Adalimumab Dose Intensification Research Articles

P478 The role of proactive measurement of adalimumab trough levels and antibodies to adalimumab in Greek patients with Inflammatory Bowel Disease

Abstract Background Therapeutic drug monitoring (TDM) of adalimumab trough levels (ADA-TLs) and antibodies to adalimumab (ADA-Abs) in patients with inflammatory bowel disease (IBD) is usually performed in a reactive setting when the disease flares. There is not enough evidence in favor of proactive TDM in these patients. Methods We aimed to evaluate the role of proactive measurement of ADA-TLs and ADA-Abs in IBD patients under treatment with adalimumab. Consecutive IBD patients on maintenance treatment with ADA, were included. ADA-TLs and Abs were measured using ELISA (Immunoguide, Aybayteche, Turkey) on serum samples drawn before ADA administration. At the same time serum biomarkers [Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cells (WBC), hemoglobin (Hgb), platelets (PLT)] as well as home-based fecal calprotectin (FC) ±3 months from blood sampling were assessed. After the measurements patients were followed and treatment changes made were recorded. Results A total of 52 patients receiving ADA maintenance therapy [48 CD, 4 UC, 31 males, mean age (±SD) 42.1±12.6 years, 8 on combination therapy with immunomodulators (IMMs), 23 under intensified dose (either 40mg/w or 80mg/2w)] were included. Median (IQR) time since ADA initiation was 31 (17.5–38.5) months and median value (IQR) of serum ADA-TLs was 8.24 μg/ml (3.32–10.02). Five out 52 (9.6%) were positive for ATIs (>3 AU/ml). Patients with positive Abs had median (IQR) ADA-TLs 0.41 μg/ml (0.10–0.71) statistically lower compared to those with negative Abs [8.86μg/ml (5.6–10.0) (p=0.0004)]. The correlations of ADA-TLs with disease characteristics, treatment and biomarkers in IBD patients are presented in Table 1. Elevated CRP was negatively associated with ADA-TLs. No other significant correlations were observed except a trend towards significance for body mass index (BMI) and ADA treatment duration (both p=0.09). After a median (IQR) follow up of 15 (11.5–16) months treatment optimization became necessary in 4 patients (8%) [adalimumab dose intensification in 2, change to a clinical trial medication in 1 and 1 underwent surgery] who initially had significantly lower ADA-TLs than the rest patients [median (IQR) ADA-TLs 0.51μg/ml (0.26-5.09-10.04) vs 8.62 (4.48–10.04); p=0.0362]. Conclusion Proactive measurement of ADA-TLs and Abs in patients under maintenance treatment with adalimumab may be worth using along with other parameters in the management of IBD patients. Additional long term research in larger populations focused on the optimal use of proactive TDM is needed.

Adalimumab Dose Intensification in Recalcitrant Hidradenitis Suppurativa/Acne Inversa

Background: Adalimumab is the only approved compound for the treatment of adult patients with moderate-to-severe hidradenitis suppurativa (HS) who did not respond to a systemic classical treatment. Despite its significant short- and long-term efficacy, a percentage of patients do not respond sufficiently. Moreover, some primary responders experience a response loss with time. Objective: To analyse the effectiveness of adalimumab dose intensification in HS patients. Methods: A case series of adalimumab 80 mg/week subcutaneously (s.c.) compassionate use in patients with HS, who did not respond sufficiently or in primary responders with progressive response loss to the registered adalimumab dose of 40 mg/week s.c. Patients were collected and evaluated retrospectively. Patients’ data were extracted from medical records. Results: The 14 patients collected were Caucasian with HS of Hurley stage II–III and moderate or severe International HS Severity Score System (IHS4) stage. Adalimumab dose intensification significantly improved IHS4 score, Pain Index, HS-Physician Global Assessment, pain, and Cardiff Dermatology Life Quality Index. Two young female patients with HS and Crohn’s disease developed psoriatic lesions during the treatment with adalimumab 80 mg/week s.c. Conclusion: An enhanced level of effectiveness was assessed in the majority of the HS patients treated with adalimumab dose intensification (80 mg/week s.c.). Larger studies are required to evaluate this observation.

Mo1850 - Lower Need for Adalimumab Dose Intensification in Inflammatory Bowel Disease Patients with Combined Immune Suppression Compared with Adalimumab Monotherapy

Mo1850 - Lower Need for Adalimumab Dose Intensification in Inflammatory Bowel Disease Patients with Combined Immune Suppression Compared with Adalimumab Monotherapy

P048 HISTORY OF CYTOMEGALOVIRUS COLITIS IS ASSOCIATED WITH POOR LONG-TERM OUTCOMES IN ADALIMUMAB THERAPY IN KOREAN PATIENTS WITH ULCERATIVE COLITIS: A HOSPITAL-BASED COHORT STUDY

