Adalimumab Dose Research Articles

Outcomes of Continuation vs Discontinuation of Adalimumab Therapy During Third Trimester of Pregnancy in Inflammatory Bowel Disease.

Adalimumab (ADA) transport across the placenta increases with gestational age advances. We evaluated child-mother health outcomes related to the timing of the last ADA dose before delivery. Using IBM MarketScan data, we collected records for all children exposed to ADA during intrauterine life. We compared milestone achievements, congenital malformations, and respiratory infections rates in children from mothers of 2 groups: (1) a late ADA group, which continued therapy until 90 days or fewer before delivery; and (2) an early ADA group, which discontinued therapy more than 90 days before delivery. We also assessed the risk of flaring for mothers in the early group. There were no significant differences in growth (P= .48), developmental delays (P= .25), or congenital malformations (P= .61) in the 427 children of the late group vs 70children of early ADA group. Continuing ADA late in pregnancy did not increase the respiratory infection rate (P= .38). No differences occurred between groups in cesarean and premature delivery, intrauterine growth retardation, and stillbirths. ADA discontinuation was the only predictor of flaring in the third trimester of pregnancy (odds ratio= 6.04, 95% confidence interval 2.66-13.7). In the late group, mothers' risk of flaring decreased (16/447 vs 13/73, P < .001). Mothers with active disease were more likely to deliver prematurely vs mothers with quiet disease (6/29 vs 31/491, P= .003). Continuation of ADA in pregnancy close to delivery is of low risk for children. Early discontinuation, however, increases the risk of flaring in mothers and the likelihood of premature deliveries.

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

P300 Crohn’s Disease Strictures Respond to Drug Treatment and Treat-to-Target Intense Combination Therapy is More Effective than Standard Anti-TNF Therapy. The STRIDENT Randomised Controlled Trial

Abstract Background Strictures are the commonest complication in Crohn’s disease. Surgery and endoscopic dilation are the main treatments; drug therapy has been considered contra-indicated. Given that most strictures have an inflammatory component we aimed to assess the efficacy of anti-inflammatory therapy, and to identify the optimal treatment. Methods In this randomised trial patients with symptomatic Crohn’s disease strictures and inflammation were assessed by imaging (MRI, colonoscopy, intestinal ultrasound) and for inflammation (faecal calprotectin and CRP). Symptoms were assessed using an Obstructive Symptom Score (OSS). Patients with short endoscopically-accessible strictures had a baseline endoscopic balloon dilation if indicated. Patients were then randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) with 40mg fortnightly maintenance plus thiopurine, with therapy increased for ongoing inflammation at 4 and 8 months, versus standard dose adalimumab mono-therapy. At 12 months primary endpoint was improved OSS. Secondary outcomes: disease activity, treatment failure, stricture morphology, inflammation, psychological well-being, disability, and quality of life. MRI was assessed blindly. Results 52 patients were randomised to the intensive and 25 to the standard treatment arm. 27 of 52 (52%) intensive treatment patients dose escalated at 4 or 8 months. Improved OSS at 12 months occurred in 41 (79%) intensive treatment and 16 (64%) standard treatment arms (P=0.17). Treatment failure was less common in the intensive treatment arm (10%) versus the standard treatment arm (28%) (P=0·045). Faecal calprotectin normalised (&amp;lt;100mcg/g) in 32 (62%) v 11 (44%) (P=0.15), and CRP normalised in 32 (62%) v 11 (44%) (P=0.15), in intensive versus standard treatment arms respectively. MRI stricture morphology improvement (MaRIA score decrease ≥25%) was seen in 31 (61%) v 9 (28%) (P=0.009) and in 40 (78%) v 14 (56%) using the simplified MaRIA score (≥1 point improvement) (P=0.047). Improvement in bowel wall thickness by &amp;gt;25% on ultrasound was seen in 22/43 (51%) and 7/21 (33%) respectively (P=0.18). MRI complete stricture resolution was seen in 10/51 (20%) and 4/25 (16%) (P=0.7). At 12 month colonoscopy 22/48 (46%) v 9/25 (36%) strictures were passable (P=0.42). 12 month median drug levels were 13.2µg/ml and 6.6µg/ml respectively (P&amp;lt;0.0001). See summary results figure 1 and case example figure 2. Conclusion Crohn’s disease strictures are responsive to drug therapy. A majority of patients experience symptom improvement and many have improved stricture morphology. Treat-to-target therapy intensification results in less treatment failure, less stricture-associated inflammation, and greater improvement in stricture morphology.

