Enzyme-linked immunosorbent assays for monitoring TNF-alpha inhibitors and antibody levels in people with rheumatoid arthritis: a systematic review and economic evaluation

The role of tumour necrosis factor-α inhibitors in the care pathway

The NICE care pathway24 states that bDMARDs, including TNF-α inhibitors, should be offered only to people with severe disease that has not been controlled with cDMARDs. 12 NICE Technology Appraisal 375 (TA375)23 recommends using ADL, ETN, IFX, CTZ and GLM, in combination with methotrexate, in severe RA (i.e. DAS28 of > 5.1) that has not responded to intensive therapy with at least two cDMARDs, including methotrexate. ADL, ETN and CTZ may also be used as monotherapy for people in whom methotrexate is contraindicated or not tolerated. As part of TA375,23 NICE also makes recommendations for two other bDMARDs (tocilizumab and abatacept),23 but these interventions are outside the scope of this appraisal.

A summary of the recommended TNF-α inhibitors relevant to this report, their contraindications and very common adverse reactions, and a list of biosimilars, is provided in Table 2. The biosimilars listed in Table 2 are thought to have bioequivalence (and are also often assumed to perform similarly) to the reference/originator products. 25 It should be noted that IFX is administered by intravenous infusion in the outpatient setting, whereas the other recommended TNF-α inhibitors may be self-administered by subcutaneous injection (usually administered by patients in their own homes). TA375 recommends that treatment should start with the least expensive drug (taking into account administration costs, required dose and product price per dose). 23

Although TNF-α inhibitors have been found to be of benefit in the treatment of RA,23 some people do not respond to these treatments (primary non-responders) and others experience a loss of response (secondary non-responders). Secondary non-response may be due to changes in the disease, the development of antibodies to the TNF-α inhibitor or fluctuations in circulating drug levels.

Current methods for monitoring treatment response

Owing to the huge variation between individuals in the severity and course of RA, and, thus, in treatment targets, it is incredibly difficult to measure changes in the disease in a standardised way. Indeed, in clinical practice, evaluation of both treatment response and symptom flare-ups is multifaceted, and may involve assessment of a number of domains (pain, fatigue, activity level, overall physical and mental health, functioning in work and education, complications and adverse effects), in addition to measuring disease activity (using standardised scales and additional imaging).

A range of classification systems and scales have been developed to measure and monitor disease activity in RA (as well as scales that are commonly used to measure other domains, e.g. disability or activity level), such as the Health Assessment Questionnaire (HAQ). 26 Disease activity is commonly measured using clinical examination (swollen joint counts and tender joint counts), laboratory test results (e.g. CRP or ESR) or composite measures based on a combination of the above [such as DAS28,27 the Clinical Disease Activity Index (CDAI),28 the Simplified Disease Activity Index (SDAI),28 the ACR20 improvement criteria29 and the EULAR response classification system30].

In current clinical practice, the DAS28 scales and the EULAR response classification system (which is based on the DAS28) are most commonly used to monitor disease activity. The use of ultrasound is not recommended for routine monitoring of disease activity in adults with RA. 12,31

Monitoring of response to tumour necrosis factor-α inhibitors

Although monitoring of response to treatment with TNF-α inhibitors typically involves the systems described above (clinical assessment, DAS28 and EULAR response criteria), there are neither gold standards nor guidelines available specifically for the monitoring of TNF-α inhibitors. More recently, biochemical enzyme-linked immunosorbent assay (ELISA) has emerged to measure blood levels of TNF-α inhibitors, or antibodies to TNF-α inhibitors, in people with RA. These testing kits and services – LISA-TRACKER (Theradiag, Croissy-Beaubourg, France), IDKmonitor (manufactured by Immundiagnostik AG, Bensheim, Germany, and distributed in the UK by BioHit Healthcare, Cheshire, UK), RIDASCREEN^® (R-Biopharm, Darmstadt, Germany), MabTrack (Sanquin, Amsterdam, the Netherlands) and Promonitor kits [Progenika Biopharma SA (a Grifols–Progenika company), Derio, Spain], and ELISAs used by Sanquin Diagnostic Services (Amsterdam, the Netherlands) – might be useful for detecting primary and secondary non-response to TNF-α inhibitors and for the optimisation of dosages for those who are responding well. For those whose response to therapy has waned, the results of the tests are frequently dichotomised using a cut-off assay result; thus, people may be classified as having either therapeutic or subtherapeutic levels of the drugs, or may be classified as having clinically significant or insignificant levels of antibodies.

These tests may also elucidate reasons for treatment non-response. For example, non-adherence to TNF-α inhibitors may play a part in failure to respond to treatment. Monitoring of blood levels of TNF-α inhibitors, or antibodies to TNF-α inhibitors, can help to reveal non-adherence. In a 3-year study assessing non-adherence to ETN (using ELISAs) in people with RA, 4.1% [95% confidence interval (CI) 2.2% to 7.2%] of patients were non-adherent to treatment (non-adherence defined as serum ETN trough concentration of < 0.1 μg/ml in the absence of a valid medical reason), and 3.4% (95% CI 0.8% to 10.4%) of treatment non-responders had insufficient ETN exposure, indicative of non-adherence. 35

The administration of TNF-α inhibitor and anti-drug antibody assays most frequently occurs just before the next administration of the TNF-α inhibitor. This enables simultaneous measurement of a ‘trough’ level of the drug. The tests may be conducted concurrently, or using a reflex testing strategy, whereby the test for TNF-α-inhibitor drug levels is conducted first and the result is used to guide follow-up testing by the laboratory without a further request from the treating clinician (i.e. TNF-α inhibitor antibody testing would be conducted only if the drug was not detected in the sample).

Promonitor

Promonitor is a portfolio of assays that measure drug levels (ETN, IFX and IFX biosimilars, ADL and GLM) and their correlating anti-drug antibodies (anti-ETN, anti-IFX, anti-ADL and anti-GLM) (see Table 4). The kits are manufactured by Progenika and distributed in the UK by Grifols–Progenika UK. They consist of strips of precoated microtitre plate (96 wells), reagents, buffers, standards, controls and ELISA cover films. The ELISAs are laboratory based and are conducted either manually or on an automated ELISA processor.

IDKmonitor ELISA kits

IDKmonitor ELISA kits are manufactured by Immundiagnostik AG and distributed in the UK by BioHit Healthcare Ltd. The 10 kits measure either levels of free TNF-α inhibitor or levels of free anti-drug antibodies, or total levels of anti-drug antibodies (free antibodies and antibodies bound to the drug) (see Table 4). The kits consist of strips of precoated microtitre plate (96 wells), reagents, buffers, standards (drug-level ELISAs only) and controls. The ELISAs are laboratory based and conducted either manually or on an automated ELISA processor.

LISA-TRACKER ELISA kits

LISA-TRACKER ELISA kits are manufactured by Theradiag. The kits measure either levels of free anti-drug antibodies or levels of free TNF-α inhibitor (see Table 4). In addition, LISA-TRACKER Duo kits (Theradiag) are available (these include assays to measure the levels of both free anti-drug antibodies and the TNF-α inhibitor). The LISA-TRACKER ELISA kits consist of precoated strips of microtitre plate (96 wells), reagents, wash buffer, standards and controls. They are laboratory-based assays that can be run simultaneously or individually, on any manual or automated standard ELISA-based processor platform.

RIDASCREEN

The RIDASCREEN ELISA kits are manufactured by R-Biopharm. The four kits are laboratory-based assays measuring either levels of free TNF-α inhibitor or levels of free anti-drug antibodies (see Table 4). The RIDASCREEN ELISAs are commercialised versions of the KU Leuven (Leuven, Belgium) in-house ELISAs, and are marketed as apDia (Turnhout, Belgium) ELISA kits in the Benelux area of Europe.

MabTrack ELISA kits and Sanquin Diagnostic Services

Sanquin is a laboratory that provides laboratory test services, including testing for TNF-α inhibitors using ELISA-based assays. The testing service, which uses validated ELISAs, is available for ETN and its correlating anti-drug antibodies, GLM drug levels and CTZ drug levels. It also provides Conformité Européenne-marked MabTrack ELISA kits for local laboratory testing for ADL and IFX levels and their correlating anti-drug antibodies (see Table 4). The MabTrack ELISA kits consist of precoated strips of microtitre plate (96 wells), reagents, wash buffer, standards or calibrators, controls and ELISA cover films.

Population

The eligible population was people with RA who were receiving treatment with a TNF-α inhibitor (ADL, ETN, IFX, CTZ and GLM) and had:

• achieved treatment target (remission or LDA) or

• experienced a primary non-response or

• experienced a secondary non-response.

Interventions

The ELISA kits or diagnostic services used to monitor response to TNF-α inhibitor treatments for people with RA were eligible for inclusion. These tests run on an ELISA technology platform and are used to measure drug levels (ADL, ETN, IFX, CTZ, and GLM) or their anti-drug antibodies (anti-ETN, anti-IFX, anti-ADL, anti-CTZ and anti-GLM). A serum sample is needed to perform an ELISA.

Eligible ELISAs can be run with or without automation platforms and may be used with any ELISA platform or the Triturus and SQII platforms. Each test needs to be run only once, potentially allowing for high throughput. The test should be intended for monitoring purposes to inform treatment decisions for biological therapies in people with RA.

The ELISA kits or diagnostic services shown below were included:

• Promonitor ELISA kits –

  • Promonitor-ADL-1DV

  • Promonitor-ANTI-ADL-1DV

  • Promonitor-ETN-1DV

  • Promonitor-ANTI-ETN-1DV

  • Promonitor-GLM-1DV

  • Promonitor-ANTI-GLM

  • Promonitor- IFX-1DV

  • Promonitor-ANTI-IFX-1DV.

• IDKmonitor ELISA kits –

  • IDKmonitor adalimumab drug level

  • IDKmonitor adalimumab free ADA

  • IDKmonitor adalimumab total ADA

  • IDKmonitor etanercept drug level

  • IDKmonitor etanercept free ADA

  • IDKmonitor golimumab

  • IDKmonitor golimumab free ADA

  • IDKmonitor infliximab drug level

  • IDKmonitor infliximab free ADA

  • IDKmonitor infliximab total ADA.

• LISA-TRACKER ELISA kits –

  • LISA-TRACKER adalimumab (LTA002)

  • LISA-TRACKER anti-adalimumab (LTA003)

  • LISA-TRACKER Duo adalimumab (LTA005)

  • LISA-TRACKER certolizumab (LTC002)

  • LISA-TRACKER anti-certolizumab (LTC003)

  • LISA-TRACKER Duo certolizumab (LTC005)

  • LISA-TRACKER etanercept (LTE002)

  • LISA-TRACKER anti-etanercept (LTE003)

  • LISA-TRACKER Duo Etanercept (LTE005)

  • LISA-TRACKER golimumab (LTG002)

  • LISA-TRACKER anti-golimumab (LTG003)

  • LISA-TRACKER Duo golimumab (LTG005)

  • LISA-TRACKER infliximab (LTI002)

  • LISA-TRACKER anti-infliximab (LTI003)

  • LISA-TRACKER Duo infliximab (LTI005).

• RIDASCREEN ELISA kits –

  • RIDASCREEN ADM monitoring (G09043)

  • RIDASCREEN anti-ADM antibodies (G09044)

  • RIDASCREEN IFX monitoring (G09041)

  • RIDASCREEN anti-IFX antibodies (G09042).

• MabTrack ELISA kits –

  • MabTrack level adalimumab M2910

  • MabTrack ADA adalimumab M2950

  • MabTrack level infliximab M2920

  • MabTrack ADA infliximab M2960.

• Sanquin Diagnostic Services (testing service using validated ELISAs) –

  • ADL drug levels

  • CTZ drug levels

  • ETN drug levels

  • ETN anti-drug antibodies

  • GLM drug levels

  • IFX drug levels.

The use of both free and total anti-drug antibody assays for these tests was assessed, depending on the availability of assessment data relating to both assays. The intervention tests were used in addition to current clinical practice (clinical assessment and monitoring using a composite score, such as the DAS28).

Comparator

The comparator was standard of care (SOC) for people with RA, in which treatment decisions are based on clinical judgements and monitoring using a composite score, such as the DAS28, without the knowledge of circulating drug levels and anti-drug antibodies by ELISA.

Outcomes

There was no restriction on when the outcomes were measured. The following outcomes were included:

• Test (procedural) outcomes –

  • number of inconclusive test results

  • time to test result.

