Identificación de las necesidades del país en los componentes ambiental,

Retrospective case series

Two retrospective case series reported the use of adalimumab, etanercept and ustekinumab from 4 to 165 weeks in children with moderate to severe psoriasis.76,77_{The key characteristics and results from these} studies are reported inTable 31.

Garberet al.76_{reported a retrospective chart review of 27 participants (19 males, 8 females) attending a} single US general dermatology clinic from 2008 to 2014. Insufficient details were reported to establish how many patients received more than one biologic over this period. Clearance rates [defined as 99% reduction on the Simple Measure for Assessing Psoriasis Severity or (S-MAPA)] were reported (seeTable 31). No SAEs were reported. Although the authors concluded that the use of adalimumab, etanercept and ustekinumab is safe in paediatric psoriasis and that these treatments are efficacious, this study provides insufficient data on the efficacy or safety profiles of these agents in practice.

TABLE 30 Reported safety outcomes in the ustekinumab trial (CADMUS) up to week 60a

Treatment

Participants with safety reports,n/N(%)

AEs SAEs Infections

Serious infections Injection site reactions Malignancies Withdrawals because of AEs UST 0.75 mg/kg 29/36 (80.6) 1/36 (2.8)b _{24/36 (66.7) 1/36 (2.8)}b _{1/36 (2.8) 0/36 (0.0) 0/36 (0.0)} UST 0.375 mg/kg 33/37 (89.2) 5/37c,d_{(13.5) 26/37 (70.3) 1/37}d_{(2.7) 0/37 (0.0) 0/37 (0.0) 2/37 (5.4)} PLB→UST 0.75 mg/kg 13/18 (72.2) 0/18 (0.0) 11/18 (61.1) 0/18 (0.0) 0/18 (0.0) 0/18 (0.0) 0/18 (0.0) PLB→UST 0.375 mg/kg 15/19 (79.0) 0/19 (0.0) 13/19 (68.4) 0/19 (0.0) 0/19 (0.0) 0/19 (0.0) 2/19 (10.5)

PLB, placebo; UST, ustekinumab.

a Incorporates week 12 and week 40 data. b Ear infection.

c In addition to events recorded before week 60, one death in an automobile accident, one case of allergic contact dermatitis and one participant with laboratory values for absolute leucocyte count, absolute neutrophil count and white blood cell count of 0.53, 0.87 and 1.62 × 103_{µl, respectively, while undergoing treatment with aciclovir for concurrent}

herpes simplex. d Pyelonephritis.

DOI: 10.3310/hta21640 HEALTH TECHNOLOGY ASSESSMENT 2017 VOL. 21 NO. 64

© Queen’s Printer and Controller of HMSO 2017. This work was produced by Duarteet al.under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

TABLE 31 Retrospective case series of adalimumab, etanercept or ustekinumab in children and young people with psoriasis

Study,

country Treatment (dose)

Number of patients Treatment duration (weeks) Age (years), median (range) Mean PGA score at baseline Reported outcomes/key AEs Garberet al., 2015,76 USA Adalimumab (40 mg every other week) 7 146 – – Achieved clearance, n=4/6; secondary failure,n=3; injection site reaction,n=1; minor infection, n=3a

Etanercept (50 mg weekly) 13 87 – – Achieved clearance,

n=6/9; injection site reaction,n=1; secondary failure, n=6; lack of response,n=3; minor infection, n=4b Ustekinumab (45 mg at weeks 0 and 4, then every 12 weeks)

3 165 – – Achieved clearance,

n=1/3

Adalimumab+methotrexate 2 11 _{– –} Achieved clearance, n=1/2

Etanercept+methotrexate 2 121 _{– –} Achieved clearance, n=2/2 Etanercept+ciclosporin 1 20 _{– – –} Klufaset al., 2016,77 USA Adalimumab (40 mg every other week) 11 3–134 16.5 (7.0–18.0)

2.4 Mean PGA scorec_0.7

Injection site reaction,n=1

Etanercept (25 or 50 mg once or twice weekly)

23 8–135 14.0 (8.0–18.0)

3.0 Mean PGA scorec_1.5

Injection site reaction,n=2

Ustekinumab (45 or 90 mg at weeks 0 and 4, then every 12 weeks)

6 4–72 16.5 (7.0–18.0)

2.6 Mean PGA scorec_1.5

Adalimumab (40 mg eow)+methotrexate

(7.5–15 mg weekly)

9 8–118 15.0 (11.0–17.0)

2.4 Mean PGA scorec_1.0

Injection site reaction,n=1

Etanercept (50 mg once or twice weekly+methotrexate

(7.5–15 mg weekly)

5 4–30 15.0 (13.0–17.0)

3.1 Mean PGA scorec_1.8

Ustekinumab (45 mg at weeks 0 and 4, then every 12 weeks)+methotrexate

(12.5 mg weekly)

2 NR 16.5

(16.0–17.0)

3.8 Mean PGA scorec_1.3

NR, not reported.

a Across all participants who received adalimumab (n=9).

b Across all participants who received etanercept (n=16).

c At 5–7 months.

