Summary
Background
Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment ...effect via topical application in patients with AD is unknown.
Objectives
Tofacitinib, a small‐molecule JAK inhibitor, was investigated for the topical treatment of AD.
Methods
In this 4‐week, phase IIa, randomized, double‐blind, vehicle‐controlled study (NCT02001181), 69 adults with mild‐to‐moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient‐reported pruritus. Safety, local tolerability and pharmacokinetics were monitored.
Results
The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0·001) for tofacitinib (−81·7%) vs. vehicle (−29·9%). Patients treated with tofacitinib showed significant (P < 0·001) improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib.
Conclusions
Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.
What's already known about this topic?
Atopic dermatitis (AD) is a common, inflammatory skin condition affecting adults and children worldwide with prevalence rates of up to 20% and increasing.
Despite unmet medical need, it has been 15 years since a new AD drug with a novel mechanism of action has been approved, highlighting the need for other effective agents.
Recent clinical and nonclinical data support the potential therapeutic benefit of Janus kinase (JAK) inhibition in treating AD.
What does this study add?
Tofacitinib ointment showed significantly greater efficacy vs. vehicle across all study end points, with early onset of effect, and comparable safety/local tolerability with vehicle.
JAK inhibition through topical delivery is potentially a promising treatment target for AD.
This study provides important information to the medical research community regarding AD treatment options that have a new mechanism of action.
Linked Comment: Damsky and King. Br J Dermatol 2016; 175:861–862.
Summary
Background
Psoriasis, Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders with overlapping genetic architecture. However, data on the frequency and risk of CD ...and UC in psoriasis are scarce and poorly understood.
Objectives
To investigate the association between CD and UC in patients with psoriasis.
Methods
All Danish individuals aged ≥ 18 years between 1 January 1997 and 31 December 2012 were linked in nationwide registers. Psoriasis severity was defined in two models: hospital visits and medication. Incidence rates per 10 000 person‐years were calculated, and incidence rate ratios (IRRs) were estimated by Poisson regression.
Results
In the total cohort (n = 5 554 100) there were 75 209 incident cases of psoriasis, 11 309 incident cases of CD and 30 310 incident cases of UC, during follow‐up. The adjusted IRRs (95% confidence intervals) of CD were 1·28 (1·03–1·59), 2·56 (1·87–3·50), 2·85 (1·72–4·73) and 3·42 (2·36–4·95) in patients with mild psoriasis, severe psoriasis (hospital), severe psoriasis (medication) and psoriatic arthritis, respectively. Similarly, the adjusted IRRs of UC were 1·49 (1·32–1·68), 1·56 (1·22–2·00), 1·96 (1·36–2·83) and 2·43 (1·86–3·17), respectively. The 10‐year incidence of CD was 2–5 per 1000 patients and of UC 7–11 per 1000 patients, depending on psoriasis severity and the presence of psoriatic arthritis. Additionally, an increased risk of incident psoriasis was found following CD or UC.
Conclusions
We observed a psoriasis‐associated increased risk of CD and UC, which was higher in severe psoriasis, and an increased risk of psoriasis in patients with inflammatory bowel disease. Increased focus on gastrointestinal symptoms in patients with psoriasis may be warranted.
What's already known about this topic?
Co‐occurrence of psoriasis and inflammatory bowel disease (IBD) has been described, but data are inconsistent.
What does this study add?
In a nationwide cohort study, we found a bidirectional relationship between psoriasis and IBD.
Plain language summary available online
Summary
Background
Ixekizumab, a high‐affinity monoclonal antibody that selectively targets interleukin (IL)‐17A, is approved for the treatment of moderate‐to‐severe psoriasis.
Objectives
This ...analysis represents an overview of the efficacy outcomes from three phase III psoriasis studies.
