Efficacy in Patients with Moderate-to-Severe Psoriasis Compared to Topical Suspension/Gel: A Subgroup Analysis of Two Phase 3 Studies.

INTRODUCTION: Psoriasis ranges from mild to severe with the majority of patients having mild disease. Mild to moderate disease is often treated with topical therapies while photo-, oral, and biologic therapies are generally reserved for moderate-to-severe disease. There is a strong scientific rationale for the combination of calcipotriene (CAL) and betamethasone dipropionate (BDP) with respect to mode of action, efficacy, and safety and CAL/BDP has shown an inhibitory effect on key pathogenic cytokines in psoriasis including tumor necrosis factor-α, interleukin (IL)-17, and IL-23. METHODS: The objective of this pooled post hoc analysis is to investigate the efficacy of CAL/BDP polyaphron dispersion (PAD)-cream in subgroups of patients with moderate-to-severe psoriasis from two completed phase 3 studies conducted in the USA and Europe. RESULTS: The proportion of patients achieving Physician Global Assessment (PGA) treatment success as well as a modified Psoriasis Area and Severity Index (mPASI)75 response was higher in the subgroup with a body surface area > 10% and mPASI > 10 and Dermatology Life Quality Index > 10 at baseline compared to the overall patient population. Furthermore, the numerical difference in treatment efficacy between CAL/BDP PAD-cream and CAL/BDP topical suspension/gel increased in patient subgroups with higher baseline severity. Similar patterns were shown for the patient-reported outcomes. CONCLUSION: In this subgroup analysis, patients who had higher disease severity at baseline achieved greater efficacy than the total patient population when treated with 8 weeks of CAL/BDP PAD-cream as compared to a currently marketed active comparator. Additionally, as indicated by this analysis, CAL/BDP PAD-cream treatment may also be more convenient and less greasy, which may reduce the burden of daily treatment and improve adherence to therapy. TRIAL REGISTRATION: NCT03308799 and NCT03802344.

Efficacy and safety of oral roflumilast for moderate-to-severe psoriasis-a randomized controlled trial (PSORRO).

Background: Roflumilast is a targeted inhibitor of phosphodiesterase (PDE)-4 and has been approved for treatment of severe chronic obstructive pulmonary disease for more than a decade. Generic versions are available in the United States. PDE-4 is involved in the psoriasis pathogenesis, but the efficacy and safety of oral roflumilast in patients with psoriasis have not previously been studied. Methods: A company-independent, multicenter, randomized, double-blind, placebo-controlled trial (ClinicalTrials.govNCT04549870). Patients were randomized 1:1 to receive monotherapy with oral roflumilast 500 µg once daily or placebo. At week 12, placebo patients were switched to open-label roflumilast through week 24. The primary endpoint was a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI75) at week 12. Findings: In all, 46 patients were randomized (roflumilast, n = 23; placebo, n = 23). At week 12, significantly more patients in the active arm achieved PASI75 (8 of 23 patients [35%]) vs. placebo (0 of 23 patients [0%], with a difference vs. placebo of 8 [35%] patients, 95% CI: 3 [13%]-13 [57%] patients) (p = 0.014). At week 24, 15 (65%), 10 (44%), 5 (22%), and 2 (9%) of patients treated with roflumilast from week 0 had PASI50, PASI75, PASI90, and PASI100 responses (key secondary endpoints), respectively. The most prevalent, drug-related adverse events in both treatment groups were transient gastrointestinal symptoms, weight-loss, headache, and insomnia. A total of three patients (roflumilast n = 2; placebo, n = 1) discontinued therapy due to adverse events. Interpretation: Oral roflumilast was efficacious and safe in treating moderate-to-severe plaque psoriasis over 24 weeks. With generic versions available, this drug may represent an inexpensive and convenient alternative to established systemic psoriasis treatments. Funding: Financial support was received from Herlev and Gentofte Hospital, University of Copenhagen, and independent grants from private foundations in Denmark. No pharmaceutical company, including the market authorization holder of roflumilast, was involved in the study at any point.

Single-Particle Tracking of Thermomyces lanuginosus Lipase Reveals How Mutations in the Lid Region Remodel Its Diffusion.

