Effectiveness, safety and impact of guselkumab on sexuality and perceived stigmatization in patients with psoriasis in routine clinical practice: Week 28 results from the prospective German multicentre G-EPOSS study.

BACKGROUND: G-EPOSS is a prospective, non-interventional, German multicentre study of patients with moderate-to-severe plaque psoriasis receiving guselkumab, a therapeutic monoclonal antibody targeting interleukin-23, in a real-world setting. OBJECTIVES: The objective of the study was to evaluate the effectiveness and safety of guselkumab, including its impact on skin, health-related quality of life (HRQoL), sexuality, and perceived stigmatization. METHODS: Patients (≥18 years old) received guselkumab per routine clinical practice. The primary endpoint was the proportion of patients achieving absolute Psoriasis Area and Severity Index (PASI) ≤ 3 at Week (W)28. Secondary endpoint assessments over 28 weeks included the Nail Psoriasis Severity Index (NAPSI), anogenital Physician's Global Assessment (aPGA), and Dermatology Life Quality Index (DLQI). Sexuality and perceived stigmatization were assessed by patients using the Relationship and Sexuality Scale (RSS) and Perceived Stigmatization Questionnaire (PSQ), respectively. RESULTS: Overall, 293 patients were included in the evaluable set population. Mean age and disease duration were 45.6 and 17.6 years, respectively. At baseline, mean PASI, aPGA and DLQI scores were 15.3, 2.7 and 11.3, respectively. In total, 25.9% of patients had received a prior biologic. Overall, 83.0% of patients achieved PASI ≤ 3, and 56.2%/35.1% achieved PASI ≤ 1/PASI = 0, respectively, at W28. Among those with NAPSI ≥ 1 and aPGA ≥ 1 at baseline, NAPSI = 0 and aPGA = 0 were achieved by 39.2% and 61.1% of patients, respectively, and 61.4% of patients achieved DLQI 0-1 at W28. Improvements were observed over 28 weeks across individual items of the DLQI, RSS and PSQ, indicating improved HRQoL and sex life, and decreased perceived stigmatization. Based on DLQI Question (Q)9, 53.6% of patients experienced sexual difficulties at baseline, which decreased to 12.1% at W28. DLQI Q9 responses were consistent with RSS item responses, highlighting DLQI Q9 as a sentinel for sexual impairment. CONCLUSIONS: Guselkumab improved overall skin symptoms and HRQoL in patients with psoriasis and decreased sexual impairment and perceived stigmatization. No new safety signals were observed. STUDY CODE: CNTO1959PSO4008.

Depression, a major comorbidity of psoriatic disease, is caused by metabolic inflammation.

Psoriatic disease is a chronic, systemic immune-mediated inflammatory disorder comprising three major domains, skin, vascular and bone/joint inflammation. It is known for a long time that psoriatic disease is associated with a number of conditions such as hypertension, dyslipidemia, diabetes (metabolic syndrome) and depression. Up to one out of five people with psoriasis show concomitant depression. In the past, this was attributed to psychological stress of suffering from a chronic condition that is often visible and itchy, leading to stigmatization and adding to a significant burden of disease. Recent data provide evidence that depression associated with psoriatic disease is linked to the specific inflammatory pattern with IL-23, IL-17 family cytokines, TNF, IL-6 and IL-8 causing neuroinflammation and subsequently depression or depressive behaviour and/or anxiety. Psoriatic disease shows a distinct pattern of immune cells (e.g. dendritic cells, Th17 cells, neutrophils), mediators (e.g. IL-17A/F, IL-23, TNF) and tissue-related factors in all major domains that is different from other inflammatory dermatoses. There is a striking similarity between the inflammatory pattern in psoriatic disease and neuroinflammation that leads to depression. A number of risk factors have been identified in psoriatic disease, the most important of which are obesity and tobacco smoking. Obesity is known as a major risk factor for depression and anxiety due to its inflammatory signature. Apart from psychotherapy and anti-depressive medication, targeted treatments for psoriasis, including TNF, IL-17 and IL-23 inhibitors, can improve depression/depressive symptoms. The review summarizes the current knowledge about depression as a comorbidity in psoriatic disease.

Effectiveness, safety and quality-of-life effects of guselkumab and ustekinumab in patients with psoriasis: Week 104 results from the non-interventional, prospective, German multicentre PERSIST study.

