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.

Assessment of Spatial and Temporal Variation in the Skin Transcriptome of Atopic Dermatitis by Use of 1.5 mm Minipunch Biopsies.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by a heterogeneous and fluctuating disease course. To obtain a detailed molecular understanding of both the temporal and spatial variation in AD, we conducted a longitudinal case-control study, in which we followed a population, the GENAD (Gentofte AD) cohort, of mild-to-moderate patients with AD and matched healthy controls for more than a year. By the use of 1.5 mm minipunch biopsies, we obtained 393 samples from lesional, nonlesional, and healthy skin from multiple anatomical regions at different time points for transcriptomic profiling. We observed that the skin transcriptome was remarkably stable over time, with the largest variation being because of disease, individual, and skin site. Numerous AD-specific, differentially expressed genes were identified and indicated a disrupted skin barrier and activated immune response as the main features of AD. We also identified potentially novel targets in AD, including IL-37, MAML1, and several long noncoding RNAs. We envisage that the application of small biopsies, such as those introduced in this study, combined with omics technologies, will enable future skin research, in which multiple sampling from the same individual will give a more detailed, dynamic picture of how a disease fluctuates in time and space.

Profiling the Atopic Dermatitis Epidermal Transcriptome by Tape Stripping and BRB-seq.

Tape stripping is a non-invasive skin sampling technique, which has recently gained use for the study of the transcriptome of atopic dermatitis (AD), a common inflammatory skin disorder characterized by a defective epidermal barrier and perturbated immune response. Here, we performed BRB-seq-a low cost, multiplex-based, transcriptomic profiling technique-on tape-stripped skin from 30 AD patients and 30 healthy controls to evaluate the methods' ability to assess the epidermal AD transcriptome. An AD signature consisting of 91 differentially expressed genes, specific for skin barrier and inflammatory response, was identified. The gene expression in the outermost layers, stratum corneum and stratum granulosum, of the skin showed highest correlation between tape-stripped skin and matched full-thickness punch biopsies. However, we observed that low and highly variable transcript counts, probably due to low RNA yield and RNA degradation in the tape-stripped skin samples, were a limiting factor for epidermal transcriptome profiling as compared to punch biopsies. We conclude that deep BRB-seq of tape-stripped skin is needed to counteract large between-sample RNA yield variation and highly zero-inflated data in order to apply this protocol for population-wide screening of the epidermal transcriptome in inflammatory skin diseases.

Patients with psoriasis have a dysbiotic taxonomic and functional gut microbiota.

BACKGROUND: Accumulating evidence supports the findings of an altered gut microbiota in patients with autoimmune disease. However, existing studies on the role of the gut microbiota in patients with psoriasis have demonstrated conflicting results and have mainly been based on 16s rRNA gene sequencing analysis. OBJECTIVES: To examine whether the gut microbiota of patients with psoriasis was altered in composition and functional potentials compared with healthy controls, and as a second approach compared with healthy cohabitant partners. A further aim was to investigate relationships to disease severity, and seasonal impact on the gut microbiota. METHODS: In a case-control study, 126 faecal samples were collected from a sample of 53 systemically untreated patients with plaque psoriasis; 52 healthy controls matched for age, sex and body mass index; and 21 cohabitant partners. A subpopulation of 18 patients with psoriasis and 19 healthy controls continued in a longitudinal study, where four to six faecal samples were collected over 9-12 months. The gut microbiota was characterized using shotgun metagenomic sequencing analysis. RESULTS: A significantly lower richness (P = 0·007) and difference in community composition (P = 0·01) of metagenomic species was seen in patients with psoriasis compared with healthy controls, and patients with psoriasis had a lower microbial diversity than their partners (P = 0·04). Additionally, the functional richness was decreased in patients with psoriasis compared with healthy controls (P = 0·01) and partners (P = 0·05). Increased disease severity was correlated with alterations in taxonomy and function, with a slight tendency towards a lower richness of metagenomic species, albeit not significant (P = 0·08). The seasonal analysis showed no shifts in community composition in healthy controls or in patients with psoriasis. CONCLUSIONS: The findings of a different gut microbiota in composition and functional potentials between patients with psoriasis and healthy controls support a linkage between the gut microbiota and psoriasis. These findings need to be validated in larger studies, and a potential causal relationship between the gut microbiota and psoriasis still needs to be shown.