The function of most lipases is controlled by the lid, which undergoes conformational changes at a water-lipid interface to expose the active site, thus activating catalysis. Understanding how lid mutations affect lipases' function is important for designing improved variants. Lipases' function has been found to correlate with their diffusion on the substrate surface. Here, we used single-particle tracking (SPT), a powerful tool for deciphering enzymes' diffusional behavior, to study Thermomyces lanuginosus lipase (TLL) variants with different lid structures in a laundry-like application condition. Thousands of parallelized recorded trajectories and hidden Markov modeling (HMM) analysis allowed us to extract three interconverting diffusional states and quantify their abundance, microscopic transition rates, and the energy barriers for sampling them. Combining those findings with ensemble measurements, we determined that the overall activity variation in the application condition is dependent on surface binding and lipase mobility when bound. Specifically, the L4 variant with a TLL-like lid and wild-type (WT) TLL displayed similar ensemble activity, but WT bound stronger to the surface than L4, while L4 had a higher diffusion coefficient and thus activity when bound to the surface. These mechanistic elements can only be de-convoluted by our combined assays. Our findings offer fresh perspectives on the development of the next iteration of enzyme-based detergent.

Single-Centre Real-World Study on Drug Survival and Effectiveness of Brodalumab for Treatment of Psoriasis and Psoriatic Arthritis.

BACKGROUND: Clinical trials have established the efficacy of brodalumab in treatment of psoriasis and psoriatic arthritis. Real-world evidence is needed to fully evaluate the drug. OBJECTIVE: Here we investigate drug survival and clinical effectiveness of brodalumab in patients with psoriasis and psoriatic arthritis in a real-world setting. METHODS: This was a retrospective single-centre study enrolling patients receiving brodalumab for psoriasis at the Department of Dermatology, Aarhus University Hospital, Denmark. The primary endpoints were drug survival, reasons for discontinuation, percentage of patients achieving a Psoriasis Area and Severity Index (PASI) ≤ 2 and clinical effectiveness against psoriatic arthritis. RESULTS: Eighty-three patients were included (mean age 49.2 ± 17.4 years, 59.0% male, 9.6% bio-naïve, mean baseline PASI 10.9 ± 6.9). Twenty-seven patients discontinued treatment primarily due to ineffectiveness and adverse events (AEs). Kaplan-Meier-estimated 1-year drug survival was 65.7%. An absolute Psoriasis Area and Severity Index (PASI) ≤ 2 was achieved by 68.2% of patients at end of follow-up, by 70.0% at weeks 12-17 and by 76.2% after 40-60 weeks of treatment. Neither drug survival nor PASI ≤ 2 was associated with baseline PASI ≥ 10, body mass index ≥ 30, previous treatment with > 2 biologics or other IL-17 inhibitors in particular (P > 0.05). Psoriatic arthritis remission or partial remission was achieved by 10 out of 18 patients with psoriatic arthritis; treatment failure was reported in 5 patients. CONCLUSIONS: Brodalumab was effective against psoriasis and psoriatic arthritis in a real-world setting. The drug survival was lower than reported in other real-world settings.

Sensory properties analysis of a calcipotriol and betamethasone dipropionate cream vehicle formulated with an innovative PAD Technology for the treatment of plaque psoriasis on the skin and scalp.

Background: In psoriasis, poor treatment adherence is frequently related to low efficacy and limited cosmetic acceptability from the patients' perspective. This study aimed to characterize the sensorial attributes of a calcipotriol (CAL) and betamethasone dipropionate (BDP)-cream vehicle based on polyaphron dispersion (PAD) Technology and to compare them with the conventional ointment and oleogel formulations for psoriasis. Methods: A panel of 16 experts assessed sensory properties at four different stages: appearance, pick up, rub out and afterfeel. Descriptive sensory analysis was used to evaluate relevant attributes. Each attribute was rated on a line scale (range 0-100%). Active ingredients were not used because panellists were healthy volunteers, and vehicle formulations needed to be used instead. Results: CAL/BDP PAD-cream vehicle was evaluated as having a low stickiness, low grease behaviour, good wetness, and good spreadability. Ointment showed the least desirable behaviour regarding these properties. Moreover, once CAL/BDP PAD-cream vehicle was absorbed, the gloss disappeared quickly, leaving low stickiness and a low amount of residue. This afterfeel behaviour was not observed with ointment. The oleogel formulation had good sensory properties, similar to CAL/BDP PAD-cream vehicle, but with lower integrity of shape, lower wetness and higher greasiness. Conclusion: Overall, CAL/BDP PAD-cream vehicle has the desirable requirements for a topical product for the treatment of psoriasis, with better sensory properties than ointment and easier manipulation than oleogel, which may lead to greater acceptance and adherence.