BACKGROUND: PERSIST was a prospective, non-interventional, real-world study of guselkumab and ustekinumab in adult patients with moderate-to-severe plaque psoriasis in Germany. OBJECTIVES: To examine effectiveness, safety and quality-of-life (QoL) outcomes to Week (W) 104 of treatment with guselkumab and ustekinumab in patients with moderate-to-severe plaque psoriasis. METHODS: Patients (≥18 years of age) received guselkumab or ustekinumab as per routine clinical practice. Outcomes to W104 were examined separately in guselkumab and ustekinumab recipients. An ad hoc exploratory analysis of outcomes with guselkumab versus ustekinumab was also performed following propensity score matching. RESULTS: Overall, 302 and 313 patients received guselkumab and ustekinumab, respectively. Patients in both cohorts experienced improvements in disease activity and QoL that were maintained to W104, with 64.7% and 63.6% of guselkumab- and 54.6% and 64.4% of ustekinumab-treated patients achieving a Psoriasis Area and Severity Index (PASI) 90 response and a Dermatology Life Quality Index (DLQI) 0/1 score, respectively. Propensity score matching yielded well-balanced baseline characteristics except for prior biologic use, which was higher in guselkumab versus ustekinumab recipients (51.7% vs. 32.0%). Achievement of PASI ≤1 at W104 was more common in guselkumab versus ustekinumab recipients (58.7% vs. 49.7%). The W104 PASI90 response rate was 65.6% with guselkumab and 56.0% with ustekinumab; corresponding rates for PASI100 were 44.3% and 28.5%. In guselkumab recipients, response rates were higher in biologic-naïve versus biologic-experienced patients (PASI90, 77.1% vs. 53.4%; PASI100, 55.0% vs. 33.0%). A high level of response for QoL outcomes was observed for both treatments. CONCLUSIONS: Ustekinumab and guselkumab led to improvements in physician-assessed and patient-reported outcomes that were sustained for up to 2 years, with no new safety signals identified. Following propensity score matching, greater improvements in PASI outcomes were observed with guselkumab versus ustekinumab. Improvements with guselkumab were highest in biologic-naïve patients, highlighting the value of early treatment.

Real-world evidence from the non-interventional, prospective, German multicentre PERSIST study of patients with psoriasis after 1 year of treatment with guselkumab.

BACKGROUND: PERSIST was a prospective, non-interventional, long-term, German multicentre study of patients with moderate-to-severe psoriasis receiving guselkumab, an approved monoclonal antibody that binds to the p19 subunit of interleukin (IL)-23, in a real-world setting. OBJECTIVES: Evaluation of the efficacy and safety of guselkumab, and its effect on health-related quality of life (HRQoL), in patients with moderate-to-severe psoriasis who have received 52 weeks of treatment. METHODS: Patients (≥18 years old) were prescribed guselkumab as per routine clinical practice. End points assessed include Psoriasis Area and Severity Index (PASI), Physician's Global Assessment (PGA), target Nail Psoriasis Severity Index (NAPSI), and the Dermatology Life Quality Index (DLQI). RESULTS: Overall, 303 patients were enrolled and treated with guselkumab. Mean disease duration was 21.0 years, and 77.2% and 51.2% of patients had received ≥1 prior conventional systemic or ≥1 prior biologic therapy, respectively. Mean PASI score decreased from 16.4 at baseline to 3.0 by Week (W) 28, and further decreased to 2.4 by W52, while the proportion of patients achieving an absolute PASI score of ≤1 increased from 1.3% at baseline, to 50.8% at W28 and to 58.4% by W52. PASI90 and PASI100 responses also showed marked improvements between W28 and W52, regardless of biologic treatment history. Clearance of psoriatic skin was observed in difficult-to-treat areas, with the percentage of patients achieving a PGA score ≤1 increasing between W28 and W52. Guselkumab improved HRQoL; mean DLQI score decreased from 13.7 at baseline to 2.8 by W28, and further decreased to 2.4 by W52. At W52, 64.6% of patients achieved a DLQI score ≤1. The cumulative probability of drug survival was 92.4% at W52. CONCLUSIONS: Guselkumab is efficacious and well tolerated regardless of previous biologic therapies, comorbidities or psoriasis manifestation in difficult-to-treat areas. No new safety signals were observed.

Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study.

BACKGROUND: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. OBJECTIVE: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. METHODS: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. RESULTS: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. CONCLUSION: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.

Oral dimethyl fumarate induces changes within the peripheral neutrophil compartment of patients with psoriasis that are linked with skin improvement.

