Brodalumab and ixekizumab, anti-interleukin-17-receptor antibodies for psoriasis: a critical appraisal

Aim  Papp et al. (N Engl J Med 2012; 366: 1181-9) and Leonardi et al. (N Engl J Med 2012; 366: 1190-9) respectively assessed the efficacy and safety of brodalumab (AMG 827), a human monoclonal antibody directed against interleukin (IL)-17RA, the receptor of IL-17A and ixekizumab (LY2439821), a humanized anti-IL-17 monoclonal antibody for the treatment of moderate-to-severe plaque psoriasis. Setting and design  In these phase II, multicentre, randomized, double-blind, placebo-controlled, dose-ranging studies, 198 patients with severe chronic plaque-type psoriasis [Psoriasis Area and Severity Index (PASI) ≥ 12, body surface area (BSA) ≥ 10] were enrolled in Papp et al. between December 2009 and April 2010 and 142 patients in Leonardi et al. between April 2010 and March 2011. Study exposure  In Papp et al., patients with chronic plaque-type psoriasis were randomly assigned to receive placebo or brodalumab at a dose of 70, 140 or 210 mg, administered subcutaneously on day 1 and at weeks 1, 2, 4, 6, 8 and 10, or at a dose of 280 mg administered subcutaneously on day 1 and at weeks 4 and 8. In Leonardi et al., patients were randomly assigned to receive subcutaneous injections of placebo or 10, 25, 75 or 150 mg of ixekizumab at 0, 2, 4, 8, 12 and 16 weeks, followed by a 4-week follow-up period. Outcomes  In both studies the PASI, static Physician's Global Assessment (sPGA), Dermatology Life Quality Index (DLQI), adverse events, and routine haematological and laboratory values were analysed. Additionally in Papp et al. the BSA and Medical Outcomes Study 36-item short-form health survey, and in Leonardi et al. the joint pain visual analogue scale (VAS), itch severity VAS, Nail Psoriasis Severity Index (NAPSI) and the Psoriasis Scalp Severity Index (PSSI) were also measured. Primary outcome measures  At week 12, in Papp et al. and Leonardi et al.: (A) The percentage improvement in PASI. In Leonardi et al. (and in Papp et al. as one of the secondary outcomes): (B) The percentage of patients who achieved a reduction in the PASI by at least 75% (PASI 75) over baseline. Results  Primary endpoints: (A) At week 12 in Papp et al., the mean improvements in PASI were significantly greater in the 140, 210 and 280 mg brodalumab groups than in the 70 mg brodalumab group (85·9%, 86·3% and 76·0%, respectively, vs. 45·0%; P  < 0·001); in addition, the mean improvement in PASI was significantly greater in each brodalumab group than in the placebo group (16·0%; P  < 0·001). (At week 16 lower but still significant percentages compared with placebo were seen). In Leonardi et al., the mean improvements in PASI of the 10, 25, 75 and 150 mg ixekizumab groups are not reported. Significant differences between the two highest dose groups and the placebo group were seen as early as 1 week in PASI. (B) At week 12 in Papp et al., the percentages of patients with PASI 75 were 33% in the 70 mg, 77% in the 140 mg, 82% in the 210 mg and 67% in the 280 mg brodalumab group. The percentages of patients with a 50%, 75%, 90% or 100% improvement in PASI at week 12 were significantly higher among patients who received brodalumab (taking into account all doses) than among patients who received placebo. The authors do not