This cohort study evaluates clinical effectiveness and reasons for discontinuation of dupilumab treatment in children, adults, and older adults with atopic dermatitis with up to 5 years of treatment in daily practice.
Key Points
Question
What is the clinical effectiveness of dupilumab for long-term use in patients with atopic dermatitis (AD), and what are reasons to discontinue dupilumab treatment?
Findings
In this 5-year cohort study of 1286 patients with AD, dupilumab maintained its clinical effectiveness, while two-thirds of patients tapered dupilumab to a dosing interval of mostly every 3 or 4 weeks. A fairly similar response was found among children, adults, and older adults, with statistically significant decreases in thymus- and activation-regulated chemokine and eosinophil levels that remained low over time; however, 23.7% of patients discontinued treatment during this follow-up period, mainly due to adverse events and/or ineffectiveness.
Meaning
Dupilumab may be an effective and safe therapeutic option for the long-term treatment of patients with AD.
Abstract
Importance
Limited data are available on the long-term effectiveness and safety of dupilumab for atopic dermatitis (AD) in daily practice.
Objective
To evaluate clinical effectiveness and reasons for discontinuation of dupilumab treatment in children, adults, and older adults with AD with up to 5 years of treatment in daily practice.
Design, Setting, and Participants
This prospective multicenter cohort study was conducted using the BioDay registry (4 academic and 10 nonacademic hospitals in the Netherlands) to identify patients with AD of all ages who were treated with dupilumab between October 2017 and December 2022.
Main Outcomes and Measures
Clinical effectiveness was evaluated by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), and numeric rating scale (NRS) for pruritus, stratified by children (<18 years), adults (18-64 years), and older adults (≥65 years). In addition, time to response, treatment responders, EASI subscores, second treatment episodes, and thymus- and activation-related chemokine and eosinophil levels were assessed. For patients who discontinued dupilumab, the reason for discontinuation was evaluated.
Results
In total, 1286 patients with AD (median [IQR] age, 38 [26-54] years; 726 [56.6%] male) were treated with dupilumab, including 130 children, 1025 adults, and 131 older adults. The median (IQR) follow-up time was 87.5 (32.0-157.0) weeks. Most patients maintained controlled AD, with EASI of 7 or lower and NRS for pruritus of 4 or lower varying between 78.6% and 92.3% and 72.2% and 88.2% for up to 5 years of treatment, respectively, while up to 70.5% of all patients prolonged the dosing interval to mostly 300 mg every 3 or 4 weeks. Mean EASI and NRS for pruritus were 2.7 (95% CI, 1.2-4.2) and 3.5 (95% CI, 2.7-4.3), respectively, after 5 years of treatment. Statistically significant differences between age groups were found over time for EASI and IGA; however, differences were rather small (week 52: EASI, 0.3-1.6; IGA, 0.12-0.26). No statistically significant differences between age groups were found for NRS for pruritus. Median thymus- and activation-related chemokine levels considerably decreased from 1751 pg/mL (95% CI, 1614-1900 pg/mL) to 390 pg/mL (95% CI, 368-413 pg/mL) after 6 months of treatment and remained low. Median eosinophil levels temporarily increased up to week 16, with a subsequently statistically significant decrease over time. In total, 306 patients (23.8%) discontinued dupilumab after a median (IQR) of 54.0 (29.0-110.00) weeks, with adverse events among 98 patients (7.6%) and ineffectiveness among 85 patients (6.6%) as the most frequently reported reasons. Forty-one patients (3.2%) restarted dupilumab, and most of these patients recaptured response.
Conclusions and Relevance
In this cohort study with up to 5 years of follow-up, dupilumab maintained its clinical effectiveness, while two-thirds of patients tapered to a dosing interval of every 3 or 4 weeks. Treatment was discontinued in 23.8% of patients mainly due to adverse events and/or ineffectiveness.
Introduction
Dupilumab, a monoclonal antibody that targets the interleukin 4 receptor α, and thereby inhibits the interleukin 4/13 signaling pathway, was the first approved biological for the treatment of moderate to severe atopic dermatitis (AD).1,2,3 Dupilumab is frequently prescribed in clinical practice, and a large number of patients with AD experience great benefit from this treatment.1,4,5,6
Since market availability in 2017, dupilumab has received extended indications for adolescents (>12 years) with moderate to severe AD, children (≥6 months) with severe AD, and patients with severe allergic asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.2,7,8 Furthermore, recently published studies reporting on tapering of dupilumab in patients with AD have shown that interval prolongation was successful and safe.9,10,11,12,13 Since AD is a chronic disease often requiring long-term treatment, it is important to evaluate the long-term effectiveness and safety in daily practice. The LIBERTY AD OLE (open-label extension) trial reported follow-up results of up to 4 years, while most daily practice studies only described results of up to 2 years of treatment.6,14,15,16,17
Therefore, the aim of this cohort study was to assess the clinical effectiveness of dupilumab in a large cohort of patients with AD with follow-up of up to 5 years of treatment in daily practice. The secondary aim was to evaluate the frequency and reasons for dupilumab treatment discontinuation.
Methods
Study Design, Patient Population, and Treatment
This ongoing, prospective, and multicenter observational study consecutively included patients with AD, including children younger than 18 years, from the BioDay registry (4 academic and 10 nonacademic Dutch hospitals), all treated with dupilumab between October 2017 and December 2022. Adults (≥18 years) received a loading dose of subcutaneous dupilumab, 600 mg, at baseline, followed by 300 mg every other week. A pragmatic patient-centered dosing regimen has been applied within the BioDay registry since 2019 and includes a standardized method for dupilumab dose reduction in case of persistent controlled disease (eFigure 1 in Supplement 1).10,12 Systemic immunosuppressive treatment was, if possible, discontinued before dupilumab initiation (washout criteria based on half-life times of <1 week for cyclosporine A, Janus kinase [JAK] inhibitors, and prednisolone; <4 weeks for long-acting immunosuppressive drugs; and <10 weeks for biologics). Patients visited the outpatient clinic at baseline and after 4 weeks of treatment. Adult patients were scheduled to visit the outpatient clinic every 3 months in the first year and then every 3 to 6 months (±4 weeks) (eg, in case of interval prolongation or uncontrolled AD, visits were scheduled every 3 months). Children visited the hospital every 3 months and were treated according to label. For patients with multiple treatment episodes, the first treatment episode was used for the main analysis.
