Cost-effectiveness of therapeutic drug monitoring (TDM) of biologic treatment in rheumatic diseases: a narrative review

Figures & data

Figure 1. PRISMA flow diagram for the study.

Table 1. Comparison of included studies.

Reference	Study design	Patients	Intervention	Comparator	Costs	Outcomes	TDM schema	ICER	Conclusion
Krieckaert CL et al. [18]	Real life, observation study and Markov modelling.	272 patients with RA starting adalimumab	Patients were followed up at 4, 16, 28, 40 and 52 weeks. Patients with response according to EULAR and with dose level <5mg/L the therapy was stopped, 5–12 mg/L continue; >12mg/L interval prolongation. Patients non-responding according to EULAR and dose level >5mg/L switch to rituximab, <5mg/L switch to etanercept.	Personalized vs. usual care	Direct medical and productivity costs.	QALYs	Personalized treatment algorithm based on EULAR response and drug level at 6 months when adalimumab should be continued, dose reduced or switch	Mean total savings are €2,561,648 and ICER is €646,266 saved per QALY.	Tailoring biological treatment to individual patient with RA starting adalimumab using drug levels and short-term outcome is cost-effective. Results underscore the potential merit of personalized biological treatment in RA.
Laine J et al. [19]	Real-life study, Markov model and cost-effectiveness analysis.	100 hypothetical patients for CEA	Retrospective review of samples from patients on adalimumab and infliximab	Adalimumab and infliximab	Drug cost, cost of suboptimal treatment for 3 months, travel, lost working, cost of tests, follow-up visits.	Drug survival and expected medication in the population within 3 years	The study is based on evaluation of real life data and defines the optimal and non-optimal response from the patients regular monitoring at every 3 months.	Routine measurements of both dose level and anti-drug antibodies can be cost-saving compared to non-testing scenario, and only 2.5–5 of 100 patients can be treated non-optimally.	Routine monitoring of antidrug antibodies is cost-beneficial in clinical practice and improves the decision making process in using TNF-α blockers.
Gomes-Arango C. et al. [20]	Non-inferiority, interventional, non-randomized, pragmatic trial	Adult patients with RA, PsA, or AS clinically stable for at least 6 months prior to inclusion with DAS28 < 3.2 or BASDAI < 4	Dose optimization strategy of adalimumab	Adalimumab vs. standard of care.	Drug treatment costs; testing; administration labor cost of drug evaluation; kits; hospitalizations;	Gomes-Arango C. et al.	Non-inferiority, interventional, non-randomized, pragmatic trial	Adult patients with RA, PsA, or AS clinically stable for at least 6 months prior to inclusion with DAS28 < 3.2 or BASDAI < 4	Dose optimization strategy of adalimumab
Laar C. et al. [21]	Markov model and Monte Carlo simulation model.	Methotrexate inadequate responders in a treatment to target strategy.	Modelled patient transition between disease states on a 12-week basis	Baricitinib vs. first biological	Medical cost and productivity loss cost.	DAS28, QALY	Treat to target – patients are initially treated with a low dose csDMARD combination therapy, in case of non-responding transferred to biological-adalimumab and then to second biological. The active group is transferred to baricitinib. After two consecutive cycles spent in remission the medication is tapered. After achieving medication-free remission, the therapy starts again with methotrexate	Baricitinib strategy yielded lower costs and higher utility over a 5-year period.	Results suggest that the use of a JAK1/JAK2 inhibitor instead of a bDMARD in a T2T approach is cost-effective in csDMARD refractory RA patients.
Ucar e. [22]	Prospective, intervention, multicenter study of utility of biologic drug monitoring with respect to the efficacy and cost of adalimumab tapering in patients with rheumatic diseases: preliminary results of ingebio study	169 patients with 3 rheumatic diagnoses RA, AS, PsA. 60 in Control group and 109 in intervention group with TDM. Followed-up for up to 18 months at 8 timepoints.	Prospective, non-randomized study of patients receiving Adalimumab with TDM	Control group of 60 patients on adalimumab without TDM.	Average cost of treatment with adalimumab per patient year	Endpoints included DAS28, BASDAI, BASFI and HAQ-DI scores at every timepoint	Patients were assessed at 8 timepoints (8 visits) for up to 18 months. Trough ADL and anti-ADL antibodies levels were measured with Promonitor-ADL and Promonitor-ANTI-ADL (Progenika, SA)	Patients on TDM had −657.83 lower costs than control group. Quality of life was significantly higher in the intervention group with each subsequent visit. Overall disease activity scores were lower in the intervention group	Preliminary results show that rheumatic patients have better quality of life, lower risk of flares and incur lower treatment costs if patient management is complemented with BDM data.
Pascual-Salcedo D. [23]	Observational study of daily clinical practice of patients with RA or AS. 7 years of data were included in the analysis.	88 patients (43 RA and 45 AS), divided in 2 time periods 2006–2009 pre-TDM and 2010–2012 post-TDM.	32 Patients treated with Infliximab, 29 with Adalimumab and 28 with Etanercept without TDM between 2006–2009	Inclusion of TDM in the treatment of all 88 patients between 2010–2012	Savings incurred in dose down-titration.	DAS 28 for RA, BASDAI for AS. Time interval between doses	Drug levels were measured by capture ELISA’s.	The monthly amount of spared drug converted into economic savings was €91.62 per patient for Ifx (70kg of mean weight), €324 per patient for Ada, €257 per patient for Etn. The yearly amount of money saved in this group of 88 patients was €233.186 .	The therapeutic dose monitoring based on serum trough drug levels, used in rheumatic patients, is a useful tool to support therapeutic clinical practice in addition to enabling cost effective savings of biologics