Impact of methotrexate and adalimumab on immune function of patients with psoriasis.

Patients with psoriasis are commonly treated with methotrexate or biologics. We examined the immune response in a whole blood assay (TruCulture®) to assess the effect of methotrexate and adalimumab. Twenty patients with psoriasis were included and cytokine levels following stimulation with LPS, R848, HKCA, PolyIC, or a blank were investigated before and after 3-6 months of treatment with methotrexate or adalimumab and in patients who had received adalimumab >5 years. Methotrexate only induced minor changes in the cytokine responses, whereas adalimumab affected a wide range of cytokines important for the immune defense towards microorganisms. In the long-term adalimumab treated group, the cytokine levels were almost equivalent to the short-term adalimumab-treated group. Overall, methotrexate was not associated with cytokine suppression. Short and long-term treatment with adalimumab lowered multiple cytokines involved in the immune defense equally emphasizing the need to continuously be aware of the risk of infections in these patients.

Characterization of the Oral and Gut Microbiota in Patients with Psoriatic Diseases: A Systematic Review.

Advances in technology have led to an increased number of studies investigating the microbiome in patients with psoriasis. This systematic review examined data regarding the oral and gut microbiota in patients with psoriasis and/or psoriatic arthritis and the effect of probiotics on the microbiota and severity of psoriasis. Of 1,643 studies, 23 were included (22 observational, 1 interventional). Studies examined the microbiota using culture or 16S rRNA gene sequencing analysis. All culture-based studies identified an increased presence of oral Candida in patients with psoriasis, whereas small variations in the oral microbiota were found in a 16S rRNA gene-based study. All 16S rRNA gene sequencing based studies agreed that the gut microbiota of patients with psoriatic disease differed from that of healthy controls, but the results were heterogeneous. Probiotics were associated with a significant improvement in the severity of psoriasis, but did not change microbiota. Overall, studies lacked relevant inclusion criteria and baseline information. In conclusion, the role of the microbiota in patients with psoriasis requires further investigation using more robust methods.

Improvement of Psoriasis, Psoriatic Arthritis, and Alopecia Universalis during Treatment with Tofacitinib: A Case Report.

Alopecia areata (AA) is the most common immune-mediated hair loss disorder with a life-time prevalence of 2%. The pathogenesis of AA is not completely understood, but interferon gamma (INF-γ) and Janus kinases (JAK) may play a key role. Here, we present a case involving a male patient with psoriasis and psoriatic arthritis, who exhibited a rapid hair loss, diagnosed as AA, during ciclosporin treatment. As ciclosporin was unable to control his psoriasis, the treatment was changed to methotrexate injections, but the hair loss progressed into alopecia universalis. During treatment with the oral JAK inhibitor tofacitinib, the patient presented an almost complete hair remission on the scalp and partly on the eyebrows, eyelashes, beard, and chest. Furthermore, the patient experienced no joint complaints and his psoriasis was improved. Based on these findings, JAK inhibitors may be an optional treatment in complicated cases involving both rheumatological and dermatological diseases.

Treatment and Burden of Disease in a Cohort of Patients with Prurigo Nodularis: A Survey-based Study.

Prurigo nodularis is a pruritic dermatosis with poor treatment options. To describe treatment patterns, comorbidities, pruritus, and quality of life a survey was administered to 92 patients with prurigo nodularis. A total of 52 patients completed the survey. The most frequently used treatments were topical corticosteroids, which were prescribed to 49/52 patients, with positive effect in 13/49. A total of 46/52 patients were treated with ultraviolet B, and 9/46 reported a positive effect. A positive effect was reported for topical corticosteroids under occlusion in 21/40, for zinc dressing treatment in 17/37, for steroid injection in 9/14, for methotrexate in 5/16, and for thalidomide in 4/12 of treated patients. Thirty-six patients reported a Pittsburgh Sleep Quality Index >5, indicating poor sleep. Patients with prurigo nodularis are severely bothered by pruritus negatively affecting quality of life. Various treatments are prescribed; most frequently topical corticosteroids and ultraviolet B. Surprisingly, patients reported topical corticosteroids under occlusion, zinc-dressing treatment and steroid injection as the most effective.