• Treatment and management outcomes –

  • number, direction and magnitude of dose changes

  • frequency of dose adjustment (e.g. dose reduction) due to monitoring response

  • frequency of treatment switch to an alternative biologic

  • discontinuation of ineffective therapy.

• Clinical outcomes –

  • change in disease activity

  • rates of disease response, relapse and remission

  • duration of response, relapse and remission

  • rates of hospitalisation

  • rates of surgical intervention

  • AEs of treatment, such as infections.

• Patient-related outcomes –

  • HRQoL.

The primary clinical outcomes were clinical and patient-related end points, including reduction in disease activity and improvement in HRQoL. The clinically important intermediate outcomes were the change in number, direction and magnitude of TNF-α inhibitor dose; the change in frequency of dose adjustment due to monitoring response; the change in frequency of treatment switch to an alternative biologic; and the discontinuation of ineffective therapy.

Study design

Both randomised controlled trials (RCTs) and non-randomised controlled studies were included, provided that they compared therapeutic drug monitoring (TDM) using ELISA tests with SOC. Observational studies (e.g. prospective cohort studies, retrospective cohort studies and studies with a historical control) that evaluated the clinical effectiveness of the intervention tests to monitor treatment response in people with RA were included, provided that they reported any of the clinical outcomes relevant for this assessment.

Exclusions

The following types of report were excluded: editorials and opinions, case reports and reports focusing on technical aspects of the technologies only (such as technical descriptions of the testing process). Non-English studies were excluded. Studies with a sample size of ≤ 20 participants were excluded owing to inadequate statistical power. For studies that included people with RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA) to be eligible, at least 70% of the study population had to be people with RA, provided other eligibility criteria were met. In the case of studies in which < 70% of participants were people with RA, we discussed relevance with clinical experts, and we contacted the study authors to try and to obtain subgroup data for people with RA. However, these 70% criteria were subsequently relaxed to avoid a paucity of evidence. If there were multiple reports for a given study or the possibility of overlapping populations could not be excluded, the most recent or most complete report was selected.

Characteristics of included studies

The characteristics of the included studies are presented in Tables 6 and 7. 42–45 All studies recruited people with RA who had achieved treatment target (remission or LDA). One study, that was reported in three abstracts,42,43,45 used Promonitor ELISA kits for monitoring drug levels and/or anti-drug antibody levels. One study44 used Sanquin ELISA kits to measure drug levels and/or anti-drug antibody levels of three TNF-α inhibitors (IFX, ADL and ETN) for the treatment of RA. The type of Sanquin test kit used in this study was not reported. The two included studies were conducted in Spain. Neither study reported funding sources.

Baseline characteristics of included studies

Baseline characteristics of included studies are presented in Tables 8 and 9. The mean age of participants enrolled in the INGEBIO study (according to Ucar et al. 42) was 53.59 years, but the mean age of participants in the observational study was not reported. The mean duration of RA was 17 years in the observational study.

The definition of remission/LDA was described as a DAS28 of < 3.2 in the observational study, but was not reported in the non-randomised controlled study (see Tables 8 and 9). Both studies included in the systematic review used one or more TNF-α inhibitors (ADL, IFX or ETN) for the treatment of RA. The mean treatment duration for participants receiving TNF-α inhibitors was 6 years in the observational study but was not reported in the non-RCT.

Only methotrexate was reported as a co-therapy in the non-RCT, whereas no co-therapies were reported in the observational study.

Ongoing study

We identified one ongoing RCT that met the inclusion criteria for this systematic review of clinical effectiveness: the Norwegian Drug Monitoring (NOR-DRUM) study. 46 Study characteristics are summarised in Appendix 3. Enrolment in the NOR-DRUM study commenced in March 2017, with an expected primary completion date of March 2020 and study completion date of March 2022.

The aim of this trial is to assess the clinical effectiveness of TDM in participants who are starting IFX and in participants who are on maintenance IFX therapy. The type of ELISA testing is not reported. The target recruitment for this study is 600 people with RA or other immunological inflammatory diseases.

The intervention of this trial will be TDM with a treatment algorithm based on measurement of serum levels of drug and anti-drug antibodies. The control group is standard care, in which clinicians will make treatment decisions without the knowledge of drug levels or status of anti-drug antibodies.

The major primary outcomes are the proportion of participants in remission and the proportion of participants experiencing sustained disease control without disease worsening. Secondary outcomes of interest include time to sustained remission, occurrence of drug discontinuation, health utility [EuroQol-5 Dimensions (EQ-5D)], HRQoL [Short Form Questionnaire-36 items (SF-36)], time to disease worsening and clinical efficacy outcomes assessed by composite disease activity scores.

Risk of bias of the included studies

The risk of bias of the included studies was assessed using the Cochrane (ROBINS-1) tool for non-randomised studies. The Cochrane (ROBINS-1) tool was also used to assess the quality of the observational study with adaptations as appropriate, although the tool was primarily designed for non-randomised controlled studies. The following domains relating to risk of bias were assessed for each individual study: confounding, selection, group classification, co-interventions, missing data, outcome measurement and selective outcome reporting. The quality assessments on the basis of all relevant domains for each study and of specific outcomes are presented in Appendix 4. Tables 10 and 11 present the quality assessment of the included studies.

Table 10 details the quality assessment of the non-randomised controlled study (the INGEBIO study). 42,43,45 This non-randomised controlled study was judged to be at serious risk of bias. There was an issue of baseline imbalance in the proportions of participants in remission or with LDA between the intervention group and the control group: at baseline 73.4% of participants were in remission in the intervention group, compared with 83.3% of participants in the control group. The remaining participants (i.e. 26.6% of participants in the intervention group and 16.7% of participants in the control group) had achieved LDA at baseline. Furthermore, there was a lack of adjustment for baseline imbalance in this variable in the analysis of clinical outcomes. These deficiencies resulted in a serious risk of bias associated with the findings.

Table 12 presents the attrition rates for each outcome of the non-randomised controlled study (the INGEBIO study). 42,43,45 As seen in Table 12, attrition rates for three outcomes (proportion of participants who remained in remission, proportion of participants who changed from LDA to remission and proportion of participants who received dose tapering) were high, ranging from 10.3% to 30.8%, which can lead to attrition bias. Furthermore, attrition rates for these outcomes were unbalanced between the intervention group and the control group.

Table 11 presents the quality assessment of the observational study. 44 The study had a historical control group and was judged to be at moderate risk of bias because there was non-contemporaneous control bias as a result of the use of historical control. It should be noted that the same group of participants were assessed during the first period (i.e. the historical control, before TDM was introduced) and the second period (after TDM was introduced). Attrition rates are shown in Table 13.

Overall, the non-randomised controlled study42,43,45 was judged to be at serious risk of bias whereas the observational study was judged to be at moderate risk of bias.

Non-randomised controlled trial

Three included abstracts42,43,45 reported the same non-randomised controlled trial (the INGEBIO study). This trial recruited participants who had achieved treatment target (remission or LDA) and had remained clinically stable for at least 6 months.

This trial recruited a mixed population of 169 participants, including 63 people with RA. The results of the total mixed population were reported in the review, as the authors were not able to provide the results for the cohort of 63 people with RA (the study was not powered to detect a meaningful difference between the intervention and the control group for the cohort of people with RA only). The three cohorts of participants who had different conditions (RA, PsA and AS) may have different treatment responses to TNF-α inhibitor therapies. Therefore, there was limited generalisability of the findings from this mixed population to the RA population. At baseline, the median trough level of ADL was 5.3 mg/l in the intervention group and 5.5 mg/l in the control group. The included abstracts were judged to be at serious risk of bias. Tables 14 and 15 present the results of this non-randomised controlled study.

Observational study

The observational study by Pascual-Salcedo et al. 44 evaluated the effect of using ELISA for monitoring response to TNF-α inhibitors in people with RA. The study included participants who had achieved treatment target (remission or LDA). The study had a historical control and was judged to be at moderate risk of bias.

Comparative controlled evidence

Three abstracts42,43,45 reporting the same non-randomised controlled trial were identified. The INGEBIO study focused on the population with RA who had achieved treatment target (remission or LDA). In this trial, levels of ADL and anti-ADL antibody were measured using Promonitor-ADL and Promonitor-ANTI-ADL. This trial recruited a mixed population of 169 participants, including a cohort of 63 people with RA. The results of the total mixed population were reported in the review, as the authors were not able to provide the results for the subgroup of people with RA.

This non-randomised controlled trial (the INGEBIO study) found a non-significant reduction in the risk of flare in the intervention group compared with the control group. In particular, participants’ HRQoL outcomes were higher in the intervention group than in the control group at all visits, with statistically significant results being observed at two visits. However, as the trial was judged to be at serious risk of bias, the results should be interpreted with caution. Ideally, randomisation of participants is required to minimise the risk of bias of study findings.

Evidence from observational studies

We identified one observational study that evaluated the effect of TDM on clinical outcomes in people with RA who had achieved remission or LDA. The study44 had a historical control.

Reliability of the findings

The non-randomised controlled study42,43,45 was judged to be at serious risk of bias. In this trial, there was an issue of baseline imbalance in disease severity between the intervention and the control groups. Furthermore, this imbalance was not adjusted for in the analysis of clinical outcomes. Attrition rates were higher for some outcomes, which can lead to attrition bias. These deficiencies resulted in the findings being at serious risk of bias. Therefore, the results should be interpreted with caution.

The historically controlled observational study44 was judged to be at moderate risk of bias because the control was non-contemporaneous, although it should be noted that the same group of participants were assessed during the first period (the historical control, before TDM was introduced) and the second period (after TDM was implemented). However, the sample size was small. Therefore, the overall poor quality of included studies compromises the reliability of the findings.

Generalisability of the findings

Given that both studies were conducted in Spain, the findings from these studies may have limited generalisability to the UK setting owing to variations in clinical practice and health policies between the two countries. Furthermore, the findings from the non-randomised controlled trial (the INGEBIO study42,43,45) and the results of changes in the therapeutic dose from the study by Pascual-Salcedo et al. 44 were presented for a mixed population. Therefore, there was limited generalisability of findings from the mixed population (including RA, PsA and/or AS) to the target RA population.

Implications for future research

We identified one ongoing Norwegian multicentre RCT (the NOR-DRUM study)46 evaluating the effect of TDM in people with RA in remission compared with standard care. This ongoing trial will provide further useful data on the impact of TDM in the target population.

Further controlled trials (especially RCTs) are required to assess the impact of using Promonitor ELISA tests for monitoring TNF-α inhibitor therapies in people with RA who have achieved remission or LDA.

No studies that assessed other eligible ELISA kits, including IDKmonitor, LISA-TRACKER, RIDASCREEN and MabTrack, were identified.

Therefore, future large RCTs are required to assess the impact of using ELISA for monitoring TNF-α inhibitor therapies in people with RA who have achieved remission or LDA. More robust evidence is also needed to evaluate the impact of using Sanquin tests to monitor TNF-α inhibitor therapies in this population.

Future RCTs are warranted to evaluate the clinical effectiveness of using ELISA tests to monitor TNF-α inhibitor therapies in people with RA who have experienced a primary non-response or a secondary non-response.

No studies among patients who were being treated with CTZ and GLM were identified. Future RCTs are required to assess the clinical effectiveness of using ELISA to monitor such TNF-α inhibitor therapies in the target populations.

Conclusions

Limited data regarding the clinical effectiveness of TDM in the target populations were identified. One non-randomised trial that compared TDM with standard care (the INGEBIO study) had serious limitations in relation to the NICE scope:48 only one-third of the participants had RA; many of the analyses were not by ITT; follow-up was only 18 months; there was no explicit algorithm to guide clinicians how to change treatment in response to the results of testing (e.g. tapering); and the study was reported in three abstracts only. In addition, we identified one observational study, but this was of limited value in informing whether or not ELISA-based monitoring is clinically effective.