P399 Higher anti-tumour necrosis factor-alpha drug levels are associated with improved radiological outcomes in patients with perianal fistulising Crohn’s disease: A retrospective multi-centre study

Abstract Background Higher anti-tumour necrosis factor-α (TNF) drug levels are associated with improved clinical fistula healing and closure in perianal fistulising Crohn’s disease (pfCD). It is hypothesised that higher drug levels will lead to improved healing on magnetic resonance imaging (MRI); but this is yet to be established. This study evaluated the association between anti-TNF drug levels and radiological outcomes in pfCD. Methods A multi-centre retrospective study (FISCAL), across 10 ANZ Inflammatory Bowel Disease Consortium sites. Patients with pfCD on stable maintenance dosing of infliximab or adalimumab, with drug levels within 6-months of a pelvic MRI from 2010 to 2020 were included. Patients receiving perianal fistula surgery between drug level and MRI were excluded. MRI disease activity was scored using the Van Assche Index (VAI), with an inflammatory sub-score (VAIinfl) derived from the VAI indices: hyperintensity on T2-weighted images, collections &amp;gt;3mm diameter, and rectal wall involvement. Primary endpoint was radiological healing (VAIinfl≤6). Secondary endpoint was radiological remission (VAIinfl=0). Drug level tertiles were correlated to changes in VAIinfl scores. ROC analyses were used to identify optimal target drug levels. Results Of 193 patients (infliximab, n=117; adalimumab, n=76), radiological healing was achieved in 47.0 and 44.7% and radiological remission in 17.1 and 15.8% of patients receiving infliximab and adalimumab, respectively. Patients with radiological healing had higher median drug levels compared to those with radiologically active disease (infliximab 6.0 vs 3.9µg/mL, P=0.03; adalimumab 9.1 vs 6.2µg/mL, P=0.02). Patients with radiological remission had higher median drug levels compared to those with radiologically active disease (infliximab 7.4 vs 3.9µg/mL, P&amp;lt;0.01; adalimumab 9.8 vs 6.2µg/mL, P=0.07). There was a significant incremental reduction in median VAIinfl with higher anti-TNF drug level tertiles, shown in Figure 1. By ROC analyses, the optimal trough infliximab levels for radiological healing and remission were 4.0µg/mL (sensitivity 69.1%, specificity 45.2%, AUC 0.62, P=0.03) and 6.5µg/mL (sensitivity 60.0%, specificity 72.2%, AUC 0.67, P=0.02), respectively. The optimal adalimumab levels for radiological healing and remission were 7.2µg/mL (sensitivity 67.6%, specificity 59.5%, AUC 0.65, P=0.03) and 9.7µg/mL (sensitivity 58.0%, specificity 70.0%, AUC 0.62, P=0.20), respectively. Conclusion In the largest study of its kind, higher anti-TNF drug levels were associated with improved MRI parameters as per the VAI in patients with pfCD; with an incremental improvement in MRI outcomes at higher anti-TNF drug level tertiles for both infliximab and adalimumab. Replication in prospective studies are awaited.

P585 IBD Reference and Biosimilar adalimumab CroSS over Study (iBaSS): a mixed methods clinical trial of patients transitioning between originator and biosimilar adalimumab. Qualitative findings from an interim analysis presenting the patient perspective

Abstract Background iBaSS is a phase IV single-centre, prospective, randomised, single-blind, cross-over study in adults with Crohn’s disease. 112 participants have been recruited from patients attending the IBD clinic for routine treatment. Eligibility criteria included mHBI &amp;lt; 8, stable on Humira™ or Imraldi™ with no expectation to discontinue or adjust adalimumab (ADA) dosing in the study period. The pragmatic study design mimics the optimal care pathway of patients transitioning between originator and biosimilar ADA, allowing all participants to experience both. Such transitions are part of routine clinical practice but with little understanding of the patient perspective. As part of iBaSS we capture the patient perspective and experience of transition, with the aim of informing future practice. Methods Purposive sampling was used to capture a wide range of perspectives from a subset of the participants treated with the originator ADA at enrolment. Interviews were semi-structured, using open-ended questions, facilitated by a topic guide developed with reference to published literature. Interviews were recorded, transcribed and analysed using thematic analysis. Thirty five participants were interviewed. Results Five themes were identified: (1) understanding and awareness of biosimilars, (2) motivation to undertake transition, (3) initial concerns, (4) reassuring factors and (5) reflection of experience. Opinions expressed were often heterogeneous, but commonly-occurring experiences were also identified. Prior awareness of biosimilars and knowledge of the biosimilar concept was low indicating a disparity between healthcare professionals and patients. Patients accept a biosimilar transition to minimise drug expenditure. Prior to undertaking biosimilar transition away from the brand they had experienced, efficacy and adverse effects were common concerns for patients. Trust in the healthcare team is critical to patient acceptance of biosimilars and important reassurances include a point of contact, education about biosimilars and specific monitoring. When reflecting on the experience, participants noted little subjective difference in efficacy or tolerability (although 22 participants specifically mentioned injection pain) following brand transition and the majority feel comfortable with future transition to another ADA biosimilar. Injection experience is important in patient satisfaction. Conclusion While biosimilars have driven a reduction in drug acquisition costs, the majority of patients have little knowledge and some concerns about transitioning to a biosimilar but accept the principles and can be reassured. The wide-ranging views elucidated suggest that a tailored, patient-centred approach is key to successful implementation.