Notes: RA-rheumatoid arthritis; PsA-psoriatic arthritis; AS-ankylosing spondylitis; TDM-therapeutic drug monitoring; DAS-disease activity score; BASDAI – Bath Ankylosing Spondylitis Disease Activity Index; CEA – cost-effectiveness analysis; ICER-incremental effectiveness ratio; QALY – quality-adjusted life year; QoL – quality of life, bDMARD – biologic disease-modifying antirheumatic drug, DAS – Disease activity score; BASFI – Bath Ankylosing Spondylitis Functional Index; HAQ-DI – The Health Assessment Questionnaire (HAQ) Disability Index.

Table 2. CHEERS final evaluation [15].

Item	N	Question	Krieckaert et al. [18]	Laine et al. [19]	Gomez-Arango et al. [20]	Laar et al. [21]
Title	1	Identify the study as an economic evaluation and specify the interventions being compared.	Yes	Yes	Yes	Yes
Abstract	2	Provide a structured summary that highlights context, key methods, results, and alternative analyses.	Yes	Yes	Yes	Yes
Introduction
Background and objectives	3	Give the context for the study, the study question, and its practical relevance for decision making in policy or practice.	Yes	Yes	Yes	No
Methods
Health economic analysis plan	4	Indicate whether a health economic analysis plan was developed and where available.	Yes	No	Yes	Yes
Study population	5	Describe characteristics of the study population (such as age range, demographics, socioeconomic, or clinical characteristics).	Yes	No	Yes	Yes
Setting and location	6	Provide relevant contextual information that may influence findings.	Yes	Yes	Yes	Yes
Comparators	7	Describe the interventions or strategies being compared and why chosen.	Yes	Yes	Yes	Yes
Perspective	8	State the perspective(s) adopted by the study and why chosen.	No	No	YES	Yes
Time horizon	9	State the time horizon for the study and why appropriate.	Yes	Yes	Yes	Yes
Discount rate	10	Report the discount rate(s) and reason chosen.	Yes	No	Not applicable	Yes
Selection of outcomes	11	Describe what outcomes were used as the measure(s) of benefit(s) and harm(s).	Yes	Yes	Yes	Yes
Measurement of outcomes	12	Describe how outcomes used to capture benefit(s) and harm(s) were measured.	Yes	Yes	Yes	No
Valuation of outcomes	13	Describe the population and methods used to measure and value outcomes.	Yes	No	Yes	Yes
Measurement and valuation of resources and costs	14	Describe how costs were valued	Yes	Yes	Yes	Yes
Currency, price date, and conversion	15	Report the dates of the estimated resource quantities and unit costs, plus the currency and year of conversion.	Yes	Yes	Yes	Yes
Rationale and description of model	16	If modelling is used, describe in detail and why used. Report if the model is publicly available and where it can be accessed.	Yes	No	Yes	Yes
Analytics and assumptions	17	Describe any methods for analysing or statistically transforming data, any extrapolation methods, and approaches for validating any model used.	Yes	No	Yes	Yes
Characterizing heterogeneity	18	Describe any methods used for estimating how the results of the study vary for subgroups.	Yes	No	Yes	Not Applicable
Characterizing distributional effect	19	Describe how impacts are distributed across different individuals or adjustments made to reflect priority populations.	Not applicable	Not applicable	Not reported	Yes
Characterizing uncertainty	20	Describe methods to characterize any sources of uncertainty in the analysis.	Yes	No	Yes	Yes
Approach to engagement with patients and others affected by the study	21	Describe any approaches to engage patients or service recipients, the general public, communities, or stakeholders (such as clinicians or payers) in the design of the study.	Not applicable	No	No	Not applicable
Results
Study parameters	22	Report all analytic inputs (such as values, ranges, references) including uncertainty or distributional assumptions	Yes	Yes	Yes	Yes
Summary of main results	23	Report the mean values for the main categories of costs and outcomes of interest and summarize them in the most appropriate overall measure.	Yes	No	Yes	Yes
Effect of uncertainty	24	Describe how uncertainty about analytic judgments, inputs, or projections affect findings. Report the effect of choice of discount rate and time horizon, if applicable.	Yes	No	Yes	Yes
Effect of engagement with patients and others affected by the study	25	Report on any difference patient/service recipient, general public, community, or stakeholder involvement made to the approach or findings of the study	Not applicable	No	Yes	Not applicable
Discussion
Study findings, limitations, generalizability, and current knowledge	26	Report key findings, limitations, ethical or equity considerations not captured, and how these could affect patients, policy, or practice.	Yes	Yes	Yes	Yes
Other relevant information
Source of funding	27	Describe how the study was funded and any role of the funder in the identification, design, conduct, and reporting of the analysis	Yes	No	Yes	Yes
Conflict of interest	28	Report authors conflicts of interest according to journal or International Committee of Medical Journal Editors requirements.	Yes	Yes	Yes	Yes
Degree of conformity to guidelines		Percentages	81.72%	42.85%	89.25%	78.57%

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Data availability statement

All data collected during the study are provided as supplementary material to this article.