Krieckaert et al.53

Krieckaert et al. 53 conducted a cost–utility study that investigated the measurement of ADL levels in people with RA. ADL levels were measured using in-house ELISA (Sanquin) for 3 years in a cohort of 272 ADL-treated participants with RA recruited at the Department of Rheumatology, Jan van Breemen Institute, Amsterdam. 55 These participants were compared with a cohort of 1034 participants from the Utrecht Rheumatoid Arthritis Cohort (URAC), who received other treatments based on clinical judgement. The clinical characteristics of these participants are not clearly discernible from the cited references. Participants in the intervention cohort were tested after 4, 16, 28, 40 and 52 weeks of treatment and every 6 months thereafter. However, in the economic analysis, the authors modelled ELISA testing at 28 weeks only. After 3 years, 76 of a total 272 participants (28%) developed anti-ADL antibodies; 51 (67%) participants developed these during the first 28 weeks of treatment. Over the course of the study, participants with measurable antibody levels were 3.6 times less likely [hazard ratio (HR) 3.6, 95% CI 1.8 to 7.2; p < 0.001] to revert to minimal disease activity (defined as a DAS28 of < 3.2) and 7.1 times less likely (HR 7.1, 95% CI 2.1 to 23.4; p < 0.001) to enter sustained remission (DAS28 of < 2.6). Clinical outcomes from Bartelds et al. 55 are summarised in Table 19.

Of note, this study55 was excluded from the clinical effectiveness systematic review because it did not meet the inclusion criteria for the population (the population was treatment naïve and had active disease). As this paper was excluded at the first-screening stage (titles and abstracts), it was not included in the list of excluded studies (see Appendix 2).

Krieckaert et al. 53 modelled a treatment algorithm (see figure 1 in Krieckaert et al. 53) based on TDM in RA patients. The authors used a Markov model with 3-month cycles and a time horizon of 3 years using microsimulation for analysis. The analysis was performed probabilistically. Discounting was applied at 4% for costs and 1.5% for utilities, following the Dutch national guidelines. 56 Results were reported from both health-care and societal perspectives. The Markov model health states were based on categorisation of DAS28 as below:

• remission (DAS28 of < 2.6)

• LDA (DAS28 of ≥ 2.6 and < 3.2)

• MDA (DAS28 of ≥ 3.2 and ≤ 5.1)

• high disease activity (HDA) (DAS28 of > 5.1).

Transition probabilities were estimated using a regression function that was derived from the URAC cohort outcome data. 55 Costs included direct medical and productivity costs. Utility was calculated based on the EQ-5D classification outcomes recorded in the URAC study.

Testing with ELISA kits was cost-saving from both the societal and the health-care perspective (Table 20). The test-based treatment strategy resulted in lower costs (due to the reduction in the treatment cost) and greater QALYs.

A probabilistic sensitivity analysis around the base-case scenario predicted that ELISA testing would dominate usual care in 72% of scenarios. Scenario sensitivity analyses around, for example, the drug level cut-offs used, or the definitions of a good EULAR response, showed that ELISA testing is generally cost-saving, although some scenarios reported loss of QALYs.

Laine et al.54

Laine and colleagues54 conducted a cost-effectiveness study in Finland. The intervention involved assessment of drug and anti-drug antibody levels in people with RA who were treated with ADL or IFX. The data on drug and anti-drug antibody levels were taken from the clinical sample registry of United Medix Laboratories Ltd (Helsinki, Finland), which included 486 and 1137 samples from participants on ADL and IFX, respectively. Drug levels were measured using ELISA, whereas antibody levels were assessed using radioimmunoassay. All measurements of antibody and ADL levels were outsourced to Sanquin Diagnostic Services. Approximately half of the measurements of IFX levels were undertaken by the United Medix Laboratories using the Promonitor test kit.

Clinical management decisions based on the test results followed the algorithm proposed by Vincent et al. 57 (see figure 1 in Vincent et al. 57). Possible treatment decisions included switching to another TNF-α inhibitor or switching to a bDMARD with a different mechanism of action.

The economic impact of clinical decision-making compared with management by clinical judgement only and without testing was modelled in a short-term (3–6 months) scenario with 100 hypothetical non-responders. The outcome measures were the change in the probability of undergoing periods of suboptimal treatment and the cost-effectiveness of routine monitoring compared with clinical judgement only. An inappropriate clinical decision was defined to lead to ineffective treatment for at least 3–6 months. The authors justified this time period by basing it on the typical follow-up visit frequencies of people with RA who were treated with biologics in Finland (no data sources were provided). This meant that all of the participants in the control arm experienced a 3-month delay in receiving appropriate treatment. This delay was estimated to cost €1471 per month, which included the estimated monthly cost of subcutaneous TNF-α inhibitor (€1140); the cost of a laboratory visit, both travel cost and lost working and leisure time (€17.40); the cost of the possible standard safety-related laboratory tests (€6.80); the cost of a follow-up visit to an outpatient specialist clinic, both travel cost and lost working and leisure time (€66.60); and specialist visits (€240.60). Long-term efficacy-related costs were not modelled. The cost of resource use was valued using national unit costs adjusted for inflation to the year 2013. 58

The authors proposed a Markov model with 6-month cycles and a 3-year time horizon. Health states were defined as ‘first TNF-α blocker’, ‘second biological (TNF-α blocker or non-TNF drug)’ and ‘quitting biologics’.

The model predicted that, over the 3-year period, in the intervention arm, 40% of participants on ADL and 50% of participants on IFX would need drug modification. Based on a hypothetical cohort of 100 participants, the cost of testing was estimated to amount maximally to €20,000 (€200 × 100 participants). Dividing the cost of the test by the cost per month of non-optimised treatment will then indicate the threshold number of person-months of suboptimal treatment that correspond with testing being considered cost-effective. Laine et al. 54 reported that the routine measurement of both drug and antibody levels would be cost-saving compared with the non-testing scenario, assuming that a minimum of 2.5% or 5% of patients are treated non-optimally for 6 or 3 months, respectively.

Gavan17

Gavan17 evaluated the cost-effectiveness of using ELISA testing to monitor people with RA who are treated with ADL. In total, 12 different ELISA-based strategies were compared with the current practice in England (i.e. no TNF-α testing) (see Table 51 in Appendix 7). These strategies were a combination of using monitoring tests during response to the drug and after remission. The author considered a frequency of testing of every 3 or 6 months in responders to therapy. Among patients in remission, testing was considered after 2 and 3 years’ remission.

In Gavan,17 four lines of treatment were modelled, as shown in Figure 2.

FIGURE 2.

Service pathway of RA treatment in England. Adapted from Gavan. 17

A discrete-event simulation modelling approach was used. The following competing events were considered: time to death, ADL failure, rituximab (Rituxan^®; Roche, Basel, Switzerland) failure, tocilizumab failure, time to development of antibodies against ADL, remission, EULAR response and HAQ progression. The model simulated 20,000 hypothetical patients, representative of the population with RA in England, using summary attributes of patients from the BSRBR-RA.

One of the test strategies considered in Gavan17 was monitoring drug and antibody levels in participants who were responding to treatment to avoid the harm associated with secondary non-response. Another possible test strategy was dose adjustment in patients in remission, informed by the results of TNF-α testing. Figure 3 shows the algorithm used by Gavan17 for management decisions in participants who had TDM performed.

FIGURE 3.

Algorithm for test interpretation used in Gavan. 17 Adapted from Gavan. 17

Utilities were calculated by mapping the HAQ score from the BSRBR-RA, by using a quadratic mapping algorithm estimated previously for the NICE TA195 by Malottki et al. 59 Costs included the costs of treatment, hospitalisations and testing. Quantities of resource utilisation were derived from published sources34,37 and unit costs were taken from the NHS Reference Costs 2015–1660 and the BNF. 21

Based on the 12 strategies that were modelled (see Appendix 7, Table 51), Gavan17 concluded that routine use of ADL testing was cost-effective compared with current practice, but was unlikely to be cost-effective relative to dose reduction (without testing) for people in remission (strategy 11). Compared with current practice, strategies 1–6 and strategy 8 were estimated to be cost-effective. Strategies 9 and 10 were estimated to be less costly, but produced a lower QALY gain than current practice. Strategy 7 was dominated by current practice, that is current practice was associated with lower costs and a higher QALY gain than strategy 7. In the incremental analysis, all but three strategies (strategies 1, 3 and 11) were shown to be dominated or extendedly dominated by another strategy, that is that another strategy or combination of strategies was cheaper and produced more QALYs. Of the three remaining strategies, strategies 1 (testing levels of ADL and anti-ADL antibodies every 3 months) and 3 (testing levels of ADL and anti-ADL antibodies every 3 months, testing ADL level in patients in remission after 2 years) were not cost-effective compared with strategy 11 (no testing, halving ADL dose in all patients after responding for 2 years, irrespective of their drug level) at a willingness to pay of £20,000–30,000 per QALY gained: the incremental cost-effectiveness ratio (ICER) for strategy 1 versus 11 was £38,575 per QALY and the ICER for strategy 3 versus 11 was £37,043 per QALY. Given that strategy 11 consists of dose reduction after 2 years for people in remission, the analysis of the chosen strategies suggests that ADL testing may not be cost-effective compared with dose reduction alone.

Search for additional clinical effectiveness evidence

Studies that were identified by the searches conducted for the clinical effectiveness systematic review but not considered eligible for inclusion (e.g. studies reporting correlations between drug/antibody levels and therapeutic outcomes, and/or studies reporting drug/antibody levels before and after dose reductions only) were used to inform the model where appropriate.

Owing to the lack of RCT evidence on the effectiveness of the tests that are defined within the NICE scope,48 an additional systematic literature review was conducted to identify RCTs that evaluated any tests used to monitor TNF-α inhibitor treatment in people with RA. The aim of this search was to identify any evidence on the effectiveness of any strategies of treatment monitoring that could be used to inform scenario analyses for modelling.

Searches were carried out in MEDLINE, MEDLINE In-Process, EMBASE, the Cochrane Library and Web of Science. Searches were limited to RCTs and were carried out in October 2018. The search strategy and inclusion criteria are provided in Appendix 9. A total of 1418 hits were identified and were independently screened by two reviewers using the inclusion criteria shown in Appendix 9, Table 54. No relevant papers were identified.

Modelling approach

The choice of the modelling approach was primarily driven by the availability and quality of the evidence that was identified in the clinical effectiveness systematic review; other factors included the multifactorial nature of decisions to adjust treatments in people with RA34 and the recent changes in the biologics market, which contributed to the uncertainty in the prices of the TNF-α inhibitors and their uptake in the UK.

The biologics market is likely to increase in complexity over the coming months and years as more originator biological medicines lose patent exclusivity and additional biosimilar medicines come to the market. 61 The patent for ADL (Humira) expired on 16 October 2018 (when this assessment was carried out). New medications with similar active properties (‘biosimilar’ versions) are likely to become available in the NHS at the end of 2018 (see Table 2). The following ADL biosimilars have already been approved for use in the UK but have not yet launched (as of 30 November 2018): Amgevita, Hulio, Hyrimoz and Imraldi. According to the Regional Medicines Optimisation Committee Briefing,62 at least two further biosimilars are expected to become available in the UK during 2019: Cyltezo (from Boehringer Ingelheim) and another will be brought to the market by Fresenius Kabi (Bad Homburg, Germany).

The NHS has established a working group to provide an oversight of implementing the use of best-value ADL using a commissioning framework that was launched in September 2017. 63 The framework, authored by the NHS’s Medicines, Diagnostics, Personalised Medicine Policy Team, proposes that ‘at least 90% of new patients be prescribed the best value biological medicine’ within 3 months of the launch of a biosimilar for a given reference product, and that 80% of existing patients be prescribed the ‘best value medicine within 12 months of a biosimilar launch’. 63

With regard to the current uptake of biosimilars in the UK, according to the Medicines Optimisation Dashboard data published by NHS England (September 2018 release),64 92% of people prescribed IFX and 85% of those prescribed ETN are taking biosimilars. However, there are regional variations in the uptake of biosimilars. 64 In the Royal Devon & Exeter NHS Foundation Trust, people with RA who have been prescribed IFX or ETN are usually given their biosimilars, whereas biosimilars for ADL have become available only recently; patients prescribed GLM or CTZ are treated mostly with the originator products (Dr Haigh, Royal Devon and Exeter NHS Foundation Trust, Exeter, November 2018, personal communication). In the Greater Manchester area, the biosimilar Amgevita is soon to be used for patients who are prescribed ADL; patients who are prescribed IFX are usually given its biosimilars, Inflectra or Remsima; and a biosimilar Benepali is used in some patients who are prescribed ETN (Dr Jani, University of Manchester, personal communication, November 2018).

Although the NICE guidance23 recommends that people with RA receive treatment with the TNF-α inhibitor with the lowest acquisition and administration costs, in practice other non-cost factors, such as patient and hospital characteristics, and changes in regional rheumatology clinical guidelines, may influence the choice of treatment. 17

Analyses conducted

Threshold and cost–utility analyses based on a decision tree model (described in Model structure) were conducted to estimate the economic outcomes of adding TDM to SOC for RA patients who were treated with TNF-α inhibitors.

