Evaluation of the cutaneous microbiome in psoriasis

Psoriasis, a highly prevalent disease of humans of unknown cause, is a chronic inflammatory disorder primarily involving skin, with distinctive clinical characteristics. With the newly developed tools that facilitate microbiome research, it now is possible to assess whether the cutaneous microbiome plays a role in the pathogenesis of this disorder. Preliminary data from our studies suggest that the cutaneous microbiome in psoriasis is complex and possibly different from normal. To deal with this complexity, we propose to examine the cutaneous microbiome in relation to psoriasis with explorations at several taxonomic and informatic levels. Our overall objective is to examine how changes in the normal cutaneous microbiome contributes to the pathogenesis of psoriasis. Since causality is complex and often difficult to prove, our overall hypothesis is that there are alterations in the cutaneous microbiome in areas of skin affected by psoriasis in comparison with the range observed in clinically unaffected areas, or in healthy persons. We also hypothesize that the characteristics of the microbiome may affect clinical responses to the immunomodulatory agents used to treat psoriasis. An alternative hypothesis is that effective treatment of psoriasis with systemic immunomodulatory agents will not substantially affect the disordered microbial ecosystem. Such observations would provide evidence for the roles of the microbiota in this disorder. Since an important consideration in microbiome research is the optimal level (e.g. phylum, genus, species, strain, gene) at which to examine a scientific question, and we are not yet certain what are the optimal levels for psoriasis, this also will be examined. Our studies of psoriasis should allow development of both approaches and tools that will have general utility for microbiome research. To test our hypothesis, we propose the following specific aims: 1. To understand the cutaneous microbiome species composition overlaying psoriatic lesions; 2. To investigate differences in metagenome content for psoriatic lesions compared to normal skin; 3. To identify differences in the transcriptional profiles of the microbiome and the host between normal skin and psoriatic lesions using high-throughput sequencing; and 4. To estimate the effects of systemic immunomodulatory therapy for psoriasis on microbiome composition. In total, these studies should help us understand the role of the microbiome in psoriasis pathogenesis

26085 Key efficacy and safety of apremilast in patients with mild to moderate plaque psoriasis in the phase 3 ADVANCE trial

Background: In ADVANCE, apremilast 30 mg BID (APR) demonstrated efficacy in mild-to-moderate psoriasis vs placebo (PBO). We report subgroup analyses by baseline psoriasis-involved BSA (≤5%, \u3e5%). Methods: Biologic-naive adults with mild-to-moderate psoriasis (sPGA 2-3, BSA 2%-15%, PASI 2-15) inadequately controlled with or intolerant to ≥1 topical were randomized to APR or PBO for 16 weeks. At Week 16, endpoints were compared between treatment groups and by baseline BSA. Results: At baseline, 284 patients had BSA ≤5% (APR: 143; PBO: 141); 311 had BSA \u3e5% (APR: 154; PBO: 157). Overall, a greater proportion of APR patients achieved the primary endpoint, sPGA response (score 0/1 [clear/almost clear] with ≥2-point reduction at Week 16) vs PBO (21.6% vs 4.1%, P 5%: 54.6% vs 14.9%, P 5%: 45.4% vs 17.6%, P 5%: 50.6% vs 19.2%, P 5%: 11.0 vs 10.0 DLQI 5-point improvement (baseline DLQI \u3e5): - BSA≤5%: 56.6% vs 31.2%, P =.0002 - BSA\u3e5%: 64.4% vs 36.4%, P ˂.0001. Conclusions: Greater proportions of patients achieved efficacy outcomes and greater improvements in QOL with APR vs PBO. Comparable improvements were observed between mild and moderate subgroups

Clinical similarity of biosimilar ABP 501 to adalimumab in the treatment of patients with moderate to severe plaque psoriasis: A randomized, double-blind, multicenter, phase III study

Background ABP 501 is a biosimilar of adalimumab. Objective We sought to compare the efficacy and safety of ABP 501 with adalimumab. Methods This 52-week, double-blind study randomized patients with moderate to severe psoriasis to ABP 501 or adalimumab. At week 16, those with 50% or more improvement in Psoriasis Area and Severity Index score from baseline on ABP 501 continued the same treatment, whereas adalimumab-treated patients were rerandomized to adalimumab or ABP 501. Clinical similarity in Psoriasis Area and Severity Index percent improvement from baseline to week 16 (primary end point) was established if the point estimate of treatment difference and its 2-sided 95% confidence interval between groups was within equivalence margin of ±15. Patients, including those undergoing a single transition at week 16, were evaluated for safety and immunogenicity. Results Psoriasis Area and Severity Index percent improvement at week 16 was 80.9 for ABP 501 and 83.1 for adalimumab (least-square mean difference −2.18 [95% confidence interval −7.39 to 3.02]). Adverse events (67.2% [117/174] vs 63.6% [110/173]) and antidrug antibody incidence (55.2% [96/174] vs 63.6% [110/173]) for ABP 501 vs adalimumab were similar. Safety, including immunogenicity, was similar among groups after single transition (week 20). Limitations The 52-week data are not reported here. Conclusions ABP 501 was shown to be clinically similar to adalimumab. Safety and immunogenicity were not impacted immediately after single transition (adalimumab to ABP 501)

Bimekizumab in patients with moderate to severe plaque psoriasis by bodyweight: Pooled results from phase 3 trials

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Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn’s Disease:an integrated analysis of Phase II/III Clinical Development Programs

IntroductionTheoretical risks of biologic agents remain under study.ObjectiveThe aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials.MethodsPatients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]).ResultsAmong 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications.ConclusionsUstekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications.Trial registrationsClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355

Association of the clinical components in the distal interphalangeal joint synovio-entheseal complex and subsequent response to ixekizumab or adalimumab in psoriatic arthritis.

