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Practice Rapid Recommendations

Proactive therapeutic drug monitoring of biologic drugs in adult patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis: a clinical practice guideline

BMJ 2024; 387 doi: https://doi.org/10.1136/bmj-2024-079830 (Published 28 October 2024) Cite this as: BMJ 2024;387:e079830
Visual summary of recommendations
Population These recommendations apply only to people with these characteristics: Adults with immune-mediated inflammatory diseases Being treated with or starting treatment with infliximab, adalimumab, or other biologic drugs May or may not apply to: other immune-mediated inflammatory diseases Does not apply to: Inflammatory diseases that are not immune-mediated Inflammatory arthritis Inflammatory bowel disease Psoriasis Rheumatoid arthritis Spondyloarthritis Psoriatic arthritis
Recommendation 1
Standard careReactive or no monitoringProactive monitoringorAdults receiving maintenancetherapy with infliximabWe suggest proactive therapeutic drug monitoringStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours standard careFavours proactive monitoringNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Events per 1000 peopleEvidence quality

Disease control and/or remission140 more560700LowMore

Based on data from 760 patients in 3 studiesProactive therapeutic drug monitoringmay increase the proportion of patientswho experience sustained diseasecontrol, sustained remission, or bothLowGRADE rating,because of:Risk of biasSeriousImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Discontinuation due to adverse...No important difference5048Very lowMore

Based on data from 705 patients in 2 studiesIt is unclear if proactive therapeuticdrug monitoring has an effect on adverseevents leading to discontinuation oftherapyVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference8078Very lowMore

Based on data from 785 patients in 3 studiesIt is unclear if proactive therapeuticdrug monitoring has any effect onserious adverse eventsVery lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes
Patient decision aids

Individual considerations

Key practical issuesStandard careProactive monitoringRequires access to laboratory with validated analyses of infliximab serum drug levels and anti-drug antibodiesDrug dosing is adjusted to keep serum drug levels in apre-defined therapeutic range, typically by using analgorithmThere is little evidence on how often proactive monitoringshould be done to be beneficialReactive therapeutic drug monitoring or no therapeuticdrug monitoring
Values and preferencesThere was no evidence about how individuals with an immune mediatedinflammatory disease would judge the success of proactive monitoring. Anassumption was made that most patients would value proactive monitoring if itincreased sustained disease control, sustained remission, or both by 5% withoutcausing additional serious harm
Recommendation 2
Standard careReactive or no monitoringProactive monitoringorAdults receiving maintenancetherapy with adalimumab andother biologicsWe suggest not using proactive therapeutic drugmonitoringStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile - data only on adalimumab

Favours standard careFavours proactive monitoringNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Events per 1000 peopleEvidence quality

Disease control and/or remission403 more560963Very lowMore

Based on data from 78 patients in 1 studyIt is unclear if proactive therapeuticdrug monitoring affects the proportionof patients who experience sustaineddisease control, sustained remission, orbothVery lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Discontinuation due to adverse...No important difference5054Very lowMore

Based on data from 1053 patients in 3 studiesProactive therapeutic drug monitoringmay have no effect on adverse eventsleading to discontinuationVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse events19 fewer8061Very lowMore

Based on data from 1053 patients in 3 studiesIt is unclear if proactive therapeuticdrug monitoring reduces the proportionof patients who experience seriousadverse eventsVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes (adalimumab)
See all outcomes (other biologics)
Patient decision aids

Individual considerations

Key practical issuesStandard careProactive monitoringProactive therapeutic drug monitoring of adalimumab andother biologics involves regularly measuring serum druglevels and anti-drug antibodiesReactive therapeutic drug monitoring or no therapeuticdrug monitoring
Values and preferencesThere was no evidence about how individuals with an immune mediatedinflammatory disease would judge the success of proactive monitoring. Anassumption was made that most patients would prefer standard care, given the verylow certainty of the evidence informing this recommendation
Recommendation 3
Standard careReactive or no monitoringProactive monitoringorAdults starting therapy withinfliximab, adalimumab, andother biologicsWe suggest not using proactive therapeutic drugmonitoringStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile - data only on infliximab

Favours standard careFavours proactive monitoringNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Events per 1000 peopleEvidence quality

RemissionNo important difference530504Very lowMore

Based on data from 398 patients in 1 studyProactive therapeutic drug monitoringmay have little or no effect onachieving remission.Very lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Discontinuation due to adverse...No important difference8054Very lowMore

Based on data from 520 patients in 2 studiesProactive therapeutic drug monitoringmay have little or no effect on adverseevents leading to discontinuation oftherapy.Very lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Serious adverse eventsNo important difference100115Very lowMore