BACKGROUND: Dimethyl fumarate (DMF) is a treatment for moderate-to-severe psoriasis and multiple sclerosis. DMF therapy typically improves skin inflammation within the first 3 months of treatment. DMF is a prodrug that generates the hydroxycarboxylic acid receptor 2 (HCA2) agonist, monomethyl fumarate (MMF). Despite widespread clinical use, DMF's mechanism of action is not fully understood. OBJECTIVES: We wished to characterize the changes induced by DMF in peripheral neutrophils within the first 3 months of treatment to better understand its early antipsoriatic effects. METHODS: Flow cytometry was used to assess T-cell and neutrophil frequencies, apoptosis and activation phenotype. In vitro culture of neutrophils with DMF and MMF was used to evaluate apoptosis and HCA2 internalization. Serum levels of neutrophil degranulation products were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with psoriasis had significantly higher leucocyte counts at baseline compared with controls, with a large population of pro-inflammatory CD62Llo  CD11bbright neutrophils. Analysis revealed that DMF treatment reduced the frequency of CD62Llo  CD11bbright neutrophils and serum levels of neutrophil activation markers. This reduction was not linked to increased apoptosis. CONCLUSIONS: Our results reveal a novel in vivo effect of DMF therapy on pro-inflammatory neutrophils that likely contributes to this treatment's antipsoriatic efficacy.

Calcipotriol/betamethasone dipropionate foam demonstrates comparable efficacy to clinical trial data in the real world, improves patient satisfaction and is cost-effective.

Real-world evidence studies are becoming increasingly important in providing insight into clinical effectiveness and safety, economic outcomes, patient-reported outcomes and health-related quality of life of treatments in the clinical setting. These studies also help to complement data reported in clinical studies. Fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) is a topical agent used for the treatment of psoriasis vulgaris. In clinical studies, Cal/BD foam has demonstrated a significantly greater efficacy and rapid onset of action compared with both single and combination formulations such as ointments and gels. To date, three observational studies have examined the real-world efficacy and safety of Cal/BD foam in clinical practice in the United States, Germany and Spain. Data gathered from these studies reinforce the positive findings reported in clinical studies assessing Cal/BD foam for the treatment of psoriasis and demonstrate improved patient satisfaction with Cal/BD foam. Using Cal/BD foam has been shown to be cost-effective based on results from randomised clinical trials and cost-effective analysis. As such, Cal/BD foam has the potential to lower treatment costs by reducing the need for some patients to progress to more expensive treatments, such as phototherapy and biologics. Cal/BD foam is therefore a cost-effective solution for the treatment of psoriasis vulgaris that should be considered when prescribing topicals.

ActiPso: definition of activity types for psoriatic disease: A novel marker for an advanced disease classification.

BACKGROUND: Assessment of psoriasis is exclusively done measuring severity using somatic scores such as the psoriasis area and severity index or patient-reported outcomes such as the dermatology life quality index. There is no established tool to measure a patient's individual psoriasis activity over time. OBJECTIVES: Development of a new tool to classify psoriasis activity types. METHODS: Open patient interviews were performed and adapted in several steps and by using different groups of patients. Wording of the tool's axis and description how to use it was optimized with the input of patients. The final ActiPso tool was used in a prospective study in psoriasis patients. RESULTS: Four activity types could be identified describing psoriasis intensity (e.g. severity, itch, pain) over one typical year and an event/trigger type describing flares. In the study in 586 psoriasis patients of the 536 patients eligible for analysis 40.9% self-classified as type 1 ('stable'), 22.6% as type 2 ('unstable'), 30.6% as type 3 ('winter type') and 6.0% as type 4 ('summer type'), respectively. Flares of psoriasis as identified by the event/trigger type were reported in 36.1% of patients with activity type 1, 67.8% with type 2, 73.8% of type 3 and 59.4% of type 4, respectively. CONCLUSIONS: Interviewed patients were able to describe their course of psoriatic disease and to name potential triggering factors. By doing so, activity types of psoriasis were defined for the first time and the importance of events/triggers for flares described and integrated into ActiPso types as a basis for advanced patient-centric management. A limitation of ActiPso is that in regions with no seasonal variations types 3 and 4 may not apply.

A multicentre open-label study of apremilast in palmoplantar pustulosis (APLANTUS).

