Assessment and Clinical Relevance of Serum IL-19 Levels in Psoriasis and Atopic Dermatitis Using a Sensitive and Specific Novel Immunoassay

Abstract

Because development of reliable biomarkers in psoriasis and atopic dermatitis has lagged behind therapeutic progress, we created a blood-based test to fill the void in objective methods available for dermatological assessments. Our novel interleukin-19 (IL-19) immunoassay was initially tested to determine concentrations of IL-19 serum levels, then correlated with the psoriasis activity and severity index (PASI) in psoriasis, and the eczema area and severity index (EASI) in atopic dermatitis. Not only was IL-19 increased in psoriasis and correlated to PASI, but ixekizumab administration led to rapid, sustained IL-19 decreases to normal levels, with decreases at 2-weeks correlating with PASI improvement at 16-weeks. IL-19 increased upon ixekizumab withdraw, prior to relapse, and decreased following re-treatment. In baricitinib- and etanercept-treated psoriasis patients, IL-19 decreases also correlated with improvement. Many patients with limited skin disease, including genital psoriasis and psoriatic arthritis patients, also had increased IL-19, which was reduced to normal levels upon ixekizumab treatment, correlating with PASI improvement. We also measured IL-19 in baricitinib-treated atopic dermatitis patients. In atopic dermatitis, IL-19 was significantly elevated, correlated with EASI scores, and decreased with skin improvement. Therefore, measurement of serum IL-19 provides clinicians with an objective disease-activity assessment tool for psoriasis and atopic dermatitis patients.

Figure 1

Baseline IL-19 levels are markedly increased in psoriasis and are highly correlated with PASI scores in psoriasis, genital psoriasis, and psoriatic arthritis patients. (a) The normal donor IL-19 geometric mean was 11 pg/mL, while in psoriasis (PsO) patients at baseline, the IL-19 geometric mean was 87 pg/mL (p < 0.0001). (b) Baseline IL-19 levels were measured in 556 patients with psoriasis (PsO), 120 patients with genital psoriasis (gPsO), and 293 patients with psoriatic arthritis (PsA). IL-19 was highly correlated with PASI (Spearman’s r = 0.64, p < 0.0001). (c) Same as Fig. 1b but restricted to PASI < 10 (Spearman’s r = 0.53, p < 0.0001). (d) Same as Fig. 1b but restricted to PASI < 5 (Spearman’s r = 0.39, p < 0.0001).

Figure 2

Circulating IL-19 levels serve as a leading indicator of PASI improvement in psoriasis patients treated with ixekizumab. (a) We obtained samples from 112 psoriasis patients enrolled in a phase 2 study (NCT01107457) for ixekizumab. Patients were assigned to five treatment groups and were administered placebo or 10, 25, 75, or 150 mg ixekizumab at 0, 2, 4, 8, 12, and 16 weeks. Circulating IL-19 concentrations were measured at baseline and after ≥16 weeks of treatment. All data from baseline and after 16 weeks of treatment are shown. Collectively, serum IL-19 levels were highly correlated with PASI (Spearman’s r = 0.74, p < 0.0001). (b) IL-19 was measured in psoriasis patients from Fig. 2a at baseline and over 16 weeks of treatment. Data are least square means ± standard error of the mean estimated from a mixed effects model using an unstructured covariance matrix. Model fitting was performed using log₁₀ transformed IL-19 concentrations. The dashed horizontal line indicates the upper limit of normal (21 pg/mL). Week 2 comparisons of ixekizumab (IXE) to placebo (PBO): 10 mg (p = 0.28), 25 mg (p = 0.0015), 75 mg (p < 0.0001), 150 mg (p < 0.0001); Week 16 comparisons: 10 mg (p = 0.71), 25 mg (p < 0.0001), 75 mg (p < 0.0001), 150 mg (p < 0.0001). (c) Representative patient profiles from Fig. 2b for IL-19 (solid) and PASI percent change from baseline (dashed). A patient treated with 75 mg of ixekizumab (IXE) is shown on top and a patient treated with 150 mg of ixekizumab is shown on bottom. The dashed vertical line indicates the baseline time point. In each case, IL-19 decreases prior to PASI improvement. (d) Serum IL-19 levels in psoriasis patients from Fig. 2b after 2 weeks (top) and 16 weeks (bottom) of placebo or doses of ixekizumab are plotted versus PASI at 16 weeks. The dashed horizontal line indicates the upper limit of normal. PASI 100 improvements at 16 weeks were preceded by IL-19 reductions to near normal levels after 2 weeks of treatment. Top panel one-way ANOVA (p < 0.0001). Bottom panel one-way ANOVA (p < 0.0001).