Model structure

A diagram of the decision tree model that was used in the threshold and cost–utility analyses is presented in Figure 4.

FIGURE 4.

Model diagram.

As shown in Table 23, approximately one-third of patients in the treatment and comparator arms of the INGEBIO study had their ADL dose tapered; flares were observed in patients from both arms. The effect of flares on costs and QALYs was modelled following Gavan. 17 Figure 5 (adapted from Gavan17) illustrates the cost and QALY profile depending on whether or not the dose is tapered. The figure shows changes in the acquisition cost and QALYs due to flares over time. Note that, for the sake of clarity, the other components of the total costs and QALYs considered in our analyses are not depicted here.

FIGURE 5.

(a) Acquisition cost and (b) QALY change owing to flare in tapered and non-tapered patients. a, Change in QALYs owing to flare. T₁ – t₀ is the time on tapered dose, t₂ – t₁ is the duration of flare and q_f is the disutility of flare. Adapted from Gavan. 17

As shown in Figure 5, all patients had their drug levels tested at t₀, resulting in tapering of the dose in some patients (see Figure 5a). It was assumed that a proportion (p) of patients on tapered doses experienced flare at t₁, prompting treatment to revert to the original dose, whereas in the remainder (1 – p) the dose remained the same (i.e. tapered). In those patients who flared, the disutility of flare (q_f) was applied for the duration of flare (t₂– t₁) (see Figure 5a). In non-tapered patients (see Figure 5b), the acquisition cost was based on the cost of the full dose; it was assumed that non-tapered patients do not experience flares.

In clinical practice, flares have been observed in patients receiving full and reduced doses of the biologics, with an increased risk of flares in tapered patients. 65 In the economic analysis, however, the occurrence of flares was modelled in all patients regardless of their treatment dose (see Figure 5a) given that the flare rates reported in the INGEBIO study were not stratified by dose.

The estimates of the mean time to the first flare were used to model the time when the dose in flared patients was restored to the full dose indefinitely (which affected the drug acquisition costs and wastage), whereas the flare rates were used to estimate the cost of flare management and the reduction in QALYs due to occurrence of flares in the treatment and control arms. It was also assumed that flares could occur in any health state. 66

Subgroups

People with RA can be grouped according to three clinical scenarios: primary non-response, secondary non-response and remission. However, with regard to particular characteristics, there are no subgroups for which the clinical effectiveness of TDM is expected to significantly vary; therefore, no subgroup analyses were considered in this assessment.

Flares

The concept of flare remains challenging to understand, as there are no generally recognised definitions of or well-validated measures for flare in RA. 70 Nevertheless, patients, clinicians and scientists commonly resort to this term to refer to episodes of worsening disease activity, which includes a range of symptoms of different duration and magnitude. 71

Several different RA flare criteria have been used in clinical research. For instance, van der Maas et al. 47 identified six previously published DAS28-based flare criteria, and Markusse et al. 72 reported three criteria (Table 25).

Smolen et al. 66 compared RA patients treated with ETN recruited in the PRESERVE trial who did or did not have flares. In this trial, a disease flare was defined as either loss of LDA, with or without a change in DAS28 of 0.6, or relapse (DAS28 of > 5.1 or DAS28 of > 3.2 at two or more consecutive time points).

In the INGEBIO study, a flare was defined as an increase in DAS28 of > 1.2 or an increase in DAS28 of > 0.6 if the current DAS28 was ≥ 3.2.

Serious adverse events

When modelling the effect of AEs on patient’s HRQoL and costs, the approach used in TA37523 was adopted: it was assumed that only serious adverse events (SAEs) (serious infections in particular) would carry a significant cost and disutility burden. 23 This assumption was considered appropriate by the EAG’s clinical advisors.

Resources and costs

Costs considered in the economic evaluation included the cost of testing, and treatment and health-care costs. Unit costs were obtained from the BNF,21 NHS Reference Costs,84 documents provided by test manufacturers and published and unpublished sources.

Cost of joint replacement surgery

The weighted average cost of joint replacement surgery was £522284 per surgery, which was estimated from HRGs relevant to hip and knee procedures for non-trauma across all clinical codes (HN12–HN14 and HN22–HN24, respectively).

Burn et al. 96 investigated hospital reimbursement for total knee replacement (TKR) and total hip replacement (THR) surgeries in NHS England between 1997 and 2014. Primary reimbursement for TKR and THR was approximately £6000 per surgery (2016/17 prices), whereas revision surgeries were approximately £8000 per surgery. These estimates were derived from the NHS primary care records of 21,128 people with osteoarthritis or RA. The authors reported on the downward trend in the costs of TKR and THR.

The average cost of joint replacement surgery in people with RA in the Royal Devon & Exeter NHS Foundation Trust is £5061.80 (standard error £5153) (see Appendix 19). This estimate was based on 15 surgeries that were conducted between April 2017 and September 2018. Of note, this estimate is slightly lower than those from the NHS Reference Costs 2017–1884 (see Table 30 and Burn et al. 96). This might be a result of the trend in the cost of surgery reported by Burn et al. 96 However, the sample size was very low and, therefore, this estimate may not be representative of the average cost of surgery in the RA patient population in the UK.

In all analyses, the annual costs of managing different health states were derived from the average cost of joint replacement surgery based on the HRGs from the NHS Reference Costs 2017–1884 (£5222 per joint replacement surgery; see Table 30).

In the analyses presented here, it was assumed, based on clinical advice, that surgery may be performed anywhere in the treatment pathway; however, the EAG is aware that older people are more likely to require surgery for RA.

Health-related quality of life

A review of HRQoL studies was conducted to inform the selection of utilities for the economic analysis. Health-state utilities, as well as disutilities for flares and SAEs (such as severe infections), that were used in the analyses are described below.

Health state utility values

The abstracts reporting the INGEBIO study provided results on the average duration of either remission42 or remission/LDA43 in both the intervention and the control arms. However, none of the sources contain any definitions of remission.

A definition of remission was provided in Krieckaert et al. 53 In this study, health states were based on the categorisation of DAS28 as below:

• remission – DAS28 of < 2.6

• LDA – 2.6 ≤ DAS28 of < 3.2

• MDA – 3.2 ≤ DAS28 of ≤ 5.1

• HDA – DAS28 of > 5.1.

The DAS28 comprises four components: counts of tender joints and counts of swollen joints (both performed by a clinician), the visual analogue scale (VAS) score of the patient’s global health and the laboratory parameter ESR. It has been shown, however, that CRP is more accurate as an indicator of inflammation than ESR, and it is also more sensitive to short-term changes. 98 A modification of the DAS28, the DAS28-CRP,99 that includes the level of CRP instead of ESR was used in Bykerk et al. 70 to define the disease activity types below:

• severe – DAS28-CRP of > 5.1

• moderate –3.2 ≤ DAS28-CRP of ≤ 5.1

• low –2.6 ≤ DAS28-CRP of < 3.2

• remission – DAS28-CRP of < 2.6.

In the study conducted by Bartelds et al. ,55 remission was defined as a DAS28 of < 2.6 at all consecutive measurements after a certain time point, with a minimum of two scores of < 2.6 in the case of participants who discontinued treatment prematurely.

In Barnabe et al. ,100 sustained remission was defined as DAS28 of ≤ 2.6 for more than 1 year, whereas non-sustained remission was defined as a DAS28 of ≤ 2.6 for less than 1 year.

In TA375,23 non-responders, moderate responders and good responders were defined according to the EULAR response criteria (see Table 3).

Health state utility value estimated from the Health Assessment Questionnaire according to Simplified Disease Activity Index, Clinical Disease Activity Index and Disease Activity Score in 28 joints

There are several composite scores to assess disease activity in RA. The definitions of the disease states (i.e. remission, LDA, MDA and HDA) according to the SDAI, the CDAI and the DAS28 from Aletaha et al. 101 are presented in Table 32.

TABLE 32 - Cut-off points to separate remission and low, moderate and high disease activity states using composite indices SDAI, CDAI and DAS28

Note

Adapted from Aletaha et al. 101

Index	Remission	LDA	MDA/HDA
CDAI	≤ 2.8	≤ 10	≤ 22
SDAI	≤ 3.3	≤ 11	≤ 26
DAS28	< 2.6	< 3.2	< 5.1

Radner et al. ,83 at the Medical University of Vienna in Austria, collected data on clinical and laboratory characteristics (including CRP, ESR, the number of swollen and tender joints, pain by VAS, patient’s global assessment of disease activity, evaluator’s global assessment of disease activity and physical function by HAQ) from 356 consecutive people with RA at routine clinic visits (every 3–4 months). In total, 716 visits were documented, with a median of two clinic visits per person (ranging from one to four clinic visits). 83 At baseline, 87 participants (24.4%) were in remission, 150 (42.1%) in LDA, 103 (28.9%) in MDA and 16 (4.5%) in HDA, as defined according to SDAI. Owing to the small number of participants in the HDA group, the MDA and HDA groups were combined in further analyses. The differences in functional disability measured by the HAQ scores at three levels of disease activity were evident, and similar conclusions were reached during a sensitivity analysis, when the disease states were assessed according to CDAI and DAS28 (see Table 31). Unless stated otherwise, in the remainder of this article, health states are assumed to be defined by SDAI.

The EAG is aware of several algorithms for converting the HAQ score to utility in RA, and that the estimates of utilities may vary when different mapping algorithms are used. 102 In TA375,23 a comparison of published relationships between utility and HAQ was conducted (see figure 115 in Stevenson et al. 34). Three of the eight compared studies reported data from the UK. Of these three studies, Bansback et al. 103 included data for UK and Canadian patients, and Kobelt et al. 104 included data for patients in the UK and Sweden; therefore, these were not considered relevant for the purposes of this analysis. Hurst et al. 105 included people with RA in Scotland only. Malottki et al. 59 used the data set from Hurst et al. 105 to estimate the coefficients of their mapping equation; therefore, there is little difference between their estimates, despite different algorithms being used.

Throughout this monograph, the EQ-5D utility values were mapped from the HAQ scores using the same formula as in Malottki et al. :59

⁽⁶⁾ EQ ‑ 5 D = ( a – b 1 ) × ( HAQ – b 2 ) × HAQ 2 ,

where a = 0.804, b₁ = 0.203 and b₂ = 0.045.

Hernández Alava et al. 106 argued that pain should be included as an explanatory variable when estimating QALYs from HAQ scores in people with RA. This approach was used in TA375. 23 However, the estimates presented in this article were obtained without pain scores because the EAG did not have access to patient-level data. Table 33 presents the EQ-5D utility values mapped from the HAQ scores at three levels of disease activity from Radner et al. 83

TABLE 33 - The EQ-5D utility scores for the states of disease activity according to the SDAI, CDAI and DAS28 mapped from HAQ scores from Radner et al.83

The corresponding HAQ scores were obtained from a sensitivity analysis in Radner et al. 83

Index	Remission		LDA		MDA/HDA
	Mean score	Range	Mean score	Range	Mean score	SD
SDAI	0.718	0.565–0.804	0.635	0.432–0.796	0.483	0.222–0.694
CDAIa	0.720	0.573–0.804	0.626	0.415–0.794	0.486	0.229–0.694
DAS28a	0.701	0.532–0.804	0.666	0.477–0.804	0.483	0.226–0.691

Ucar et al. 42 reported the mean duration of remission in the intervention and control arms. In the economic analysis based on this source, the EQ-5D utility value for remission, 0.718, was applied. The utility value of 0.568 used for a mixed-disease state (LDA/active disease) was approximated by the average of the estimates for LDA and MDA/HDA weighted by the proportion of patients in each health state from Radner et al. 83 Of note, when the weighted average of HAQ scores was computed instead and mapped to EQ-5D, the utility value was very similar, 0.571.

As the health states in Arango et al. 43 (remission/LDA and active disease) were defined differently from those in Ucar et al. ,42 in analyses based on the former source,43 the EQ-5D utility score of 0.483 for MDA/HDA was used as the utility value for active disease health state, and the weighted average of the estimates for remission and LDA, 0.665, was used to approximate the utility value for the mixed-health state. When the alternative approach (described above) was used, the resulting utility value was 0.666.

Health state utility values (HSUVs) obtained from HAQ scores reported in Stevenson et al. 34 (as described in the following section were assumed in scenario analyses.