Association of adalimumab trough concentrations and treatment response in patients with juvenile idiopathic arthritis

To assess the relationship of adalimumab trough concentrations and treatment response in paediatric patients with juvenile idiopathic arthritis (JIA). Monocentric cohort study of JIA patients treated with adalimumab. Clinical data and samples were collected during routine follow-up. Adalimumab trough concentrations were quantified by a novel liquid chromatography-tandem mass spectrometry assay. Anti-adalimumab antibodies were measured in samples with trough concentrations ≤5mg/l. Disease activity was evaluated using the clinical Juvenile Arthritis Disease Activity Score with 71 joint-count (cJADAS71). Response to adalimumab was defined according to recent international treat-to-target guidelines. 35 adalimumab trough samples were available from 34 paediatric patients with JIA. Although there was no significant difference in adalimumab dose, trough concentrations were significantly lower in patients with secondary failure (median 1.0 mg/l; IQR 1.0-5.3) compared with patients with primary failure (median 13.97 mg/l; IQR 11.81-16.67) or an adequate response (median 14.94 mg/l; IQR 10.31-16.19) to adalimumab. Adalimumab trough concentrations were significantly lower in JIA patients with secondary failure compared with patients with primary failure or an adequate response to adalimumab. Results suggest that trough concentration measurements could identify JIA patients who require increased adalimumab doses to achieve or maintain therapeutic drug concentrations.

The influence of adalimumab treatment on the systemic gene expression in patients with psoriatic arthritis - preliminary report.

The primary goal of psoriasis treatment is to reduce the inflammatory response and associated complications. In severe cases of psoriasis that are resistant to local treatment (e.g., keratolytic preparations) and at least two types of general treatment methods (e.g., retinoids and cyclosporine A), biological therapy is used. This study aimed to assess the systemic effects of adalimumab at a given stage of treatment in patients with psoriatic arthritis and evaluate how the drug can improve the clinical condition of the patients. The study group consisted of patients with diagnosed psoriatic arthritis, while the control group consisted of individuals from whom peripheral blood mononuclear cells were obtained. The effects of the administration of adalimumab were assessed by analyzing the gene expression using oligonucleotide microarrays. The apoptosis process was found to be one of the overrepresented categories (the PANTHER classification system 13.1 program, overrepresentation test, p < 0.05). The dermatological indexes decreased, indicating an improvement in the clinical conditions of the patients 3 months after the first dose of adalimumab. We found that adalimumab affects apoptosis, which is crucial in the development and course of psoriasis. The differential gene expression in peripheral blood mononuclear cells of patients with psoriatic arthritis indicated the potential systemic effects of adalimumab therapy. The analyses of dermatological (the Psoriasis Area and Severity Index, body surface area and Dermatology Life Quality Index) and inflammatory (Biernacki's reaction) parameters revealed the effectiveness of the therapy.

Comprehensive evaluation of microneedle‐based intradermal adalimumab delivery vs. subcutaneous administration: results of a randomized controlled clinical trial

AimsTo evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle.MethodsIn this single‐centre double‐blind, placebo‐controlled, double‐dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography, clinical photography, thermal imaging, and laser speckle contrast imaging to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device.ResultsWhile feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 100‐point visual analogue scale). Initial absorption rate and relative bioavailability were higher after i.d. adalimumab (time to maximum plasma concentration = 95 h [47–120]; Frel = 129% [6.46%]) compared to s.c. adalimumab (time to maximum plasma concentration = 120 h [96–221]). Anti‐adalimumab antibodies were detected in 50% and 83% of the subjects after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (P < .0001). Cytokine secretion after whole blood lipopolysaccharide challenge was comparable between administration routes.ConclusionsIntradermal injection of adalimumab using hollowing microneedles was perceived as more painful and less accepted than s.c. administration, but yields a higher relative bioavailability with similar safety and pharmacodynamic effects.