The BioDay registry was considered a noninterventional study by the local medical ethics committee and was conducted in accordance with the Declaration of Helsinki. Each patient, and if applicable parent(s)/legal representative(s), provided written informed consent.
Outcome Measures
Primary clinical effectiveness outcomes included the Eczema Area and Severity Index (EASI),18 Investigator Global Assessment (IGA) (on 6-point scale),19 and the weekly average numeric rating scale (NRS) for pruritus in the past week,20 with a subanalysis for age groups (children, <18 years; adults, 18-64 years; and older adults, ≥65 years). Secondary outcomes included cutoff scores (EASI ≤7,21 IGA ≤117 and/or ≥2-point improvement on IGA-Controlled,22 and NRS for pruritus ≤421) and EASI responses (EASI 50/75/90).21 Patients were defined as a responder if EASI of 7 or lower and NRS for pruritus of 4 or lower were achieved. In addition, stricter cutoff scores of EASI 4 or lower, NRS for pruritus of 3 or lower, and NRS for pruritus of 1 or lower12 and EASI subscores of the 4 anatomical body regions (combined severity and area involvement as percentages of the total subscore) were evaluated. The potency and amount of the most frequently used topical corticosteroids were collected during each visit. To explore the course of dupilumab-induced eosinophilia, eosinophil levels were assessed during routine diagnostics.23 In addition, in a subgroup of patients serum biomarker thymus- and activation-regulated chemokine (TARC) was measured using enzyme-linked immunosorbent assay. TARC has been previously identified as the most reliable clinical biomarker for AD, as it correlates well with disease severity and therefore enables evaluation of the effect of treatment on an immune level.24
Treatment Discontinuation
Patients who discontinued dupilumab treatment were recorded as dropouts. The reason for discontinuation and the adverse events (AEs) that led to treatment discontinuation were evaluated. Secondary treatment episodes were analyzed separately.
Statistical Analysis
Primary outcomes (ie, continuous EASI, IGA, NRS for pruritus) were analyzed with a linear mixed model. A random intercept and heterogeneous autoregressive residual covariance matrix were included in the model to correct for multiple measurements per patient and varying standard deviations of the outcomes over time. First, we performed an analysis in which the exposure of interest (ie, follow-up time on dupilumab treatment) was modeled. Second, we evaluated differences between age groups by including an interaction between time and age groups. Likelihood ratio tests were used to calculate P values for time and the time by age groups interaction. Results were described with estimated means and 95% CIs. In addition, TARC and eosinophil levels were analyzed as described for the primary outcomes of EASI, IGA, and NRS for pruritus. As TARC and eosinophil levels showed a highly skewed distribution, we log transformed the values prior to the analyses, and values of 0 (below the detection limit) were replaced with the lowest observed value divided by 2. Outcomes were transformed back to the original scale as medians with 95% CIs.25
Secondary outcomes and outcomes of interest were descriptively reported as percentages, means with SDs, or medians with IQRs. Differences in baseline characteristics between age groups were analyzed for continuous outcomes by a Kruskal-Wallis test for not normally distributed data and a one-way analysis of variance for normally distributed data. For categorical outcomes, a Fisher exact test was used. Distributional assumptions of the models for the primary continuous outcomes (ie, normality, heteroscedasticity) were assessed by graphically inspecting residuals. Distribution of the secondary outcomes was assessed by Q-Q plots and the Shapiro-Wilk test. Analyses were performed using SPSS Statistics, version 26.0.0.1 (IBM), and SAS, version 9.4 (SAS Institute). A P < .05 was considered statistically significant. Prism, version 8.3 (GraphPad), was used to construct figures.
Results
Baseline and Treatment Characteristics
In total, 1286 patients were included, with a median (IQR) age of 38 (26-54) years, and 726 patients (56.6%) were male. The median (IQR) follow-up time was 87.5 (32.0-157.0) weeks for the total cohort, 33.5 (6.0-74.0) weeks for children, 97.0 (39.0-163.0) weeks for adults, and 95.0 (31.0-162.0) weeks for older adults. At baseline, the mean (SD) EASI and NRS for pruritus were 17.8 (11.8) and 6.8 (2.3), respectively. A total of 1032 patients (80.2%) scored a moderate to very severe disease activity based on the IGA. Statistically significant differences were found between age groups regarding self-reported atopic diseases, age of AD onset, and eosinophil and TARC levels (eTable in Supplement 1). All other baseline and patient characteristics are summarized in Table 1.