Based on data from 520 patients in 2 studiesProactive therapeutic drug monitoringmay have little or no effect on seriousadverse events.Very lowGRADE rating,because of:Risk of biasSeriousImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes (infliximab)
See all outcomes (adalimumab and other biologics)
Patient decision aids

Individual considerations

Key practical issuesStandard careProactive monitoringProactive therapeutic drug monitoring of infliximabinvolves regularly measuring serum drug levels andanti-drug antibodiesReactive therapeutic drug monitoring or no therapeuticdrug monitoring
Values and preferencesThere was no evidence about how individuals with an immune mediatedinflammatory disease would judge the success of proactive monitoring. Anassumption was made that most patients would prefer standard care, given the verylow certainty of the evidence informing this recommendation

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Find recommendations, evidence summaries and consultation decision aids for use in your practice
  1. Leticia Kawano-Dourado, senior researcher and methods co-chair1 2 3 *,
  2. Eirik Klami Kristianslund, clinician scientist and clinical chair4 *,
  3. Dena Zeraatkar, associate professor, methodologist1 5 6,
  4. Meghna Jani, NIHR advanced fellow, rheumatologist7 8,
  5. Govind Makharia, gastroenterologist, professor9,
  6. Glen Hazlewood, rheumatologist, associate professor10 11,
  7. Catherine Smith, dermatologist, professor12,
  8. Tine Jess, gastroenterologist, professor13 14,
  9. Camilla Stabell, patient partner15,
  10. Arne Schatten, patient partner16,
  11. Andrew Owen, pharmacologist, professor17,
  12. Johanna Gehin, medical biochemist, senior consultant18,
  13. Leolin Katsidzira, gastroenterologist, consultant physician19,
  14. David Weinberg, gastroenterologist, professor20,
  15. Iazsmin Bauer-Ventura, rheumatologist, clinician21,
  16. Peter Tugwell, rheumatologist, professor22 23,
  17. Paul Moayyedi, gastroenterologist, professor24,
  18. Ana Veronica Wolff Cecchi, rheumatologist, clinician25 26,
  19. Andrea Shimabuco, rheumatologist, clinician27,
  20. Siri Seterelv, clinician scientist28,
  21. Gordon Gyuatt, distinguished professor, methodologist1 29 30,
  22. Thomas Agoritsas, professor, methodologist1 29 31,
  23. Per Olav Vandvik, professor, methods chair1 32 33
  1. 1MAGIC Evidence Ecosystem Foundation, Oslo, Norway
  2. 2Hcor Research Institute, Hcor Hospital, Sao Paulo, Brazil
  3. 3Pulmonary Division, Heart Institute (InCor), University of Sao Paulo
  4. 4Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo
  5. 5Department of Anesthesia, McMaster University, Hamilton, Canada
  6. 6Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton
  7. 7Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
  8. 8NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester
  9. 9Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
  10. 10Department of Medicine, University of Calgary
  11. 11McCaig Institute for Bone and Joint Health, University of Calgary
  12. 12St John’s Institute of Dermatology, Kings College London, London
  13. 13Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
  14. 14Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg
  15. 15Patient representative. Norwegian Rheumatism Association, Oslo
  16. 16Patient representative. Norwegian Gastrointestinal Association, Oslo
  17. 17Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool, Liverpool
  18. 18Department of Medical Biochemistry, Oslo University Hospital, Oslo
  19. 19Department of Internal Medicine, Faculty of Medicine and Health Sciences, University of Zimbabwe, Zimbabwe
  20. 20Department of Medicine, Fox Chase Cancer Center, Philadelphia, USA
  21. 21Rheumatology Division, University of Chicago, Chicago
  22. 22Department of Medicine, University of Ottawa, Ottawa
  23. 23Bruyère Research Institute, Ottawa
  24. 24Farncombe Family Digestive Health Research Institute (FFDHRI), McMaster University, Hamilton
  25. 25Hospital del Salvador, Santiago, Chile
  26. 26Rheumatology Division, Universidad de Chile, Santiago
  27. 27Rheumatology Division, Hospital da Clinicas, Medical School of the University of Sao Paulo
  28. 28Department of Research, Lovisenberg Diaconal Hospital, Oslo
  29. 29Department of Health Research Methods, Evidence, and Impact, McMaster, Hamilton
  30. 30Department of Medicine, McMaster University, Hamilton
  31. 31Division General Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland
  32. 32Department of Medicine, Lovisenberg Diaconal Hospital, Oslo
  33. 33Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo
  34. *Both authors contributed equally to the manuscript
  1. Correspondence to:
    L Kawano-Dourado leticia{at}magicevidence.org; E K Kristianslund eirikklami.kristianslund{at}diakonsyk.no

Abstract

Clinical question In adult patients with inflammatory bowel disease, inflammatory arthritis (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis), or psoriasis taking biologic drugs, does proactive therapeutic drug monitoring (TDM) improve outcomes as compared with standard care?