Real-world experience of adalimumab in the treatment of hidradenitis suppurativa

Real-world experience of adalimumab in the treatment of hidradenitis suppurativa

Immunogenicity of Tumor Necrosis Factor Antagonists and Effect of Dose Escalation on Anti-Drug Antibodies and Serum Drug Concentrations in Inflammatory Bowel Disease.

Infliximab and adalimumab concentrations are associated with important outcomes in inflammatory bowel disease (IBD). Antibodies to infliximab (ATI) and adalimumab (ATA) are associated with reduced drug concentrations and worse outcomes. Because the efficacy of dose escalation to overcome antibodies is unclear, we assessed the impact of this strategy to overcome immunogenicity in IBD. Infliximab and adalimumab dosing, drug, and antibody concentrations were extracted from a database of patients with IBD having specimens collected for therapeutic drug monitoring. The primary outcome compared proportions with either infliximab ≥5 μg/mL or adalimumab ≥7.5 μg/mL and undetectable antibodies between dose-escalated and non-escalated patients. Area under the receiver operating characteristic curve analyses determined antibody concentrations below which dose escalation was associated with the primary outcome. The study included 63,176 patients treated with infliximab and 46,429 patients treated with adalimumab. We detected ATI and ATA in 23.6% (n = 14,900) of patients treated with infliximab and 19.6% (n = 9101) of patients treated with adalimumab. In patients with ATI, infliximab dose escalation (n = 453) yielded higher proportions achieving the primary outcome (47.5% vs 30.9%; P < 0.001), greater drug concentration increases (5.9 μg/mL vs 0.2 μg/mL; P < 0.001), and ATI reductions (4.3 U/mL vs 1.9 U/mL; P = 0.002) compared to no escalation (n = 204). An ATI threshold of 8.55 U/mL was associated with achieving the primary outcome with dose escalation (area under the curve = 0.66). For patients with ATI ≤8.55 U/mL (n = 274), higher proportions (59.1% vs 29.6%; P < 0.001) achieved the primary outcome compared with those with ATI >8.55 U/mL (n = 179). No patients treated with adalimumab achieved the primary outcome (0/390), regardless of dose escalation (n = 87). Dose escalation increased drug concentrations and eliminated antibodies with infliximab but not adalimumab. Initial ATI ≤8.55 U/mL was associated with increased efficacy of dose escalation using this assay.

Adalimumab Increases Follicle Reserve and Follicle Development in Rat Ovary: The Effect of Adalimumab on Ovarian Reserve.

IntroductionAdalimumab is used in the treatment of many chronic inflammatory diseases, especially rheumatoid arthritis. The aim of this experimental study is to determine the histological and biochemical effects of adalimumab on rat ovary.MethodsWistar albino female rats were randomly divided into three groups prior to the experiment: a healthy control group, a 2 mg/kg adalimumab group, and a 5 mg/kg adalimumab group. Then, histopathological findings and biochemical examinations were made in the ovaries of the rats. Hematoxylin-eosin staining, morphometric examination, and Masson trichrome staining were performed. Antimullerian hormone (AMH) levels were measured in the biochemical examination.ResultsOvarian follicle count and AMH level were significantly higher in the groups given low-dose adalimumab and high-dose adalimumab (p <0.001). In addition, fibrosis decreased in proportion to the dose of adalimumab (p <0.001).ConclusionAdalimumab is an important biological agent that contributes to the preservation of ovarian function by increasing ovarian follicle reserve and has shown that it can help preserve ovarian reserve in women of reproductive age suffering from chronic inflammatory diseases.