Studies regarding long-term outcomes of adalimumab treatment in non-Caucasian patients with ulcerative colitis (UC) are still lacking. We analyzed long-term outcomes of Korean UC patients on adalimumab treatment in Asan Medical Center, Korea. Between July 2013 and June 2017, adalimumab treatment was commenced on in 72 patients; 49 males (68.1%), median age 40.5 years (Interquartile range [IQR], 24.25–50.00), and median disease duration 39.5 months (IQR, 22.00–85.00) at initiation of adalimumab. Twelve patients (16.7%) had a history of cytomegalovirus colitis within 3 months prior to starting adalimumab. Median duration of adalimumab therapy was 10.50 months (IQR, 2.00–26.75). Seventeen out of 72 patients (23.6%) were primary non-responders, and 7 out of those (9.7%) finally received colectomy. Out of 55 patients who received scheduled adalimumab maintenance therapy, 9 (16.4%) and 3 (5.5%) stopped adalimumab treatment due to loss of response and patients’ preference for discontinuation/loss to follow-up, respectively. Adalimumab dose intensification was required in 22 (40.0%) and corticosteroid rescue therapy was needed in 15 (27.3%) out of 55 patients during adalimumab maintenance therapy. The cumulative proportion of patients without adalimumab discontinuation was 61.0% at 1 year and 56.5% at 3 years among 72 patients who received adalimumab treatment more than once, and 80.1% at 1 year and 74.1% at 3 years among 55 patients who received adalimumab maintenance therapy. History of cytomegalovirus colitis within 3 months prior to starting adalimumab treatment was turned to be a predictor of adalimumab discontinuation (hazard ratio, 3.976; 95% confidence interval, 1.149–13.755; p = 0.029). Long-term outcomes of adalimumab treatment in Korean UC patients appears to be comparable to Western studies. Furthermore, a recent history of cytomegalovirus colitis was a predictor for adalimumab discontinuation.

P706 Lower need for adalimumab dose intensification in IBD patients treated with combined immune suppression compared with adalimumab monotherapy

P706 Lower need for adalimumab dose intensification in IBD patients treated with combined immune suppression compared with adalimumab monotherapy

P048 HISTORY OF CYTOMEGALOVIRUS COLITIS IS ASSOCIATED WITH POOR LONG-TERM OUTCOMES IN ADALIMUMAB THERAPY IN KOREAN PATIENTS WITH ULCERATIVE COLITIS: A HOSPITAL-BASED COHORT STUDY

Studies regarding long-term outcomes of adalimumab treatment in non-Caucasian patients with ulcerative colitis (UC) are still lacking. We analyzed long-term outcomes of Korean UC patients on adalimumab treatment in Asan Medical Center, Korea. Between July 2013 and June 2017, adalimumab treatment was commenced on in 72 patients; 49 males (68.1%), median age 40.5 years (Interquartile range [IQR], 24.25-50.00), and median disease duration 39.5 months (IQR, 22.00-85.00) at initiation of adalimumab. Twelve patients (16.7%) had a history of cytomegalovirus colitis within 3 months prior to starting adalimumab. Median duration of adalimumab therapy was 10.50 months (IQR, 2.00-26.75). Seventeen out of 72 patients (23.6%) were primary non-responders, and 7 out of those (9.7%) finally received colectomy. Out of 55 patients who received scheduled adalimumab maintenance therapy, 9 (16.4%) and 3 (5.5%) stopped adalimumab treatment due to loss of response and patients’ preference for discontinuation/loss to follow-up, respectively. Adalimumab dose intensification was required in 22 (40.0%) and corticosteroid rescue therapy was needed in 15 (27.3%) out of 55 patients during adalimumab maintenance therapy. The cumulative proportion of patients without adalimumab discontinuation was 61.0% at 1 year and 56.5% at 3 years among 72 patients who received adalimumab treatment more than once, and 80.1% at 1 year and 74.1% at 3 years among 55 patients who received adalimumab maintenance therapy. History of cytomegalovirus colitis within 3 months prior to starting adalimumab treatment was turned to be a predictor of adalimumab discontinuation (hazard ratio, 3.976; 95% confidence interval, 1.149-13.755; p = 0.029). Long-term outcomes of adalimumab treatment in Korean UC patients appears to be comparable to Western studies. Furthermore, a recent history of cytomegalovirus colitis was a predictor for adalimumab discontinuation.

Response to Ustekinumab in a Patient with Severe Psoriasis when Adalimumab Dose Escalation Fails

Objectives: To report a case of response to ustekinumab in a patient with severe psoriasis when adalimumab dose escalation fail.Case Description: A 35-year-old Caucasian male was diagnosed as having psoriasis. He was started on methotrexate followed cyclosporine. Despite these treatments, the patient experienced an abrupt deterioration of his psoriasis [PASI 35]. The patient started treatment with adalimumab: initial dose of 80mg followed by 40mg in week 2. At week 3 he continued on adalimumab 40mg/two weeks with significant reduction of psoriasis. After 8 months of adalimumab therapy, he referred that adalimumab was effective only during the first week of treatment. The patient gave his written informed consent for adalimumab dose intensification. He started adalimumab 40mg/week, with an improvement of psoriasis. After 7 months of adalimumab dose intensification, the psoriasis worsened [PASI score =25 and CDLQI score 20]. We discontinued adalimumab and started therapy with ustekinumab, 45mg subcutaneously, was administered at weeks 0, 4 and every 12 weeks. The clinical response was impressive; at week 12 a PASI 90 response was achieved while the CDLQI score fell to the scale of 7. Efficacy was maintained after a 12 months of ustekinumab therapy.Conclusions: This case report provides valuable insight into the efficacy and tolerability of ustekinumab in a patient with severe psoriasis when adalimumab dose escalation fails. To our knowledge this is the first case published to date that describes the clinical efficacy of ustekinumab when adalimumab intensification dose escalation fails.

