Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). METHODS: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

Commutability of proficiency testing material containing tobramycin: a study within the framework of the Dutch Calibration 2.000 project.

BACKGROUND: Results from external quality assessment schemes (EQASs) can provide information about accuracy and comparability of different measurement methods, provided that the material used in these schemes behave identical to patient samples among the different methods, a characteristic also known as commutability. The aim of this study was to assess the commutability of different matrices for the material used in an EQAS for tobramycin. METHODS: Proficiency testing material (PTM) and patient samples containing tobramycin were prepared, collected, pooled, and distributed to participating laboratories for analysis. Low, medium, and high tobramycin concentrations in liquid human, liquid bovine and lyophilized bovine serum were tested in this study. The patient serum results of every laboratory were plotted against each of the other laboratories, and the distances of the PTM results to the patient serum regression line were calculated. For comparison, these distances were divided by the average within-laboratory standard deviation (SDwl) of the results reported in the official EQAS for tobramycin, resulting in a relative residual. The commutability decision limit was set at 3 SDwl. RESULTS: With 10 laboratories participating in this study, 45 laboratory couples were formed. For human serum, only one relative residual for high concentrations of tobramycin was found outside the commutability decision limit. For liquid and lyophilized bovine sera, the number of relative residuals outside the decision limit was between 15 and 18 for low, medium, and high tobramycin concentrations. CONCLUSIONS: The PTM used for tobramycin is preferably prepared with human serum.

A Multilaboratory Commutability Evaluation of Proficiency Testing Material for Carbamazepine and Valproic Acid: A Study Within the Framework of the Dutch Calibration 2000 Project.

BACKGROUND: Medical laboratories are required to participate in interlaboratory comparisons of the analyses they perform. The materials used in these comparisons need to be of sufficient quality so that the comparison provides a picture of the performances. One of the main characteristics of the testing material is commutability, which is the ability of a material to yield the same numerical relationships between results of measurements as those relationships obtained when the same procedures are applied to patient samples. The aim of this study was to assess the commutability of 3 different matrices for the preparation of proficiency testing material (PTM) for the analysis of carbamazepine and valproic acid. METHODS: Patient samples and PTM containing various concentrations of carbamazepine and valproic acid were collected, prepared, and shipped to different laboratories for analysis. Reported results for patient samples from each laboratory were plotted against results for patient samples of each of the other laboratories, and the corresponding regression line was calculated. The distance of results from PTM to the regression line is a measure for commutability. The distance is expressed as a multiple of the SDwl (average within-laboratory SD as calculated from external quality assessment scheme results) and referred to as relative residual. A commutability decision limit of 2 SDwl was set. RESULTS: For carbamazepine and valproic acid, a total of 78 and 105 laboratory couples respectively could be formed. The number of relative residuals for liquid human serum outside the commutability decision limit was 1, 4, and 0 for low, medium, and high concentrations of carbamazepine, respectively and 3, 1, and 0 for low, medium, and high concentrations of valproic acid, respectively. In both liquid and lyophilized bovine sera, the number of relative residuals outside the commutability decision limit was between 2 and 15 and between 6 and 21 for carbamazepine and valproic acid, respectively. CONCLUSIONS: Although not all results for PTM with carbamazepine and valproic acid are within the commutability decision limits, a preference for human serum can be seen.

Routine Assessment of Patient Index Data 3 (RAPID3) alone is insufficient to monitor disease activity in rheumatoid arthritis in clinical practice.

Objective: To test the longitudinal association between patient-reported outcome, Routine Assessment of Patient Index Data 3 (RAPID3) and the Disease Activity Score in 28 joints that includes the erythrocyte sedimentation rate (DAS28-ESR) in routine-care patients with rheumatoid arthritis (RA). Methods: Patients with RA treated with disease-modifying antirheumatic drugs were included in this prospective observational cohort. The longitudinal association between RAPID3 (0-10) and DAS28-ESR and its individual components (swollen joint count (SJC), erythrocyte sedimentation rate (ESR) (mm/hour), tender joint count (TJC) and patient global assessment (PGA)) was tested using generalised estimating equations in patients with more than two consecutive visits with data on RAPID3 and DAS28-ESR. Interactions between RAPID3 and gender, pain, PGA and age at baseline were tested, and if significant (p<0.20) and clinically relevant, models were fit in the corresponding strata. Results: In total, 330 patients were included (mean follow-up 10.7 (SD 9.7) months, female gender 67.9%). The longitudinal association between RAPID3 and DAS28-ESR was weak (ß=0.29 (95% CI 0.24 to 0.35), n=207), meaning that one unit increase in RAPID3 corresponded to a 0.29 unit increase in Disease Activity Score in 28 joints (DAS28). RAPID3 was most strongly associated with subjective (TJC: ß=0.89 (95% CI 0.61 to 1.17); PGA: ß=0.94 (95% CI 0.84 to 1.04)) and not with objective components of DAS28 (SJC: ß=0.29 (95% CI 0.17 to 0.41), n=172). The association between RAPID3 and ESR was poor but modified by gender, being only significant in men (ß=0.37 (95% CI 0.08 to 0.67)). Conclusions: These data suggest that RAPID3 does not sufficiently capture changes in objective inflammatory signs. Monitoring by RAPID3 alone is therefore insufficient to follow disease activity in patients wth RA in clinical practice.