Table 1. Baseline and Patient Characteristics.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Total cohort (N = 1286) | Adults aged 18-64 y (n = 1025) | Older adults aged ≥65 y (n = 131) | Children aged <18 y (n = 130) | |
| Sex | ||||
| Female | 560 (43.5) | 441 (43.0) | 57 (43.5) | 62 (47.7) |
| Male | 726 (56.5) | 584 (57.0) | 74 (56.5) | 68 (52.3) |
| Age, median (IQR), y | 38.0 (26.0-54.0) | 38.0 (28.0-51.0) | 70.0 (67.0-76.0) | 15.0 (11.0-17.0) |
| Age at onset of atopic dermatitis | ||||
| Childhood (<12 y) | 1076 (83.7) | 875 (85.4) | 71 (54.2) | 130 (100) |
| Adolescence (12-17 y) | 64 (5.0) | 54 (5.3) | 10 (7.6) | 0 |
| Adult (≥18 y) | 114 (8.9) | 69 (6.7) | 45 (34.4) | 0 |
| Missing | 32 (2.5) | 32 (2.7) | 4 (3.1) | 0 |
| Atopic disease at baseline | 1054 (82.0) | 864 (84.3) | 79 (60.3) | 111 (85.4) |
| Allergic asthma | 692 (53.8) | 574 (56.0) | 50 (38.2) | 68 (52.3) |
| Missing | 23 (2.8) | 19 (1.9) | 4 (3.1) | 0 |
| Allergic rhinitis | 844 (65.6) | 697 (68.0) | 53 (40.5) | 94 (72.3) |
| Missing | 33 (2.6) | 27 (2.6) | 4 (3.1) | 2 (1.5) |
| Allergic conjunctivitis | 693 (53.9) | 577 (56.3) | 40 (38.2) | 66 (50.8) |
| Missing | 50 (3.9) | 41 (4.0) | 4 (3.1) | 5 (3.8) |
| Food allergy | 543 (42.2) | 457 (51.7) | 23 (17.6) | 63 (48.5) |
| Missing | 42 (3.5) | 38 (3.7) | 4 (3.1) | 2 (1.5) |
| ≥2 Atopic comorbidities | 847 (65.9) | 703 (86.6) | 54 (41.2) | 90 (69.2) |
| History of conventional immunosuppressive drugs | ||||
| Cyclosporine A | 986 (76.7) | 849 (82.8) | 93 (71.0) | 44 (33.8) |
| Methotrexate | 417 (32.4) | 327 (31.9) | 77 (58.8) | 13 (10.0) |
| Azathioprine | 134 (10.4) | 110 (10.7) | 23 (17.6) | 1 (0.8) |
| Mycophenolate mofetil | 117 (9.1) | 89 (8.7) | 27 (20.6) | 1 (0.8) |
| Oral tacrolimus | 19 (1.5) | 17 (1.7) | 2 (1.5) | 0 |
| Tioguanine | 5 (0.4) | 4 (0.4) | 1 (0.8) | 0 |
| ≥1 Immunosuppressive | 1113 (86.5) | 941 (91.8) | 121 (92.4) | 51 (39.2) |
| ≥2 Immunosuppressives | 437 (34.0) | 361 (35.2) | 68 (51.9) | 8 (6.2) |
| History of biological | ||||
| Tralokinumab | 3 (0.2) | 3 (0.3) | 0 | 0 |
| Discontinued tralokinumab due to end of clinical trial | 3 (100) | 3 (100) | NA | NA |
| History of Janus kinase inhibitor | ||||
| Baricitinib | 9 (0.7) | 7 (0.9) | 2 (1.5) | 0 |
| Discontinued due to ineffectiveness | 6 (66.6) | 4 (57.1) | 2 (100) | NA |
| Discontinued due to adverse events | 3 (33.3) | 3 (42.9) | 0 | NA |
| Upadacitinib | 15 (1.2) | 12 (1.2) | 2 (1.5) | 1 (0.8) |
| Discontinued due to ineffectiveness | 6 (40.0) | 6 (50.0) | 0 | NA |
| Discontinued due to adverse events | 6 (40.0) | 4 (33.3) | 1 (50.0) | 1 (100) |
| Discontinued due to end of clinical trial | 3 (20.0) | 2 (16.7) | 1 (50.0) | NA |
| Abrocitinib | 3 (0.2) | 2 (0.2) | 0 | 1 (0.8) |
| Discontinued due to ineffectiveness | 1 (33.3) | 0 | NA | 1 (100) |
| Discontinued due to adverse events | 2 (66.6) | 2 (100) | NA | NA |
| Immunosuppressive therapy at baselinea | 373 (29.0) | 301 (29.4) | 41 (31.3) | 31 (23.8) |
| Cyclosporine A | 154 (12.0) | 133 (13.0) | 3 (2.3) | 18 (13.8) |
| Methotrexate | 63 (4.9) | 50 (4.9) | 8 (6.1) | 5 (3.8) |
| Prednisolone | 156 (12.1) | 122 (11.9) | 28 (21.4) | 6 (4.6) |
| Tralokinumab | 1 (0.1) | 1 (0.1) | 0 | 0 |
| Baricitinib | 3 (0.2) | 2 (0.2) | 1 (0.8) | 0 |
| Upadacitinib | 1 (0.1) | 1 (0.1) | 0 | 0 |
| Abrocitinib | 1 (0.1) | 1 (0.1) | 0 | 0 |
| Eczema Area and Severity Index, mean (SD) | 17.8 (11.8) | 17.6 (11.9) | 18.2 (11.1) | 19.4 (11.6) |
| Missing | 33 (2.6) | 27 (2.6) | 2 (1.5) | 4 (3.1) |
| Investigator Global Assessment | ||||
| 0 (Clear) | 1 (0.1) | 1 (0.1) | 0 | 0 |
| 1 (Almost clear) | 40 (3.1) | 37 (3.6) | 2 (1.5) | 1 (0.8) |
| 2 (Mild) | 171 (13.3) | 142 (13.9) | 22 (16.8) | 7 (5.4) |
| 3 (Moderate) | 528 (41.1) | 420 (41.0) | 44 (33.6) | 64 (49.2) |
| 4 (Severe) | 409 (31.8) | 317 (30.9) | 51 (38.9) | 41 (31.5) |
| 5 (Very severe) | 95 (7.4) | 75 (7.3) | 8 (6.1) | 12 (9.2) |
| Missing | 42 (3.3) | 33 (3.2) | 4 (3.1) | 5 (3.8) |
| Weekly numeric rating scale for pruritus, mean (SD) | 6.8 (2.3) | 6.8 (2.2) | 6.9 (2.4) | 6.5 (2.3) |
| Missing | 187 (14.5) | 134 (13.1) | 17 (13.0) | 36 (27.7) |
| Laboratory assessments | ||||
| Eosinophil levels, median (IQR), /μLb | 350 (200-600) | 350 (200-590) | 300 (140-450) | 690 (330-1000) |
| Missing | 169 (13.1) | 121 (11.8) | 24 (18.3) | 24 (18.5) |
| TARC levels, median (IQR), pg/mL | 1559.0 (750.0-3612.0) | 1542.0 (746.5-3442.0) | 2519.0 (1063.0-5343.0) | 1358.0 (631.0-4440.0) |
| Missing | 379 (29.5) | 304 (29.7) | 40 (30.5) | 35 (26.9) |
Abbreviations: NA, not applicable; TARC, thymus- and activation-regulated chemokine.
