The number needed to treat (NNT) and cost per responder for systemic therapies for moderate-to-severe atopic dermatitis
This appendix describes in detail the effectiveness evidence and cost information shown in Table «»1. The selection of the effectiveness evidence had following steps: the literature search and selection of effectiveness evidence, quality appraisal and crosscheck with Current Care Guideline evidence summaries. We chose the network meta-analysis by Pereyra-Rodrigues et al. (2021) as the base of the effectiveness evidence. Table «Included RCTs of selected interventions in the network meta-analysis by Pereyra-Rodriguez et al. (2021) »3 describe the studies included in the Pereyra-Rodrigues et al. (2021) network meta-analysis.
Source of the effectiveness evidence: Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, Galán-Gutiérrez M, Ruiz-Villaverde R, Vilar-Palomo S, Armario-Hita JC. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review and Network Meta-Analysis. Life (Basel). 2021 Sep 6;11(9):927. doi: 10.3390/life11090927. «https://www.mdpi.com/2075-1729/11/9/927»1
Literature search and selection
The literature search included network meta-analyses, meta-analyses and systematic reviews of systemic therapies (biologic therapies and JAK inhibitors) for atopic dermatitis. Information specialist conducted the literature search in August 2022. The timeframe for the search was 2000–2022. The search found 85 references. We searched for the most recent evidence by viewing only network meta-analyses published in 2022 and 2021, if satisfactory number of comprehensive studies were found. A total of seven network meta-analyses were published in 2022 and 2021 (Table «Description of the network meta-analyses of systemic therapies for atopic dermatitis published in 2021 and 2022»1).
| Citation | Research aim | Number of trials, date of literature search | EASI-75 outcome measure | Interventions | Comments |
|---|---|---|---|---|---|
| Drucker et al. 2022 «Drucker AM, Morra DE, Prieto-Merino D, et al. Systemic Immunomodulatory Treatments for Atopic Dermatitis: Update of a Living Systematic Review and Network Meta-analysis. JAMA Dermatol 2022;158:523-532»1 | To compare reported measures of efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis | 60 RCTs, 15.6.2021 | No | abrocitinib, apremilast, baricitinib, dupimumab, fevipiprant, GBR 830, lebrikizumab, nemolizumab, tezepelumab, tralokinumab, upadacitinib, ustekinumab, ZPL3893787 | Outcome measures did not include EASI-75. |
| Mostafa et al. 2021 «Mostafa N, Phan K, Lai B, et al. Comparing quality of life outcomes of JAK inhibitors and biological treatments for atopic dermatitis: a systematic review and network meta-analysis. Expert Rev Clin Ph»2 | To compare quality of life outcomes of JAK inhibitors and biological treatments for atopic dermatitis. | NA | No | NA | Outcome measures did not include EASI-75. |
| Pereyra-Rodriguez et al. 2021 «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3 | To evaluate the efficacy and safety of biological agents and small molecules in atopic dermatitis. | 30 RCTs, 19.12.2020 | Yes | abrocitinib, apremilast, baricitinib, dupilumab, lebrikizumab,3 nemolizumab, tezepalumab, tralokinumab, upadacitinib | Comprehensive, includes all selected interventions. |
| Silverberg et al. 2022 «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6 | To assess the comparative efficacy of targeted systemic therapies without the addition of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) in adults with moderate to severe atopic dermatitis. | 9 RCTs, 17.5.2021 | Yes | abrocitinib, baricitinib, dupilumab, tralokinumab, upadacitinib | Comprehensive, includes all selected interventions. |
| Silverberg et al. 2021 «Silverberg JI, Thyssen JP, Fahrbach K, et al. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analys»7 | To provide an up-to-date analysis of the comparative efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis as monotherapy and in combination with topical therapies. | 19 RCTs, 24.10.2019 | Yes | abrocitinib, baricitinib, dupilumab, lebrikizumab, nemolizumab, tralokinumab, upadacitinib | Comprehensive, includes all selected interventions. |
| Wan et al. 2022 «Wan H, Jia H, Xia T, et al. Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther 2022;35:e1563»8 | To determine the comparative efficacy and safety of three common oral JAK inhibitors including abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis. | 10 RCTs, July 2021 | Yes | abrocitinib, baricitinib, upadacitinib | Only JAK inhibitors. |
| Zhang et al. 2021 «Zhang L, Wang L, Jiang X The efficacy of Janus kinase inhibitors in patients with atopic dermatitis: A systematic review and network meta-analysis. Dermatol Ther 2021;34:e15098 »9 | To compare the efficacy of JAK inhibitors for atopic dermatitis treatment. | 6 RCTs, 28.3.2021 | No | abrocitinib, baricitinib, delgocitinib, ruxolitinib, tofacitinib, upadacitinib | Outcome measures did not include EASI-75. Only JAK inhibitors. |
NA= not applicable
We selected three studies (Pereyra-Rodrigues et al. 2021; Silverberg et al. 2021; 2022) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3, «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6, «Silverberg JI, Thyssen JP, Fahrbach K, et al. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analys»7 for further examination as they were the most recent, comprehensive, included all selected interventions and reported the effectiveness outcome (EASI-75) selected by the Current Care working group. Pereyra-Rodrigues et al. (2021) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3 and Silverberg et al. (2021) «Silverberg JI, Thyssen JP, Fahrbach K, et al. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analys»7evaluated monotherapies and combination therapies separately. Silverberg et al. (2022) «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6was an update to Silverberg et al. (2021) «Silverberg JI, Thyssen JP, Fahrbach K, et al. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analys»7network meta-analysis for monotherapies. Our analysis concentrated in the monotherapies and therefore, we excluded Silverberg et al. (2021).