Health state utility values estimated from the Health Assessment Questionnaire by European League Against Rheumatism response category

In TA375,23 the model was based on a EULAR response category (good/moderate/none) to be consistent with the NICE guidance on biologics in RA36 and to align more closely with UK clinical practice in terms of the assessment of response to therapies. The HAQ scores were estimated from the BSRBR-RA database,67 which contains values measured at 6-month intervals for up to 3 years for all people with RA on the register. The analysis conducted in TA37523 was restricted to those with the full set of baseline characteristics and at least two additional HAQ measurements while on bDMARDs. The database included data from 10,186 patients. Of these, 2417, 5492 and 2277 were classed as EULAR good responders, moderate responders and non-responders, respectively (see Table 3).

Figure 6 shows the HAQ trajectory in people with RA treated with bDMARDs. It was observed that the mean HAQ scores for patients with good, moderate or no response (according to the EULAR response criteria shown in Table 3) decreased during the first 6 months after the start of biological therapy (when the magnitude of decrease grows with the level of EULAR response), stabilised at around 6 months and remained rather flat over the remaining 2.5 years of measurement.

FIGURE 6.

Mean HAQ score by EULAR response category for patients receiving biologics. Reproduced from Stevenson et al. 34 Contains information licensed under the Non-Commercial Government Licence v2.0, which is available at www.nationalarchives.gov.uk/doc/non-commercial-government-licence/version/2/.

Reproduced from Stevenson et al. 34 Contains information licensed under the Non-Commercial Government Licence v2.0, which is available at www.nationalarchives.gov.uk/doc/non-commercial-government-licence/version/2/.

The HAQ scores that were measured after 6 months of therapy with biologics for all three categories of responders were mapped to EQ-5D utilities, which elicited the values shown in Table 34.

TABLE 34 - Utility values based on BSRBR-RA data after 6 months of treatment with bDMARDs

Note

The estimates are based on data reported in Stevenson et al. 34

Type of patient	Number of patients in the BSRBR-RA dataset	HAQ score	Utility
Non-responder	2277	1.95	0.237
Moderate responder	5492	1.7	0.329
Good responder	2417	1.2	0.496

The utility for the remission health state was based on the utility value for good responders (0.496, see Table 34), whereas the utility for the LDA/active disease health state was estimated as the average of utility values for moderate responders and non-responders weighted by their proportions in the BSRBR-RA database, resulting in the utility value of 0.302. These HSUVs were used in sensitivity analyses.

Threshold analyses

Threshold analyses were conducted for both Ucar et al. 42 and Arango et al. (Table 36). 43

The results suggest that, if the outcomes reported in Ucar et al. 42 are used, then, under the list price of Humira, the cost of testing per patient would need to be less than £225 per year in order for TDM to be judged as a cost-effective option at the thresholds of £20,000 per QALY gained; for the threshold of £30,000 per QALY gained, the cost of testing should be below £274 per patient-year. For the lower bound, with the annual acquisition cost of £1000 per patient-year, the corresponding threshold values for the cost of testing were £197 and £246 per patient-year.

For the outcomes reported in Arango et al. 43 and at the list price of Humira, the cost of testing should not exceed £18 per year to be considered as cost-effective at the threshold of £20,000 per QALY gained. However, the other threshold values obtained for outcomes reported in this source were negative (see Table 36). This means that, when using the trial results as presented in Arango et al. ,43 there are no (positive) values of the cost of testing at which it would be a cost-effective option at £30,000 per QALY gained, as well as for the lower ADL acquisition cost of £1000 per patient-year.

The qualitatively different results obtained in the threshold analyses can be explained by the difference in the mean duration of remission42 and remission/LDA43 between the control and the intervention arms. As reported in Arango et al. ,43 patients from the control group were in remission/LDA for longer, on average, than patients in the intervention group (475.2 days vs. 460.2 days), whereas Ucar et al. 42 reported a longer duration of remission in patients in the intervention group than in the control group (344 days vs. 329 days).

The results of the threshold analyses are inconclusive for two reasons: they are inconsistent and they are based on very small and uncertain differences in outcomes, with the incremental QALYs of < 0.01.

Cost-effectiveness analyses

As in the threshold analyses, economic results were obtained for outcomes from both reports of the INGEBIO study. 42,43 The incremental costs and QALYs for testing versus SOC (Table 37) were estimated assuming that:

• patients are treated with Humira and are tested regularly using Promonitor assays

• the frequency of testing is one test per patient per year

• testing of drug and antibody levels is carried out concurrently (single dilution) at a UK laboratory

• the other testing costs are as reported in Jani et al. 37

As shown in Table 37, the major cost components in both the intervention and the control arms were the drug acquisition costs and the costs of managing health states, whereas the incremental costs were mostly driven by the cost of the initial phlebotomy appointment and the cost of managing flares. The incremental QALYs, defined primarily by QALYs accrued in different health states, were very small (of the order < 0.01). The ICER in scenario 1 (based on Ucar et al. 42) was £5575 per QALY gained, whereas in scenario 2 (based on Arango et al. 43) the results suggest that SOC dominated the intervention.

The results of the cost–utility analyses are inconclusive: using data from Ucar et al. 42 and Arango et al. 43 produced qualitatively different results, which were based on very small and uncertain differences in outcomes (with incremental QALYs of < 0.01).

One-way deterministic sensitivity analyses

Uncertainty in some of the parameters that were used to estimate the ICERs in scenario 1 and scenario 2 (detailed in Table 37) was evaluated in one-way deterministic sensitivity analyses (Table 38).

In the analysis, assuming a 20% increase and 20% decrease in the proportion of patients on tapered doses in the intervention and control arms, respectively, the intervention was less costly and less effective, with the ICER of £28,570 per QALY gained located in the south-west quadrant of the cost-effectiveness plane.

Reducing the flare rate in the intervention arm by 20% and increasing it by the same amount in the control arm resulted in negative incremental costs and QALYs (see Table 38), with an ICER of £15,867 per QALY gained.

When the costs of managing health states were reduced by 20%, SOC was dominant.

The same outcome was obtained when the time in remission/LDA in the intervention and control arms was varied by +10% and –10% of the differential time in remission/LDA across the treatment arms, respectively.

Probabilistic sensitivity analyses

Probabilistic sensitivity analyses were not conducted because of time constraints and the lack of clarity as to which model assumptions would be most relevant to the NHS, owing to a substantial variation in clinical practice with respect to disease management in people with RA, as well as uncertainty in the TNF-α testing strategies (given that therapeutic monitoring for RA is not currently part of NHS practice). These variations were explored in numerous clinically relevant scenario analyses detailed in the following sections.

Scenario analyses

Comparative controlled evidence

Three articles42,43,45 reported the same non-RCT (the INGEBIO study), which focused on the population who had achieved treatment target (remission or LDA). In this trial, ADL and anti-ADL antibody levels were measured using Promonitor-ADL and Promonitor-ANTI-ADL (Grifols–Progenika) ELISA kits. TDM results were revealed to physicians in the intervention arm but not to physicians in the control arm. This reflected standard care in Spain, where treatment decisions are based on clinical judgements without knowledge of levels of drug and anti-drug antibodies in patients. The INGEBIO study recruited a mixed population of 169 people, including a cohort of 63 people with RA. The results of the total mixed population were reported in the review, as the authors were not able to separately provide the results for the cohort of people with RA. The three cohorts with different conditions (RA, PsA and AS) may have different treatment responses to TNF-α inhibitor therapies. Therefore, there was limited generalisability of findings from this mixed population to the target RA population.

The findings from this trial42 showed that, at 18-month follow-up, the rate of flares per patient-year was 0.463 for the intervention group and 0.639 for the control group, with a rate difference of –0.176 (95% CI –0.379 to 0.0289). There was a non-significant reduction in risk of flare in the intervention group compared with the control group (IRR 0.7252, 95% CI 0.4997 to 1.0578). The median time to the first flare was 145 days for participants in the intervention group and 136.5 days for participants in the control group. This trial42 also presented the results of HRQoL outcomes. The results showed that HRQoL (EQ-5D-5L) measures were higher in the intervention group than in the control group at all visits. However, statistically significant results were observed only at visit 2 (p = 0.001) and visit 3 (p = 0.035). Further details of results for this outcome were not reported.

Overall, the findings from this non-randomised controlled trial (the INGEBIO study) showed that there was a non-significant reduction in the risk of flare in the intervention group (i.e. when treatment decisions were made on the basis of the results of TDM) compared with the control group (i.e. standard care, when treatment decisions were based on clinical judgements without knowledge of patient’s drug and anti-drug antibody levels). HRQoL outcomes were higher in the intervention group than in the control group at all visits, with statistically significant results being observed at two visits. However, the trial was judged to be at a serious risk of bias due to potential attrition bias and baseline imbalance in disease severity between the two groups. Therefore, the results should be interpreted with caution.

Evidence from observational studies

One observational study44 was identified that evaluated the effect of TDM on clinical outcomes in people with RA who had achieved either remission or LDA, or had experienced a primary or secondary non-response.

Search strategy

1. (anti-TNF* or antiTNF* or (TNF* adj2 (inhibit* or block*))).tw.

2. anti* tumo?r* necrosis* factor*.tw.

3. Tumor Necrosis Factor-alpha/

4. (biologic* adj2 DMARD*).tw.

5. ((antirheumati* or anti rheumati* or anti-rheumati*) adj4 biologic*).tw.

6. ((disease modify* or disease-modify*) adj4 biologic*).tw.

7. exp Antibodies, Monoclonal/

8. anti* drug* antibod*.tw.

9. ADAb.tw.

10. etanercept.tw. or ETANERCEPT/

11. (tnr001 or “tnr 001” or tnr-001 or 185243-69-0).tw.

12. (ETA or ETN).tw.

13. (enbrel or erelzi or benepali or lifmior or brenzys).tw.

14. (anti-etanercept* or antietanercept* or (anti adj3 etanercept*)).tw.

15. adalimumab.tw. or ADALIMUMAB/

16. (d 2e7 or d2e7 or d-2e7 or 331731-18-1).tw.

17. (ADA or ADL or ADM).tw.

18. (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz).tw.

19. (anti-adalimumab* or antiadalimumab* or (anti adj3 adalimumab*)).tw.

20. infliximab.tw. or INFLIXIMAB/

21. (170277-31-3 or ta650 or ta 650 or ta-650).tw.

22. (INF or IFX).tw.

23. (anti-infliximab* or antiinfliximab* or (anti adj3 infliximab*)).tw.

24. (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi).tw.

25. Certolizumab Pegol/or certolizumab.tw.

26. (cdp870 or cdp 870 or cdp-870 or 428863-50-7 or 1132819-27-2).tw.

27. (CER or CZP).tw.

28. cimzia.tw.

29. (anti-certolizumab* or anticertolizumab* or (anti adj3 certolizumab*)).tw.

30. golimumab.tw.

31. (cnto 148 or cnto148 or cnto-148 or 476181-74-5).tw.

32. (GOL or GLM).tw.

33. simponi.tw.

34. (anti-golimumab* or antigolimumab* or (anti adj3 golimumab*)).tw.

35. (biologic* adj2 agent*).tw.

36. (CT-P13 or CTP13 or CT P13 or SB2 or SB-2 or SB 2 or SB4 or SB-4 or SB 4 or SB-5 or SB5 or SB 5).tw.

37. (biosimilar* or (bio* adj1 similar*)).tw.

38. or/1-37

39. exp Enzyme-Linked Immunosorbent Assay/

40. (immundiagnostik* or immunodiagnostik* or immunediagnostik*).tw.

41. biohit healthcare.tw.

42. (proteomika* or *).tw.

43. (enzyme* adj3 immunoassay*).tw.

44. (enzyme* adj3 (immuno* assay* or immuno* test*)).tw.

45. ELISA*.tw.

46. (idkmonitor* or (idk adj3 monitor*) or idk-monitor*).tw.

47. ((lisa adj3 tracker*) or lisa-tracker* or lisatracker*).tw.

48. (ridascreen* or (rida adj3 screen*) or rida-screen*).tw.

49. (mabtrack* or (mab adj3 track*) or mab-track*).tw.

50. sanquin.tw.

51. theradiag.tw.

52. (grifols or progenika).tw.

53. (r-biopharm or rbiopharm or r biopharm).tw.

54. ((drug* or trough) adj3 (level* or concentration)).tw.

55. or/39-54

56. exp Arthritis, Rheumatoid/

57. RA.tw.

58. Rheumarthrit*.tw.

59. ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) adj4 (arthrit* or arthros* or polyarthrit* or factor*)).tw.