SI conversion factor: To convert eosinophils to ×109/L, multiply by 0.001.
Washout criteria based on half-life times include less than 1 week for cyclosporine A, Janus kinase inhibitors, and prednisolone; less than 4 weeks for long-acting immunosuppressive drugs, and less than 10 weeks for biologics.
The normal range for adults is 0 to 400/μL and for children is 0 to 600/μL.
Long-Term Clinical Effectiveness
A flowchart of patients together with dupilumab dosing intervals stratified by age is shown in eFigure 2 in Supplement 1. The mean EASI significantly improved to 5.1 (95% CI, 4.8-5.5), 4.1 (95% CI, 3.8-4.5), and 2.7 (95% CI, 1.2-4.2) after 16 weeks, 2 years, and 5 years of treatment, respectively (all P < .001). The NRS for pruritus also showed a significant improvement to 3.4 (95% CI, 3.2-3.5) at week 16 and remained consistently low up to 5 years of follow-up (P < .001; Figure 1). Furthermore, most patients maintained controlled AD, as EASI of 7 or lower was achieved by 772 (75.2%) at week 16 and by 361 (83.2%) and 12 (92.3%) at 2 and 5 years of treatment, respectively. In addition, NRS for pruritus of 4 or lower was reached by 669 of 939 patients (71.2%) and 15 of 17 patients (88.2%) after 16 weeks and 5 years of treatment, respectively (Table 2 and Figure 2A). Responder rates (EASI ≤7 and NRS for pruritus ≤4) varied between 63.6% at week 16 and 78.1% for up to 5 years of treatment, and the median (IQR) time to response was 17.0 (6.0-32.0) weeks (eFigure 3 in Supplement 1). Remarkably, up to 70.5% of all patients tapered dupilumab over time (eFigure 2 in Supplement 1). Of 884 patients, 430 (48.6%) used more than 30 g per week of topical corticosteroids at baseline, while during follow-up this amount was reduced to approximately 60% using 0 to 10 g per week (eFigure 4 in Supplement 1). The use (or washout) of concomitant systemic treatments decreased from 373 patients (29.0%) at baseline to none up to 5 years of follow-up. All other outcomes can be found in Table 2 and Figures 1 and 2.
Figure 1. Primary Continuous Outcomes Among 1286 Patients With Atopic Dermatitis During 5 Years of Dupilumab Treatment, Stratified by the Total Cohort and Age Subgroups.
The P values for the total cohort are based on overall likelihood ratio tests for time, and the P values for the age groups are based on overall likelihood ratio tests for time and time by age group interaction. All data were derived from the linear mixed-model analysis, including a random intercept and heterogeneous autoregressive residual covariance matrix. Error bars represent 95% CIs.
Table 2. Descriptive Clinical Effectiveness Outcomes Among 1286 Patients With Atopic Dermatitis During 5 Years of Dupilumab Treatment.
| Outcome | Follow-up time, No. (%) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 28 wk (n = 981) | 52 wk (n = 796) | 1.5 y (n = 652) | 2 y (n = 543) | 2.5 y (n = 391) | 3 y (n = 308) | 3.5 y (n = 209) | 4 y (n = 157) | 4.5 y (n = 74) | 5 y (n = 17) | |
| Patients who discontinued treatment or were lost to follow-up, cumulative | 75 (5.8) | 162 (12.6) | 214 (16.6) | 257 (20.0) | 277 (21.5) | 307 (23.9) | 321 (25.0) | 333 (25.9) | 344 (26.7) | 348 (27.1) |
| Patients who did not reach the corresponding visit, cumulative | 230 (17.9) | 328 (25.5) | 420 (32.7) | 486 (37.8) | 618 (48.1) | 671 (52.2) | 756 (58.8) | 796 (61.9) | 868 (67.5) | 921 (71.6) |
| Concomitant use of oral systemic treatmentsa | 49 (5.0) | 43 (5.4) | 26 (4.0) | 20 (3.7) | 12 (3.1) | 14 (4.5) | 3 (1.4) | 3 (1.9) | 0 | 0 |
| Physician-reported outcomes | ||||||||||
| EASI, mean (SD) | 4.8 (5.0) | 3.9 (3.9) | 3.6 (4.0) | 3.9 (4.4) | 3.6 (4.1) | 3.5 (4.1) | 3.2 (3.4) | 3.2 (3.2) | 2.5 (3.2) | 2.9 (2.5) |
| Missing, No. | 33 | 93 | 132 | 109 | 82 | 38 | 26 | 21 | 9 | 4 |
| Patients achieving EASI ≤7 | 676 (78.6) | 584 (83.0) | 452 (86.9) | 361 (83.2) | 263 (85.1) | 235 (87.0) | 164 (89.6) | 120 (88.2) | 59 (90.8) | 12 (92.3) |
| Patients achieving EASI ≤4 | 497 (57.8) | 462 (65.6) | 356 (68.5) | 296 (68.2) | 213 (68.9) | 185 (68.5) | 129 (70.5) | 94 (69.1) | 49 (75.4) | 9 (69.2) |
| Patients achieving EASI 50 | 702 (81.6) | 606 (86.1) | 447 (86.0) | 363 (83.6) | 268 (86.7) | 241 (89.3) | 165 (90.2) | 127 (93.4) | 63 (96.9) | 13 (100) |
| Patients achieving EASI 75 | 475 (55.2) | 447 (63.5) | 347 (66.7) | 272 (62.7) | 199 (64.4) | 181 (67.0) | 136 (74.3) | 110 (80.9) | 56 (86.2) | 11 (84.6) |