Quality of the selected network meta-analyses
We evaluated the quality of the Pereyra-Rodrigues et al. (2021) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3 and Silverberg et al. (2022) «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6 network meta-analyses by using AMSTAR 2 «Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358:j400»5. The results of the quality appraisal are shown in table «Critical appraisal of selected network meta-analyses by using AMSTAR 2 »2.
We also crosschecked the three studies with Current Care Guideline evidence summaries to evaluate the comprehensiveness of the network meta-analysis. Compared to evidence summaries, the studies had a few differences. Pereyra-Rodrigues et al. (2021) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3 did not include one study which studied adolescent population (Simpson et al. 2020) «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6. Silverberg et al. (2022) «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6 did not include phase 2 studies (Gooderham et al. 2019; Thaci et al. 2016) and one study of adolescent population (Simpson et al. 2020).
The network meta-analyses differed in the comprehensiveness. Pereyra-Rodrigues et al. (2021) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3 had one study (Guttman-Yassky et al. 2019) which was not included in the Silverberg et al. (2022) «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6. Silverberg et al. (2022) «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6 had one study (Simpson et al. 2021) which was not included in the Pereyra-Rodrigues et al. (2021) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3.
| Pereyra-Rodrigues et al. 2021 «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3 | Silverberg et al. 2022 «Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network M»6 | |||
|---|---|---|---|---|
| Question | Answer | Comments | Answer | Comments |
| Did the research questions and inclusion criteria for the review include the components of PICO? | Yes | Yes | ||
| Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? | Yes | No | No written protocol or guide cited. | |
| Did the review authors explain their selection of the study designs for inclusion in the review? | Yes | Yes | ||
| Did the review authors use a comprehensive literature search strategy? | Partial yes | Unclear if the reference lists/bibliographies of included studies were searched. | Partial yes | Unclear if the reference lists/bibliographies of included studies were searched. |
| Did the review authors perform study selection in duplicate? | Yes | Yes | ||
| Did the review authors perform data extraction in duplicate? | No | Unclear, if the data extraction was performed in duplicate. | Yes | |
| Did the review authors provide a list of excluded studies and justify the exclusions? | Yes | Partial yes | No reference list of excluded studies with justification for exclusion. Justifications for exclusions reported in the PRISMA diagram. | |
| Did the review authors describe the included studies in adequate detail? | Yes | Yes | ||
| Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? | Yes | Yes | ||
| Did the review authors report on the sources of funding for the studies included in the review? | No | Study did not report the sources of funding of the included studies. | No | Study did not report the sources of funding of the included studies. |
| If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? | Yes | Yes | ||
| If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? | Yes | No | Unclear if only low RoB studies was included or how the pooled estimate of variable RoB studies impacted on summary estimates of effect. | |
| Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? | Yes | No | Unclear if only low RoB studies was included and did not provide a discussion of the likely impact of RoB on the results. | |
| Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? | Yes | Yes | ||
| If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? | Yes | No | Did not perform graphical or statistical tests for publication bias and discuss the likelihood and magnitude of impact of publication bias. | |
| Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? | Yes | No | Study was industry funded and did not describe how they managed potential conflict of interest. | |
| Summary of the quality | Yes n=13, Partial yes n=1, No n=2. | Yes n=8, Partial yes n=2, No n=6. | ||
RoB=Risk of Bias
We chose to use the effectiveness estimates provided by Pereira-Rodriquez at al. (2021) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3as it had the highest quality of the three studies and was the most comprehensive study by including all the selected interventions. The crosscheck with the evidence summaries showed that the Pereyra-Rodriguez et al. (2021) included comprehensively relevant effectiveness studies.
The effectiveness evidence
The Pereyra-Rodriguez et al. (2021) «Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review»3 reported ORs and 95%CIs for the Current Care working group's selected interventions. We converted the ORs to NNTs «Schünemann HJ, Vist GE, Higgins JPT et al. Chapter 15: Interpreting results and drawing conclusions. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Hand»4. Assumed comparator risk was the weighted average of the RCTs placebo groups' EASI-75 responses.