Cotreatment with methotrexate in routine care patients with rheumatoid arthritis receiving biological treatment yields better outcomes over time.

Objectives: We aimed to evaluate the effects of methotrexate (MTX) comedication added to biological disease-modifying antirheumatic drugs (bDMARD) on disease activity measures in patients with rheumatoid arthritis (RA) in routine care. Methods: Patients with RA on treatment with either bDMARDs or conventional synthetic DMARDs were included in this prospective cohort study. The effect of (time-varying) combination therapy with bDMARD and MTX compared with bDMARD monotherapy was tested in longitudinal generalised estimating equation models using as outcomes: (1) the likelihood to be in remission according to the 28-joint Disease Activity Score (DAS28) erythrocyte sedimentation rate (ESR) (<2.6) and to the Routine Assessment of Patient Index Data 3 (RAPID3) (0-30; ≤3), a patient-reported outcome measure about RA symptoms; and (2) DAS28-ESR and RAPID3 as continuous variables. All models were adjusted for potential confounders: age, gender, drugs for comorbidities (yes/no), oral steroids (yes/no) and non-steroidal anti-inflammatory drug (yes/no). Results: In total, 330 patients were included (mean (SD) follow-up; 10.7 (9.7) months). Compared with bDMARD monotherapy, MTX combination therapy was significantly associated with a 55% higher likelihood to be in DAS28 remission, but not RAPID3 remission, over time. Combination therapy resulted in slightly, but statistically significant, lower levels of DAS28-ESR over time (ß=-0.42 (95% CI -0.67 to - 0.17)), but not RAPID3 (ß=-0.58 (95% CI -0.65 to 0.49)). The effect on DAS28-ESR was entirely explained by lower swollen joint counts and was persistent after correction for confounders. Conclusion: These results give support to the policy that MTX should be continued in routine care patients with RA on biological therapy since this leads to better objective but not subjective clinical outcomes.

Commutability of proficiency testing material containing amitriptyline and nortriptyline: A study within the framework of the Dutch Calibration 2.000 project.

BACKGROUND: External quality assessment schemes (EQAS) can provide important information regarding accuracy and comparability of different measurement methods if the sample matrices are composed of commutable material. The aim of this study was to assess the commutability of different matrices for the material used in an EQAS for amitriptyline and nortriptyline. METHODS: Proficiency testing material (PTM) and patient samples containing amitriptyline and nortriptyline were prepared, collected, pooled, and distributed to participating laboratories for analysis. Low, medium and high concentrations of both drugs in liquid pooled human, lyophilized human and lyophilized bovine serum were tested in this study. The measurement deviation of the PTM results to the patient serum regression line were normalized by dividing trough the average within-laboratory SD (SDwl) derived from the results reported in the official EQAS, resulting in a relative residual. The commutability decision limit was set at 3 SDwl. RESULTS: With 10 laboratories participating in this study, 45 laboratory couples were formed. All matrix types delivered several relative residuals outside the commutability decision limit. The number and the magnitude of relative residuals for both drugs were lower for liquid human sera as compared to lyophilized human and bovine sera. CONCLUSIONS: The PTM used for amitriptyline and nortriptyline is preferably prepared with human serum, although not all relative residuals are within the commutability decision limit.

Evaluating patient reported outcomes in routine practice of patients with rheumatoid arthritis treated with biological disease modifying anti rheumatic drugs (b-DMARDs).

OBJECTIVES: In this study the concordance between the Routine Assessment of Patient Index Data 3 (RAPID3) and the Disease Activity Score 28-joint count (DAS28) was investigated in a clinical routine outpatient setting. PATIENTS AND METHODS: A sample of 150 adult patients with stable RA treated with biological DMARDs (bDMARDs) was asked to complete the RAPID3 (digital or on paper) just before their outpatient routine visit during which DAS28 assessment took place. The RAPID3 correlation with and the agreement in four DAS28 categories was studied using Spearman's rank order and Cohen's observed kappa statistics respectively. The positive (PPV) and negative (NPV) predictive values were calculated to test whether RAPID3 could make distinction in active disease (DAS28 >3.2) or not. RESULTS: A moderate correlation (ρ 0.576) and a poor kappa value of 0.13 were found in the whole study population. Patients reported a higher disease severity than was measured by DAS28. The PPV of RAPID3 for active disease by DAS28 was 0.59 (95 % CI 0.50-0.68) and the NPV was 0.91 (95 % CI 0.75-0.98) with a sensitivity and specificity of 96 and 40 % respectively. DISCUSSION: While RAPID3 correlates to some extent with DAS28 at the group level, agreement between RAPID3 and DAS28 at the individual patient level is to poor to rely on RAPID3 results in monitoring patients with RA. RAPID3 tends to over-report disease activity as assessed by DAS28.