give an explanation for the lower improvements at week 16. In Leonardi et al., the PASI 75 occurred in significantly more patients in the 25 mg (76·7%), 75 mg (82·8%) and 150 mg (82·1%) ixekizumab groups vs. placebo (7·7%; P  < 0·001). No significant difference was seen for the 10 mg group. Significant differences between the 150 mg group and the placebo group were seen as early as 2 weeks in PASI 75. Differences were sustained through 20 weeks for all clinical measures in the ixekizumab study. Secondary endpoints: At week 12, in Papp et al., significant decreases of BSA, sPGA and DLQI were also seen. In Leonardi et al., significantly higher percentages of patients in the three highest ixekizumab dose groups had an sPGA score of 0 (clear of disease) or of 0 or 1 (minimal disease) for each dose and score group vs. placebo (P  < 0·05). Significant reductions in the mean ± SD DLQI scores were detected at 8 weeks in the 150 mg ixekizumab group (-7·8 ± 5·7), the 75 mg ixekizumab group (-8·5 ± 5·1) and the 25 mg ixekizumab group (-7·1 ± 6·5) as compared with placebo (-2·4 ± 4·4) for all comparisons (P  < 0·001). In addition, at 16 weeks, significantly more patients had a DLQI score of 0 in the 150, 75 and 25 mg ixekizumab groups (39·3%, 37·9% and 31·0%, respectively) as compared with placebo (0%) for all comparisons (P  < 0·05). In Leonardi et al., significant reductions were seen in the PSSI, in the NAPSI and in the itch severity (VAS scores). Significant reductions from baseline of the joint pain VAS were also observed in the 150 mg ixekizumab group at 12 weeks, and this reduction was sustained through 20 weeks. At week 16: with respect to the other secondary efficacy endpoints and patient-reported outcomes, significant improvements in scores were seen compared with placebo, but some of these differences were lower than observed at week 12. Safety  Papp et al. summarized that during the first 12 weeks of the trial, 68% of the patients in the 70 mg brodalumab group, 69% (140 mg), 82% (210 mg), 73% (280 mg) and 62% in the placebo group had at least one adverse event. Although the authors mentioned only three serious adverse events, four were reported during the study: renal colic (70 mg brodalumab group), two patients with grade 3 asymptomatic neutropenia (210 mg brodalumab group; Papp et al. clarified that only one of these episodes was a serious adverse event) and an ectopic pregnancy in one patient in the placebo group. Leonardi et al. reported that there were no serious adverse events in any group. The frequency of adverse events was similar between the combined ixekizumab groups and the placebo group. A few patients were withdrawn from the trial due to adverse events including hypertriglyceridaemia (placebo group), peripheral oedema (10 mg ixekizumab), hypersensitivity (10 mg ixekizumab) and urticaria (25 mg ixekizumab). Conclusions  Papp et al. and Leonardi et al. concluded that brodalumab and ixekizumab, respectively, significantly improved plaque psoriasis in 12-week, phase II studies. For difficult-to-treat areas such as the scalp and nails, significant differences from placebo were observed with ixekizumab treatment. These trials were not large enough or of long enough duration to ascertain uncommon adverse events or to assess the risk of infection or cardiovascular event