| Patients achieving EASI 90 | 224 (26.0) | 218 (31.0) | 171 (32.9) | 139 (32.0) | 117 (37.9) | 100 (37.0) | 74 (40.4) | 60 (44.1) | 38 (58.5) | 6 (46.2) |
| IGA, median (IQR) | 2.0 (1.0-2.0) | 1.0 (1.0-2.0) | 1.0 (1.0-2.0) | 2.0 (1.0-2.0) | 1.0 (1.0-2.0) | 1.0 (1.0-2.0) | 1.0 (1.0-2.0) | 1.0 (1.0-2.0) | 1.0 (1.0-2.0) | 2.0 (1.0-2.0) |
| Missing, No. | 123 | 93 | 130 | 114 | 80 | 39 | 27 | 22 | 8 | 4 |
| Patients achieving IGA ≤1 | 383 (44.5) | 364 (51.7) | 269 (51.5) | 209 (48.7) | 172 (55.3) | 152 (56.5) | 105 (57.7) | 70 (51.9) | 42 (63.6) | 6 (46.2) |
| Patients achieving ≥2-point reduction in IGA from baseline | 436 (50.7) | 413 (58.7) | 301 (57.7) | 232 (54.1) | 175 (56.3) | 160 (59.5) | 113 (62.1) | 89 (65.9) | 48 (72.7) | 8 (61.5) |
| Patients achieving IGA-Controlled | 516 (60.0) | 479 (68.0) | 340 (65.1) | 273 (63.6) | 208 (66.9) | 185 (68.8) | 128 (70.3) | 96 (71.1) | 51 (77.3) | 8 (61.5) |
| Patient-reported outcomes | ||||||||||
| Weekly NRS for pruritus, mean (SD) | 3.2 (2.3) | 2.9 (2.2) | 2.9 (2.1) | 3.0 (2.2) | 2.9 (2.2) | 2.9 (2.2) | 2.7 (2.2) | 2.7 (2.2) | 2.3 (2.1) | 2.8 (2.2) |
| Missing, No. | 165 | 119 | 117 | 116 | 85 | 31 | 17 | 9 | 1 | 0 |
| Patients achieving NRS for pruritus ≤4 | 591 (72.2) | 517 (76.3) | 410 (76.6) | 327 (76.6) | 235 (76.8) | 213 (76.9) | 152 (79.2) | 120 (81.1) | 61 (83.6) | 15 (88.2) |
| Patients achieving NRS for pruritus ≤3 | 503 (61.5) | 451 (66.5) | 351 (65.6) | 278 (65.1) | 202 (66.0) | 183 (66.1) | 132 (68.8) | 104 (70.3) | 55 (75.3) | 12 (70.6) |
| Patients achieving NRS for pruritus ≤1 | 221 (27.0) | 201 (29.6) | 162 (30.3) | 121 (28.3) | 93 (30.4) | 87 (31.4) | 72 (37.5) | 53 (35.8) | 31 (42.5) | 5 (29.4) |
Abbreviations: EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment; NRS, numeric rating scale.
Oral systemic treatments include prednisolone, methotrexate, oral tacrolimus, mycophenolate mofetil, tioguanine, hydrocortisone, and dexamethasone.
Figure 2. Outcome Measures and Laboratory Assessments Among 1286 Patients With Atopic Dermatitis During 5 Years of Dupilumab Treatment.
A and B, Data are as observed. C and D, Data are derived from linear mixed model analysis, including random intercept and heterogeneous autoregressive residual covariance matrix. P values for the total cohort are based on overall likelihood ratio tests for time and for the age groups are based on overall likelihood ratio tests for time and time by age group interaction. Normal eosinophil range for adults is 0 to 400/μL and for children is 0 to 600/μL (to convert to ×109/L, multiply by 0.001). EASI indicates Eczema Area and Severity Index; NRS, numeric rating scale. Error bars represent IQRs.
Regional Body Areas
During dupilumab treatment, all 4 EASI subscores decreased over time and tended to show a similar trend, which persisted throughout the whole observation period (Figure 2B). The EASI of the head and neck region decreased from a median of 16.7% to 2.8%, the trunk improved from 19.4% to 2.1%, and the upper and lower extremities improved from 25.0% to 2.8% and 18.1 to 0%, respectively. In patients who discontinued dupilumab treatment due to ineffectiveness, the head and neck region was usually not more severely involved (eFigure 5 in Supplement 1).
Laboratory Assessments
Median TARC levels significantly decreased from 1751 pg/mL (95% CI, 1614-1900 pg/mL) to 390 pg/mL (95% CI, 368-413 pg/mL) after 6 months of treatment and remained low over time (P < .001; Figure 2C). Median eosinophil levels slightly increased up to week 16 but considerably decreased below baseline levels during long-term follow-up and remained within normal ranges (children, 0-600/μL; adults and older adults, 0-400/μL [to convert to ×109/L, multiply by 0.001]; Figure 2D).
Clinical Effectiveness of Dupilumab By Different Age Groups
For EASI, IGA, and NRS for pruritus, the adult and the older adult groups showed a similar response to dupilumab treatment, while the pediatric population experienced slightly higher scores on several time points (Figure 1). Adults, older adults, and children showed a fairly similar tendency in the decrease of TARC levels during treatment (Figure 2C), and a statistically significant difference in eosinophil levels over time was found between the age groups (Figure 2D).
