Systemic Immunomodulatory Treatments for Atopic Dermatitis

Key Points Question What is the relative efficacy and harm of lebrikizumab, the most recently approved biologic medication for atopic dermatitis compared with other systemic treatments? Findings This systematic review and meta-analysis including 97 studies and 24 679 patients found moderate-certainty evidence that lebrikizumab is similarly effective to dupilumab for improving signs, symptoms, and quality of life for adults with atopic dermatitis after 16 weeks of treatment; however, a higher proportion of participants achieved treatment success with dupilumab according to binary outcomes. Meaning These findings indicate that lebrikizumab, a new biologic medication, has comparable efficacy to dupilumab for the treatment of atopic dermatitis in adults.

Details on data abstraction for these continuous outcomes have been published previously. 2 We also assessed 4 binary efficacy outcomes: the proportion of patients with 50%, 75%, and 90% improvement in EASI (EASI-50, -75, -90) and success on the Investigator Global Assessment (IGA) scales, prioritizing a reduction of 2 points and score of 0 or 1. Safety outcomes included the proportion of participants experiencing serious adverse events and withdrawal due to adverse events.
We performed random-effects bayesian NMA for each outcome using the GeMTC package for R, version 1.0-2 (van Valkenhoef G).We generate network plots where each node represents a unique dosing regimen for each medication.The width of each line connecting 2 treatments (nodes) is proportional to the number of head-to-head trials for that comparison.We qualitatively describe the geometry of the networks.
For continuous outcomes, we calculated mean differences with 95% credible intervals (CrI).Where outcome domains are measured using varied scales in different trials, we calculated standardized mean differences.Given that, with the exception of NMAs, the relative efficacy of most treatments in the network is uncertain, we used noninformative prior distributions for continuous efficacy outcomes. 7For binary outcomes, we calculated odds ratios (ORs) and 95% CrI between each pair of nodes in the network.We used a normal prior distribution on the log ORs such that the 95% coverage included log(1/30) to log(30). 8We summarized treatment rankings using Surface Under the Cumulative Ranking. 9e conducted analyses separately for trials of adults vs children, but included trials done in combined populations of adults and adolescents in the adult analysis if most of the study sample was composed of adults.We conducted stratified analyses among trials that allow vs do-not-allow concomitant topical anti-inflammatory medications.We conducted sensitivity analyses including only trials with low risk of bias.We assessed network coherence using node-splitting to compare direct and indirect estimates.We used Gelman-Rubin-Brooks plots of the Gelman-Rubin shrink factor and visually inspected trace plots and posterior density distributions.
We assessed the certainty of evidence for continuous efficacy outcomes and safety outcomes using Grading of Recommendations Assessment, Development and Evaluation

Key Points
Question What is the relative efficacy and harm of lebrikizumab, the most recently approved biologic medication for atopic dermatitis compared with other systemic treatments?Findings This systematic review and meta-analysis including 98 studies and 24 707 patients found moderate-certainty evidence that lebrikizumab is similarly effective to dupilumab for improving signs, symptoms, and quality of life for adults with atopic dermatitis after 16 weeks of treatment; however, a higher proportion of participants achieved treatment success with dupilumab according to binary outcomes.

Meaning
These findings indicate that lebrikizumab, a new biologic medication, has comparable efficacy to dupilumab for the treatment of atopic dermatitis in adults.
(GRADE) criteria for NMAs (eMethods in Supplement 2). 10,113][14][15] We defined "no important difference" as less than half of the MID; "a small important reduction" as half to just less than the MID; and "a large important reduction" as greater than or equal to the MID.We used these thresholds for GRADE imprecision ratings.
In this article, we present effect estimates, CrI, Surface Under the Cumulative Ranking values, and certainty assessments for approved doses of abrocitinib, baricitinib, dupilumab, lebrikizumab, tralokinumab, and upadacitinib, and placebo for EASI, POEM, PP-NRS, and DLQI; results for complete networks and other outcomes are available from the authors on request.

