Real-World Implementation and Outcomes of Adalimumab Therapeutic Drug Monitoring in Psoriasis: A National Specialized Center Experience.

Serum adalimumab concentration is a biomarker of treatment response but therapeutic drug monitoring (TDM) is yet to be implemented in routine psoriasis care. We incorporated adalimumab TDM in a national specialized psoriasis service and evaluated it using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation science framework. We undertook pre-implementation planning (validating local assays) and implementation interventions targeted to patients (pragmatic sampling at routine reviews), clinicians (introduction of a TDM protocol), and healthcare systems (adalimumab TDM as a key performance indicator). Over 5 months, 170 of 229 (74%) individuals treated with adalimumab received TDM. Clinical improvement after TDM-guided dose escalation occurred in 13 of 15 (87%) nonresponders with serum drug concentrations <8.3 µg/ml (median PASI reduction of 3.2 [interquartile range = 2.2-8.2] after 23.4 weeks) and in all nonresponders who had TDM-guided switch in biologic due to supratherapeutic drug concentrations (>8.3 µg/ml; n = 2) or positive antidrug antibody (n = 2) (PASI reduction of 7.8 [interquartile range = 7.5-12.9] after 20.0 weeks). Proactive TDM led to dose reduction in five individuals with clear skin and subtherapeutic or supratherapeutic drug concentrations; four (80%) sustained clear skin after 50 weeks (range = 42-52). Adalimumab TDM based on pragmatic serum sampling is clinically viable and may lead to patient benefit. Context-specific implementation interventions and systematic implementation assessment may bridge the biomarker research-to-practice gap.

Adalimumab and Infliximab Impair SARS-CoV-2 Antibody Responses: Results from a Therapeutic Drug Monitoring Study in 11 422 Biologic-Treated Patients.

BACKGROUND AND AIMS: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown. METHODS: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021. RESULTS: Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94-9.96] vs 5.02 [2.18-18.70], p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39-68.10, p < 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels [<0.8 mg/L] were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were treated with anti-TNF. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% [12/152] of patients after a median time of 183.5 days [129.8-235.3], without differences between drugs. CONCLUSION: Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results.

An observational study of switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with first or second switch.

BACKGROUND: Biologics account for a significant cost in inflammatory bowel disease (IBD) management; however, switching from infliximab originator to its biosimilars has enabled cost saving without compromising disease control. The effects on IBD activity and infliximab trough levels of a second switch to another biosimilar are, however, uncertain. AIMS: To assess the effects on disease activity and infliximab trough levels associated with switching from infliximab biosimilar CT-P13 to another biosimilar SB2 and compare outcomes in those switching for the first and second time. METHODS: IBD patients on CT-P13, including some previously switched from originator, were prospectively followed during a switch to SB2. C-reactive protein (CRP), trough infliximab level and clinical disease activity indices were collected at baseline, Infusion 3 or 4 ('early' after switch), and 1 year. RESULTS: One hundred eighty-six patients (n = 99 second switch) on stable infliximab dosing underwent switching. Compared with baseline, there was no significant change in CRP, clinical disease activity scores or median trough infliximab level at the early time point among first-switch (baseline vs early: 5.7 vs 6.6 µg/mL, P = 0.05) and second-switch (4.3 vs 4.9 µg/mL, P = 0.07) patients nor at 1 year (median infliximab trough levels, baseline vs 1 year, in first-switch [5.7 vs 5.7 µg/mL, P = 0.37] and second-switch [4.3 vs 4.7 µg/mL, P = 0.06] patients). The proportion of patients in clinical remission did not significantly change at the early (92% vs 91% at baseline, P = 0.75) or 1 year (95% vs 91% at baseline, P = 0.16) time points. There was no significant difference in time to loss of response between patients switching for the first or second time (P = 0.69). CONCLUSIONS: Switching from one infliximab biosimilar to another had no adverse impact on infliximab trough levels, and clinical and biochemical disease activity, regardless of whether switching for the first or second time.

Therapeutic thresholds for golimumab serum concentrations during induction and maintenance therapy in ulcerative colitis: results from the GO-LEVEL study.