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Klufaset al.77_{similarly reported a retrospective case series evaluating 51 children with moderate to severe} psoriasis treated with systemic therapies for AE occurrence and PGA-measured disease response. For all biologics (alone or in combination with methotrexate), mean PGA values fell at 5–7 months’follow-up. In total, 29 AEs were reported in relation to 80 treatment data points (some patients received more than one biologic); most were minor subjective side effects, with no infections or SAEs reported. Again, limitations in the sample size and study design preclude strong inferences being drawn from these data.

Registry data

Published findings or papers detailing study design were identified for 16 registries. Information on biological drug safety in their psoriasis cohorts was published by nine registries, with 11 articles on biological efficacy and nine articles including drug survival data. This does not necessarily mean that the other registries did not record these outcomes, but they were not covered in the identified literature output.

Registry data for children

Further screening was carried out to find registry publications making explicit reference to children with psoriasis and specifically providing information on the survival of biological treatment. Two registries (Child-CAPTURE and DERMBIO) were found to include children with psoriasis who were treated with biologics. Child-CAPTURE (the Netherlands) contained seven children treated with etanercept,90_{but did} not differentiate between biological and non-biological therapies in drug survival analyses. We identified from the 2014 annual report91_{by the DERMBIO (Denmark) registry that there are 37 children enrolled who} are undergoing treatment with adalimumab, etanercept or ustekinumab, although data for this group were not reported separately. Cox regression modelling of covariates in two studies found no significant predictive relationship between patient age and drug survival, suggesting that treatment withdrawal rates among children were similar to those in adults.92,93

Wider registry data

In one 2015 DERMBIO study following 1277 (predominantly adult) psoriasis patients for up to 10 years,92 median drug survival for etanercept was 30 months (95% CI 25.1 to 34.9 months), which was significantly lower than for adalimumab (59 months, 95% CI 45.6 to 72.4 months) and ustekinumab (median not reached). Year-on-year drug survival for etanercept (estimated from the Kaplan_–Meier curve) was 0.70 at 1 year, 0.53 at year 2 and 0.30 at year 5, whereas year-on-year drug survival for ustekinumab was 0.85 after 1 year, 0.78 at year 2 and 0.65 at year 5 (Table 32). Loss of efficacy was the most likely reason for drug discontinuation, but this was of greater significance proportionally for etanercept than for the other biologics analysed.

Findings from the British Association of Dermatologists Biologic Interventions Register (BADBIR) were broadly similar to those seen in the Danish cohort. A study by Warrenet al.94_{on drug survival over 3 years in 3523} biologic-naive patients found that 77% of patients remained on biologic treatment over the first year, falling to 53% by the third year. Again, there were significant differences in the treatment withdrawal rates between biologics. Ustekinumab exhibited the highest first-course survival rate at 0.89 at year 1 and 0.75 at year 3. Adalimumab showed the highest survival of the anti-TNF-α_{drugs, at 0.79 at year 1 and 0.59 at}

year 3. Disregarding the very small population of patients on infliximab, etanercept was consistently the

TABLE 32 Survival of first biologic in the DERMBIO registry92

Biologic

Drug survival

1 year 2 years 5 years

Adalimumab (n=567) 0.77 0.67 0.48

Etanercept (n=364) 0.70 0.53 0.30

Infliximab (n=176) 0.75 0.62 0.43

Ustekinumab (n=170) 0.85 0.78 0.65

DOI: 10.3310/hta21640 HEALTH TECHNOLOGY ASSESSMENT 2017 VOL. 21 NO. 64

© Queen’s Printer and Controller of HMSO 2017. This work was produced by Duarteet al.under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

worst-performing drug in terms of treatment withdrawal, with a 1-year survival rate of 0.70, dropping to 0.40 at 3 years (Table 33). Etanercept was also found to be a significant predictor of discontinuation of therapy because of loss of efficacy. Other significant predictors of treatment withdrawal were female sex, smoking status and a higher baseline Dermatology Life Quality Index (DLQI) score.