Influence of Trough Serum Levels and Immunogenicity on Long-term Outcome of Adalimumab Therapy in Crohn's Disease

(A) Short-term outcome in 168 patients with CD treated with adalimumab who previously failed to respond to infliximab therapy. Fourteen patients received placebo as an induction scheme (weeks 0 and 2), 28 received 80/40 mg adalimumab, and 126 received 160/80 mg. Subsequently, all patients received adalimumab either 40 mg every other week or 40 mg every week. No significant difference was observed in clinical response between the 2 arms that received active drug as induction scheme both at week 4 (*P = .57) and week 12 (**P = .23). (B) Long-term outcome of adalimumab therapy. The initial cohort comprised 168 patients with CD. Twelve patients (7%) discontinued treatment by week 4 mainly due to inefficacy. A total of 156 patients (93%) entered the maintenance phase; from these patients, 60 (38.5%) discontinued adalimumab therapy (*) due to loss of response (26.3%), adverse events (7.1%), and other reasons described in the text (5.1%). Ninety-six patients (61.5%) demonstrated sustained clinical response until the end of follow-up. ^aMedian follow-up period, 20.4 (11.7–30.0) months. ^bMedian treatment duration if adalimumab stopped, 29.3 [8.7–52.8] weeks. ADA, adalimumab; CR, clinical response; eow, every other week; ew, every week; plc, placebo; pts, patients.

(A) Sustained clinical benefit of adalimumab in the patients of the maintenance group according to dose escalation. The curve represents the proportion of patients with sustained clinical benefit who did not experience an escalation of dose during follow-up. At risk represents the patients who continued treatment demonstrating a sustained clinical response at given time points, considering those with available data on dose escalation as the initial cohort (n = 138). (B) Sustained clinical benefit of adalimumab in the overall cohort. The curve represents the proportion of patients with a sustained clinical response during follow-up. At risk represents the patients who continued treatment demonstrating a sustained clinical response at given time points, considering as initial cohort the study population (n = 168).

Influence of induction schedule on (A) median (IQR) adalimumab trough serum concentration (for 160/80 mg: 11.6 [6.7–14.7] vs 3.6 [2.3–5.2] μg/mL for 80/40 mg; P < .0001), (B) the relationship between therapy discontinuation by week 4 and median adalimumab trough serum concentration (for discontinuation: 2.5 [0.8–4.3] vs 5.9 [3.2–11.9] μg/mL for continuation; P = .012), and (C) the relationship between increase of median adalimumab trough serum concentration and clinical response to dose escalation (for responders: 5.9 [1.9–8.3] vs 0.0 [0.0–1.7] μg/mL for nonresponders; P < .0001). Mann–Whitney tests; the asterisk and small circle represent mild outliers; the upper and lower whiskers indicate the distance from the end of the box to the largest and smallest observed values that are less than 1.5 box lengths from either end of the box; the top and bottom of the box indicate the 75th and 25th percentiles, respectively; and the band near the middle of the box indicates the 50th percentile. ADA, adalimumab; CR, clinical response; ew, every week; TR, trough serum concentration.

Comparison of median (IQR) adalimumab trough serum concentration at (A) week 4 (for discontinuation: 3.8 [1.1–6.9] vs 6.2 [3.5–11.9] μg/mL for continuation; P = .04), (B) week 12 (for discontinuation: 1.6 [0.3–8.0] vs 8.9 [4.9–12.6] μg/mL for continuation; P = .016), and (C) week 24 (for discontinuation: 0.4 [0.1–8.4] vs 8.9 [4.4–14.2] μg/mL for continuation; P = .03) of the patients who discontinued therapy by month 6 and those who continued treatment beyond that point and at (D) week 2 (for discontinuation: 6.5 [5.6–8.0] vs 10.4 [7.9–11.5] μg/mL for continuation; P = .02), (E) week 12 (for discontinuation: 5.6 [1.1–8.9] vs 9.3 [5.2–12.9] μg/mL for continuation; P = .02), and (F) week 24 (for discontinuation: 5.3 [0.1–8.8] vs 9.9 [4.8–13.6] μg/mL for continuation; P = .04) of the patients who discontinued therapy and those who sustained clinical benefit by the end of follow-up. Mann–Whitney tests; small circles represent mild or extreme outliers; the upper and lower whiskers indicate the distance from the end of the box to the largest and smallest observed values that are less than 1.5 box lengths from either end of the box; the top and bottom of the box indicate the 75th and 25th percentiles, respectively; and the band near the middle of the box indicates the 50th percentile. ADA, adalimumab; TR, trough serum concentration.

Relationship between antibodies against adalimumab and adalimumab trough serum concentration in different time points. AAA, antibodies against adalimumab; ADA, adalimumab; TR, trough serum concentration.

(A) Sustained clinical benefit stratified by adalimumab trough serum concentration of 0.33 μg/mL (sensitivity, 95%; positive predictive value, 81%). Filled diamonds and open triangles indicate patients with adalimumab levels greater than and less than 0.33 μg/mL, respectively, who discontinued treatment throughout follow-up. The curves indicate the proportion of patients in each group with a sustained clinical response during follow-up. Log-rank test was used to compare hazard rates between the 2 groups. (B) Sustained clinical benefit stratified by concomitant therapy with immunomodulators. Filled diamonds and open triangles indicate patients without and with immunomodulator therapy at baseline, respectively, who discontinued treatment throughout follow-up. The curves indicate the proportion of patients in each group with sustained clinical response during follow-up. Log-rank test was used to compare hazard rates between the 2 groups. At risk indicates patients who continued treatment in either group at given time points while demonstrating sustained clinical response. (C) Sustained clinical benefit stratified by concomitant use of corticosteroids. Filled diamonds and open triangles indicate patients without and with corticosteroid therapy at baseline, respectively, who discontinued treatment throughout follow-up. The curves indicate the proportion of patients with a sustained clinical response during follow-up. Log-rank test was used to compare hazard rates between the 2 groups. At risk indicates patients who continued treatment in either group at given time points while demonstrating a sustained clinical response. (D) Sustained clinical benefit stratified by normalization of CRP levels by week 4 in patients with an increased baseline CRP level. Filled diamonds and open triangles indicate patients with and without CRP normalization, respectively, who discontinued treatment throughout follow-up. The curves indicate the proportion of patients with sustained clinical response during follow-up. Log-rank test was used to compare hazard rates between the 2 groups. At risk indicates patients who continued treatment in either group at given time points while demonstrating a sustained clinical response. ADA, adalimumab; CS, corticosteroids; IMS; immunomodulator; TR, trough serum concentration.