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      Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis

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          Abstract

          Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator's global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator's global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.).

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          Most cited references14

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          Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.

          The most commonly used tool for self-report of pruritus intensity is the visual analogue scale (VAS). Similar tools are the numerical rating scale (NRS) and verbal rating scale (VRS). In the present study, initiated by the International Forum for the Study of Itch assessing reliability of these tools, 471 randomly selected patients with chronic itch (200 males, 271 females, mean age 58.44 years) recorded their pruritus intensity on VAS (100-mm line), NRS (0-10) and VRS (four-point) scales. Re-test reliability was analysed in a subgroup of 250 patients after one hour. Statistical analysis showed a high reliability and concurrent validity (r>0.8; p<0.01) for all tools. Mean values of all scales showed a high correlation. In conclusion, high reliability and concurrent validity was found for VAS, NRS and VRS. On re-test, higher correlation and less missing values were observed. A training session before starting a clinical trial is recommended.
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            Clinical Validation and Guidelines for the SCORAD Index: Consensus Report of the European Task Force on Atopic Dermatitis

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              The 5-D itch scale: a new measure of pruritus.

              Itching is a subjective and multidimensional experience which is difficult to quantify. Most methodologies to assess itching suffer from being unidimensional, for example only measuring intensity without impact on quality of life, or only measuring scratching activity. None has actually been demonstrated to be able to detect change over time, which is essential to using them as an outcome measure of response to an intervention. The 5-D itch scale was developed as a brief but multidimensional questionnaire designed to be useful as an outcome measure in clinical trials. The five dimensions are degree, duration, direction, disability and distribution. To study the 5-D with respect to validity, reliability and response to change. The 5-D was administered to 234 individuals with chronic pruritus due to liver disease (n = 63), kidney disease (n = 36), dermatological disorders (n = 56), HIV/AIDS (n = 28) and burn injuries (n = 51). The 5-D was administered at baseline and after a 6-week follow-up period. A subset of 50 untreated patients was retested after 3 days to assess test-retest reliability. The 5-D score correlated strongly with a visual analogue score: r = 0.727 at baseline (P < 0.0001), r = 0.868 at the 3-day repeat (P < 0.0001), and r = 0.892 at the 6-week follow-up (P < 0.0001). There was no change in mean 5-D score between day 1 and day 3 in untreated individuals (intraclass correlation coefficient = 0.96, P < 0.0001). The 5-D did, however, detect significant changes in pruritus over the 6-week follow-up period (P < 0.0001). Subanalysis of the different patient groups revealed similar response patterns and scores, with the exception of lower total scores for the burn victims due to lower scores on the distribution domain because they itched only at the site of their burn. The 5-D, therefore, is a reliable, multidimensional measure of itching that has been validated in patients with chronic pruritus to able to detect changes over time. The 5-D should be useful as an outcome measure in clinical trials.
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                Massachusetts Medical Society
                0028-4793
                1533-4406
                July 10 2014
                July 10 2014
                : 371
                : 2
                : 130-139
                Article
                10.1056/NEJMoa1314768
                25006719
                69950c78-ac38-4ee2-b031-f0c519522ae4
                © 2014
                History

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