Discontinuing adalimumab in patients with controlled juvenile idiopathic arthritis-associated uveitis (ADJUST\u2014Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial): study protocol for a randomised controlled trial

BackgroundJuvenile idiopathic arthritis (JIA)-associated uveitis is a chronic paediatric ocular inflammatory condition that can result in visual impairment. Adalimumab, a tumour necrosis factor (TNF)-alpha inhibitor, effectively controls joint and eye inflammation; however, its long-term use may increase the risk of adverse health outcomes and place an undue financial burden on the patient and healthcare system given its high cost. There is great interest for patients to stop adalimumab following remission due to these reasons but there is a lack of information on the ability to maintain control after discontinuing adalimumab.MethodsThe Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Trial (ADJUST) is a multicentred, international trial that will randomise 118 participants aged 2 years and older with controlled JIA-associated uveitis to either continue adalimumab or discontinue adalimumab and receive a placebo. The trial will compare the time to uveitis recurrence between the two groups over 12 months. All participants will receive the standard weight-based dose of adalimumab or placebo: 20 mg biweekly (if < 30 kg) or 40 mg biweekly (if ≥ 30 kg).DiscussionThis is the first randomised controlled trial to assess the efficacy of discontinuing adalimumab after demonstrating control of JIA-associated uveitis for at least 12 months. The results of ADJUST will provide information on clinical outcomes to guide clinicians in their decision-making regarding discontinuation of adalimumab.Trial registrationClinicalTrials.gov NCT03816397. Registered on 25 January 2019. EudraCT 2019-000412-29. Registered on 17 January 2019

S2278 What Happens When SARS-COV2 Infection Overlaps With Administration of Anti-TNF Therapy in an IBD Patient?

INTRODUCTION: COVID-19 is now a global pandemic and immunosuppression is widely suspected to be a risk factor for more severe outcomes. We present a worst-case scenario of COVID-19 establishing itself at the time of maintenance administration of anti-TNF therapy in a patient. CASE DESCRIPTION/METHODS: The patient is a 60-year-old female with a history of Rheumatoid Arthritis, Systemic Lupus Erythematosus, and ileocolonic inflammatory Crohn’s disease in remission on weekly adalimumab and methotrexate. She presented to the emergency department (ED) with one day of fevers and generalized myalgias and was discharged home with a diagnosis of influenza-like illness. She was asked to quarantine pending COVID-19 test results, which returned positive three days later. Her last dose of adalimumab was administered 5 days prior and methotrexate 7 days prior. The next day she developed gastrointestinal symptoms including diarrhea, nausea, emesis, and abdominal cramping, not consistent with her usual Crohn’s flares. She also noted new onset shortness of breath and returned to the ED. Vitals were Tmax 101.1F, BP 152/80, HR 109, RR 17, O2 Sat 99% on room air. CT scan of chest and abdomen revealed patchy lung consolidations, and colitis in the proximal sigmoid colon. Clostridium difficile stool test was negative, fecal calprotectin was normal at 19. She was treated with our COVID-19 hospitalization protocol, which consisted of hydroxychloroquine, azithromycin, and ascorbic acid. Supplemental oxygen was required for two days. She defervesced after day 4 of hospitalization and was discharged after day 5. DISCUSSION: This case provides some of the details in regard to timing of infection and administration of immunosuppressive therapy. Theoretically, immunosuppressed inflammatory bowel disease (IBD) patients are at the highest risk for morbidity and mortality from COVID-19. SARS-CoV-2 has an average incubation period of five days, we estimate our patient administered adalimumab and methotrexate during the pre-symptomatic post infection period (Figure 2). Although we expected her condition would deteriorate, within two days she improved with interventions recently shown to have no benefit in the treatment of COVID-19. We hypothesize that the adalimumab may have interfered with COVID-19’s aberrant immune response, leading to a less severe disease course. We are hopeful this case and additional outcomes studies will help clarify concerns about immunosuppressed populations during the pandemic.Table 1.: Laboratory TrendFigure 1.: CT ABDOMEN AND PELVIS.Figure 2.: TIMELINE.

S0881 Therapeutic Drug Monitoring Dosing Regimen With Adalimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the SERENE-UC Maintenance Study