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic skin disease with painful erythematous scaly or crusty lesions and pustules on the palms and soles. Apremilast is a phosphodiesterase 4 inhibitor that has proven effective in the therapy of psoriasis, psoriatic arthritis and in oral ulcers associated with Behcet's disease. OBJECTIVE: To explore the efficacy of apremilast in PPP. METHODS: APLANTUS was a phase 2 single-arm multicentre study of apremilast in 21 subjects with moderate-to-severe PPP. Primary endpoint was the per cent change of the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at week 20 compared to baseline. RESULTS: 20 weeks of oral treatment with apremilast in patients with moderate-to-severe PPP resulted in a significant decrease of the PPPASI with a median reduction of 57.1% (p < 0.001), and 61.9% of patients achieved at least a 50% improvement of the PPPASI relative to baseline. The total number of pustules per patient decreased significantly relative to baseline with 76.2% of patients achieving at least a 50% reduction in total pustules count at week 20. Improvement of PPP was also apparent in a significant decrease of the dermatologic life quality index (DLQI). The median DLQI score dropped from 8.5 at baseline to 2.0 at week 20 (p = 0.030). Apremilast was generally well tolerated, and no serious adverse events occurred. CONCLUSIONS: Patients with PPP treated with apremilast showed benefit both in objective and subjective disease parameters. Apremilast should be investigated further in this difficult-to-treat skin condition. EudraCT number: 2016-005122-11.

Secukinumab treatment leads to normalization of quality of life and disease symptoms in psoriasis patients with or without prior systemic psoriasis therapy: the PROSE study results.

INTRODUCTION: Psoriatic disease is associated with considerable impairment of quality of life (QoL). The PROSE study (NCT02752776) investigated the impact of secukinumab treatment on patient-reported outcomes (PRO) in patients with moderate to severe psoriasis stratified by their treatment history. METHODS: PROSE was a prospective, non-randomised, multicentre study. Patients were categorized at baseline according to treatment history as naïve [naïve to any systemic therapy (N = 663)], conventional systemic [previously exposed to ≥1 conventional systemic (CS) therapy (N = 673)] and biologics [previously exposed to ≥1 biologic therapy (N = 324)]. QoL PROs, efficacy and safety of secukinumab 300 mg were assessed for a period of 52 weeks. RESULTS: The primary objective was met with 70.8% patients achieving a Dermatology Life Quality Index (DLQI) 0/1 response at Week 16 (naϊve, 74.7%; CS, 71.3%; biologic, 61.7%), with effects sustained up to Week 52. Mean Family DLQI (FDLQI) score decreased from 11.5 at baseline (naϊve, 11.3; CS, 11.4; biologic, 12.1) to 2.5 at Week 16 (naϊve, 2.5; CS, 2.3; biologic: 3.5). Substantial improvements in EuroQoL 5-Dimension Health Questionnaire, Numeric Rating Scale for pain, itching and scaling, Health Assessment Questionnaire-Disability Index, Treatment Satisfaction Questionnaire for Medication, and Patient Benefit Index were also observed at Week 16. The QoL gains were associated with substantial improvements in Psoriasis Area and Severity Index and Investigator Global Assessment mod 2011 0/1 response. No meaningful difference was observed in the efficacy or QoL improvements across patient subpopulations. All QoL and efficacy parameter improvements were sustained up to Week 52. Secukinumab treatment was well-tolerated, and no new safety signals were observed. CONCLUSION: Secukinumab treatment resulted in complete normalization of QoL in a substantial proportion of psoriasis patients, and their families, regardless of their prior treatment history.

Continued treatment with secukinumab is associated with high retention or regain of response.