Figure 3

IL-19 is highly correlated with PASI in psoriasis patients treated with the JAK1/2 inhibitor baricitinib. (a) We obtained samples from 270 patients enrolled in a phase 2 psoriasis study (NCT01490632) for the JAK1/2 inhibitor baricitinib. Patients were administered placebo or 2, 4, 8, or 10 mg of baricitinib QD for 12 weeks. Samples were collected at baseline and after 12 weeks of treatment. Circulating IL-19 was measured at baseline and after 12 weeks of treatment with baricitinib (2, 4, 8, or 10 mg QD) or placebo in patients with psoriasis. All data from baseline and after 12 weeks of treatment are shown. Collectively, serum IL-19 levels were highly correlated with PASI (Spearman’s r = 0.72, p < 0.0001). (b) Serum IL-19 was measured in psoriasis patients at baseline and after 12 weeks of treatment with placebo (PBO) or baricitinib (BARI) (2, 4, 8, or 10 mg QD). Data plotted are least square means ± standard error of the mean estimated from a mixed effects model using an unstructured covariance matrix. Model fitting was performed using log₁₀ transformed IL-19 concentrations. The dashed horizontal line indicates the upper limit of normal (21 pg/mL). Week 12 comparisons of baricitinib to placebo: 2 mg (p = 0.31), 4 mg (p = 0.063), 8 mg (p = 0.022), and 10 mg (p < 0.0001). (c) Serum IL-19 levels in psoriasis patients after 12 weeks of treatment with placebo or baricitinib (2, 4, 8, or 10 mg QD) are plotted versus PASI at 12 weeks. The dashed horizontal line indicates the upper limit of normal. PASI >75 improvements at 12 weeks were correlated with reduction of circulating IL-19 concentrations. One-way ANOVA (p < 0.0001).

Figure 4

Serum IL-19 is highly correlated with PASI in psoriatic arthritis, and ixekizumab treatment causes a rapid, sustained decrease in IL-19, with levels serving as a leading indicator of PASI improvement. (a) Baseline, 4-week, and 12-week treatment samples were collected from 309 psoriatic arthritis patients throughout the induction period of a phase 3 study (SPIRIT-P1, NCT02349295), during which patients were administered placebo or ixekizumab (a loading dose of 160 mg followed by 80 mg Q2W or 80 mg every four weeks [Q4W]) for 12 weeks. Patients enrolled in this study had no minimum baseline PASI. Circulating IL-19 was measured at baseline and after 12 weeks of treatment with ixekizumab (80 mg Q2W or 80 mg Q4W) or placebo. All data from baseline and after 12 weeks of treatment are shown. Collectively, serum IL-19 results were highly correlated with PASI (Spearman’s r = 0.66, p < 0.0001). (b) Circulating IL-19 was measured in psoriatic arthritis patients at baseline and during 12 weeks of treatment with placebo (PBO) or ixekizumab (IXE) (80 mg Q2W or 80 mg Q4W). Data are least square means ± standard error of the mean estimated from a mixed effects model using an unstructured covariance matrix. Model fitting was performed using log₁₀ transformed IL-19 concentrations. The dashed horizontal line indicates the upper limit of normal (21 pg/mL). Week 4 comparisons of ixekizumab to placebo: 80 mg Q2W (p < 0.0001), 80 mg Q4W (p < 0.0001); Week 12 comparisons: 80 mg Q2W (p < 0.0001), 80 mg Q4W (p < 0.0001). (c) Serum IL-19 levels in psoriatic arthritis patients with baseline PASI ≥5 after 4 weeks (top) of placebo or ixekizumab (80 mg Q2W or 80 mg Q4W) treatment, or 12 weeks (bottom) of placebo or ixekizumab (80 mg Q2W or 80 mg Q4W) treatment are plotted versus PASI at 12 weeks. The dashed horizontal line indicates the upper limit of normal. PASI 100 improvements at 12 weeks were preceded by reduction of IL-19 to near normal levels after 4 weeks of treatment. Top panel one-way ANOVA (p < 0.0001). Bottom panel one-way ANOVA (p < 0.0001).