Results
As of November 3, 2023, there were 98 trials totaling 24 707 participants included in this systematic review and NMA (Figure 1).  The cracteristics of the trials currently included in the living systematic review, including extracted outcomes and risk of bias assessments, are included in Supplement 1 and can be accessed through our website (http://www.eczematherapies.com/research).
Network plots for all outcomes among adults reflect the predominance of placebo-controlled trials, with few direct connections between approved therapies (eFigure 1-8 in Supplement 2).Lebrikizumab was only connected to each network through placebo.
There were no substantial differences in analyses separating trials that included topical anti-inflammatory treat-ments from those that did not.Excluding trials at high or uncertain risk of bias decreased the precision of estimates but did not change interpretation.Node splitting did not demonstrate significant incoherence.Networks limited to trials among children were associated with very imprecise estimates between treatments precluding clinically meaningful interpretations.Gelman-Rubin-Brooks plots, Gelman-Rubin shrink

Discussion
In this update of a living systematic review and NMA, there was moderate-certainty evidence that lebrikizumab has similar efficacy up to 16 weeks of treatment compared to dupilumab in improving signs, symptoms and quality of life associated with atopic dermatitis in adults.Dupilumab was associated with higher odds of achieving efficacy in binary outcomes than lebrikizumab.
The findings of this NMA are largely consistent with the findings of other recently published systematic reviews with NMA of systemic treatments for atopic dermatitis. 108,109hu et al 108 used a GRADE minimally contextualized approach to create categories of medications based on their relative efficacy.With that approach, they concluded that lebrikizumab, tralokinumab, and baricitinib are in a lower efficacy category than dupilumab when comparing improvements in EASI scores.In contrast, we used published MID values to contextualize the results as part of our GRADE assessment.This approach avoids creating arbitrary efficacy categories, and instead provides comparisons with GRADE certainty assessments between individual medications, taking into account the magnitude of the difference between and the certainty of that estimate.The study by Chu et al 108 included more trials in its networks than we did because it included results for children and adults in the same networks and had broader inclusion criteria.For example, that study 108 did not exclude trials of shorter duration (whereas this study excluded those with <8 weeks of intervention) and it included some interventions that we did not consider to be systemic immunomodulators, such as phototherapy, histidine, and vitamin D. We believe these differences may make our review less prone to violations of the transitivity assumption, whereas Chu et al were able to make more comparisons within larger treatment networks.Chu et al also used different safety outcomes.They found statistical differences in overall adverse events between medications, whereas we did not detect important differences in withdrawals due to adverse events or serious adverse events, which are less common.The NMA by Silverberg et al 109 was limited to studies of new targeted agents used without concomitant topical corticosteroids.Although that approach may improve transitivity compared to the more inclusive approach we used, we did not find any substantial differences with our secondary analyses limited to studies al- lowing vs not allowing concomitant topical anti-inflammatory therapy.

Limitations
Trials including children with atopic dermatitis remain sparse, limiting the generalizability of our main findings for a disease that is more common among children.Atopic dermatitis is often chronic, necessitating long-term therapy.Because our study did not include long-term extension data from studies in which participants were rerandomized to different maintenance regimens, we were unable to draw conclusions about the relative of long-term dosing strategies.One of our objectives was to compare the safety of the medications under study, but our safety analyses were not clinically useful because of imprecise effect estimates.Furthermore, because broad adverse event categories (eg, serious adverse events and withdrawals) in trials for skin disease are nonspecific, with flares of the underlying disease often categorized as adverse events, safety data from randomized clinical trials can be difficult to interpret. 110While node splitting does not suggest incoherence in our networks, the limited number of head-to-head trials means those analyses were underpowered or, for most comparisons, not feasible.With multiple systemic treatments now available in routine clinical practice, trial populations may be changing over time.Specifically, baseline severity scores may be decreasing, which could affect the NMA transitivity assumption. 111Still, inclusion criteria are consistent across included trials over time, and it is unclear whether baseline differences would affect placebo and intervention groups differently.As more head-to-head trials are published for medications already approved, analyses can be done to assess the influence of these temporal trends.

Conclusions
The findings of this update to a living systematic review and NMA support lebrikizumab as another effective biologic medication for treating atopic dermatitis.Although binary efficacy outcomes favored dupilumab, the differences in efficacy between dupilumab and lebrikizumab on continuous scales were small.

Figure 1 .
Figure 1.Study Screening and Selection Process for the Living Systematic Review of Systemic Immunomodulatory Treatments for Atopic Dermatitis, Including Results Up to the November 3, 2023 Search