BACKGROUND: Conventional analyses present aggregate data, masking late responders and efficacy reductions. Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows sustained efficacy in moderate-to-severe psoriasis. OBJECTIVES: To determine stability of response to secukinumab, changes in efficacy were assessed in individual patients. METHODS: This is a post hoc analysis of two phase III randomized controlled trials, FIXTURE (trial registration: NCT01358578) and CLEAR (trial registration: NCT02074982). Patients received secukinumab 300 mg (FIXTURE and CLEAR), etanercept 50 mg (FIXTURE) or ustekinumab 45 or 90 mg (CLEAR) over 52 weeks. Mutually exclusive response categories were defined: ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI 90) ('excellent'), ≥ 75% improvement in PASI (PASI 75) and < PASI 90 ('good') and < PASI 75 ('insufficient'). Reductions in efficacy were defined as shifts from higher to lower response categories between two consecutive visits maintained for a third consecutive visit. Loss of efficacy was defined as a reduction of efficacy resulting in 'insufficient' response. All comparisons are descriptive. RESULTS: At 52 weeks, in CLEAR, 90·2% (303/336) of patients on secukinumab achieved stable efficacy without loss and 77·7% (261/336) showed stable efficacy without any reduction of response [74·3% (252/339) and 59·9% (203/339) of patients for ustekinumab]. In FIXTURE, 83·5% (273/327) and 66·4% (217/327) of patients on secukinumab had stable efficacy without loss or reduction of response [58·3% (190/326) and 42·6% (139/326) for etanercept]. Response was regained by continuing secukinumab treatment in 50% (8/16) of patients in CLEAR and 26% (9/34) in FIXTURE. Similar patterns were observed for other response definitions. CONCLUSIONS: Efficacy with secukinumab was stable over 52 weeks of treatment in most patients. Continued treatment with secukinumab resulted in regain of efficacy in some patients. Persistent loss of response was uncommon. What's already known about this topic? Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows significant and sustained efficacy in the treatment of moderate-to-severe psoriasis. Secondary loss of response may be experienced by a minority of patients treated with secukinumab, as with other biologics, but the extent of this and the potential for regain of efficacy with continued treatment is not well understood. What does this study add? To determine stability of response to secukinumab and inform clinical practice, changes in efficacy were assessed at individual patient level using response categories. Efficacy with secukinumab was stable over 52 weeks of treatment in most patients, and continued treatment with secukinumab resulted in efficacy regain after loss in some patients. Persistent loss of response was uncommon. Patient factors such as body weight may affect the likelihood of loss of efficacy.

Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment. METHODS: Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines. RESULTS: Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab. CONCLUSIONS: Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks.

Effects of secukinumab on metabolic and liver parameters in plaque psoriasis patients.

BACKGROUND: Psoriasis is associated with metabolic, liver and cardiovascular comorbidity. Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A, has shown significant and sustained efficacy in the treatment of moderate to severe psoriasis. OBJECTIVES: This was an exploratory post hoc analysis of pooled data from three phase 3 studies in plaque psoriasis patient populations. The objective was to show the course of metabolic and liver parameters under secukinumab, etanercept or placebo treatment over time. A further objective was to assess the impact of selected comorbidities and metabolic characteristics on high-sensitivity C-reactive protein (hs-CRP), as a surrogate marker of systemic inflammation. METHODS: Data from the phase 3 randomized controlled trials [FIXTURE (NCT01358578), ERASURE (NCT01365455) and SCULPTURE (NCT01406938); n = 3010] were included in this analysis. Patients were treated with secukinumab 150 mg or 300 mg, placebo or etanercept 50 mg (FIXTURE only) as active comparator. A set of metabolic and liver parameters was longitudinally assessed over 52 weeks. Multivariate regression analyses assessed the impact of selected comorbidities and metabolic characteristics on hs-CRP levels at baseline and under treatment. RESULTS: Secukinumab treatment reduced hs-CRP levels. Body weight and uric acid levels tended to decrease over 52 weeks with secukinumab. Secukinumab showed a neutral effect on fasting plasma glucose, lipid parameters and liver enzymes. Psoriatic arthritis, metabolic syndrome, obesity, impaired glucose metabolism, and hyperuricemia were each associated with increased hs-CRP levels at baseline. Concomitant obesity attenuated the decline in hs-CRP under treatment. CONCLUSIONS: These analyses suggest neutral to favourable long-term trends in metabolic and liver parameters under secukinumab treatment. Metabolic comorbidities were associated with increased hs-CRP levels, reflecting the role of systemic inflammatory processes in their pathophysiology.

Baseline characteristics of patients with moderate-to-severe psoriasis according to previous systemic treatment exposure: the PROSE study population.