Critically Appraised Topics in the British Journal of Dermatology: response from Jonathan Batchelor and Phyllis Spuls, section editors for BJD's 'Putting Papers into Practice'

We were very pleased to see the correspondence from Dr Mike Sladden regarding the Critically Appraised Topic (CAT) that we published in the BJD recently(1) . We agree that it is a very helpful CAT, addressing a question that is commonly encountered in dermatological practice. The inclusion of the patient's perspective is a good way of keeping the CAT grounded in the principles of shared decision making (although it is not a mandatory part of a CAT as such). This article is protected by copyright. All rights reserve

Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial: a critical appraisal

Arits et al. aimed to assess whether the effectiveness of imiquimod and fluorouracil is not inferior to methyl aminolaevulinic acid (MAL) photodynamic therapy (PDT) in patients with superficial basal cell carcinoma. This single-blind, noninferiority, randomized controlled trial was conducted at one coordinating academic hospital and six peripheral dermatological departments in the Netherlands between March 2008 and August 2010. Patients with a superficial basal cell carcinoma were randomly assigned to be treated with PDT (two treatments); or imiquimod 5% cream, once daily five times a week for 6 weeks; or fluorouracil 5% cream twice daily for 4 weeks. Follow-up visits were planned after 3 months and 1 year. The primary outcome was defined as the probability that a patient was free of tumour reoccurrence at both 3 and 12 months' follow-up. Secondary outcomes were aesthetic outcome of the treated area, compliance and adverse reactions. In total 911 patients were assessed for eligibility, of whom 601 were randomized: 202 to receive MAL-PDT, 198 to receive imiquimod cream and 201 to receive fluorouracil cream. The proportions (95% confidence intervals) of patients tumour free at both 3 and 12 months were 72·8% (66·8-79·4) for MAL-PDT, 83·4% (78·2-88·9) for imiquimod cream and 80·1% (74·7-85·9) for fluorouracil cream. For patients treated with MAL-PDT, moderate-to-severe pain and burning sensation were reported most often during the treatment itself. For the creams, moderate-to-severe local swelling, erosion, crust formation and itching of the skin were mentioned most often. Arits et al. conclude that topical fluorouracil was noninferior and imiquimod was superior to MAL-PDT for treatment of superficial basal cell carcinoma. Imiquimod cream is suggested as the preferred treatmen

Photo(chemo)therapy in the management of atopic dermatitis: an updated systematic review with implications for practice and research

Photo(chemo)therapy is a common treatment modality in patients with atopic dermatitis (AD), but evidence on its effectiveness has not been recently systematically reviewed. To evaluate the effect of treatment with photo(chemo)therapy in patients with AD and to make treatment recommendations on basis of the evidence. We performed an electronic literature search in MEDLINE (OVID), EMBASE (OVID), the Cochrane Central Register of Controlled Trials (CENTRAL), Global Resource of EczemA Trials (GREAT) and prospective trial registers, complemented with a search of PubMed to find recent studies not yet available in OVID MEDLINE. All randomized controlled trials (RCTs) on phototherapy for the treatment of AD were considered for data extraction. Nineteen studies were included (905 participants). The identified RCTs were generally clinically and qualitatively heterogeneous. Therefore a formal meta-analysis was not feasible. Conclusions must be drawn carefully because of small sample sizes, varying study quality and sometimes the absence of direct comparisons, but on the basis of the included evidence, ultraviolet (UV) A1 and narrowband (NB)-UVB appeared the most effective treatment modalities for the reduction of clinical signs and symptoms. No difference between high-dose UVA1 and medium-dose UVA1 was seen. UVAB was shown to be more effective than UVA and broadband-UVB for the improvement of clinical symptoms, but not compared with UVA1. Other effective treatment options include full-spectrum light, psoralen plus UVA and balneophototherapy. No serious side-effects were reported. Phototherapy can be a valid therapeutic option for patients with AD. Based on the results of this review, preference is given to UVA1 and NB-UVB. Further well-designed, adequately powered RCTs are require

Reporting of outcomes in randomised controlled trials on nail psoriasis; a Systematic Review

Harmonization of outcome measures is needed to increase the value of clinical trials on nail psoriasis. To provide the first step in core outcome set (COS) development, a systematic review was conducted to identify outcome domains and instruments reported in (ongoing) randomised controlled trials (RCTs) on nail psoriasis. Identified outcome domains included clinical signs, quality of life, symptoms and delivery of care. A NAPSI was most commonly used to assess clinical signs (73.8% of studies). Other outcome instruments used included the NAS, composite fingernail score, a physician global assessment, individual nail features or a combination of these. Heterogeneity in type and reporting (e.g. NAPSI 50, NAPSI 75) of outcome instruments was high and characteristics were often insufficient reported. 43.1% of studies assessed quality of life, with 3.1% of studies using a nail psoriasis specific tool. Assessment of symptoms and delivery of care was limited. In conclusion, heterogeneity in type and reporting of nail psoriasis outcome instruments needs to be addressed in the process towards COS development. Sufficient reporting of instrument characteristics should be encouraged. As nail psoriasis is generally assessed secondary to psoriasis of the skin or joints, collaboration between different research groups in COS development is needed. This article is protected by copyright. All rights reserve