Methods
Data were integrated from the 12‐week induction period of three studies in which patients received ixekizumab 80 mg every 2 weeks (IXE Q2W; n = 1169) or every 4 weeks (IXE Q4W; n = 1165) after an initial 160‐mg dose for both; etanercept (50 mg biweekly; n = 740; two studies) or placebo (n = 792). The coprimary end points were the percentages of patients with response of static Physician's Global Assessment (sPGA; score 0 or 1) and ≥ 75% improvement in baseline Psoriasis Area and Severity Index (PASI 75) at week 12. Response rates were compared between treatments using the Cochran–Mantel–Haenszel test stratified by study. Treatment comparisons with placebo included data from three studies, whereas etanercept comparisons were based on two studies.
Results
Ixekizumab treatment was superior to placebo (P < 0·001) and etanercept (P < 0·001) on sPGA (0, 1) and PASI 75, with significant differences in PASI improvement at week 1. With IXE Q2W, at week 12, the frequencies of patients achieving PASI 75, 90 and 100 were nearly 90%, 70% and 40%, respectively. Ixekizumab‐treated patients showed significantly greater improvement vs. placebo and etanercept in percentage body surface area involvement and fingernail psoriasis. IXE Q2W was superior to IXE Q4W on all treatment outcomes.
Conclusions
Ixekizumab therapy at both dosing regimens demonstrated rapid onset and superior efficacy to placebo and etanercept, with IXE Q2W providing better outcomes than IXE Q4W during the first 12 weeks of treatment.
What's already known about this topic?
Study results have been reported from each of the pivotal phase III trials that compared two dose schedules of ixekizumab (a high‐affinity anti‐interleukin‐17A antibody) with placebo and/or etanercept (a tumour necrosis factor blocker) in the treatment of plaque psoriasis.
What does this study add?
We provide a comprehensive overview of ixekizumab therapy for moderate‐to‐severe plaque psoriasis by presenting integrated 12‐week efficacy outcomes for two ixekizumab dosing regimens from the pivotal phase III studies.
Linked Comment: Fleming. Br J Dermatol 2018; 178:585–586
Plain language summary available online
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Summary
Background
Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate‐to‐severe plaque psoriasis.
Objectives
To compare outcomes following tofacitinib ...withdrawal with outcomes of continuation.
Methods
In this phase 3 study (NCT01186744), patients received tofacitinib 5 mg (n = 331) or 10 mg (n = 335) twice daily for 24 weeks. The patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) score from baseline and Physician's Global Assessment (PGA) of ‘clear’ or ‘almost clear’ (PGA response) received a placebo (withdrawal) or the previous dose. At relapse (> 50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose.
Results
Initial treatment: 33·5% and 55·2% achieved both PASI 75 and PGA responses with tofacitinib 5 and 10 mg twice daily, respectively, making them eligible for the treatment‐withdrawal period. Withdrawal: 56·2%, 62·3%, 23·3% and 26·1% maintained PASI 75 responses with tofacitinib 5, 10 mg, placebo (5 mg) and placebo (10 mg) twice daily, respectively; 49·9%, 63·9%, 22·9% and 18·0% maintained PGA responses; and 92·3%, 93·0%, 32·8% and 42·9% did not relapse. Elevations in low‐density lipoprotein–cholesterol levels following initial treatment (mean increase: 8·71 mg dL−1 with 5 mg twice daily, 10·26 mg dL−1 with 10 mg twice daily) were reversed upon withdrawal. Retreatment: 36·8% and 61·0% of patients who relapsed achieved PASI 75 responses with tofacitinib 5 or 10 mg after 16 weeks; 44·8% and 57·1% regained PGA responses.
Conclusions
Patients who received continuous treatment maintained a response more effectively when compared with placebo recipients. Safety profiles were comparable in both the continuous treatment group and retreatment group. Of those patients who relapsed, up to 60% recaptured a response with tofacitinib.
What's already known about this topic?
Tofacitinib inhibits Janus kinase (JAK)1/JAK3 implicated in psoriasis pathogenesis. Oral tofacitinib was effective in treating psoriasis in a phase 2b study.
Patients may need to stop treatment temporarily.
What does this study add?
Continuous tofacitinib treatment was most effective in psoriasis, but if treatment had been interrupted, retreatment was possible.