Adalimumab in prevention of postoperative recurrence of Crohn's disease in high-risk patients

To evaluate the effectiveness of adalimumab in preventing recurrence after intestinal resection for Crohn's disease in high-risk patients. A multicenter, prospective, observational study was conducted from June 2009 until June 2010. We consecutively included high-risk Crohn's disease patients who had undergone an ileal/ileocolonic resection. High-risk patients were defined as two or more criteria: smokers, penetrating pattern, one or more previous surgical resections or prior extensive resection. Subcutaneous adalimumab was administered 2 wk (± 5 d) after surgery at a dose of 40 mg eow, with an initial induction dose of 160/80 mg at weeks 0 and 2. Demographic data, previous and concomitant treatments (antibiotics, 5-aminosalicylates, corticosteroids, immunomodulators or biologic therapies), smoking status at the time of diagnosis and after the index operation and number of previous resections (type and reason for surgery) were all recorded. Biological status was assessed with C-reactive protein, erythrocyte sedimentation rate and fecal calprotectin. One year (± 3 mo) after surgery, an ileocolonoscopy and/or magnetic resonance enterography was performed. Endoscopic recurrence was defined as Rutgeerts score ≥ i2. Morphological recurrence was based on magnetic resonance (MR) score ≥ MR1. Twenty-nine patients (55.2% males, 48.3% smokers at diagnosis and 13.8% after the index operation), mean age 42.3 years and mean duration of the disease 13.8 years were included in the study. A mean of 1.76 (range: 1-4) resections previous to adalimumab administration and in 37.9% was considered extensive resection. 51.7% had previously received infliximab. Immunomodulators were given concomitantly to 17.2% of patients. Four of the 29 (13.7%) developed clinical recurrence, 6/29 (20.7%) endoscopic recurrence and 7/19 (36.8%) morphological recurrence after 1-year. All patients with clinical recurrence showed endoscopic and morphological recurrence. A high degree of concordance was found between clinical-endoscopic recurrence (κ = 0.76, P < 0.001) and clinical-morphological recurrence (κ = 0.63, P = 0.003). Correlation between endoscopic and radiological findings was good (comparing the 5-point Rutgeerts score with the 4-point MR score, a score of i4 was classified as MR3, i3 as MR2, and i2-i1 as MR1) (P < 0.001, r(s) = 0.825). During follow-up, five (17.2%) patients needed adalimumab dose intensification (40 mg/wk); Mean time to intensification after the introduction of adalimumab treatment was 8 mo (range: 5 to 11 mo). In three cases (10.3%), a biological change was needed due to a worsening of the disease after the dose intensification to 40 mg/wk. One patient suffered an adverse event. Adalimumab seems to be effective and safe in preventing postoperative recurrence in a selected group of patients who had undergone an intestinal resection for their CD.

Loss of Response and Need for Adalimumab Dose Intensification in Crohn's Disease: A Systematic Review

The objective of this study was to review loss of response and need for adalimumab dose intensification in adult and pediatric patients with Crohn's disease. Studies were identified through the electronic databases of MEDLINE and the annual meetings of Digestive Disease Week, of the United European Gastroenterology Week, and of the American College of Gastroenterology and the European Crohn's and Colitis Organization meetings. Studies evaluating loss of efficacy and/or need for dose intensification were included. Thirty-nine studies were included. The mean percentage of loss of response to adalimumab among primary responders was 18.2% and the annual risk was 20.3% per patient-year. The mean percentage of patients who required dose intensification among primary responders to adalimumab was 37% and the annual risk was 24.8% per patient-year. When considering initial responders and patients with primary non-response, the mean percentage of patients who needed an adalimumab dose escalation was 21.4% and the annual risk was 24.4% per patient-year. Pooled analysis showed that dose escalation permitted response to be regained in 71.4% and remission in 39.9% of patients. Predictors for loss of response or dose escalation were male gender, current/former smoker status, family history of inflammatory bowel disease, isolated colonic disease, extra-intestinal manifestations, 80/40 mg induction therapy, longer disease duration, greater baseline Crohn's Disease Activity Index, concomitant corticosteroid use, no deep remission at week 12, low serum trough concentrations of adalimumab, previous infliximab non-response and being previously treated with an anti-tumor necrosis factor agent. Overall, around one fifth of adult patients require dose intensification and experience a loss of response after initiation of adalimumab therapy. Adalimumab dose escalation permits response to be regained in the majority of patients.