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The potential value of blood monitoring of biologic drugs used in the treatment of rheumatoid arthritis.

ABSTRACT: The advent of biological therapies has been a major therapeutic advance in rheumatology. Many patients now enjoy improved quality of life through better disease control. The number of therapies continues to grow both within drug class (including biosimilar drugs) and via new mechanisms. For the first time, nonbiological drugs such as small-molecule inhibitors (Janus kinase inhibitors) have shown clinical equivalence. However, clinical unmet need remains with up to a third of patients commenced on a biologic therapy having minimal or no response: (a) Generally, the first biologic used secures the best response, with likelihood of remission falling thereafter with successive therapies; (b) the success of strategy trials using biological therapies can be difficult to replicate in clinical practice due to a combination of patient factors and service limitations. Accordingly, ensuring optimization of initial treatment is an important consideration before switching to alternatives. Therapeutic drug monitoring (TDM) is the measurement of serum levels of a biologic drug with the aim of improving patient care. It is usually combined with detection of any antidrug antibodies that could neutralize the effect of the therapy. This technology has the potential to be a form of 'personalized medicine' by individualizing therapy, in particular, dosing and likelihood of sustained treatment response. It requires a clear relationship between drug dose, blood concentration and therapeutic effect. This paper will outline the technology behind TDM and unpack what we can learn from our colleagues in gastroenterology, where the adoption of TDM is at a more advanced stage than in rheumatology. It will explore and set out a number of clinical scenarios where rheumatologists might find TDM helpful in day-to-day practice. Finally, an outline is given of international developments, including regulatory body appraisals and guideline development.

SUBMITTER: Perry M

PROVIDER: S-EPMC7011331 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The potential value of blood monitoring of biologic drugs used in the treatment of rheumatoid arthritis.

Perry Martin M Abdullah Azhar A Frleta Marina M MacDonald Jonathan J McGucken Andrew A

Therapeutic advances in musculoskeletal disease 20200207

The advent of biological therapies has been a major therapeutic advance in rheumatology. Many patients now enjoy improved quality of life through better disease control. The number of therapies continues to grow both within drug class (including biosimilar drugs) and <i>via</i> new mechanisms. For the first time, nonbiological drugs such as small-molecule inhibitors (Janus kinase inhibitors) have shown clinical equivalence. However, clinical unmet need remains with up to a third of patients comm ...[more]

PMID: 32095163

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Project description:ImportanceThere are conflicting data on the association of antidrug antibodies with response to biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA).ObjectiveTo analyze the association of antidrug antibodies with response to treatment for RA.Design, setting, and participantsThis cohort study analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of patients with RA from 27 recruiting centers in 4 European countries (France, Italy, the Netherlands, and the UK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD. Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018, and data were analyzed in June 2022.ExposuresPatients were treated with a new bDMARD: adalimumab, infliximab (grouped as anti-tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab according to the choice of the treating physician.Main outcomes and measuresThe primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay.ResultsOf the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%]) were analyzed. At month 12, antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab. There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P < .001) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P < .001). A similar association was found for tocilizumab alone (OR, 0.18; 95% CI, 0.04-0.83; P = .03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factor were independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody-negative vs antidrug antibody-positive status (mean difference, -9.6 [95% CI, -12.4 to -6.9] mg/L; P < 001). Drug concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) and adalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05).Conclusions and relevanceResults of this prospective cohort study suggest an association between antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrug antibodies could be considered in the treatment of these patients, particularly nonresponders to biologic RA drugs.

Project description:Objective: use comprehensive molecular profiling to understand the molecular mechanisms that affect clinical response to anti-TNF therapy in rheumatoid arthritis (RA) and to identify predictive markers to differentiate good responders and non-responders. Methods: two independent cohorts of 40 and 36 biologic-naïve RA patients were selected from the Corrona (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) CERTAIN registry and categorized by EULAR response criteria. Whole-blood RNA and plasma samples from baseline and after 3 months of anti-TNF treatment were profiled using RNA-seq, shotgun proteomics and glycopeptide analysis. A cell type-specific transcriptional data analysis was applied to RNA-seq data to evaluate the impact of the most common immune cell sub-populations. Results: a treatment-related molecular signature was identified that showed a high level of correlation (ρ=0.62; permutation p<0.01) between cohorts. Treatment led to a reduction of neutrophils, independent of the status of response. Gene expression differences between good responders and non-responders at baseline did not manifest statistically significant concordance genome-wide between the two cohorts. However, a cell type-specific analysis indicated increased representation of innate cell type signatures in good responders and, conversely, increased expression of adaptive cell type signatures in non-responders at baseline in both cohorts. This result was confirmed by applying the cell-type specific analysis to other publicly available RA datasets. Evaluation of the neutrophil to lymphocyte ratio (NLR) at baseline in the remaining patients (n=1962) from the CERTAIN database using a logistic regression model further confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03 – 1.41; p = 0.02]). Conclusion: differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

Project description:ImportanceBiosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA).ObjectivesTo assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA.Data sourcesMEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021.Study selectionHead-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed.Data extraction and synthesisTwo authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.Main outcomes and measuresEquivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire-Disability Index (HAQ-DI) (ie, SMD, -0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity.ResultsA total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, -0.04; 95% CrI, -0.11 to 0.02; τ2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics.Conclusion and relevanceIn this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.

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The potential value of blood monitoring of biologic drugs used in the treatment of rheumatoid arthritis.

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The potential value of blood monitoring of biologic drugs used in the treatment of rheumatoid arthritis.

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