Up to 50% of patients recaptured a ≥ 75% improvement in Psoriasis Area Severity Index score upon retreatment.
Tofacitinib is well tolerated. No patients experienced psoriasis rebound during treatment withdrawal.
Several novel biologics are available or in development for moderate‐to‐severe plaque psoriasis. These drugs may differ in time until Psoriasis Area and Severity Index (PASI) response is obtained. In ...this systematic review, we examined the time to onset of action for interleukin (IL)‐17 and IL‐23 agents in the treatment of psoriasis. The primary objective was the weighted mean time needed for 25% and 50% of patients with psoriasis to achieve PASI90. The medical databases PubMed, Web of Science and EMBASE were searched using the following terms: psoriasis AND (ixekizumab OR secukinumab OR brodalumab OR risankizumab OR guselkumab OR tildrakizumab). A total of 27 studies were included for data extraction and qualitative synthesis, and 26 of these were quantitatively analysed. The shortest time to 25% and 50% of patients to achieved PASI90 were seen with brodalumab 210 mg every 2 weeks (Q2W; 3.5 weeks and 6.2 weeks, respectively) followed by ixekizumab 80 mg Q2W (4.1 and 7.4 weeks, respectively) and ixekizumab 80 mg Q4W (4.6 and 8.1 weeks, respectively) dosages. In conclusion, clinical trials yielded shorter time to onset of action in studies assessing approved dosing ranges of IL‐17 inhibitors compared with studies assessing IL‐23 inhibitors.
Background
Psoriasis and periodontitis are chronic inflammatory disorders with overlapping inflammatory pathways, but data on risk of periodontitis in psoriasis are scarce and a possible pathogenic ...link is poorly understood.
Objective
We investigated the association between psoriasis and periodontitis in a nationwide cohort study.
Methods
All Danish individuals aged ≥18 years between 1 January 1997 and 31 December 2011 (n = 5,470,428), including 54 210 and 6988 patients with mild and severe psoriasis, and 6428 with psoriatic arthritis, were linked through administrative registers. Incidence rate ratios (IRRs) were estimated by Poisson regression.
Results
Incidence rates of periodontitis per 10 000 person‐years were 3.07 (3.03–3.12), 5.89 (1.07–6.84), 8.27 (5.50–12.45) and 11.12 (7.87–15.73) for the reference population, mild psoriasis, severe psoriasis and psoriatic arthritis respectively. Adjusted IRRs were (1.66; 1.43–1.94) for mild psoriasis, (2.24; 1.46–3.44) for severe psoriasis and (3.48; 2.46–4.92) for psoriatic arthritis. Similar results were found when a case–control design was applied.
Conclusions
We found a significant psoriasis‐associated increased risk of periodontitis, which was highest in patients with severe psoriasis and psoriatic arthritis.
Summary
Background
Psoriasis is a common inflammatory skin disease, and inflammation may affect suicidal behaviour. Current data on the incidence and risk of suicidal behaviour in patients with ...psoriasis are scarce.
Objectives
We investigated the association between psoriasis and the risk of self‐harm and suicide attempts and suicides.
Methods
All Danish patients aged ≥ 18 years with mild or severe psoriasis (cases) from 1 January 1997 to 31 December 2011 were matched on age, sex and calendar time 1 : 5 with healthy controls. The outcome was a diagnosis of self‐harm or a nonfatal suicide attempt, or completed suicide. Incidence rates per 10 000 person‐years were calculated, and incidence rate ratios (IRRs) and confidence intervals (CIs) were estimated by Poisson regression models.
Results
The study cohort comprised 408 663 individuals, including 57 502 and 11 009 patients with mild and severe psoriasis, respectively. In total 280 cases of self‐harm or suicide attempts, and 574 suicides occurred during follow‐up. There was no increased risk of self‐harm or suicide attempts in patients with mild psoriasis (IRR 1·01, 95% CI 0·17–2·01), but this risk was significantly increased in severe psoriasis (IRR 1·69, 95% CI 1·00–2·84). There was no increased risk of suicides in mild (IRR 1·05, 95% CI 0·84–1·32) or severe psoriasis (IRR 0·78, 95% CI 0·45–1·36). Similar results were found when suicides were confirmed by official forensic investigations, and when psoriasis was compared with atopic dermatitis.
