A value proposition for trough level-based anti-TNFα drug dosing.

Treatment of inflammatory bowel diseases and rheumatic disorders with anti-tumor necrosis factor alpha (TNFα) drugs is expensive, while a significant proportion of patients does not show adequate clinical response. Therapeutic drug monitoring (TDM) enables patient-specific anti-TNFα therapy. The role of laboratory tests in clinical care has recently been described in a value proposition framework. It describes care processes, stakeholders, costs, risks, benefits and patient outcomes based on the use of a laboratory test in a clinical care pathway. We have applied this concept to the use of TDM for anti-TNFα drugs, describing evidence that supports the intervention and its cost effectiveness, steps that need to be adjusted in the care pathway, possible treatment algorithms and measures to assess adoption of this framework into clinical practice. For effective TDM, an assay for measurement of drug levels together with appropriate target ranges and an anti-drug-antibody assay have to be implemented. Also, instead of only reporting the drug concentration, laboratorians, pharmacists and clinicians should deliver added value by introducing a TDM-based treatment algorithm into clinical practice. Thus, to maximize effectiveness of TDM of anti-TNFα therapy in routine care, adjustment of current care pathways and cooperation of many stakeholders are needed.

Switching from infliximab innovator to biosimilar in patients with inflammatory bowel disease: a 12-month multicentre observational prospective cohort study.

BACKGROUND: Infliximab biosimilars have become available for treatment of inflammatory bowel disease (IBD). However, data showing long-term safety and effectiveness of biosimilars in IBD patients are limited. AIM: To study prospectively the switch from infliximab innovator to biosimilar in an IBD cohort with 12 months follow-up to evaluate safety and effectiveness. METHODS: Adult IBD patients from two hospitals treated with infliximab innovator (Remicade; Janssen Biotech,  Horsham ,  Pennsylvania, USA) were switched to infliximab biosimilar (Inflectra; Hospira, Lake Forest, Illinois, USA) as part of routine care, but in a controlled setting. Blood samples were taken just before the first, second, fourth and seventh infusion of biosimilar. Infliximab trough levels, antibodies-to-infliximab (ATI), CRP and ESR were measured and disease activity scores were calculated. RESULTS: Our cohort consisted of 133 IBD patients (64% CD, 36% UC). Before switching we found widely varying infliximab levels (median 3.5 µg/mL). ATI were detected in eight patients (6%). Most patients were in remission or had mild disease (CD: 82% UC: 90%). After switching to biosimilar, 35 patients (26%) discontinued therapy within 12 months, mostly due to subjective higher disease activity (9%) and adverse events (AE, 9.8%). AE included general malaise/fatigue (n = 7), arthralgia (n = 2), skin problems (n = 2) and infusion reactions (n = 2). No differences in IFX levels, CRP, and disease activity scores were found between the four time points (P ≥ .0917). CONCLUSIONS: We found no differences in drug levels and disease activity between infliximab innovator and biosimilar in our IBD cohort, indicating that biosimilars are safe and effective. The high proportions of discontinuers were mostly due to elective withdrawal or subjective disease worsening.

Thyroid disease symptoms during early pregnancy do not identify women with thyroid hypofunction that should be treated.

OBJECTIVE: To evaluate whether women during early pregnancy with "hypothyroidism" symptoms are at risk of biochemically defined hypothyroidism. The 2017 Guidelines of the American Thyroid Association (ATA) recommend case-finding on the basis of symptoms to identify these women during pregnancy, while evidence is lacking. DESIGN: Construct validation of a thyroid hypofunction symptom checklist during the first trimester of pregnancy comparing high scores with biochemically defined hypothyroidism. PATIENTS: A total of 2198 healthy pregnant women from an iodine-sufficient area in 2013-2014. MEASUREMENTS: Completion of a draft questionnaire with "classical" symptoms of hypothyroidism at 12 weeks of gestation. The 2.5th and 97.5th percentiles of TSH and fT4 during pregnancy in TPO-Ab-negative (<35 kU/L) women were used to define euthyroid women and those with overt (clinical) and subclinical hypothyroidism. The prevalence of overt (subclinical) hypothyroidism was compared between women with high symptom scores and those with low symptom scores. RESULTS: According to fT4 and TSH cut-offs (0.23-4.0 mIU/L and 11.5-18.0 pmol/L, respectively), there were 15 women with "to treat hypofunction" (overt hypothyroidism or TSH >10 mIU/L) and 68 women with subclinical hypothyroidism. Questionnaire construct validation revealed a 12-item hypothyroid checklist with normally distributed scores. The cut-off indicating high scores of OH was set at 1 SD > mean. Women with high symptom scores did not present more often with biochemically defined thyroid hypofunction. CONCLUSION: This study does not support the ATA recommendation that pregnant women who require levothyroxine therapy can be identified by case-based screening of women with symptoms of thyroid disease.

Therapeutic drug monitoring (TDM) as a tool in the switch from infliximab innovator to biosimilar in rheumatic patients: results of a 12-month observational prospective cohort study.

The objective of this study is to apply therapeutic drug monitoring (TDM) as an objective tool to monitor the switch from infliximab innovator (INX) to infliximab biosimilar (INB) in our diverse rheumatic cohort in daily clinical practice. All rheumatic patients on INX treatment (Remicade®) and ≥18 years were switched to INB (Inflectra®) as part of routine care, but in a controlled setting. Patients were monitored by taking blood samples just before the first infusion of INB (T1), and after the second (T2), fourth (T3), and seventh (T4) infusion of INB. T4 reflects the patients' status after ∼12 months. Infliximab trough levels, antibodies-to-infliximab (ATI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and validated disease activity scores (if possible) were measured. Our population consisted of 27 patients with seven different rheumatic diseases who had received INX for 143 (58-161) months (median (IQR)). Half of the patients (52%) received concomitant immunosuppressives. We found widely varying infliximab levels, with only 56% within the proposed therapeutic range of 1-5 µg/mL. One patient had very high ATI levels (>880 au/mL), and two had low ATI levels (≤30 au/mL). After switching to INB, seven patients (26%) discontinued the therapy, partially due to subjective reasons. No difference in infliximab levels, CRP levels, and disease activity scores was found between the four time points (p ≥ 0.2460). In conclusion, no pharmacokinetic or clinical differences were found between INX and INB in our diverse rheumatic cohort. TDM is a helpful tool to monitor patients switching from INX to INB.

Antimicrobial susceptibility testing in 90 min by bacterial cell count monitoring.

The rise in antimicrobial resistance has become a serious global health problem. Restrictive use of antibiotics seems the only option to temper this accession since research in new antibiotics has halted. Antimicrobial stewardship programmes rely on quick access to susceptibility data. This study evaluated the concept of bacterial cell count monitoring as a fast method to determine susceptibility. Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus strains were tested for amoxicillin/piperacillin and gentamicin by three conventional methods (VITEK2(®) , Etest(®) and broth-macrodilution). Bacterial cell count monitoring reliably predicted susceptibility after 90 min for Escherichia coli and after 120 min for Pseudomonas aeruginosa and Staphylococcus aureus without any minor, major or very major discrepancies. Time-to-result was reduced by 74%, 83% and 76%, respectively. Bacterial cell count monitoring shows great potential for rapid susceptibility testing.