60. (Chronic* adj4 (polyarthrit* or poly arthrit* or poly-arthrit* or rheumati*)).tw.

61. ((Inflammat* or pain* or swell* or stiff*) adj4 (joint* or synovial*)).tw.

62. (Beauvais* adj2 disease*).tw.

63. or/56-62

64. 38 and 55 and 63

65. animals/not humans/

66. 64 not 65.

Search strategy

1. (anti-TNF* or antiTNF* or (TNF* adj2 (inhibit* or block*))).tw.

2. anti* tumo?r* necrosis* factor*.tw.

3. Tumor Necrosis Factor-alpha/

4. (biologic* adj2 DMARD*).tw.

5. ((antirheumati* or anti rheumati* or anti-rheumati*) adj4 biologic*).tw.

6. ((disease modify* or disease-modify*) adj4 biologic*).tw.

7. disease modifying antirheumatic drug/

8. monoclonal antibody/

9. anti* drug* antibod*.tw.

10. ADAb.tw.

11. etanercept.tw. or ETANERCEPT/

12. (tnr001 or “tnr 001” or tnr-001 or 185243-69-0).tw.

13. (ETA or ETN).tw.

14. (enbrel or erelzi or benepali or lifmior or brenzys).tw.

15. (anti-etanercept* or antietanercept* or (anti adj3 etanercept*)).tw.

16. adalimumab.tw. or ADALIMUMAB/

17. (d 2e7 or d2e7 or d-2e7 or 331731-18-1).tw.

18. (ADA or ADL or ADM).tw.

19. (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz).tw.

20. (anti-adalimumab* or antiadalimumab* or (anti adj3 adalimumab*)).tw.

21. infliximab.tw. or INFLIXIMAB/

22. (170277-31-3 or ta650 or ta 650 or ta-650).tw.

23. (INF or IFX).tw.

24. (anti-infliximab* or antiinfliximab* or (anti adj3 infliximab*)).tw.

25. (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi).tw.

26. Certolizumab Pegol/or certolizumab.tw.

27. (cdp870 or cdp 870 or cdp-870 or 428863-50-7 or 1132819-27-2).tw.

28. (CER or CZP).tw.

29. cimzia.tw.

30. (anti-certolizumab* or anticertolizumab* or (anti adj3 certolizumab*)).tw.

31. golimumab/or golimumab.tw.

32. (cnto 148 or cnto148 or cnto-148 or 476181-74-5).tw.

33. (GOL or GLM).tw.

34. simponi.tw.

35. (anti-golimumab* or antigolimumab* or (anti adj3 golimumab*)).tw.

36. (biologic* adj2 agent*).tw.

37. (CT-P13 or CTP13 or CT P13 or SB2 or SB-2 or SB 2 or SB4 or SB-4 or SB 4 or SB-5 or SB5 or SB 5).tw.

38. biological product/or biosimilar agent/

39. (biosimilar* or (bio* adj1 similar*)).tw.

40. or/1-39

41. exp Enzyme-Linked Immunosorbent Assay/

42. (immundiagnostik* or immunodiagnostik* or immunediagnostik*).tw.

43. biohit healthcare.tw.

44. (proteomika* or promonitor*).tw.

45. (enzyme* adj3 immunoassay*).tw.

46. (enzyme* adj3 (immuno* assay* or immuno* test*)).tw.

47. ELISA*.tw.

48. (idkmonitor* or (idk adj3 monitor*) or idk-monitor*).tw.

49. ((lisa adj3 tracker*) or lisa-tracker* or lisatracker*).tw.

50. (ridascreen* or (rida adj3 screen*) or rida-screen*).tw.

51. (mabtrack* or (mab adj3 track*) or mab-track*).tw.

52. sanquin.tw.

53. theradiag.tw.

54. (grifols or progenika).tw.

55. (r-biopharm or rbiopharm or r biopharm).tw.

56. ((drug* or trough) adj3 (level* or concentration)).tw.

57. or/41-56

58. exp Arthritis, Rheumatoid/

59. RA.tw.

60. Rheumarthrit*.tw.

61. ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) adj4 (arthrit* or arthros* or polyarthrit* or factor*)).tw.

62. (Chronic* adj4 (polyarthrit* or poly arthrit* or poly-arthrit* or rheumati*)).tw.

63. ((Inflammat* or pain* or swell* or stiff*) adj4 (joint* or synovial*)).tw.

64. (Beauvais* adj2 disease*).tw.

65. or/58-64

66. 40 and 57 and 65

67. (exp animal/or nonhuman/) not exp human/

68. 66 not 67.

Search strategy

1. #1. TS = (anti-TNF* or antiTNF* or (TNF* near/1 (inhibit* or block*))) OR TS = tumo$r* necrosis* factor* alpha OR TS = (biologic* near/1 DMARD*) OR TS = (biologic* near/3 antirheumati*) OR TS = (anti rheumati* near/3 biologic*) OR TS = (disease modify* near/3 biologic*) OR TS = anti* drug* antibod* OR TS = ADAb OR TS = anti* tumo$r* necrosis* factor* OR TS = monoclonal antibod*

2. #2. TS = etanercept OR TS = (tnr001 or tnr 001 or tnr-001 or 185243-69-0) OR TS = (ETA or ETN) OR TS = (enbrel or erelzi or benepali or lifmior or brenzys) OR TS = (anti-etanercept* or antietanercept* or anti near/2 etanercept*)

3. #3. TS = adalimumab OR TS = (d 2e7 or d2e7 or d-2e7 or 331731-18-1) OR TS = (ADA or ADL or ADM) OR TS = (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz) OR TS = (anti-adalimumab* or antiadalimumab* or anti near/2 adalimumab*)

4. #4. TS = infliximab OR TS = (170277-31-3 or ta650 or ta 650 or ta-650) OR TS = (INF or IFX) OR TS = (anti-infliximab* or antiinfliximab* or anti near/2 infliximab*) OR TS = (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi)

5. #5. TS = certolizumab OR TS = (cdp870 or cdp 870 or cdp-870 or 428863-50-7 or 1132819-27-2) OR TS = (CER or CZP) OR TS = cimzia OR TS = (anti-certolizumab* or anticertolizumab* or anti near/2 certolizumab*)

6. #6. TS = golimumab OR TS = (cnto 148 or cnto148 or cnto-148 or 476181-74-5) OR TS = (GOL or GLM) OR TS = simponi OR TS = (anti-golimumab* or antigolimumab* or anti near/2 golimumab*)

7. #7. TS = (biologic* near/1 agent*) OR TS = (CT-P13 or CTP13 or CT P13 or SB2 or SB-2 or SB 2 or SB4 or SB-4 or SB 4 or SB-5 or SB5 or SB 5) OR TS = (biosimilar* or bio* similar*)

8. #8. #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1

9. #9. TS = (immundiagnostik* or immunodiagnostik* or immunediagnostik*) OR TS = biohit healthcare OR TS = (proteomika* or promonitor*) OR TS = (enzyme* near/2 immunoassay*) OR TS = (enzyme* near/2 immuno* assay*) OR TS = (enzyme* near/2 immuno* test*) OR TS = ELISA*

10. #10. TS = (idkmonitor* or idk near/2 monitor* or idk-monitor*) OR TS = (lisa near/2 tracker* or lisa-tracker* or lisatracker*) OR TS = (ridascreen* or rida near/2 screen* or rida-screen*) OR TS = (mabtrack* or mab near/2 track* or mab-track*) OR TS = (sanquin or theradiag) OR TS = (grifols or progenika) OR TS = (r-biopharm or rbiopharm or r biopharm) OR TS = ((drug* or trough) near/2 (level* or concentration))

11. #11. #10 OR #9

12. #12. TS = RA OR TS = Rheumarthrit* OR TS = ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) near/3 (arthrit* or arthros* or polyarthrit* or factor*)) OR TS = (chronic* near/3 polyarthrit*) OR TS = (chronic* near/3 poly arthrit*) OR TS = (chronic* near/3 rheumati*) OR TS = ((Inflammat* or pain* or swell* or stiff*) near/3 (joint* or synovial*)) OR TS = (Beauvais* adj2 disease*)

13. #13. #12 AND #11 AND #8 Indexes = SCI-EXPANDED, CPCI-S Timespan = 1900-2018;

Search strategy

1. #1. (anti-TNF* or antiTNF* or (TNF* near/2 (inhibit* or block*))):ti,ab,kw

2. #2. “anti* tumo*r* necrosis* factor*”:ti,ab,kw

3. #3. MeSH descriptor: [Tumor Necrosis Factor-alpha] this term only

4. #4. (biologic* near/2 DMARD*):ti,ab,kw

5. #5. ((antirheumati* or “anti rheumati*” or anti-rheumati*) near/4 biologic*):ti,ab,kw

6. #6. ((“disease modify*” or disease-modify*) near/4 biologic*):ti,ab,kw

7. #7. MeSH descriptor: [Antibodies, Monoclonal] explode all trees

8. #8. “anti* drug* antibod*”:ti,ab,kw

9. #9. ADAb:ti,ab

10. #10. etanercept:ti,ab,kw

11. #11. MeSH descriptor: [Etanercept] this term only

12. #12. (tnr001 or “tnr 001” or tnr-001 or 185243-69-0):ti,ab

13. #13. (ETA or ETN):ti,ab

14. #14. (enbrel or erelzi or benepali or lifmior or brenzys):ti,ab,kw

15. #15. (anti-etanercept* or antietanercept* or (anti near/3 etanercept*)):ti,ab,kw

16. #16. adalimumab:ti,ab,kw

17. #17. MeSH descriptor: [Adalimumab] this term only

18. #18. (“d 2e7” or d2e7 or d-2e7 or 331731-18-1):ti,ab

19. #19. (ADA or ADL or ADM):ti,ab

20. #20. (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz):ti,ab,kw

21. #21. (anti-adalimumab* or antiadalimumab* or (anti near/3 adalimumab*)):ti,ab,kw

22. #22. infliximab:ti,ab,kw

23. #23. MeSH descriptor: [Infliximab] this term only

24. #24. (170277-31-3 or ta650 or “ta 650” or ta-650):ti,ab

25. #25. (INF or IFX):ti,ab

26. #26. (anti-infliximab* or antiinfliximab* or (anti near/3 infliximab*)):ti,ab,kw

27. #27. (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi):ti,ab,kw

28. #28. certolizumab:ti,ab,kw

29. #29. MeSH descriptor: [Certolizumab Pegol] this term only

30. #30. (cdp870 or “cdp 870” or cdp-870 or 428863-50-7 or 1132819-27-2):ti,ab

31. #31. (CER or CZP):ti,ab

32. #32. cimzia:ti,ab,kw

33. #33. (anti-certolizumab* or anticertolizumab* or (anti near/3 certolizumab*)):ti,ab,kw

34. #34. golimumab:ti,ab,kw

35. #35. (“cnto 148” or cnto148 or cnto-148 or 476181-74-5):ti,ab

36. #36. (GOL or GLM):ti,ab

37. #37. simponi:ti,ab,kw

38. #38. (anti-golimumab* or antigolimumab* or (anti near/3 golimumab*)):ti,ab,kw

39. #39. (biologic* near/2 agent*):ti,ab,kw

40. #40. (CT-P13 or CTP13 or “CT P13” or SB2 or SB-2 or “SB 2” or SB4 or SB-4 or “SB 4” or SB-5 or SB5 or “SB 5”):ti,ab

41. #41. (biosimilar* or “bio* similar*”):ti,ab,kw

42. #42. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41

43. #43. MeSH descriptor: [Enzyme-Linked Immunosorbent Assay] explode all trees

44. #44. (immundiagnostik* or immunodiagnostik* or immunediagnostik*):ti,ab,kw

45. #45. “biohit healthcare”:ti,ab,kw

46. #46. (proteomika* or promonitor*):ti,ab,kw

47. #47. (enzyme* near/3 immunoassay*):ti,ab,kw

48. #48. (enzyme* near/3 (“immuno* assay*” or “immuno* test*”)):ti,ab,kw

49. #49. ELISA*:ti,ab,kw

50. #50. (idkmonitor* or (idk near/3 monitor*) or idk-monitor*):ti,ab,kw

51. #51. ((lisa near/3 tracker*) or lisa-tracker* or lisatracker*):ti,ab,kw

52. #52. (ridascreen* or (rida near/3 screen*) or rida-screen*):ti,ab,kw

53. #53. (mabtrack* or (mab near/3 track*) or mab-track*):ti,ab,kw

54. #54. (sanquin or theradiag):ti,ab,kw

55. #55. (grifols or progenika):ti,ab,kw

56. #56. (r-biopharm or rbiopharm or “r biopharm”):ti,ab,kw

57. #57. ((drug* or trough) near/3 (level* or concentration)):ti,ab,kw

58. #58. #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57

59. #59. MeSH descriptor: [Arthritis, Rheumatoid] explode all trees

60. #60. RA:ti,ab

61. #61. Rheumarthrit*.ti,ab,kw

62. #62. ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) near/4 (arthrit* or arthros* or polyarthrit* or factor*)):ti,ab,kw

63. #63. (Chronic* near/4 (polyarthrit* or poly arthrit* or poly-arthrit* or rheumati*)):ti,ab,kw

64. #64. ((Inflammat* or pain* or swell* or stiff*) near/4 (joint* or synovial*)):ti,ab,kw

65. #65. (Beauvais* near/2 disease*):ti,ab,kw

66. #66. #59 or #60 or #61 or #62 or #64 or #65

67. #67. #42 and #58 and #66

Search strategy

1. (anti-TNF* or antiTNF* or (TNF* adj2 (inhibit* or block*))).tw.

