*3.4. Efficacy Outcomes*

#### 3.4.1. EASI-75 Response

Twelve studies (involving 3498 patients) reported EASI-75 response as the indicator of efficacy outcome. A random-effects meta-analysis showed that patients treated with JAK inhibitors (both oral and topical) were associated with higher rates of achieving EASI-75 response (RR = 2.84; 95% CI = 2.20–3.67) than those treated with placebo (Figure 1); no significant heterogeneity was observed (I<sup>2</sup> = 38.9%; *P* = 0.08).


**Table 1.**Characteristics of studies included in the meta-analysis.


**Table 1.** *Cont.*

11


**Table 1.***Cont.*

AAD, American Academy of Dermatology; AD, atopic dermatitis; ADSS, atopic dermatitis sleep scale; AE, adverse event; AEDC, adverse events leading to drug discontinuation; BSA, body surface area; CDLQI, children's dermatology life quality index; COI, conflict of interest; DLQI, dermatology life quality index; EASI, eczema area and severity index; HADS, hospital anxiety and depression scale; IGA, investigator global assessment; JAK, Janus kinase; JDA, Japanese Dermatological Association; mEASI, modified eczema area and severity index; NA, not applicable; NRS, numerical rating scale; POEM, patient-oriented eczema measure; PSAAD, pruritus and symptoms assessment for atopic dermatitis; RCT, randomized controlled trial; SAE, serious adverse event; SCORAD, scoring atopic dermatitis; SYK, spleen tyrosine kinase; TEAE, treatment-emergent adverse event; TYK: tyrosine kinase; WPAI, work productivity and activity impairment questionnaire \* BREEZE-AD4 is an ongoing RCT. Its safety outcomes were presented in Bieber et al. (2020).


*J. Pers. Med.* **2021**, *11*, x FOR PEER REVIEW 7 of 18

We used the Risk-of-Bias VISualization tool to create "traffic light" plots of domainlevel judgments [48]. Most of the enrolled RCTs were judged to have a "low" risk of bias

Twelve studies (involving 3498 patients) reported EASI-75 response as the indicator of efficacy outcome. A random-effects meta-analysis showed that patients treated with JAK inhibitors (both oral and topical) were associated with higher rates of achieving EASI-75 response (RR = 2.84; 95% CI = 2.20–3.67) than those treated with placebo (Figure 1); no

= 38.9%; *P* = 0.08).

*3.3. Risk of Bias Assessment* 

*3.4. Efficacy Outcomes*  3.4.1. EASI-75 Response

significant heterogeneity was observed (I<sup>2</sup>

(Figure S2).

**Figure 1.** Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a 75% improvement in Eczema Area and Severity Index (EASI) score from the baseline (EASI-75 response). CI, confidence interval. **Figure 1.** Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a 75% improvement in Eczema Area and Severity Index (EASI) score from the baseline (EASI-75 response). CI, confidence interval.

#### 3.4.2. IGA Response 3.4.2. IGA Response

Eleven studies (involving 2417 patients) reported IGA responses. Figure 2 shows that patients treated with JAK inhibitors (both oral and topical) were associated with higher rates of achieving IGA responses (RR = 2.99; 95% CI = 2.26–3.95) than those treated with placebo; no significant heterogeneity was observed (I<sup>2</sup> = 0%; *P* = 0.60). Eleven studies (involving 2417 patients) reported IGA responses. Figure 2 shows that patients treated with JAK inhibitors (both oral and topical) were associated with higher rates of achieving IGA responses (RR = 2.99; 95% CI = 2.26–3.95) than those treated with placebo; no significant heterogeneity was observed (I<sup>2</sup> = 0%; *P* = 0.60). *J. Pers. Med.* **2021**, *11*, x FOR PEER REVIEW 8 of 18


**Figure 2.** Association of Janus kinase (JAK) inhibitors versus placebo achieving of an Investigator Global Assessment (IGA) of 0 (clear) or 1 (almost clear) with at least a two-point reduction from the baseline (IGA response). CI, confidence interval. **Figure 2.** Association of Janus kinase (JAK) inhibitors versus placebo achieving of an Investigator Global Assessment (IGA) of 0 (clear) or 1 (almost clear) with at least a two-point reduction from the baseline (IGA response). CI, confidence interval.

**Figure 3.** Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a four-point improvement in pru-

ritus Numerical Rating Scale (NRS) score from the baseline (pruritus-NRS response). CI, confidence interval.

rates of achieving pruritus-NRS responses (RR = 2.52; 95% CI = 1.90–3.35) compared with those treated with placebo (Figure 3). No significant heterogeneity was observed (I<sup>2</sup>

=

3.4.3. Pruritus-NRS Response

39.4%; *P* = 0.12).

#### 3.4.3. Pruritus-NRS Response Eight studies (involving 3036 patients) reported pruritus-NRS responses. The meta-

3.4.3. Pruritus-NRS Response

Eight studies (involving 3036 patients) reported pruritus-NRS responses. The metaanalysis revealed that patients treated with JAK inhibitors were associated with higher rates of achieving pruritus-NRS responses (RR = 2.52; 95% CI = 1.90–3.35) compared with those treated with placebo (Figure 3). No significant heterogeneity was observed (I<sup>2</sup> = 39.4%; *P* = 0.12). analysis revealed that patients treated with JAK inhibitors were associated with higher rates of achieving pruritus-NRS responses (RR = 2.52; 95% CI = 1.90–3.35) compared with those treated with placebo (Figure 3). No significant heterogeneity was observed (I<sup>2</sup> 39.4%; *P* = 0.12).

=


**Figure 2.** Association of Janus kinase (JAK) inhibitors versus placebo achieving of an Investigator Global Assessment (IGA)

*J. Pers. Med.* **2021**, *11*, x FOR PEER REVIEW 8 of 18

**Figure 3.** Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a four-point improvement in pruritus Numerical Rating Scale (NRS) score from the baseline (pruritus-NRS response). CI, confidence interval. **Figure 3.** Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a four-point improvement in pruritus Numerical Rating Scale (NRS) score from the baseline (pruritus-NRS response). CI, confidence interval.
