Tralokinumab plus topical corticosteroids in adults with severe atopic dermatitis and inadequate response to or intolerance of ciclosporin A: a placebo-controlled, randomized, phase III clinical trial (ECZTRA 7).

BACKGROUND: Patients with severe atopic dermatitis (AD) not controlled with topical therapy have limited treatment options. Ciclosporin A (CSA) is a commonly used, broad immunosuppressant in AD, but treatment with CSA requires monitoring for potentially serious adverse effects. In a previous phase III trial, tralokinumab plus topical corticosteroids (TCS) as needed provided early and sustained improvements in AD signs and symptoms. OBJECTIVES: To evaluate the efficacy and safety of tralokinumab plus TCS in adult patients with severe AD whose disease was not adequately controlled with CSA or who had contraindications to oral CSA. METHODS: In this 26-week, multicentre, parallel, randomized, double-blind, placebo-controlled, phase III trial, European adults with severe AD were randomized 1 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks plus TCS as needed. The primary endpoint was a 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. RESULTS: In total, 277 patients were randomized. At week 16, more patients treated with tralokinumab plus TCS vs. placebo plus TCS achieved EASI 75 [64·2% vs. 50·5%; difference 14·1% (95% confidence interval 2·5-25·7); P = 0·018], which increased further up to week 26. Improvements in AD severity were accompanied by early improvements in patient-reported outcomes, including Dermatology Life Quality Index, Patient-Oriented Eczema Measure, pruritus and sleep interference. Tralokinumab plus TCS also showed a higher EASI75 response at week 16 among patients who had previously failed CSA therapy vs. placebo plus TCS (57% vs. 41%). The overall incidence of adverse events was similar between treatment arms. CONCLUSIONS: Tralokinumab 300 mg plus TCS as needed was effective and well tolerated in patients with severe AD whose disease was not adequately controlled with CSA or who had contraindications to oral CSA.

Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial.

BACKGROUND: Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate-to-severe AD who were candidates for systemic therapy. METHODS: This was a double-blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks. RESULTS: At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9-21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8-30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups. CONCLUSIONS: Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate-to-severe AD.

The patient-reported disease burden in adults with atopic dermatitis: a cross-sectional study in Europe and Canada.

BACKGROUND: Cross-sectional data on patient burden in adults with atopic dermatitis (AD) from real-world clinical practice are limited. OBJECTIVE: This study compared patient-reported burden associated with adult AD across severity levels from clinical practices in Canada and Europe. METHODS: This study included adults (18-65 years) diagnosed with AD by dermatologists, general practitioners or allergists. Participants categorized as mild (n = 547; 37.3%), moderate (n = 520; 35.4%) or severe (n = 400; 27.3%) based on Investigator's Global Assessment completed a questionnaire that included pruritus and pain numerical rating scales, Patient-Oriented-Scoring of Atopic Dermatitis (PO-SCORAD) itch and sleep visual analogue scales, Dermatology Life Quality Index (DLQI), and the Hospital Anxiety and Depression Scale (HADS). Participants were also stratified by inadequate efficacy/intolerance/contraindication to cyclosporine [Cyclo; n = 62 (4 mild, 18 moderate, 40 severe)] and any systemic immunomodulatory agent [IMM; n = 104 (13 mild, 31 moderate, 60 severe)] and compared with the severe group excluding participants identified as Cyclo/IMM. RESULTS: Age was similar across severity groups; the proportion of women was higher in the mild group relative to severe (61.2% vs. 50.5%; P < 0.001). Compared with moderate and mild, participants with severe AD had more comorbidities, higher itch and pain severity, worse sleep and higher levels of anxiety and depression (all P < 0.001). Mean ± SD DLQI score among participants with severe AD (16.2 ± 6.9) showed a large effect on quality of life that was higher than those with moderate (10.2 ± 6.3) and mild (5.5 ± 4.9) (both P < 0.001). The burden among Cyclo and IMM subgroups was generally similar to that of participants with severe AD. CONCLUSIONS: Adults with AD reported a substantial burden across multiple domains that was significantly higher in those with severe disease. The burden among participants in the Cyclo/IMM subgroups was similar to those with severe AD.

Rapid onset of action of calcipotriol/betamethasone dipropionate cutaneous foam in psoriasis, even in patients with more severe disease.