Conclusions
We found limited evidence to suggest an increased risk of self‐harm and nonfatal suicide attempts in patients with psoriasis. Importantly, after adjustment for psoriatic arthritis this risk was no longer significantly increased. The risk of completed suicide was also not increased, regardless of psoriasis severity.
What's already known about this topic?
Psoriasis is an inflammatory disease with severe impact on quality of life, and inflicts a substantial psychosocial burden on patients.
What does this study add?
Psoriasis may be associated with a small increased risk of self‐harm and nonfatal suicide attempts, but the risk of completed suicide is not increased.
Importantly, after adjustment for psoriatic arthritis, the risk of self‐harm and nonfatal suicide attempts was no longer significantly increased.
Linked Comment: Sbidian. Br J Dermatol 2016; 175:456–457.
Plain language summary available online
Summary
Background
Palmoplantar pustulosis (PPP) is a chronic pustular skin condition on the palms and soles. The disease is often seen in combination with plaque psoriasis, and whether PPP is a ...variant of psoriasis has been debated. The disease prevalence of PPP and co‐occurring psoriasis is not yet established and the patient group remains understudied.
Objectives
To estimate the prevalence of PPP and co‐occurring psoriasis in three population‐based cohorts and to provide information on patient demographics and characteristics.
Methods
Administrative healthcare registries and insurance databases from the U.S.A., Denmark and Germany were used as data sources. Patients with PPP were defined by a single International Classification of Diseases 10th Revision code for PPP during a 1‐year period. Information regarding co‐occurring plaque psoriasis and other comorbidities was extracted. Furthermore, use of antipsoriatic medication was identified.
Results
In total 1435, 751 and 1832 patients with PPP were identified in the U.S., Danish and German populations, with estimated 1‐year prevalences of 0·009%, 0·005% and 0·08%, respectively. Plaque psoriasis was present in 14·2–61·3% of patients with PPP. Patients with co‐occurring psoriasis had an overall higher prevalence of psoriatic arthritis. Similarly, medication use was more prevalent in patients with PPP with co‐occurring psoriasis, and especially pronounced was the use of biologic therapies.
Conclusions
This large observational study on patients with PPP provides detailed information regarding patient demographics, comorbidities and medication use. The 1‐year prevalence of PPP varied in the three studied populations, possibly due to differences in diagnostics and recording practices. Psoriasis frequently co‐occurred in patients with PPP.
What's already known about this topic?
Palmoplantar pustulosis (PPP) is a skin disease of the palms of the hands and soles of the feet and is known to be related to psoriasis.
Whether PPP is a distinct disease or a variant of psoriasis is not yet established.
The condition is understudied in terms of disease prevalence, disease predictors, patient characteristics and comorbidity.
What does this study add?
In this study using data from three large population‐based cohorts we found low prevalence rates (< 0·1%) of PPP.
The prevalence of psoriasis was estimated at between 14·2% and 61·3% in patients with psoriasis.
Patients with PPP with co‐occurring psoriasis have a higher prevalence of psoriatic arthritis and use of antipsoriatic drugs.
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Linked Comment: Haidari and Feldman. Br J Dermatol 2019; 181:887–888.
Plain language summary available online
Summary
Background
Head‐to‐head randomized studies comparing ixekizumab and secukinumab in the treatment of psoriasis are not available.
Objectives
To assess efficacy and quality of life using ...matching‐adjusted indirect comparisons for treatment with ixekizumab vs. secukinumab.