[Multicentric reticulohistiocytosis is a rare form of paraneoplasia].

A 59-year-old woman developed a rash and severe arthralgia, which primarily affected her fingers. She displayed digital arthritis and nodules on the hands, chest, face, and oral cavity. Blood samples were normal. Skin biopsies revealed histiocytic proliferation. The surface marker profile and clinical findings were consistent with multicentric reticulohistiocytosis, which may occur as a paraneoplastic phenomenon. On workup, she was diagnosed with an otherwise asymptomatic stage IVC fallopian tube cancer. She experienced little effect of prednisolone, but her condition improved on antineoplastic treatment.

Health-related Quality of Life in Children and Adolescents with Psoriasis: A Systematic Review and Meta-analysis.

Studies demonstrating the negative impact of paediatric psoriasis on health-related quality of life (HRQOL) are accumulating, but little is known about moderators of HRQOL. The objectives of this review were to summarize studies on HRQOL in paediatric psoriasis and to explore the potential moderating influences of demographic and clinical variables. Searches were conducted by 2 independent researchers in PubMed, Embase, CINAHL, PsycINFO, and Scopus for papers published between 1995 (the date the first dermatology-specific HRQOL-instrument for children was introduced) and 2016. Eligible studies were required to report HRQOL data for children and/or adolescents with psoriasis (4-18 years) using validated HRQOL questionnaires. Seven-teen eligible studies (number of patients=1,185) were identified. Moderation analyses revealed that study samples with a higher percentage of girls were associated with better HRQOL (ß = 0.19), while a higher mean age of onset (ß = 0.83) and study quality (ß = 0.28) were associated with lower HRQOL (all p<0.05). Several papers did not provide the information necessary for exploring between-study differences, thus the moderation analysis results should be interpreted with caution. In conclusion, children and adolescents with psoriasis experience moderate impairment of HRQOL. Certain demographic characteristics (e.g. sex) and clinical characteristics (e.g. age at onset) appear to moderate this impact.

Incidence of otitis media in a contemporary Danish National Birth Cohort.

OBJECTIVES: In recent years welfare in Denmark has increased which might be expected to reduce otitis media (OM) incidence. We examined the age-specific incidence of OM in a nation-wide cohort of children aged 0-7 years born in 1996-2003 (Danish National Birth Cohort, DNBC). Only selection was ability to understand and speak Danish. METHODS: Information of OM and ventilation tubes (VT) was collected through three maternal interviews at 6-month, 18-month and 7-years of age and based on this age-specific and cumulative incidence of OM was calculated. As different numbers of the total population answered the different interviews, the calculations are done with different denominators. The information in DNBC was validated against two population based registries containing information of VT insertions. RESULTS: Cumulative incidence of OM at 7 years was 60.6% (31,982/52,755). For children with OM, 16.2% (7143/44194) had their first OM episodes between 0-6 months of age, 44.3% (19579/44194) between 7-18 months, and 39.5% (17472/44194) between 19 months and 7 years. Four or more OM episodes before 7 years were reported by 39.5% (12620/31982) and by 64.0% (2482/3881) of those who had their OM debut between 0-6 months; by 48.2% (4998/10378) with debut between 7-18 months; and by 28.7% (4996/17344) with debut between 19 months and 7 years. These figures are essentially unchanged from earlier figures from Denmark. VT insertion at least once was reported by 26,1% in the 7-year interview. Assuming recordings in the Danish National Patient Registry to be gold standard, maternal self-reportings in DNBC of insertion of VT showed high sensitivity (96.4%), specificity (98.2%), and positive (94.8%) and negative predictive values (98.8%). CONCLUSION: OM affects nearly 2/3 of preschool children in Denmark despite reduction in known OM risk factors.