INTRODUCTION: Psoriatic disease is associated with considerable impairment of Quality of Life (QoL). The PROSE study (NCT02752776) examined the impact of secukinumab on patient-reported outcomes in patients with moderate-to-severe psoriasis (PsO) stratified by previous exposure to systemic treatment. METHODS: In this prospective, non-randomized, multicentre study, patients were categorized at baseline according to previous exposure to systemic treatment: naïve [naïve to any systemic treatment (N = 663)], conventional systemic [previously exposed to ≥1 conventional systemic therapy (N = 673)] and biologics [previously exposed to ≥1 biologic (N = 324)]. Baseline demographics including age, gender, race, body weight and body mass index, disease characteristics and patient-reported QoL outcomes [Dermatology Life Quality Index (DLQI), Family DLQI (F-DLQI)] of patients enrolled in the study are reported here. RESULTS: Baseline demographic characteristics were well balanced across the three subpopulations. Naïve patients had a shorter time since diagnosis (15.5 ± 12.1 years) compared with the conventional systemic (19.1 ± 12.5 years) and biologic patients (23.0 ± 12.5 years), and lower rates of psoriatic arthritis (6.6% vs. 17.4% and 27.8%, respectively). Metabolic syndrome (37.6-43.5%), obesity (16.9-19.1%), hyperlipidaemia (15.3-21.9%) and diabetes mellitus (6.8-14.2%) were reported at numerically higher rate in the biologic group. The mean PASI (19.7 ± 7.9), affected Body Surface Area (28.2 ± 15.3%) as well as the Investigator Global Assessment score (patients with score 4: 33.7%) indicated severe disease at baseline and were comparable for the three groups. QoL impairment was evident from mean DLQI (14.1 ± 7.1: naïve = 13.5 ± 6.8; conventional systemic = 14.3 ± 7.0; biologic = 14.8 ± 7.7) and mean F-DLQI (11.5 ± 7.0: naïve = 11.3 ± 7.1; conventional systemic = 11.4 ± 6.7; biologic = 12.1 ± 7.7) also indicated derangement of QoL of patients and their families. CONCLUSION: Patients naïve to systemic treatment had shorter disease journey compared with patients previously exposed to systemic treatments; despite this, the severe impact of disease on patient and family QoL outcomes can be as apparent in naïve patients as in systemically treated patients at baseline.

Long-term follow-up of 22 psoriatic patients treated with ixekizumab after failure of secukinumab.

Switching of biologic agents in treatment of plaque psoriasis is a common strategy. Only a few studies are available on switching between IL17A-blockers. In a retrospective study, we identified 22 psoriasis patients who, after failing secukinumab as a first IL17A-blocker received ixekizumab with an observation period of at least 24 weeks. At last observation 10/22 patients had a good response (PASI75 or PASI<3) using ixekizumab therapy. None of five patients with primary non-response to secukinumab reached a good, durable response to ixekizumab. In conclusion, ixekizumab appears to be a therapeutic option as a second IL17A-blocker in psoriasis patients who did not show a primary non-response to secukinumab.

Long-term follow-up of 22 psoriatic patients treated with ixekizumab after failure of secukinumab.

The original article was published on February 15, 2020 and corrected on March 26, 2020. The revised version of the article amends the table and figure, while leaving the text largely unchanged. The changes appear in the revised online PDF copy of this article.

The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

Small dense LDL cholesterol in human subjects with different chronic inflammatory diseases.

BACKGROUND AND AIMS: Chronic inflammatory diseases (CID) are associated with a profound increase in cardiovascular (CV) risk resulting in reduced life expectancy. However, LDL-cholesterol is reported to be low in CID patients which is referred to as the "LDL paradoxon". The aim of the present study was to investigate whether LDL-particles in CID exhibit an increased content of the highly atherogenic small-dense LDL subfraction (sdLDL). METHODS AND RESULTS: In this prospective, single center, observational study we enrolled 141 patients with CID (RA n = 59, inflammatory bowel disease (IBD) n = 35, ankylosing spondylitis (SpA) n = 25, Psoriasis n = 22) in 2011 through 2013 to evaluate sdLDL levels before as well as 6 and 26 weeks after initiation of different anti-cytokine therapies (anti-TNFα, anti-IL-6R antibodies). sdLDL levels were compared to 141 healthy individuals in a case control design. Compared to healthy controls, all CID patients displayed a significantly higher sdLDL content within the LDL cholesterol fraction: RA 35.0 ± 9.2% (p < 0.001), SpA 42.5 ± 10.5% (p < 0.001), IBD 37.5 ± 7.1% (p < 0.001), Psoriasis 33.6 ± 4.6% (p < 0.01). Furthermore, the sdLDL/LDL ratio was significantly higher in male compared to female RA subjects (p < 0.05). Neither anti-TNFα nor anti-IL6R medication altered sdLDL levels despite a significant improvement of disease activity. CONCLUSION: In several different chronic inflammatory disease entities, LDL-cholesterol is shifted toward a pro-atherogenic phenotype due to an increased sdLDL content which might in part explain the LDL paradoxon. Since premature CV disease is a major burden of affected patients, specifically targeting lipid metabolism should be considered routinely in clinical patient care. CLINICAL TRIALS: Registration at German Clinical Trial Register (DRKS): DRKS00005285.