The clinical relevance of dupilumab serum concentration in patients with atopic dermatitis: a two-center prospective cohort study

Figures & data

Table 1. Adverse events.

Number of patients with adverse events – no. (%)	72 (48.3)
Total number of adverse events – no.	126
Relatedness – no.^a
Not related	27
Doubtful	18
Possible	67
Probable	13
Very likely	0
Definite	0
Action on adverse event – no.^b
Treatment discontinuation	8
Adjustment of treatment schedule	8
No treatment adjustment	39
Course of adverse event – no.
Recovered/resolved	42
Recovered/resolved with sequelae	23
Not recovered/resolved	49
Fatal	0
Unknown	12
Type of adverse event – no.
Eye disorders	49
(Kerato)conjunctivitis	25
Combined diagnoses	13
Other^c	11
Infections and infestations	20
Skin and subcutaneous tissue disorders	12
Eczema flare	4
Facial redness	4
Perioral dermatitis	1
Panniculitis e.c.i.	1
Molluscum contagiosum	1
Basalcelcarcinoma	1
Gastrointestinal disorders	8
Cardiac disorders	6
Musculoskeletal and connective tissue disorders	4
Nervous system disorders	4
Respiratory, thoracic and mediastinal disorders	4
Renal and urinary disorders	4
General disorders and administration site conditions	4
Psychiatric disorders	2
Injury, poisoning and procedural complications	2
Endocrine disorders	2
Reproductive system and breast disorders	1
Blood and lymphatic systemic disorders	1
Investigations	1
Surgical and medical procedures	1
Ears and labyrinth disorders	1
Serious adverse events – no.	12
Median (IQR) number of days between start dupilumab and event	59 (14–125)

^aMissing data: n = 1.

^bNL data only; missing data: n = 71.

^cOther: blepharitis (2×), vision loss, epiphora (2×), sicca complaints (3×), eyelid spasm, swelling eyelid, eye irritation.

Definitions: In the Netherlands only severe AEs were registered. Severe AEs were defined as any undesirable experience occurring during dupilumab treatment resulting in referral to another specialist, prescription of medication (excluding antihistamines and indifferent treatments), treatment schedule adjustments or discontinuation, or causing considerable interference with usual activities, whether or not considered related to this treatment. Events that resulted in death, were life-threatening, required (prolonging of) hospitalization, resulted in persistent or significant disability, or congenital anomaly or birth defect, were also considered serious (20). In the UK all AEs were registered, regardless of severity.

Further detail on the specific events are available from the corresponding author on reasonable request.

Table 2. Patient characteristics at baseline (n = 149).

Sex – no. (%)
Female	55 (36.9)
Male	94 (63.1)
Age in years – median (IQR)	43 (27.5–53.0)
Fitzpatrick skin type – no. (%)^1
I	16 (10.7)
II	63 (42.3)
III	38 (25.5)
IV	8 (5.4)
V	11 (7.4)
VI	6 (4.0)
Ethnicity – no. (%)^2
White	112 (75.2)
Black-African, Afro Caribbean	6 (4.0)
South Asian	9 (6.0)
Asian-Chinese	2 (1.3)
Asian-other	4 (2.7)
Mixed^a	6 (4.0)
Other	1 (0.7)
BMI – median (IQR)^3	24.7 (22.3–27.6)
Previous use of systemic therapies for AD – no. (%)
Ciclosporin	124 (83.2)
Systemic corticosteroids	96 (64.4)
Methotrexate	90 (60.4)
Azathioprine	45 (30.2)
Mycophenolic acid/mycophenolate mofetil	44 (29.5)
Investigational medication	10 (6.7)
Upadacitinib/placebo (JAK inhibitor)	4 (2.7)
Baricitinib/placebo (JAK inhibitor)	3 (2.0)
Tralokinumab/placebo (mAb, IL-13)	2 (1.3)
Tralokinumab (mAb, IL-13)	1 (0.7)
Omalizumab	1 (0.7)
Other medication (including dupilumab)	0 (0)
Number of previously used systemic therapies per patient– no. (%)
1	23 (15.4)
2	46 (30.9)
3	42 (28.2)
4	21 (14.1)
5	17 (11.4)
Concomitant systemic therapy at baseline – no. (%)
None	51 (34.2)
Prednisone	18 (12.1)
Discontinued during study	14 (9.4)
Continued until study cutoff	4 (2.7)
Systemic antihistamines	89 (59.7)
Systemic antibiotics^b	4 (2.7)
Systemic immunotherapy	0 (0.0)
EASI – median (IQR)^4	16.8 (10.8–24.8)
NRS 24 h pruritus – median (IQR)^1	7.0 (6.0–8.0)
POEM – median (IQR)^1	21.0 (16.0–25.0)
DLQI – median (IQR)^5	15.0 (9.0–20.0)

AD: atopic dermatitis; BMI: body mass index; IQR: interquartile range; No.: number; EASI: eczema area severity index; NRS: numeric rating scale (NRS peak pruritus past 24 h (NL), NRS mean pruritus past 7 d (UK)); POEM: patient oriented eczema measure; DLQI: dermatology life quality index.