INTRODUCTION: Adalimumab(ADA) is efficacious and well tolerated in adults with ulcerative colitis(UC).1,2 SERENE-UC evaluated higher ADA dosing regimens for induction and maintenance in UC. Results of fixed-dosed maintenance arms were previously reported.3,4 We report outcomes of adjusting ADA dosing based on proactive monitoring of ADA serum levels and symptoms in the therapeutic drug monitoring(TDM) exploratory maintenance arm. METHODS: SERENE-UC was a Phase 3 study in adults with moderately to severely active UC. Following completion of induction study at Week (Wk) 8, all patients (pts) were re-randomized 2:2:1 to 44 wks of maintenance therapy with either ADA 40 mg every week (40EW), every other week (40EOW), or exploratory TDM regimens. Pts were stratified by induction regimen, clinical response status and clinical remission (CRem) status at Wk8 among Wk8 responders. All pts in TDM arm received ADA 40 mg at Wk8 and Wk10. Pts meeting dose-adjustment criteria(Rectal Bleeding Subscore ≥1 and/or ADA serum concentration < 10 μg/mL) as measured at prior study visit, could escalate to 40EW followed by a single dose of 160 mg. Mayo score(endoscopic component) was scored via central reading. TDM regimen was exploratory, and only descriptive statistics were provided. Safety was also assessed. RESULTS: Overall, 757/852 pts completed induction and were re-randomized at Wk8; 151 pts were in TDM arm. At Wk52, 36.5% (n = 27/74) of Wk8 responders in TDM arm achieved CRem, while 23.2% (35/151) of all pts and 10.4% (8/77) of Wk8 non-responders receiving TDM were in CRem. Proportion of Wk8 responders completing Wk52 escalating to TDM 40EW increased over time (Table); at Wk52, 83.6% (46/55) of pts received 40EW. Mean(SD) serum drug levels at Wk52 for the TDM 40EW, TDM 40EOW, and TDM 160 mg to 40EW regimens were 19.0(8.2) μg/mL, 13.9(4.0) μg/mL, and 10.3(7.8) μg/mL, respectively. Of the 71 pts who had dose escalation, 65% (46/71) were driven solely by an ADA serum concentration of < 10 μg/mL (Table). Safety profile of TDM arm was consistent with EW and EOW maintenance arms4; rates of treatment-emergent infections and serious infections were 33.8% and 2.0%, respectively. CONCLUSION: The SERENE-UC TDM 44 wk maintenance exploratory arm showed majority of patients escalated ADA to 40 EW, driven mainly by ADA serum levels. No new long-term safety concerns observed in TDM maintenance arm. Observed safety profile was comparable with known EOW maintenance safety profile.4Table 1

The Case | Glomerulonephritis in a patient with rheumatoid arthritis

A 49-year-old man was referred to the hospital because of acute kidney injury. He was diagnosed with seronegative rheumatoid arthritis (RA) ∼2 years before admission owing to typical clinical symptoms and joint erosions in radiographs of hands and wrist. Of note, antinuclear antibodies and anti–double-stranded DNA antibodies were negative at this time point. He had received a single dose of adalimumab 2 months previously after experiencing intolerance to leflunomide and etanercept (3 doses). The patient reported only fatigue and calf pain and had not taken any nephrotoxic medications.

Point-of-Care Assays Could Be Useful for Therapeutic Drug Monitoring of IBD Patients in a Proactive Strategy with Adalimumab.

The objective of the study was to evaluate whether Point-of-Care (POC) assays are equivalent to ELISAs for measuring residual trough levels of adalimumab (ADA) in a cohort of Inflammatory Bowel Disease (IBD) patients. ADA trough levels obtained by POC assays were used to optimize patients in daily clinical practice. Different assays (three ELISAs (Enzyme-Linked ImmunoSorbent Assay) from two different suppliers and two POC assays) were compared to measure ADA trough levels in a first cohort of 31 IBD patients. All assays revealed a high correlation within the assays, ranging from 0.86 to 0.99. Cut-off values were always higher with ELISAs than with POC assays. Then, a small prospective clinical study with a second cohort of 37 IBD patients was performed to compare POC assays and ELISAs for their ability to optimize patients on the basis of the measured ADA trough levels. The use of a POC assay to monitor ADA trough levels did not improve the follow-up of patients with loss of response, as they were always optimized whatever their ADA residual rate. For patients in clinical remission, a POC assay can be useful in some clinical situations to maintain or de-escalate ADA doses according to the measured trough levels. In conclusion, different assays for ADA monitoring are quite equivalent. A POC assay could be only useful for a proactive strategy for asymptomatic patients with a sub-therapeutic dose of ADA, but new therapeutic thresholds need to be identified.