BACKGROUND: Significant associations between serum golimumab concentrations and favourable outcomes have been observed during both induction and maintenance therapy in ulcerative colitis (UC). However, data regarding optimal therapeutic serum golimumab concentration thresholds are limited. AIMS: To identify optimal serum golimumab concentration thresholds during induction and maintenance treatment with golimumab. METHODS: GO-LEVEL was an open label, phase IV study that included a prospective cohort of UC patients commencing golimumab, as well as a cross-sectional cohort receiving maintenance treatment. Patients commencing induction for active UC (defined as a simple clinical colitis activity index [SCCAI] >5 in addition to a raised faecal calprotectin [FC] >59µg/g or, raised C-reactive protein [CRP] [>5mg/L] or, Mayo endoscopic disease activity 2 or 3) were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare or during remission. Combined clinical-biochemical remission was defined as SCCAI ≤2 and FC <250µg/g. Serum golimumab concentrations were measured using a commercially available ELISA (LISATRACKER, Theradiag). RESULTS: Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined clinical-biochemical remission at week 6. The median serum golimumab concentration of those in combined clinical-biochemical remission was significantly higher than those who were not (5.0 vs 3.1 µg/mL, respectively, P = 0.03). Receiver operating characteristic (ROC) curve analysis demonstrated 3.8 µg/mL as the optimal threshold (sensitivity 0.71, specificity 0.65, area under curve [AUC] 0.72, positive predictive value [PPV] 0.59 and negative predictive value [NPV] 0.79). Sixty-three patients were included in the maintenance cohort; 31 (49%) were in combined remission, 32 (51%) were not. The median serum golimumab concentration of those in combined remission was significantly higher (2.9 vs 2.1 µg/mL, respectively, P = 0.01). ROC curve analysis demonstrated 2.4 µg/mL as the optimal threshold (sensitivity 0.68, specificity 0.66, AUC 0.68, PPV 0.65 and NPV 0.66). CONCLUSIONS: GO-LEVEL (NCT03124121) offers further evidence regarding golimumab's exposure-response relationship. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested therapeutic thresholds of 3.8 µg/mL at week 6 and 2.4 µg/mL during maintenance.

Wide variation in the use and understanding of therapeutic drug monitoring for anti-TNF agents in inflammatory bowel disease: an inexact science?

BACKGROUND: We aimed to understand the way in which therapeutic drug monitoring (TDM) is used, understood and interpreted for anti-TNF agents in IBD. RESEARCH DESIGN AND METHODS: We designed an 18-question survey that included 5 TDM-based clinical scenarios, for which the 'most appropriate' responses were based on the BRIDGe groups 'Anti-TNF Optimizer'. This resource combines TDM evidence with expert consensus. RESULTS: We received 110 complete responses: 50 (45%) consultants, 30 (27%) trainees, 25 (23%) IBD nurse specialists and 5 (5%) gastroenterology pharmacists. Over half (61, 55%) only carry out TDM in non-response. The remainder use TDM routinely, including during stable maintenance therapy for patients in remission. Lower therapeutic thresholds used were variable. Most (82, 75%) were unsure whether their laboratory uses a drug-tolerant or drug-sensitive antidrug antibody assay and few (15, 14%) understand the difference. Consultants, high-frequency users (> 3requests/month) and clinicians with larger anti-TNF cohorts (> 100) were significantly more likely to select the 'most appropriate' answer to at least 1 of the 5 TDM-based clinical scenarios. CONCLUSIONS: There exists marked heterogeneity in the practical use, understanding and interpretation of biologic TDM. Biologic decision-making, informed by TDM, should involve consultation with experienced clinicians who are frequent TDM users, ideally, as part of a multidisciplinary, biologics-focused IBD meeting. ABBREVIATIONS: TDM: therapeutic drug monitoring; CNS: clinical nurse specialist; ELISA: enzyme-linked immunosorbent assay; RIA: radioimmunoassays; HMSA: homogenous mobility shift assays; BSG: British Society of Gastroenterology.

The Clinical and Cost-Effectiveness of 4 Enzyme-Linked Immunosorbent Assay Kits for Monitoring Infliximab in Crohn Disease Patients: Protocol for a Validation Study.

BACKGROUND: Currently, treatment decisions for people with Crohn disease are based on clinical judgment and trial and error. Consequently, people may continue to receive high drug dosages and experience unnecessary toxicity when it is possible to reduce or discontinue without a detrimental effect on clinical outcomes. Therapeutic drug monitoring (TDM) involves regularly testing blood samples for drug and antibody levels that could help clinicians identify the optimal treatment strategy and pre-empt treatment failure. However, heterogeneity in the assays can lead to a discrepancy in results and difficulties in decision-making. Standardization of the kits, and therefore results, would allow clinicians to optimize the use of biologics. Currently, there is also a lack of evidence for the cost-effectiveness of TDM using commercial test kits. OBJECTIVE: This study aims to analyze the clinical and cost-effectiveness of 4 commercial enzyme-linked immunosorbent assay (ELISA) kits (LISA TRACKER, IDKmonitor, Promonitor, and RIDASCREEN) to generate evidence which could support a recommendation for wider adoption in the National Health Service. METHODS: We propose to carry out a prospective-retrospective predictive biomarker validation study using the blood samples and clinical/utilization data collected during the ongoing SPARE trial (NCT02177071). A total of 200 stored samples from people with Crohn's disease who respond to treatment with infliximab will be used along with clinical and cost data from the trial. We will investigate the relationship between the drug and antidrug antibody levels with the main clinical outcomes (relapse rate at 2 years and time spent in remission), as well as resource utilization and quality of life. RESULTS: Funding is being sought to conduct this research. CONCLUSIONS: This is the first study to compare the 4 ELISA kits for monitoring infliximab in patients with Crohn disease. It aims to address the uncertainties in the potential benefits of using the technologies for TDM. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11218.