BACKGROUND: The effectiveness of topical therapies in psoriasis is dependent on, amongst other factors, patient adherence. Together with treatment effectiveness and reduction of symptoms, speed of onset and health-related quality of life (HRQoL) are important influencers of adherence. METHODS: This pooled analysis of three Phase II/III trials evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) vs. foam vehicle at early timepoints in mild-to-severe psoriasis using clinically meaningful modified Psoriasis Area and Severity Index (mPASI) and Dermatology Life Quality Index (DLQI) targets. RESULTS: A greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved absolute mPASI targets 0 (15.1% vs. 1.0%), ≤1 (41.4% vs. 5.2%), ≤3 (78.5% vs. 29.2%) and ≤5 (90.2% vs. 62.5%) at week 4 (P < 0.001; all targets). Significant differences between Cal/BD-foam- vs. foam-vehicle-treated patients were observed as early as week 1 in those achieving mPASI ≤1 (6.8% vs. 1.5%; P < 0.01), ≤3 (40.4% vs. 22.8%; P < 0.001) and ≤5 (69.7% vs. 50.8%; P < 0.001). In patients with more severe psoriasis (baseline mPASI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved mPASI ≤1 (20.2% vs. 5.9%; P < 0.05), ≤3 (49.2% vs. 8.8%; P < 0.001) and ≤5 (63.7% vs. 26.5%; P < 0.001) at week 4. In patients with severely impaired HRQoL (baseline DLQI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved target DLQI ≤1 or 0 (week 4: DLQI ≤1, 25.0% vs. 4%; P = 0.001; DLQI 0, 17.4% vs. 2.0%; P = 0.006). CONCLUSION: We report rapid onset of action and greater efficacy with Cal/BD foam vs. foam vehicle, even in patients with more severe psoriasis, manageable with topical treatments. This may support physician management of patient expectations and improve patient adherence, translating into overall topical treatment effectiveness.

Itch relief in patients with psoriasis: effectiveness of calcipotriol plus betamethasone dipropionate foam.

BACKGROUND: Itch is common in psoriasis, adversely affecting health-related quality of life (HRQoL) and sleep. OBJECTIVE: We evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) on itch, itch-related sleep loss and HRQoL vs. foam vehicle. METHODS: We pooled data from three Phase II/III trials (NCT01536886/NCT01866163/NCT02132936) of Cal/BD foam vs. foam vehicle in adults with mild-severe psoriasis. For itch-related analyses, patients with baseline itch visual analogue scale (VAS) >40 (range 0-100) were analysed. Outcomes included the following: itch VAS reduction >40, ≥70% improvement in itch (Itch70) or itch-related sleep loss, 75% improvement in modified Psoriasis Area and Severity Index (excluding head; mPASI75) and Dermatology Life Quality Index (DLQI) scores 0/1 through 4 weeks. RESULTS: Of 837 patients, 800 had baseline itch VAS >0 (Cal/BD foam, n = 610; foam vehicle, n = 190); 484 had baseline itch VAS >40. There was no correlation between itch VAS score and mPASI at baseline (R2  = 0.021). In patients with baseline itch VAS >40, more patients achieved itch VAS reduction >40 in the active vs. vehicle group from Day 5 onwards (Day 5: 57.5% vs. 40.2% [P < 0.05]; Week 4: 83.0% vs. 45.8% [P < 0.001]). More Cal/BD-foam-treated patients achieved Itch70 at Day 3 (34.2% vs. 22.5%; P < 0.05) through to Week 4 (79.3% vs. 38.1%; P < 0.001). In patients with baseline itch VAS >40 and sleep loss >20, improvements in itch-related sleep loss occurred at Week 1 and continued through 4 weeks. Itch-related improvements occurred before improvements in mPASI75. There were significant differences in the proportion of Cal/BD-foam- vs. foam-vehicle-treated patients with baseline DLQI >10 (n = 172 vs. n = 50) achieving DLQI ≤1 (25.0% vs. 4.0%; P = 0.001) and DLQI 0 (17.4% vs. 2.0%; P = 0.006) at Week 4. CONCLUSION: Compared with foam vehicle, Cal/BD foam offers more rapid and effective itch relief, with associated significant improvements in sleep and DLQI.

Antinuclear antibodies associate with loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study.

BACKGROUND: An increasing number of patients with severe psoriasis are failing to respond to antitumour necrosis factor (TNF)-alpha therapy (etanercept, infliximab and adalimumab). OBJECTIVES: We observed that many of these patients developed antinuclear antibodies (ANA) and antidouble-stranded DNA (anti-dsDNA) antibodies while on treatment prompting us to investigate whether their development is associated with anti-TNF treatment failure. METHODS: All patients with psoriasis who had received anti-TNF therapies were identified and their blood results and treatment histories were obtained from electronic patient records and case notes. RESULTS: A total of 97 patients had been treated with anti-TNF agents (60 were on their first agent, 22 had been on and stopped one agent, nine had been on and stopped two agents and six had been on and stopped all three agents). ANA developed in 17% of patients on their first treatment, 54% of patients who had failed one treatment, 78% of patients who had failed two treatments and 83% of patients who had failed all three treatments. Anti-dsDNA antibodies developed in 2%, 27%, 33% and 83% of patients from the same respective groups. Significantly, the antibodies developed before treatment had failed with all three agents and their development was not related to the total time that patients had been on anti-TNF therapy. CONCLUSIONS: This study suggests that the development of ANA and anti-dsDNA antibodies on anti-TNF treatment may act as a marker of forthcoming treatment failure. Large-scale prospective studies are required to assess the importance of this observation.