2. anti* tumo?r* necrosis* factor*.tw.

3. Tumor Necrosis Factor-alpha/

4. (biologic* adj2 DMARD*).tw.

5. ((antirheumati* or anti rheumati* or anti-rheumati*) adj4 biologic*).tw.

6. ((disease modify* or disease-modify*) adj4 biologic*).tw.

7. exp Antibodies, Monoclonal/

8. anti* drug* antibod*.tw.

9. ADAb.tw.

10. etanercept.tw. or ETANERCEPT/

11. (tnr001 or “tnr 001” or tnr-001 or 185243-69-0).tw.

12. (ETA or ETN).tw.

13. (enbrel or erelzi or benepali or lifmior or brenzys).tw.

14. (anti-etanercept* or antietanercept* or (anti adj3 etanercept*)).tw.

15. adalimumab.tw. or ADALIMUMAB/

16. (d 2e7 or d2e7 or d-2e7 or 331731-18-1).tw.

17. (ADA or ADL or ADM).tw.

18. (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz).tw.

19. 19. (anti-adalimumab* or antiadalimumab* or (anti adj3 adalimumab*)).tw.

20. infliximab.tw. or INFLIXIMAB/

21. (170277-31-3 or ta650 or ta 650 or ta-650).tw.

22. (INF or IFX).tw.

23. (anti-infliximab* or antiinfliximab* or (anti adj3 infliximab*)).tw.

24. (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi).tw.

25. Certolizumab Pegol/or certolizumab.tw.

26. (cdp870 or cdp 870 or cdp-870 or 428863-50-7 or 1132819-27-2).tw.

27. (CER or CZP).tw.

28. cimzia.tw.

29. (anti-certolizumab* or anticertolizumab* or (anti adj3 certolizumab*)).tw.

30. golimumab.tw.

31. (cnto 148 or cnto148 or cnto-148 or 476181-74-5).tw.

32. (GOL or GLM).tw.

33. simponi.tw.

34. (anti-golimumab* or antigolimumab* or (anti adj3 golimumab*)).tw.

35. (biologic* adj2 agent*).tw.

36. (CT-P13 or CTP13 or CT P13 or SB2 or SB-2 or SB 2 or SB4 or SB-4 or SB 4 or SB-5 or SB5 or SB 5).tw.

37. (biosimilar* or (bio* adj1 similar*)).tw.

38. or/1-37

39. exp Enzyme-Linked Immunosorbent Assay/

40. (immundiagnostik* or immunodiagnostik* or immunediagnostik*).tw.

41. biohit healthcare.tw.

42. (proteomika* or promonitor*).tw.

43. (enzyme* adj3 immunoassay*).tw.

44. (enzyme* adj3 (immuno* assay* or immuno* test*)).tw.

45. ELISA*.tw.

46. (idkmonitor* or (idk adj3 monitor*) or idk-monitor*).tw.

47. ((lisa adj3 tracker*) or lisa-tracker* or lisatracker*).tw.

48. (ridascreen* or (rida adj3 screen*) or rida-screen*).tw.

49. (mabtrack* or (mab adj3 track*) or mab-track*).tw.

50. sanquin.tw.

51. theradiag.tw.

52. (grifols or progenika).tw.

53. (r-biopharm or rbiopharm or r biopharm).tw.

54. ((drug* or trough) adj3 (level* or concentration)).tw.

55. or/39-54

56. exp Arthritis, Rheumatoid/

57. RA.tw.

58. Rheumarthrit*.tw.

59. ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) adj4 (arthrit* or arthros* or polyarthrit* or factor*)).tw.

60. (Chronic* adj4 (polyarthrit* or poly arthrit* or poly-arthrit* or rheumati*)).tw.

61. ((Inflammat* or pain* or swell* or stiff*) adj4 (joint* or synovial*)).tw.

62. (Beauvais* adj2 disease*).tw.

63. or/56-62

64. 38 and 55 and 63

65. animals/not humans/

66. 64 not 65

67. Economics/

68. exp “Costs and Cost Analysis”/

69. Economics, Nursing/

70. Economics, Medical/

71. Economics, Pharmaceutical/

72. exp Economics, Hospital/

73. Economics, Dental/

74. exp “Fees and Charges”/

75. exp Budgets/

76. budget*.ti,ab,kf.

77. (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic* or pharmaco-economic* or expenditure or expenditures or expense or expenses or financial or finance or finances or financed).ti,kf.

78. (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic* or pharmaco-economic* or expenditure or expenditures or expense or expenses or financial or finance or finances or financed).ab./freq = 2

79. (cost* adj2 (effective* or utilit* or benefit* or minimi* or analy* or outcome or outcomes)).ab,kf.

80. (value adj2 (money or monetary)).ti,ab,kf.

81. exp models, economic/

82. economic model*.ab,kf.

83. markov chains/

84. markov.ti,ab,kf.

85. monte carlo method/

86. monte carlo.ti,ab,kf.

87. exp Decision Theory/

88. (decision* adj2 (tree* or analy* or model*)).ti,ab,kf.

89. or/67-88

90. 66 and 89.

Search strategy

1. (anti-TNF* or antiTNF* or (TNF* adj2 (inhibit* or block*))).tw.

2. anti* tumo?r* necrosis* factor*.tw.

3. (biologic* adj2 DMARD*).tw.

4. ((antirheumati* or anti rheumati* or anti-rheumati*) adj4 biologic*).tw.

5. ((disease modify* or disease-modify*) adj4 biologic*).tw.

6. anti* drug* antibod*.tw.

7. ADAb.tw.

8. etanercept.tw.

9. (tnr001 or “tnr 001” or tnr-001 or 185243-69-0).tw.

10. (ETA or ETN).tw.

11. (enbrel or erelzi or benepali or lifmior or brenzys).tw.

12. (anti-etanercept* or antietanercept* or (anti adj3 etanercept*)).tw.

13. adalimumab.tw.

14. (d 2e7 or d2e7 or d-2e7 or 331731-18-1).tw.

15. (ADA or ADL or ADM).tw.

16. (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz).tw.

17. (anti-adalimumab* or antiadalimumab* or (anti adj3 adalimumab*)).tw.

18. infliximab.tw.

19. (170277-31-3 or ta650 or ta 650 or ta-650).tw.

20. (INF or IFX).tw.

21. (anti-infliximab* or antiinfliximab* or (anti adj3 infliximab*)).tw.

22. (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi).tw.

23. certolizumab.tw.

24. (cdp870 or cdp 870 or cdp-870 or 428863-50-7 or 1132819-27-2).tw.

25. (CER or CZP).tw.

26. cimzia.tw.

27. (anti-certolizumab* or anticertolizumab* or (anti adj3 certolizumab*)).tw.

28. golimumab.tw.

29. (cnto 148 or cnto148 or cnto-148 or 476181-74-5).tw.

30. (GOL or GLM).tw.

31. simponi.tw.

32. (anti-golimumab* or antigolimumab* or (anti adj3 golimumab*)).tw.

33. (biologic* adj2 agent*).tw.

34. (CT-P13 or CTP13 or CT P13 or SB2 or SB-2 or SB 2 or SB4 or SB-4 or SB 4 or SB-5 or SB5 or SB 5).tw.

35. (biosimilar* or (bio* adj1 similar*)).tw.

36. or/1-35

37. (immundiagnostik* or immunodiagnostik* or immunediagnostik*).tw.

38. biohit healthcare.tw.

39. (proteomika* or promonitor*).tw.

40. (enzyme* adj3 immunoassay*).tw.

41. (enzyme* adj3 (immuno* assay* or immuno* test*)).tw.

42. ELISA*.tw.

43. (idkmonitor* or (idk adj3 monitor*) or idk-monitor*).tw.

44. ((lisa adj3 tracker*) or lisa-tracker* or lisatracker*).tw.

45. (ridascreen* or (rida adj3 screen*) or rida-screen*).tw.

46. (mabtrack* or (mab adj3 track*) or mab-track*).tw.

47. sanquin.tw.

48. theradiag.tw.

49. (grifols or progenika).tw.

50. (r-biopharm or rbiopharm or r biopharm).tw.

51. ((drug* or trough) adj3 (level* or concentration)).tw.

52. or/37-51

53. RA.tw.

54. Rheumarthrit*.tw.

55. ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) adj4 (arthrit* or arthros* or polyarthrit* or factor*)).tw.

56. (Chronic* adj4 (polyarthrit* or poly arthrit* or poly-arthrit* or rheumati*)).tw.

57. ((Inflammat* or pain* or swell* or stiff*) adj4 (joint* or synovial*)).tw.

58. (Beauvais* adj2 disease*).tw.

59. or/53-58

60. 36 and 52 and 59

61. budget*.ti,ab,kf.

62. (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic* or pharmaco-economic* or expenditure or expenditures or expense or expenses or financial or finance or finances or financed).ti,kf.

63. (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic* or pharmaco-economic* or expenditure or expenditures or expense or expenses or financial or finance or finances or financed).ab./freq = 2

64. (cost* adj2 (effective* or utilit* or benefit* or minimi* or analy* or outcome or outcomes)).ab,kf.

65. (value adj2 (money or monetary)).ti,ab,kf.

66. economic model*.ab,kf.

67. markov.ti,ab,kf.

68. monte carlo.ti,ab,kf.

69. (decision* adj2 (tree* or analy* or model*)).ti,ab,kf.

70. or/61-69

71. 60 and 70.

Search strategy

1. (anti-TNF* or antiTNF* or (TNF* adj2 (inhibit* or block*))).tw.

2. anti* tumo?r* necrosis* factor*.tw.

3. Tumor Necrosis Factor-alpha/

4. (biologic* adj2 DMARD*).tw.

5. ((antirheumati* or anti rheumati* or anti-rheumati*) adj4 biologic*).tw.

6. ((disease modify* or disease-modify*) adj4 biologic*).tw.

7. disease modifying antirheumatic drug/

8. monoclonal antibody/

9. anti* drug* antibod*.tw.

10. ADAb.tw.

11. etanercept.tw. or ETANERCEPT/

12. (tnr001 or “tnr 001” or tnr-001 or 185243-69-0).tw.

13. (ETA or ETN).tw.

14. (enbrel or erelzi or benepali or lifmior or brenzys).tw.

15. (anti-etanercept* or antietanercept* or (anti adj3 etanercept*)).tw.

16. adalimumab.tw. or ADALIMUMAB/

17. (d 2e7 or d2e7 or d-2e7 or 331731-18-1).tw.

18. (ADA or ADL or ADM).tw.

19. (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz).tw.

20. (anti-adalimumab* or antiadalimumab* or (anti adj3 adalimumab*)).tw.

21. infliximab.tw. or INFLIXIMAB/

22. (170277-31-3 or ta650 or ta 650 or ta-650).tw.

23. (INF or IFX).tw.

24. (anti-infliximab* or antiinfliximab* or (anti adj3 infliximab*)).tw.

25. (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi).tw.

26. Certolizumab Pegol/or certolizumab.tw.

27. (cdp870 or cdp 870 or cdp-870 or 428863-50-7 or 1132819-27-2).tw.

28. (CER or CZP).tw.

29. cimzia.tw.

30. (anti-certolizumab* or anticertolizumab* or (anti adj3 certolizumab*)).tw.

31. golimumab/or golimumab.tw.