Treatment Discontinuation
Of the 1286 patients, 306 (23.8%) discontinued dupilumab treatment after a median (IQR) of 54.0 (28.0-110.00) weeks. The most frequently reported reason for treatment discontinuation was the development of AEs in 98 patients (7.6%) after a median (IQR) of 44.0 (26.3-95.5) weeks (Table 3). Of these AEs, dupilumab-associated ocular surface disease was most frequently recorded as the dropout reason among 38 patients (3.0%), followed by muscle/joint pain in 8 (0.6%) and lymphoid reactions in 7 (0.5%). Interestingly, 218 patients (71.2%) stopped treatment between December 2020 and 2022 when other new advanced systemic drugs became available for the treatment of AD. A drug survival analysis and discontinuation probabilities stratified for patients who initiated treatment prior to or after JAK inhibitor availability is shown in eFigure 6 in Supplement 1. Five patients (0.4%) were diagnosed with a cancer, leading to treatment discontinuation. One patient appeared to have misdiagnosed mycosis fungoides (reassessed biopsy-proven mycosis fungoides before starting dupilumab treatment). Interestingly, this patient showed an initial response to dupilumab treatment but clinically worsened after a few weeks of treatment. Another patient, diagnosed with a systemic T-cell lymphoma, restarted dupilumab treatment (after consultation with a hematologist) due to relapsed AD after dupilumab discontinuation. Six patients (0.5%) died during treatment, with severe COVID-19 infection being the cause of death in 2 patients. The other patients died due to progressive amyotrophic lateral sclerosis, lung cancer, suspected myocardial infarction, or euthanasia (due to severe left hemisphere failure). Eighty-five patients (6.6%) discontinued treatment due to ineffectiveness while being treated with dupilumab, 300 mg, every other week, and 10 patients (0.8%) stopped due to controlled disease.
Table 3. Reasons for and Time to Dupilumab Discontinuation Among 1286 Patients With Atopic Dermatitis During 5 Years of Treatment.
| Reason for discontinuation | No. (%) | Duration of treatment, median (IQR), wk |
|---|---|---|
| Status of treatment by data lock | ||
| Active | 936 (72.8) | 107.0 (43.0-175.8) |
| Discontinued | 306 (23.8) | 54.0 (28.0-110.0) |
| Lost to follow-up | 44 (3.4) | 74.0 (38.5-108.0) |
| Discontinuation event | ||
| Controlled disease | 10 (0.8) | 145.5 (115.5-218.8) |
| Ineffective | 85 (6.6) | 51.0 (24.0-98.5) |
| Adverse events | 98 (7.6) | 44.0 (26.3-95.5) |
| Both ineffective and adverse events | 28 (2.2) | 59.5 (32.5-125.0) |
| Pregnant or wish to become pregnant | 28 (2.2) | 82.0 (39.0-128.8) |
| Patient wish | 34 (2.6) | 61.5 (19.5-114.0) |
| Death | 6 (0.5) | 43.5 (5.5-122.8) |
| Other | 17 (1.3) | 37.0 (15.5-75.5) |
| Adverse events | ||
| Ocular-related conditions | 50 (3.9) | NA |
| Conjunctivitis (DAOSD) | 38 (3.0) | 54.0 (17.8-126.8) |
| Limbitis (DAOSD) | 6 (0.5) | 32.0 (19.3-39.0) |
| Uveitis | 3 (0.2) | 28.0 (4.0-NA) |
| Cornea perforation (DAOSD) | 1 (0.1) | 17.0 (NA) |
| Retina ablation | 1 (0.1) | 98.0 (NA) |
| Skin-related conditions | 13 (1.0) | |
| Lymphoid reaction | 7 (0.5) | 85.0 (11.0-161.0) |
| Psoriasiform lesions | 2 (0.2) | 74.0 (65.0-NA) |
| Rosacea | 3 (0.2) | 91.0 (3.0-NA) |
| HND | 1 (0.1) | 21.0 (NA) |
| Alopecia areata | 1 (0.1) | 44.0 (NA) |
| Musculoskeletal-related conditions | 10 (0.8) | |
| Muscle and joint pain | 8 (0.6) | 70.0 (48.0-162.0) |
| Polymyalgia rheumatica | 1 (0.1) | 30.0 (NA) |
| Cervical myelopathy | 1 (0.1) | 42.0 (NA) |
| Cancer | 5 (0.4) | |
| Systemic T-cell lymphoma | 1 (0.1) | 159.0 (NA) |
| Pancreatic carcinoma | 1 (0.1) | 224.0 (NA) |
| Nodular paragranuloma (Hodgkin disease) | 1 (0.1) | 94.0 (NA) |
| Adenocarcinoma | 1 (0.1) | 12.0 (NA) |
| Mycosis fungoidesa | 1 (0.1) | 60.0 (NA) |
| General complaints | 6 (0.5) | NA |
| Agitation | 1 (0.1) | 133.0 (NA) |
| Malaise | 1 (0.1) | 18.0 (NA) |
| Headache | 1 (0.1) | 31.0 (NA) |
| Stomach pain | 1 (0.1) | 92.0 (NA) |
| Angioedema | 1 (0.1) | 49.0 (NA) |
| Paraesthesia | 1 (0.1) | 4.0 (NA) |
| Combination of adverse events | 14 (1.1) | |
| DAOSD, joint pain | 2 (0.2) | 56.0 (31.0-NA) |
| DAOSD, HND | 1 (0.1) | 155.0 (NA) |
| DAOSD, nausea | 1 (0.1) | 42.0 (NA) |
| DAOSD, verruca filiformis | 1 (0.1) | 40.0 (NA) |
| DAOSD, rosacea, muscle and joint pain | 1 (0.1) | 81.0 (NA) |
| DAOSD, hair loss, weight gain | 1 (0.1) | 91.0 (NA) |
| DAOSD, hair loss, fatigue | 1 (0.1) | 6.0 (NA) |
| DAOSD, HND, hair loss | 1 (0.1) | 19.0 (NA) |
| Lymphoid reaction, psoriasis | 1 (0.1) | 54.0 (NA) |
| Paraesthesia, headache | 1 (0.1) | 38.0 (NA) |
| Weight gain, joint pain | 1 (0.1) | 34.0 (NA) |
| Hair loss, fatigue, joint pain | 1 (0.1) | 28.0 (NA) |
| Malaise, muscle and joint pain | 1 (0.1) | 42.0 (NA) |
Abbreviations: DAOSD, dupilumab-associated ocular surface disease; HND, head and neck dermatitis; NA, not applicable.