Methods
Psoriasis Area and Severity Index (PASI) improvement of at least 75%, 90% and 100% and Dermatology Life Quality Index (DLQI) 0/1 response rates for approved dosages of ixekizumab (160 mg at Week 0, then 80 mg every two weeks for the first 12 weeks) and secukinumab (300 mg at Weeks 0, 1, 2, 3 and 4, then 300 mg every 4 weeks) treatment were compared using data from active (etanercept and ustekinumab) and placebo‐controlled studies. Comparisons were made using the Bucher (BU) method and two modified versions of the Signorovitch (SG) method (SG total and SG separate). Subsequently, results based on active treatment common comparators were combined using generic inverse‐variance meta‐analysis.
Results
In the meta‐analysis of studies with active comparators, PASI 90 response rates were 12·7% 95% confidence interval (CI) 5·5–19·8, P = 0·0005, 10·0% (95% CI 2·1–18·0, P = 0·01) and 11·2% (95% CI 3·2–19·1, P = 0·006) higher and PASI 100 response rates were 11·7% (95% CI 5·9–17·5, P < 0·001), 12·7% (95% CI 6·0–19·4, P < 0·001) and 13·1% (95% CI 6·3–19·9, P < 0·001) higher for ixekizumab compared with secukinumab using BU, SG total and SG separate methods. PASI 75 results were comparable when SG methods were used and favoured ixekizumab when the BU method was used. Week 12 DLQI 0/1 response rates did not differ significantly.
Conclusions
Ixekizumab had higher PASI 90 and PASI 100 responses at week 12 compared with secukinumab using adjusted indirect comparisons.
What's already known about this topic?
Interleukin‐17A antagonists are highly effective new therapies for the treatment of moderate‐to‐severe psoriasis; however, head‐to‐head studies are lacking.
What does this study add?
Efficacy and quality of life were compared using a matching‐adjusted indirect comparison for ixekizumab and secukinumab treatment.
In terms of response differences, ixekizumab had higher Psoriasis Area and Severity Index (PASI) 90 and PASI 100 responses at week 12 compared with secukinumab.
Dermatology Life Quality Index response rates did not differ.
Linked Comment: Paul. Br J Dermatol 2018; 178:1003–1005.
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Background
There is concern that increased bodyweight may impact efficacy of some therapies used to treat psoriasis.
Objective
To evaluate the effect of bodyweight on response to ixekizumab treatment ...in patients with moderate‐to‐severe psoriasis.
Methods
Patients were characterized under three bodyweight categories (<80 kg, 80 to <100 kg, ≥100 kg) in this preplanned subgroup analysis from an integrated database of three multicenter, randomised, double‐blind, controlled Phase 3 clinical studies (UNCOVER‐1, UNCOVER‐2 and UNCOVER‐3). In the first 12 weeks of each study, patients were randomly assigned to receive subcutaneous placebo, 80‐mg ixekizumab every 2 weeks (IXE Q2W) or every 4 weeks (IXE Q4W) after a starting dose of 160‐mg ixekizumab, or 50‐mg etanercept twice weekly (UNCOVER‐2 and UNCOVER‐3 only).
Results
This analysis included 3855 patients with baseline bodyweight in the IXE Q4W (N = 1159), IXE Q2W (N = 1168), placebo (N = 789) and etanercept (N = 739) groups. Distribution of patients across bodyweight categories was similar between treatment groups. Baseline demographics and patients characteristics were generally consistent across treatment groups within each bodyweight category. Across all bodyweight categories, a significantly higher percentage of patients treated with IXE Q2W or IXE Q4W than with placebo or etanercept achieved PASI 75, PASI 90 or PASI 100 at Week 12. No meaningful differences in PASI 75 response rates were observed across bodyweight categories. Some numerical differences in PASI 90 and PASI 100 response rates were observed between bodyweight categories with IXE Q2W providing numerically higher response rates than IXE Q4W. The incidence of treatment‐emergent adverse events was similar in the treatment groups and across bodyweight categories.
Conclusion
Ixekizumab was efficacious in the treatment of moderate‐to‐severe psoriasis regardless of bodyweight. The safety profile of ixekizumab was also similar across bodyweight categories, and no safety signals were identified specific to any of the bodyweight categories.
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