FRI0295 ADALIMUMAB LEVELS ARE ASSOCIATED WITH DRUG RETENTION RATES IN AXIAL SPONDYLOARTHRITIS PATIENTS

Background:Production of anti-drug antibodies (ADA) could cause low serum anti-TNF levels and low drug retention rates.Objectives:To assess the relationship between serum adalimumab (ADL) levels and drug retention rates in patients with axial SpA.Methods:Single-center prospective study in patients with axial SpA, according to ASAS criteria, being treated with ADL. In the first part of the study, from December 2010 to June 2016, data was collected and serum samples were taken. In a second part of the study, clinical records were reviewed to find out the dates and reasons of treatment discontinuation. Information was collected on age gender, body mass index (BMI), date of diagnosis of SpA, laboratory data, including HLAB27, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), prior biological treatment for SpA, concomitant conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). SpA disease activity was assessed by BASDAI, ASDAS and PGA scores. A serum sample was taken from all patients just before the next adalimumab dose. ADL and ADA levels were analysed with ELISA Promonitor®, (Proteomika, Progénica, Griffols) and correlated with SpA activity using BASDAI and ASDAS scores. Cox proportional hazards model was performed in order to assess the relation of variables with drug interruption.Results:Up to January 2016, 51 consecutive patients were included. The mean (range) age was 46,9 (18–68) and 47.1% were women. HLAB27 was positive in 82,4% of patients. Mean disease duration was 122,9 months (2-408) and mean duration of treatment with adalimumab was 17,8 months (1-69). ADL was the first biological agent received in 36 patients (70.6%). Eleven patients (21.6%) were on concomitant treatment with receiving concomitant csDMARDs, mainly methotrexate (MTX) (15.7%) and sulfasalazine (5.9%). The mean (SD) activity scores were BASDAI 4,0 ± 2,3; ASDAS-PCR 2,1 ± 1,1 and ASDAS-VSG 2,1 ± 1,0.ADA prevalence was 27.5%, with none detected in the 21.6% taking csDMARDs (p = 0.021). ADL level was normal (&gt; 3 mg/l) in 36 patients (70.6%), all without ADA. Fifteen patients (29.4%) had subtherapeutic ADL levels (&lt; 3 mg/l), with ADA in 14 (93%).Total ADL treatment time was 241,16 patient/years, and mean ADL treatment time was 4,73 years. Cox model results were resumed in table 1. Multivariate study show that ADL level &gt; 3 mg/L was a protective factor for ADL interruption (HR 0.01 (0.00-0.59, p=0.026), while previous etanercept treatment was a risk factor for ADL interruption 9.54 (1.23-74.08, p=0.031).Table 1.Cox model.ContinueDiscon=tinueUnivariateHRMultivariateHRADL level&lt;3 mg/L13 (86,7%)2 (13,3%)0.05 (0.00-0.65, p=0.022)0.01 (0.00-0.59, p=0.026)≥3 mg/L28 (77,8%)8 (22,2%)Concomitant DMARDYes8 (72,7%)3 (27,3%)0.56 (0.14-2.26, p=0.419)0.28 (0.05-1.65, p=0.159)No33 (82,5%)7 (17,5%)BMINormal13 (86,7%)2 (13,3%)2.56 (0.54-12.23, p=0.239)0.48 (0.02-9.75, p=0.634)Overweight/obese27 (77,1%)8 (22,9%)AgeMean (SD)46,4 (12,2)48,7 (11,6)0.93 (0.24-3.60, p=0.912)0.60 (0.10-3.84, p=0.594)GenderMen19 (70,4%)8 (29,6%)0.43 (0.09-2.03, p=0.283)0.58 (0.03-10.06, p=0.705)Women22 (91,7%)2 (8,3%)InfliximabpreviousYes4 (40,0%)6 (60,0%)3.31 (0.92-11.87, p=0.066)1.37 (0.23-8.24, p=0.731)No37(90,2%)4 (9,8%)EtanerceptpreviousYes2 (22,2%)7 (77,7%)8.17 (2.09-31.90, p=0.003)9.54 (1.23-74.08, p=0.031)No39 (92,9%)3 (7,1%)ADL: adalimumab; BMI: body mass index; DMARD: disease modifying antirheumatic drug; SD: standard deviation.Conclusion:Adalimumab drug levels &gt; 3 mg/L is a protective factor against treatment interruption.Etanercept previous treatment was a risk factor for treatment interruption.Acknowledgments:The study was supported by a grant from “Asociación para la Investigación en Reumatología de la Marina Baixa” (AIRE-MB).Disclosure of Interests:None declared

AB0802 SAFETY PROFILES OF IXEKIZUMAB VERSUS ADALIMUMAB: 52-WEEK RESULTS FROM A HEAD-TO-HEAD COMPARISON IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS

Background:Ixekizumab (IXE) was shown to be superior to adalimumab (ADA) in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with active psoriatic arthritis (PsA) and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).1Objectives:To compare the safety and tolerability profile of IXE vs ADA in patients with PsA up to 52 weeks of treatment.Methods:SPIRIT-H2H (NCT03151551) was an open-label, head-to-head, blinded assessor clinical trial which included patients with active PsA (≥3 tender joint count + ≥3 swollen joint count) and plaque psoriasis (BSA ≥3%) who were inadequate responders to csDMARD therapy but naïve to biologic DMARDs. Patients were randomized (1:1) to approved dosing of IXE or ADA. Safety events were assessed at each patient visit up to Week 52. Frequencies of adverse events (AEs) were based on the number of patients in the safety population (patients who received ≥1 dose of study drug). Cases of inflammatory bowel disease (IBD) and cerebro-cardiovascular events were adjudicated by external committees. Kaplan-Meier analysis of time to onset of serious adverse events (SAEs) was performed.Results:Of the 283 patients randomized to each treatment, 87% (246/283) of patients who received IXE and 84% (237/283) of patients who received ADA completed 52 weeks of treatment. The frequency of treatment-emergent AEs (TEAEs) was similar between the groups (74% IXE vs 69% ADA), however fewer severe TEAEs were reported in the IXE group (3.2% IXE vs 7.1% ADA) (Table). SAEs were significantly more frequent in the ADA group compared to the IXE group (12% vs 4.2%; p&lt;0.001), and the time to develop a patient’s first SAE was significantly shorter for ADA versus IXE (p&lt;0.001; Figure). Discontinuations due to AEs were numerically more frequent in the ADA group versus the IXE group (7.4% vs 4.2%; p=0.15). IXE-treated patients reported more injection-site reactions (ISR) than ADA-treated patients (11% vs. 3.5%; p=0.002). Study withdrawals due to ISR were comparable, and only one injection-site reaction was severe on ADA (Table). There were two IBD cases reported for IXE; one case was confirmed as IBD.Conclusion:Safety results were consistent with previous trials with IXE and ADA. Compared with IXE, patients with PsA treated with ADA had significantly more serious AEs.

Biomarkers of disease activity and other factors as predictors of adalimumab pharmacokinetics in inflammatory bowel disease

Inflammatory bowel disease (IBD) is commonly treated with adalimumab. The main objective of the study was to develop a population pharmacokinetic model of adalimumab in IBD patients evaluating the potential biomarkers of disease activity and other factors and its implications in adalimumab dosing.A prospective observational study was performed in adult patients diagnosed with Crohn's disease and ulcerative colitis treated with adalimumab and following a proactive therapeutic drug monitoring of serum concentrations. Adalimumab serum concentrations (ASC) were quantified mainly prior the administration using an enzyme-linked immunosorbent assay (ELISA). A population pharmacokinetic model was developed based on 303 ASC data of 104 IBD patients using non-linear mixed effect modelling approach. Sixty-five ASC from 20 additional patients were randomly selected as an external validation group.A one-compartment model with first order absorption and elimination best describe the ASC time course. Body mass index (BMI), faecal calprotectin (FCP), unexplained decline in ASC and the specific administration pen device exhibited significant influence on apparent clearance (p-value < 0.001).FCP was the inflammatory activity biomarker showing the most relevant impact on adalimumab exposure, higher than C-reactive protein and albumin, and may be useful for adalimumab dosing adjustment.The population-based pharmacokinetic model developed adequately characterized adalimumab exposure in IBD patients. The unexplained decline in ASC, FCP, BMI and the specific administration pen device were identified as meaningful variables significantly influencing adalimumab pharmacokinetics.

Escalation to Weekly Adalimumab for the Treatment of Ocular Inflammation

ABSTRACT Purpose: To report the outcomes of the escalation of adalimumab (ADA) dose for refractory ocular inflammatory diseases. Methods: A retrospective case series of 15 patients (29 eyes) diagnosed with ocular inflammatory disease, including uveitis and scleritis, which was not adequately controlled with standard, every other week ADA dosing, leading to an escalation to weekly dosing. Results: Ten of fifteen patients escalated to weekly ADA achieved control of their inflammation; neither of the two patients increased for control of cystoid macular edema (CME) had resolution and required regional corticosteroids. One patient discontinued weekly ADA due to serious infection. The median length of follow up was 12 months. Conclusion: Our series suggests that the escalation of ADA can be a useful strategy for treating recalcitrant ocular inflammation, but may not be adequate to treat refractory CME.