^aBlack and Asian (n = 2), Black and White (n = 1), Asian and White (n = 2).

^bMinocycline 2dd 50 mg, flucloxacillin 3dd 500 mg, flucloxacillin 4dd 500 mg (2×).

Missing data: ¹n = 7, ²n = 9, ³n = 10, ⁴n = 4, ⁵n = 2.

Table 3. Outcome measures and dupilumab serum concentrations at baseline and during follow-up.

	EASI (0–72)		NRS (0–10)		POEM (0–28)		DLQI (0–30)		Serum concentration (μg/mL)
	Median	IQR	Median	IQR	Median	IQR	Median	IQR	Median	IQR
Baseline	16.8	10.8–24.8	7.0	6.0–8.0	21.0	16.0–25.0	15.0	9.0–20.0	0	0–0
2 weeks	12.5	7.1–19.8	3.5	2.3–5.0	23.5	8.0–18.0	7.0	4.0–10.0	57.4	45.9–67.8
12 weeks	6.1	2.8–11.2	3.0	1.0–5.0	8.0	4.0–13.0	4.0	1.0–8.0	69.5	44.6–94.1
24 weeks	5.5	3.1–9.3	2.0	1.0–6.0	9.0	4.0–15.0	3.5	1.3–7.0	72.4	47.8–101.0
48 weeks	4.4	2.1–8.4	3.0	1.5–5.0	9.0	5.0–14.0	3.0	1.0–8.0	72.0	48.4–101.7

IQR: interquartile range; EASI: eczema area severity index; NRS: numeric rating scale (NRS peak pruritus past 24 h (NL), NRS mean pruritus past 7 d (UK)); POEM: patient oriented eczema measure; DLQI: dermatology life quality index. The range of concentrations was 1.9, 77.8, 224.0, 172.5 and 251.0 at respectively baseline, 2 weeks, 12 weeks, 24 weeks and 48 weeks.

Figure 1. (A) Dupilumab serum levels over time. Dot plot of the dupilumab levels at different time points (with mean and SDs in red). (B) The ratio of dupilumab serum levels. Dot plot of the ratios of the dupilumab levels at different time points (with mean and SDs in red), which approach 1 (i.e., the concentrations are similar over time).

Figure 2. (A) The concentration-effect curve for dupilumab level and ΔEASI at 24 weeks. A concentration-effect curve showing the dupilumab serum level in μg/mL at 24 weeks on the x-axis and correlating ΔEASI at 24 weeks (versus baseline) on the y-axis. All patients were sorted from low to high drug concentration, with each dot representing the mean concentration with SDs and correlating ΔEASI for 10 patients (last group 9 patients). (B) The concentration-effect curve for dupilumab level and ΔEASI at 12 weeks. The concentration-effect curve showing the dupilumab serum level in μg/mL at 12 weeks on the x-axis and correlating ΔEASI at 12 weeks (versus baseline) on the y-axis. All patients were sorted from low to high drug concentration, with each dot representing the mean concentration with SDs and correlating ΔEASI for 10 patients (last group 11 patients).

Figure 3. (A) ROC curve for patients reaching EASI ≤ 7 at 24 weeks of treatment and dupilumab serum level at 2 weeks. The AUC in the ROC curve is not significantly different from 0.5, indicating that dupilumab concentration does not have the ability to distinguish between the group that reached EASI ≤ 7 (AUC 0.760, 95% CI: 0.591–0.929, p = .022). At 64.1 μg/mL, a sensitivity of 60% and a specificity of 100% was found. (B) ROC curve for patients reaching EASI ≤ 7 at 24 weeks of treatment and dupilumab serum level at 12 weeks. The AUC in the ROC curve is significantly different from 0.5, indicating that the dupilumab concentration has the ability to distinguish the group that reached EASI ≤ 7 (AUC 0.664, 95% CI: 0.552–0.777, p = .011). At 32.7μg/mL, a sensitivity of 95% and a specificity of 26% was found. (C) ROC curve for patients reaching EASI ≤ 7 at 24 weeks of treatment and dupilumab serum level at 24 weeks. The AUC in the ROC curve is not significantly different from 0.5, indicating that dupilumab concentration does not have the ability to distinguish between the group that reached EASI ≤ 7 (AUC 0.638, p = .053, borderline significant). At 59.6μg/mL, a sensitivity of 67% and a specificity of 58% was found for EASI ≤ 7.

Williams HC, Burney PG, Pembroke AC, et al. The U.K. Working party’s diagnostic criteria for atopic dermatitis. III. Independent hospital validation. Br J Dermatol. 1994;131(3):406–416.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.