EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases.

OBJECTIVE: To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs). METHODS: The points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale. RESULTS: Six overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals. CONCLUSION: These points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial.

OBJECTIVE: High adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations >8 µg/mL can prolong their dosing interval by 50% without a clinically relevant change in disease activity. METHODS: Consecutive patients with RA, treated with adalimumab 40 mg every other week for at least 28 weeks, were approached for this randomised, open-label, non-inferiority trial. Patients with adalimumab trough concentrations >8 µg/mL were randomly (1:1) assigned to dose-interval prolongation of once every 3 weeks or continuation of every other week. Primary outcome was the change in disease activity score of 28 joints (ΔDAS28-ESR) after 28 weeks, with a non-inferiority margin of 0.6 points. RESULTS: In total, 147 patients were screened. Fifty-five patients had concentrations >8 µg/mL and were randomised. Mean ΔDAS28 after 28 weeks was -0.14±SD 0.61 in the prolongation group and 0.30±0.52 in the continuation group. Mean difference was significantly in favour of the prolongation group: 0.44 (95% CI 0.12 to 0.76, p=0.01). CONCLUSIONS: Adalimumab-treated patients with RA with trough concentrations >8 µg/mL can prolong their standard dosing interval to once every 3 weeks without loss of disease control. TRIAL REGISTRATION NUMBER: NTR3509; Results.