In retrospect, the patient was misdiagnosed and appeared to have mycosis fungoides prior to taking dupilumab and worsened after the start of dupilumab treatment.
Second Treatment Episodes
Forty-one patients (3.2%) restarted dupilumab treatment after a median (IQR) stop period of 36.0 (16.5-56.5) weeks (eFigure 7 in Supplement 1). The most frequently reported reasons for initially discontinuing treatment were pregnancy or wish to become pregnant among 11 patients (26.8%), AEs among 9 (22.0%), ineffectiveness among 7 (17.1%), and controlled disease among 3 (7.3%) (eFigure 7 in Supplement 1). During the first year of the second treatment episode, the mean (SD) EASI decreased from 16.8 (11.9) to 4.2 (5.8) and NRS for pruritus improved from 7.0 (2.0) to 2.0 (1.0). Eight patients (19.5%) discontinued treatment for a second time due to ineffectiveness among 3, AEs among 3, loss to follow-up in 1, and diagnosis of hyper-IgE syndrome in 1 (eFigure 7 in Supplement 1). Three of 9 patients who had initially discontinued treatment due to AEs redeveloped AEs, which led to permanent treatment discontinuation in the second treatment episode (eFigure 7 in Supplement 1).
Discussion
In this multicenter daily practice study with up to 5 years of follow-up among 1286 patients with AD of all ages, dupilumab showed clinical effectiveness, and the clinical response was maintained for most patients throughout the whole observation period, with the percentage of patients achieving EASI of 7 or lower and NRS for pruritus of 4 or lower between 63.6% and 78.1%. A fairly similar response was found for children, adults, and older adults. However, while dupilumab treatment was effective in most patients, 306 patients (23.8%) discontinued treatment after a median (IQR) of 54.0 (29.0-110.00) weeks, with AEs among 98 (7.6%) and ineffectiveness among 85 (6.6%) being the most frequently reported reasons.
Three pediatric and two adult daily practice studies with 1-year and 2-year follow-up found comparable results regarding the decrease in EASI and NRS for pruritus over time (mean and median of 1.7-3.0 and 1.3-2.3 during follow-up, respectively).6,16,26,27,28 Vittrup et al6 also found similar percentages of adults achieving EASI 50/75/90 and EASI of 7 or lower. However, the study by Kojanova et al16 and the aforementioned pediatric studies found higher proportions of patients achieving EASI 50/75/90 (adults: 97.9%, 95.8%, and 60.4%, respectively; children: maximum 100.0%, 100.0%, and 73.6%,26,27,28 respectively). A possible explanation is that the higher mean baseline EASI ranges from 23.3 to 49.1, which makes it easier to achieve relative outcomes such as EASI 50/75/90.14,26,27,28 The long-term LIBERTY AD OLE trial also reported higher percentages of adult patients achieving EASI 50/75/90 after 4 years of treatment (94.9%, 90.9%, and 75.8%, respectively). However, the methodology of the LIBERTY AD OLE study substantially differs from the present daily practice study (eg, inclusion criteria for parent trial), which may explain different outcomes.17 Noteworthy is that up to 70.5% of patients were able to prolong their dosing interval to mostly every 3 or 4 weeks while maintaining controlled disease. The study of Worm et al,13 however, previously reported that interval prolongation resulted in a diminution of response, although this was primarily found in patients using dupilumab every 8 weeks. Moreover, from clinical practice we have experienced that successful dose reduction relies on patient motivation and physician-associated factors, such as adequately informing patients about the possibility of marginal flaring and/or emphasizing the importance of temporarily increasing their topical corticosteroids use, next to the capability to motivate their patients to taper.
Regarding eosinophil levels, a transient increase in levels during the first weeks of dupilumab treatment has previously been reported.29 Interestingly, we found a statistically significant decrease in eosinophil levels (with small 95% CIs) from week 16 up to 5 years of treatment, with levels even below baseline values.
Furthermore, we observed a similar response to dupilumab treatment for adults and older adults, while the pediatric population tended to have slightly higher EASI and IGA. However, these differences were rather small; in the first treatment year we found a maximum of 1.6 and 0.36 points difference in mean EASI and IGA, respectively. The clinical relevance of the statistically significant trends in EASI and IGA over time between age groups is therefore questionable, and the significant P values are most likely caused by the large number of patients and follow-up visits leading to high statistical power. The more recent approval of dupilumab treatment for use in children might also explain the slightly higher outcomes, as the first patients (ie, relatively high proportion) were the most difficult to treat. Other daily practice studies also reported similar clinical effectiveness of dupilumab treatment in older adults and children.6,30 Furthermore, a statistically significant but nonclinically relevant trend was found in eosinophil levels between the different age groups, as all mean levels remained within normal range. Regarding EASI subscores, we found that dupilumab treatment tended to have a similar clinical effect on the 4 anatomical body regions, which persisted over time. Similar findings were reported in post hoc analyses of clinical trials in both adults and children.31,32 Conversely, the daily practice study of Vittrup et al6 stated that dupilumab was unable to effectively treat AD in the head and neck region. An explanation for the difference in findings might be that they reported on the percentage of patients with AD involvement in specific body areas (ie, extent of AD lesions), while clinical trials and the present study analyzed both severity and extent of AD lesions of the affected body regions.6,31,32 Remarkably, while head neck dermatitis is frequently reported as an AE during dupilumab treatment,33 only 1 patient in this study discontinued treatment for this reason.