Figure 5

Serum IL-19 is highly correlated with PASI in genital psoriasis, with circulating levels serving as a leading indicator of PASI improvement following ixekizumab treatment. (a) Baseline, 2-, 4-, and 12-week treatment samples were collected from 120 genital psoriasis patients throughout the induction period of a phase 3b study (NCT02718898), during which patients were administered placebo or ixekizumab (160 mg loading dose followed by 80 mg Q2W) for 12 weeks. Subjects with moderate‐to‐severe genital psoriasis defined as a baseline static Physician’s Global Assessment of Genitalia (sPGA‐G) score of ≥3, with BSA ≥1% were randomized 1:1 to receive placebo or ixekizumab. At baseline, 47 patients had BSA <10% with an IL-19 geometric mean of 57 pg/mL, while 73 patients had BSA ≥10% with an IL-19 geometric mean of 131 pg/mL. The difference was statistically significant (p = 0.0001). (b) Circulating IL-19 concentrations were measured at baseline and after 12 weeks of treatment with placebo or ixekizumab 80 mg Q2W in patients with genital psoriasis. All data from baseline and after 12 weeks of treatment are shown. Collectively, serum IL-19 levels were highly correlated with PASI (Spearman’s r = 0.79, p < 0.0001). (c) IL-19 was measured in genital psoriasis patients at baseline and over 12 weeks of treatment with placebo (PBO) or ixekizumab (IXE) 80 mg Q2W. Data are least square means ± standard error of the mean estimated from a mixed effects model using an unstructured covariance matrix. Model fitting was performed using log₁₀ transformed IL-19 concentrations. The dashed horizontal line indicates the upper limit of normal (21 pg/mL). Comparisons between placebo and ixekizumab at weeks 2, 4, and 12 were statistically significant (p < 0.0001). (d) Serum IL-19 levels in genital psoriasis patients after 2 (top) and 12 weeks (bottom) of placebo or ixekizumab 80 mg Q2W are plotted versus PASI at 12 weeks. The dashed horizontal line indicates the upper limit of normal. PASI 100 improvements at 12 weeks were preceded by IL-19 reductions to near normal levels after 2 weeks of treatment. One-way ANOVA (p < 0.0001) for both panels.

Figure 6

Etanercept decreases circulating IL-19 concentrations in psoriasis patients, but decreases are not as rapid or robust as those observed with ixekizumab. (a) Samples were collected from psoriasis patients enrolled in a phase 3 ixekizumab study (UNCOVER-2, NCT01597245), which included an etanercept active comparator arm. Circulating IL-19 was measured at baseline and after 12 weeks of treatment with the TNFα inhibitor etanercept in 163 patients with psoriasis. All data from baseline and after 12 weeks of treatment are shown. Collectively, serum IL-19 results were highly correlated with PASI (Spearman’s r = 0.60, p < 0.0001). (b) Overlaid histograms were prepared for end-of-induction (week 12) PASI scores for etanercept (ETN) (purple, n = 334, all etanercept patients; 36% of all etanercept patients were sPGA = 0, 1 responders) and ixekizumab (IXE) induction responders who were randomized to placebo and then re-administered ixekizumab upon relapse (blue, n = 94 out of 341 patients initially treated with ixekizumab; 83% of all ixekizumab patients were sPGA = 0, 1 responders). (c) Serum IL-19 levels in psoriasis patients were measured at baseline and during 12 weeks of treatment with etanercept (ETN) or ixekizumab (IXE). Data from 164 etanercept patients, 31 ixekizumab responder patients, and 35 of the best-responding etanercept patients (matched for ixekizumab response), were plotted as least square means ± standard error of the mean estimated from a mixed effects model using an unstructured covariance matrix. Model fitting was performed using log₁₀ transformed IL-19 concentrations. The dashed horizontal line indicates the upper limit of normal (21 pg/mL). Comparisons between etanercept patients and ixekizumab patients at weeks 1, 4, and 12 were all statistically significant (p < 0.0001). (d) Serum IL-19 levels after 4 weeks (top) or 12 weeks (bottom) of etanercept treatment are plotted versus PASI at 12 weeks for 164 etanercept patients matched to the overall etanercept PASI distribution. The dashed horizontal line indicates the upper limit of normal. Lower IL-19 levels after treatment with etanercept for 4 weeks or 12 weeks were correlated with improved PASI response at 12 weeks. Top panel one-way ANOVA (p < 0.0001). Bottom panel one-way ANOVA (p < 0.0001).