Network meta-analysis included 10 RCTs of selected interventions compared against placebo. All the studies were phase 3 studies, expect two phase 2b studies (Thaci et al. 2016; Gooderham et al. 2019). All the studies had 16 weeks study duration, expect two studies of abrocitinib which had 12 weeks study duration (Simpson et al. 2020; Silverberg et al. 2020). The characteristics of original RCTs are presented in the table «Included RCTs of selected interventions in the network meta-analysis by Pereyra-Rodriguez et al. (2021) »3.
| Study | Interventions and control | Baseline EASI Score (Mean) |
|---|---|---|
| Solo-1 Simpson et al. 2016 | Placebo (n=224) | 31,8 |
| Dupilumab 300 mg every other week (n=224) | 30,4 | |
| Solo-2 Simpson et al. 2016 | Placebo (n=236) | 30,5 |
| Dupilumab 300 mg every other week (n=233) | 28,6 | |
| Thaci et al. 2016 | Placebo (n=61) | 32,9 |
| Dupilumab 300 mg every other week (n=64) | 33,8 | |
| Breeze-AD-1 Simpson et al. 2020 | Placebo (n=249) | 32 |
| Baricitinib 2mg once a day (n=123) | 31 | |
| Baricitinib 4mg once a day (n=125) | 32 | |
| Breeze-AD-2 Simpson et al. 2020 | Placebo (n=244) | 33 |
| Baricitinib 2mg once a day (n=123) | 35 | |
| Baricitinib 4mg once a day (n=123) | 33 | |
| Gooderham et al. 2019 | Placebo (n=56) | 25,4 |
| Abrocitinib 100mg once a day (n=56) | 26,7 | |
| Abrocitinib 200mg once a day (n=55) | 24,6 | |
| Jade-mono-1 Simpson et al. 2020 | Placebo (n=77) | 28,7 |
| Abrocitinib 100mg once a day (n=156) | 31,3 | |
| Abrocitinib 200mg once a day (n=154) | 30,6 | |
| Jade-mono-2 Silverberg et al. 2020 | Placebo (n=78) | 28,0 |
| Abrocitinib 100mg once a day (n=158) | 28,4 | |
| Abrocitinib 200mg once a day (n=155) | 29,0 | |
| Measure up-1 Guttman et al. 2021 | Placebo (n=281) | 28,8 |
| Upadacitinib 15mg once a day (n=281) | 30,6 | |
| Upadacitinib 30mg once a day (n=285) | 29,0 | |
| Measure up-2 Guttman et al. 2021 | Placebo (n=278) | 29,1 |
| Upadacitinib 15mg once a day (n=276) | 28,6 | |
| Upadacitinib 30mg once a day (n=282) | 29,7 |
Costs of medicines
The costs of the medicines are taken from drug database available at Terveysportti health portal (Duodecim Publishing Company Ltd) «https://www.terveysportti.fi/»2. We use retail prices based on the cheapest product price per dose of the medical substance in question. All packaging sizes are included. Any other direct or indirect costs or reimbursements are not included. If a biosimilar is also available, then it is presented as a separate product alongside the original product. The 52-week cost includes only maintenance dose costs. The 16-week cost also includes loading dose costs.
References
- Drucker AM, Morra DE, Prieto-Merino D, et al. Systemic Immunomodulatory Treatments for Atopic Dermatitis: Update of a Living Systematic Review and Network Meta-analysis. JAMA Dermatol 2022;158:523-532 «PMID: 35293977»PubMed
- Mostafa N, Phan K, Lai B, et al. Comparing quality of life outcomes of JAK inhibitors and biological treatments for atopic dermatitis: a systematic review and network meta-analysis. Expert Rev Clin Pharmacol 2021;14:1435-1444 «PMID: 34410205»PubMed
- Pereyra-Rodriguez JJ, Alcantara-Luna S, Domínguez-Cruz J, et al. Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review and Network Meta-Analysis. Life (Basel) 2021;11(9) «PMID: 34575076»PubMed
- Schünemann HJ, Vist GE, Higgins JPT et al. Chapter 15: Interpreting results and drawing conclusions. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
- Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358:j4008 «PMID: 28935701»PubMed
- Silverberg JI, Hong HC, Thyssen JP, et al. Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network Meta-analysis. Dermatol Ther (Heidelb) 2022;12:1181-1196 «PMID: 35435637»PubMed
- Silverberg JI, Thyssen JP, Fahrbach K, et al. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analysis. J Eur Acad Dermatol Venereol 2021;35:1797-1810 «PMID: 33991374»PubMed
- Wan H, Jia H, Xia T, et al. Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther 2022;35:e15636 «PMID: 35703351»PubMed
- Zhang L, Wang L, Jiang X The efficacy of Janus kinase inhibitors in patients with atopic dermatitis: A systematic review and network meta-analysis. Dermatol Ther 2021;34:e15098 «PMID: 34392600»PubMed