In up to 5 years of follow-up, 23.8% of patients discontinued dupilumab treatment, which is slightly higher than reported in most other daily practice studies (4.4%-20%) that only reported up to 2 years of follow-up.6,14,16,34,35 The higher percentage found in this study is, however, comparable with the recently published 4-year drug survival study of Pezzolo et al,36 who reported a discontinuation rate of 23.6% after 4 years of treatment. Another explanation for the lower dropout rate in the other daily practice studies is that some studies applied a data lock at the end of 2020.34,35 Since 2021, JAK inhibitors and tralokinumab entered the market for the treatment of moderate to severe AD. The advent of these new systemic treatments likely influenced the number of patients who discontinued dupilumab treatment, as they provided alternative therapeutic options. Regarding discontinuation reasons, the development of AEs (dupilumab-associated ocular surface disease specifically) and ineffectiveness were most frequently reported in the present study, which is in line with other daily practice studies.6,14,34,35 To our knowledge, no other daily practice studies have reported cancer as the stop reason for dupilumab treatment (besides other BioDay studies), which might be associated with the relatively short follow-up period in these studies.36 A large study investigating the global cancer incidence found that in the Netherlands, 400 to 500 of 100 000 people are diagnosed with cancer each year.37 This is consistent with the 5 patients with cancer in the current study, suggesting that dupilumab treatment did not lead to an increased cancer rate.
Although 306 patients (23.8%) discontinued dupilumab treatment, 41 patients (3.2%) restarted treatment, with most of these patients recapturing clinical response. These findings are in line with the study by Vittrup et al,6 who reported that most patients with a second treatment episode again benefited from treatment with dupilumab, comparable with the initial response. In contrast with the present study, they found a less impressive itch response in these dupilumab restarters. Interestingly, of 41 restarted patients, 17.1%, 22.0%, and 2.4% initially stopped dupilumab treatment due to ineffectiveness, AEs, or a combination of both, respectively.
Strengths and Limitations
Strengths of this study are the long follow-up period together with the large cohort of included children, adults, and older adults treated in a daily practice setting. The observational and prospective design, including data from 14 different hospitals across the Netherlands, is another strength. However, due to the daily practice setting of this study and the COVID-19 pandemic, there are missing data on the included outcomes. For the primary outcomes, we applied a mixed model with random effect, which is robust for missing data and dropouts over time under the missing-(completely)-at-random assumption.38 However, the dropouts may be considered missing not at random, which may have introduced a positive selection bias in the long-term follow-up results. Also, analysis on age groups was only performed on 2-year data due to the lack of pediatric patients reaching longer follow-up. The relatively low number of pediatric patients with visits at 1 year and 6 months, 1 year and 9 months, and 2 years, together with the low number of adults with visits at 5 years, may have resulted in relatively better outcomes compared to earlier time points. Moreover, this study lacks a full 5-year follow-up period of all patients, as dupilumab was initiated at a different time point for every patient. Nevertheless, this reflects an daily practice study.
Conclusions
In this cohort study, dupilumab maintained its clinical effectiveness during a 5-year observation period, while two-thirds of the patients tapered to a dosing interval of mostly every 3 or 4 weeks. A total of 23.8% of patients discontinued treatment, mainly due to AEs and/or ineffectiveness. TARC and eosinophil levels showed a statistically significant decrease and remained low over time. This study highlights the importance of multicenter registries to evaluate long-term treatment effects in large daily practice cohorts. Future studies in patients who discontinued dupilumab due to controlled disease may contribute to the knowledge on the disease course and possible disease modification after treatment discontinuation. In addition, (translational) research focused on the pediatric population is needed to evaluate the immune-modulating and long-term effects of dupilumab treatment in children.
eTable. Differences between age groups in baseline and patient characteristics
eFigure 1. Protocol of the pragmatic patient-centered dupilumab dosing regimen of the BioDay registry
eFigure 2. Flowchart of the included 1286 AD patients with mean EASI, IGA and NRS pruritus and treatment dosage per follow-up visit
eFigure 3. Proportion of patients with long-term control defined by responders (EASI≤7 and NRS pruritus≤4) during a 5-year follow-up period
eFigure 4. Topical steroids use over a 5-year follow-up period
eFigure 5. Median EASI subscores in 85 AD patients who discontinued dupilumab treatment due to ineffectiveness, stratified for head/neck, trunk, upper and lower extremities in percentage of total subscore
eFigure 6. Drug survival prior to and after JAKi availability of dupilumab treatment in AD patients and probability of discontinuation prior to and after JAKi availability of dupilumab treatment in AD patients
eFigure 7. Second treatment episodes of 41 patients who restarted dupilumab treatment
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable. Differences between age groups in baseline and patient characteristics
eFigure 1. Protocol of the pragmatic patient-centered dupilumab dosing regimen of the BioDay registry
eFigure 2. Flowchart of the included 1286 AD patients with mean EASI, IGA and NRS pruritus and treatment dosage per follow-up visit
eFigure 3. Proportion of patients with long-term control defined by responders (EASI≤7 and NRS pruritus≤4) during a 5-year follow-up period
eFigure 4. Topical steroids use over a 5-year follow-up period
eFigure 5. Median EASI subscores in 85 AD patients who discontinued dupilumab treatment due to ineffectiveness, stratified for head/neck, trunk, upper and lower extremities in percentage of total subscore
eFigure 6. Drug survival prior to and after JAKi availability of dupilumab treatment in AD patients and probability of discontinuation prior to and after JAKi availability of dupilumab treatment in AD patients
eFigure 7. Second treatment episodes of 41 patients who restarted dupilumab treatment
Data Sharing Statement