Figure 7

Serum IL-19 levels increase when psoriasis patients treated with ixekizumab are transitioned to placebo and decrease again upon ixekizumab re-treatment. (a) Samples were collected from psoriasis patients enrolled in a phase 3 ixekizumab study (UNCOVER-2, NCT01597245). Serum IL-19 and PASI (percent change from baseline) are shown for responders selected at random who were administered ixekizumab (80 mg Q2W) for 12 weeks and achieved sPGA = 0, 1 (83% of ixekizumab patients were sPGA = 0, 1 responders). After responding, patients were transitioned to placebo and re-treated with ixekizumab when their skin response dissipated. Time course profiles are shown for IL-19 (top) and PASI (bottom) for each individual patient during the initial treatment with ixekizumab, during washout after patients had responded (sPGA = 0, 1), and following re-treatment. Twenty-seven of the 31 ixekizumab patients are included in the analysis (patients with baseline IL-19 levels ≤21 pg/mL were excluded). (b) Individual patient time-course profiles from Fig. 7a were linearly interpolated to enable a weekly geometric mean ± standard error for IL-19 and a weekly mean ± standard error for PASI. Interpolated time course profiles are shown for IL-19 (top) and PASI (bottom). The dashed horizontal line indicates the upper limit of normal IL-19 concentrations (21 pg/mL). The rise in IL-19 levels between weeks 12 and 20 is influenced by interpolation because many patients did not have serum samples drawn at every time point when PASI assessments were performed.

Figure 8

Circulating IL-19 concentrations are increased in atopic dermatitis, correlate with EASI, and serve as a leading indicator of skin improvement. (a) Samples were obtained from 123 atopic dermatitis patients enrolled in a phase 2 study (NCT02576938) for baricitinib. Patients received topical corticosteroids as a standardization period for 4 weeks, and were then randomly assigned to placebo, or baricitinib 2 mg or 4 mg QD for 16 weeks. During the 16-week treatment period, all patients remained on topical corticosteroids. Serum samples for IL-19 measurement were obtained at baseline (following the 4 weeks of lead-in topical corticosteroids), and after 4 weeks and 16 weeks of treatment. In atopic dermatitis (AD), the baseline IL-19 geometric mean is 34 pg/mL (p < 0.0001 versus normals). Data from normal subjects and psoriasis (PsO) patients are shown for comparison. (b) Circulating IL-19 was measured at baseline and during 16 weeks of QD treatment with placebo, 2 mg, or 4 mg of baricitinib in patients with atopic dermatitis. All data from baseline and after 16 weeks of treatment are shown. Collectively, serum IL-19 results were highly correlated with EASI (Spearman’s r = 0.59, p < 0.0001). (c) Serum IL-19 levels in atopic dermatitis patients after 4 weeks (top) or 16 weeks (bottom) of QD placebo, 2 mg, or 4 mg of baricitinib are plotted versus EASI at 16 weeks. The dashed horizontal line indicates the upper limit of normal (21 pg/mL). EASI improvements of >90 at 16 weeks were preceded by reduction of circulating IL-19 to near normal concentrations after 4 weeks of treatment. Top panel one-way ANOVA (p = 0.0002). Bottom panel one-way ANOVA (p < 0.0001).