Objectives: To assess the frequency of simultaneous distal interphalangeal (DIP) joint disease and adjacent nail psoriasis (finger unit) among patients with psoriatic arthritis (PsA) and compare the efficacy of the IL-17A antagonist ixekizumab (IXE) and the TNF-α inhibitor adalimumab (ADA). Methods: This post hoc analysis evaluated the simultaneous occurrence of DIP joint involvement (tenderness and/or swelling) and adjacent nail psoriasis among patients with PsA from the SPIRIT-H2H (NCT03151551) trial comparing IXE to ADA. Among patients with simultaneous DIP joint involvement and adjacent nail psoriasis in ≥1 digit at baseline, treatment effects were assessed through week 52 for each affected finger unit; ‘finger unit’ defines the connected DIP joint and adjacent nail of an individual digit. Results: A total of 354 patients had simultaneous DIP joint involvement and adjacent nail psoriasis in ≥1 finger unit at baseline. Among them, 1309 (IXE: 639; ADA: 670) finger units had baseline DIP joint tenderness and/or swelling and adjacent nail psoriasis. Proportions of affected finger units achieving complete resolution were significantly higher with IXE vs ADA as early as week 12 (38.8% vs 28.4%, P < 0.0001) and at all post-baseline assessments through week 52 (64.9% vs 57.5%, P = 0.0055). Conclusion: In this study cohort, patients with DIP joint involvement almost always had adjacent nail psoriasis. Greater resolution of DIP joint tenderness, swelling and adjacent nail psoriasis was achieved at all time points over 52 weeks through targeting IL-17A with IXE than TNF-α with ADA, which is noteworthy given prior comparable musculoskeletal outcomes for both drug classes

Bimekizumab efficacy and safety through two years in patients with moderate psoriasis: Analysis of pooled data from five phase 3/3b clinical trials

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Spesolimab treatment for the prevention of flares in people with generalized pustular psoriasis (GPP): a plain language summary of the Effisayil ™ 2 study

What is this study about?: Generalized pustular psoriasis (shortened to GPP) is a rare, potentially life-threatening disease in which pus-filled blisters or pustules may suddenly form all over the body. The drug spesolimab has been approved to treat worsening GPP (known as flares) in many countries. However, it was not known if spesolimab could prevent the symptoms of GPP. This summary reports the results from a clinical study called Effisayil™ 2, that was done to understand if spesolimab was a safe and effective way to prevent flares in people with GPP. In the study, 123 participants, recruited in 20 different countries, were given one of three different doses of spesolimab (low, medium, or high) or a non-active medicine (placebo) over 48 weeks. What were the results?: Participants who received spesolimab had fewer GPP flares over the course of the 48-week study. Different doses of the drug were tested and compared to placebo, and a high dose of spesolimab worked better than low and medium doses. Using spesolimab also reduced the chance of developing skin symptoms, such as redness or pustules, and prevented quality of life getting worse over 48 weeks. While some participants experienced unwanted effects, they were mostly mild or moderate and most did not appear to be caused by spesolimab, or the dose at which it was given. What do the results of the study mean?: The results indicate that a high dose of spesolimab works well to prevent GPP flares and stop the disease getting worse. Health authorities are looking at the results of this study to decide if spesolimab can also be prescribed for the prevention of GPP flares

Substantial Alterations of the Cutaneous Bacterial Biota in Psoriatic Lesions

For psoriasis, an idiopathic inflammatory disorder of the skin, the microbial biota has not been defined using cultivation-independent methods. We used broad-range 16S rDNA PCR for archaea and bacteria to examine the microbiota of normal and psoriatic skin. From 6 patients, 19 cutaneous samples (13 from diseased skin and 6 from normal skin) were obtained. Extracted DNA was subjected to the broad range PCR, and 1,925 cloned products were compared with 2,038 products previously reported from healthy persons. Using 98% sequence identity as a species boundary, 1,841 (95.6%) clones were similar to known bacterial 16S rDNA, representing 6 phyla, 86 genera, or 189 species-level operational taxonomic unit (SLOTU); 84 (4.4%) clones with <98% identity probably represented novel species. The most abundant and diverse phylum populating the psoriatic lesions was Firmicutes (46.2%), significantly (P<0.001) overrepresented, compared to the samples from uninvolved skin of the patients (39.0%) and healthy persons (24.4%). In contrast, Actinobacteria, the most prevalent and diverse phylum in normal skin samples from both healthy persons (47.6%) and the patients (47.8%), was significantly (P<0.01) underrepresented in the psoriatic lesion samples (37.3%). Representation of Propionibacterium species were lower in the psoriatic lesions (2.9±5.5%) than from normal persons (21.1±18.2%; P<0.001), whereas normal skin from the psoriatic patients showed intermediate levels (12.3±21.6%). We conclude that psoriasis is associated with substantial alteration in the composition and representation of the cutaneous bacterial biota