32. (cnto 148 or cnto148 or cnto-148 or 476181-74-5).tw.

33. (GOL or GLM).tw.

34. simponi.tw.

35. (anti-golimumab* or antigolimumab* or (anti adj3 golimumab*)).tw.

36. (biologic* adj2 agent*).tw.

37. (CT-P13 or CTP13 or CT P13 or SB2 or SB-2 or SB 2 or SB4 or SB-4 or SB 4 or SB-5 or SB5 or SB 5).tw.

38. biological product/or biosimilar agent/

39. (biosimilar* or (bio* adj1 similar*)).tw.

40. or/1-39

41. exp Enzyme-Linked Immunosorbent Assay/

42. (immundiagnostik* or immunodiagnostik* or immunediagnostik*).tw.

43. biohit healthcare.tw.

44. (proteomika* or promonitor*).tw.

45. (enzyme* adj3 immunoassay*).tw.

46. (enzyme* adj3 (immuno* assay* or immuno* test*)).tw.

47. ELISA*.tw.

48. (idkmonitor* or (idk adj3 monitor*) or idk-monitor*).tw.

49. ((lisa adj3 tracker*) or lisa-tracker* or lisatracker*).tw.

50. (ridascreen* or (rida adj3 screen*) or rida-screen*).tw.

51. (mabtrack* or (mab adj3 track*) or mab-track*).tw.

52. sanquin.tw.

53. theradiag.tw.

54. (grifols or progenika).tw.

55. (r-biopharm or rbiopharm or r biopharm).tw.

56. ((drug* or trough) adj3 (level* or concentration)).tw.

57. or/41-56

58. exp Arthritis, Rheumatoid/

59. RA.tw.

60. Rheumarthrit*.tw.

61. ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) adj4 (arthrit* or arthros* or polyarthrit* or factor*)).tw.

62. (Chronic* adj4 (polyarthrit* or poly arthrit* or poly-arthrit* or rheumati*)).tw.

63. ((Inflammat* or pain* or swell* or stiff*) adj4 (joint* or synovial*)).tw.

64. (Beauvais* adj2 disease*).tw.

65. or/58-64

66. 40 and 57 and 65

67. (exp animal/or nonhuman/) not exp human/

68. 66 not 67

69. Economics/

70. Cost/

71. exp Health Economics/

72. Budget/

73. budget*.ti,ab,kw.

74. (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic* or pharmaco-economic* or expenditure or expenditures or expense or expenses or financial or finance or finances or financed).ti,kw.

75. (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic* or pharmaco-economic* or expenditure or expenditures or expense or expenses or financial or finance or finances or financed).ab./freq = 2

76. (cost* adj2 (effective* or utilit* or benefit* or minimi* or analy* or outcome or outcomes)).ab,kw.

77. (value adj2 (money or monetary)).ti,ab,kw.

78. Statistical Model/

79. economic model*.ab,kw.

80. Probability/

81. markov.ti,ab,kw.

82. monte carlo method/

83. monte carlo.ti,ab,kw.

84. Decision Theory/

85. Decision Tree/

86. (decision* adj2 (tree* or analy* or model*)).ti,ab,kw.

87. or/69-86

88. 68 and 87.

Search strategy

1. #1. TS = (anti-TNF* or antiTNF* or (TNF* near/1 (inhibit* or block*))) OR TS = tumo$r* necrosis* factor* alpha OR TS = (biologic* near/1 DMARD*) OR TS = (biologic* near/3 antirheumati*) OR TS = (anti rheumati* near/3 biologic*) OR TS = (disease modify* near/3 biologic*) OR TS = anti* drug* antibod* OR TS = ADAb OR TS = anti* tumo$r* necrosis* factor* OR TS = monoclonal antibod*

2. #2. TS = etanercept OR TS = (tnr001 or tnr 001 or tnr-001 or 185243-69-0) OR TS = (ETA or ETN) OR TS = (enbrel or erelzi or benepali or lifmior or brenzys) OR TS = (anti-etanercept* or antietanercept* or anti near/2 etanercept*)

3. #3. TS = adalimumab OR TS = (d 2e7 or d2e7 or d-2e7 or 331731-18-1) OR TS = (ADA or ADL or ADM) OR TS = (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz) OR TS = (anti-adalimumab* or antiadalimumab* or anti near/2 adalimumab*)

4. #4. TS = infliximab OR TS = (170277-31-3 or ta650 or ta 650 or ta-650) OR TS = (INF or IFX) OR TS = (anti-infliximab* or antiinfliximab* or anti near/2 infliximab*) OR TS = (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi)

5. #5. TS = certolizumab OR TS = (cdp870 or cdp 870 or cdp-870 or 428863-50-7 or 1132819-27-2) OR TS = (CER or CZP) OR TS = cimzia OR TS = (anti-certolizumab* or anticertolizumab* or anti near/2 certolizumab*)

6. #6. TS = golimumab OR TS = (cnto 148 or cnto148 or cnto-148 or 476181-74-5) OR TS = (GOL or GLM) OR TS = simponi OR TS = (anti-golimumab* or antigolimumab* or anti near/2 golimumab*)

7. #7. TS = (biologic* near/1 agent*) OR TS = (CT-P13 or CTP13 or CT P13 or SB2 or SB-2 or SB 2 or SB4 or SB-4 or SB 4 or SB-5 or SB5 or SB 5) OR TS = (biosimilar* or bio* similar*)

8. #8. #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1

9. #9. TS = (immundiagnostik* or immunodiagnostik* or immunediagnostik*) OR TS = biohit healthcare OR TS = (proteomika* or promonitor*) OR TS = (enzyme* near/2 immunoassay*) OR TS = (enzyme* near/2 immuno* assay*) OR TS = (enzyme* near/2 immuno* test*) OR TS = ELISA*

10. #10. TS = (idkmonitor* or idk near/2 monitor* or idk-monitor*) OR TS = (lisa near/2 tracker* or lisa-tracker* or lisatracker*) OR TS = (ridascreen* or rida near/2 screen* or rida-screen*) OR TS = (mabtrack* or mab near/2 track* or mab-track*) OR TS = (sanquin or theradiag) OR TS = (grifols or progenika) OR TS = (r-biopharm or rbiopharm or r biopharm) OR TS = ((drug* or trough) near/2 (level* or concentration))

11. #11. #10 OR #9

12. #12. TS = RA OR TS = Rheumarthrit* OR TS = ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) near/3 (arthrit* or arthros* or polyarthrit* or factor*)) OR TS = (chronic* near/3 polyarthrit*) OR TS = (chronic* near/3 poly arthrit*) OR TS = (chronic* near/3 rheumati*) OR TS = ((Inflammat* or pain* or swell* or stiff*) near/3 (joint* or synovial*)) OR TS = (Beauvais* adj2 disease*)

13. #13. #12 AND #11 AND #8

14. 14. TS = ((pharmacoeconomic* or socioeconomics or economic* or pric* or cost* or cba or cea or cua or “health utilit*” or “value for money”))

15. 15. #14 and #15.

Search strategy

1. #1. (anti-TNF* or antiTNF* or (TNF* near/2 (inhibit* or block*))):ti,ab,kw

2. #2. “anti* tumo*r* necrosis* factor*”:ti,ab,kw

3. #3. MeSH descriptor: [Tumor Necrosis Factor-alpha] this term only

4. #4. (biologic* near/2 DMARD*):ti,ab,kw

5. #5. ((antirheumati* or “anti rheumati*” or anti-rheumati*) near/4 biologic*):ti,ab,kw

6. #6. ((“disease modify*” or disease-modify*) near/4 biologic*):ti,ab,kw

7. #7. MeSH descriptor: [Antibodies, Monoclonal] explode all trees

8. #8. “anti* drug* antibod*”:ti,ab,kw

9. #9. ADAb:ti,ab

10. #10. etanercept:ti,ab,kw

11. #11. MeSH descriptor: [Etanercept] this term only

12. #12. (tnr001 or “tnr 001” or tnr-001 or 185243-69-0):ti,ab

13. #13. (ETA or ETN):ti,ab

14. #14. (enbrel or erelzi or benepali or lifmior or brenzys):ti,ab,kw

15. #15. (anti-etanercept* or antietanercept* or (anti near/3 etanercept*)):ti,ab,kw

16. #16. adalimumab:ti,ab,kw

17. #17. MeSH descriptor: [Adalimumab] this term only

18. #18. (“d 2e7” or d2e7 or d-2e7 or 331731-18-1):ti,ab

19. #19. (ADA or ADL or ADM):ti,ab

20. #20. (humira or amgevita or cyltezo or imraldi or solymbic or hyrimoz or halimatoz):ti,ab,kw

21. #21. (anti-adalimumab* or antiadalimumab* or (anti near/3 adalimumab*)):ti,ab,kw

22. #22. infliximab:ti,ab,kw

23. #23. MeSH descriptor: [Infliximab] this term only

24. #24. (170277-31-3 or ta650 or “ta 650” or ta-650):ti,ab

25. #25. (INF or IFX):ti,ab

26. #26. (anti-infliximab* or antiinfliximab* or (anti near/3 infliximab*)):ti,ab,kw

27. #27. (remicade or inflectra or remsima or flixabi or zessly or renflexis or ixifi):ti,ab,kw

28. #28. certolizumab:ti,ab,kw

29. #29. MeSH descriptor: [Certolizumab Pegol] this term only

30. #30. (cdp870 or “cdp 870” or cdp-870 or 428863-50-7 or 1132819-27-2):ti,ab

31. #31. (CER or CZP):ti,ab

32. #32. cimzia:ti,ab,kw

33. #33. (anti-certolizumab* or anticertolizumab* or (anti near/3 certolizumab*)):ti,ab,kw

34. #34. golimumab:ti,ab,kw

35. #35. (“cnto 148” or cnto148 or cnto-148 or 476181-74-5):ti,ab

36. #36. (GOL or GLM):ti,ab

37. #37. simponi:ti,ab,kw

38. #38. (anti-golimumab* or antigolimumab* or (anti near/3 golimumab*)):ti,ab,kw

39. #39. (biologic* near/2 agent*):ti,ab,kw

40. #40. (CT-P13 or CTP13 or “CT P13” or SB2 or SB-2 or “SB 2” or SB4 or SB-4 or “SB 4” or SB-5 or SB5 or “SB 5”):ti,ab

41. #41. (biosimilar* or “bio* similar*”):ti,ab,kw

42. #42. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41

43. #43. MeSH descriptor: [Enzyme-Linked Immunosorbent Assay] explode all trees

44. #44. (immundiagnostik* or immunodiagnostik* or immunediagnostik*):ti,ab,kw

45. #45. “biohit healthcare”:ti,ab,kw

46. #46. (proteomika* or promonitor*):ti,ab,kw

47. #47. (enzyme* near/3 immunoassay*):ti,ab,kw

48. #48. (enzyme* near/3 (“immuno* assay*” or “immuno* test*”)):ti,ab,kw

49. #49. ELISA*:ti,ab,kw

50. #50. (idkmonitor* or (idk near/3 monitor*) or idk-monitor*):ti,ab,kw

51. #51. ((lisa near/3 tracker*) or lisa-tracker* or lisatracker*):ti,ab,kw

52. #52. (ridascreen* or (rida near/3 screen*) or rida-screen*):ti,ab,kw

53. #53. (mabtrack* or (mab near/3 track*) or mab-track*):ti,ab,kw

54. #54. (sanquin or theradiag):ti,ab,kw

55. #55. (grifols or progenika):ti,ab,kw

56. #56. (r-biopharm or rbiopharm or “r biopharm”):ti,ab,kw

57. #57. ((drug* or trough) near/3 (level* or concentration)):ti,ab,kw

58. #58. #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57

59. #59. MeSH descriptor: [Arthritis, Rheumatoid] explode all trees

60. #60. RA:ti,ab

61. #61. Rheumarthrit*.ti,ab,kw

62. #62. ((Rheumatoid* or rheumatic* or inflammat* or idiopathic* or deforman*) near/4 (arthrit* or arthros* or polyarthrit* or factor*)):ti,ab,kw

63. #63. (Chronic* near/4 (polyarthrit* or poly arthrit* or poly-arthrit* or rheumati*)):ti,ab,kw

64. #64. ((Inflammat* or pain* or swell* or stiff*) near/4 (joint* or synovial*)):ti,ab,kw

65. #65. (Beauvais* near/2 disease*):ti,ab,kw

66. #66. #59 or #60 or #61 or #62 or #64 or #65

67. #67. #42 and #58 and #66.