Context and current practice Standard care for immune mediated inflammatory diseases includes prescribing biologic drugs at pre-determined doses. Dosing may be adjusted reactively, for example with increased disease activity. In proactive TDM, serum drug levels and anti-drug antibodies are measured irrespective of disease activity, and the drug dosing is adjusted to achieve target serum drug levels, usually within pre-specified therapeutic ranges. The role of proactive TDM in clinical practice remains unclear, with conflicting guideline recommendations and emerging evidence from randomised controlled trials.

The evidence Linked systematic review and pairwise meta-analysis which identified 10 trials including 2383 participants. Inflammatory bowel disease, inflammatory arthritis, and psoriasis were grouped together as best current research evidence on proactive TDM did not suggest heterogeneity of effects on outcomes of interest. Proactive TDM of intravenous infliximab during maintenance treatment may increase the proportion of patients who experience sustained disease control or sustained remission without considerable additional harm. For adalimumab, it remains unclear if proactive TDM during maintenance treatment has an effect on sustained disease control or sustained remission. At induction (start) of treatment, proactive TDM of intravenous infliximab may have little or no effect on achieving remission. No eligible trial evidence was available for proactive TDM of adalimumab at induction (start) of treatment. No eligible trial evidence was available for proactive TDM of other biologic drugs in maintenance or at induction (start) of treatment.

Recommendations The guideline panel issued the following recommendations for patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis:

1. A weak recommendation in favour of proactive TDM for intravenous infliximab during maintenance treatment

2. A weak recommendation against proactive TDM for adalimumab and other biologic drugs during maintenance treatment

3. A weak recommendation against proactive TDM for intravenous infliximab, adalimumab, and other biologic drugs during induction (start) of treatment.

Understanding the recommendations When considering proactive TDM, clinicians and patients should engage in shared decision making to ensure patients make choices that reflect their values and preferences. The availability of laboratory assays to implement proactive TDM should also be considered. Further research is warranted and may alter recommendations in the future.

How this guideline was created An international panel including patient partners, clinicians, and methodologists produced these recommendations based on a linked systematic review and pairwise meta-analysis which identified 10 trials including 2383 participants. The panel followed standards for trustworthy guidelines and used the GRADE approach, explicitly considering the balance of benefits and harms and burdens of treatment from an individual patient perspective.

Why is the guideline needed?

Inflammatory bowel disease, inflammatory arthritis (rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis), and psoriasis are chronic immune mediated inflammatory diseases with a high burden on patients’ health, quality of life, and use of healthcare resources.1234567 Emerging treatment options for these conditions have improved patient outcomes over the past two decades, especially after the introduction of biologic drugs such as tumour necrosis factor inhibitors (TNFi).368910 Biologic drugs are used by a substantial proportion of patient populations worldwide, with usage varying with disease and geographical location.111213141516

Despite these advances, some patients do not reach disease remission and/or disease control.3457 Biologic drugs are usually dosed according to body mass and/or fixed dosing to all patients, and large variations in patient serum drug levels are seen even among patients on the same dose. For several of these drugs (including infliximab and adalimumab), higher serum drug levels are associated with treatment effectiveness.1718 A proportion of patients develop anti-drug antibodies, which can block the action of the drug and increase drug clearance, reducing the effectiveness of the treatment.19202122

Therapeutic drug monitoring (TDM) of biologic drugs is being investigated as a method to optimise treatment to improve effectiveness and reduce side effects.23 TDM may be proactive or reactive. Proactive TDM is the measurement of drug concentrations and anti-drug antibodies at timed intervals irrespective of disease control. Reactive TDM is the measurement of drug concentrations and anti-drug antibodies triggered by a clinical event (a disease flare, for example). Both proactive and reactive TDM aim to optimise individual patient dosage regimens and therefore improve outcomes. Proactive TDM has the additional aim of preventing disease flares.24 With proactive TDM, individual patient drug doses are adjusted based on the results of periodic measurements to avoid patients falling outside the target serum drug levels.17 Practical information on serum drug and anti-drug antibody measurements can be found on MAGICapp: https://app.magicapp.org/#/guideline/7735/section/146829.

Despite randomised controlled trials (RCTs) showing promising results with proactive TDM of biologic drugs, current guideline recommendations diverge concerning whether to use this novel approach, when to use it, and for what diseases.610172024252627 Surveys among US, UK, Indian, and Scandinavian gastroenterologists show that proactive TDM of TNFi has been variably adopted in clinical practice (20-60%), reflecting the diverging guidelines.28293031 We have not identified any guideline applying appropriate standards and methods that includes the most recent trial evidence. Our guideline was triggered by a RCT investigating the use of proactive TDM in the maintenance treatment of inflammatory arthritis, inflammatory bowel disease, and psoriasis with intravenous infliximab.24 This trial reported a benefit with proactive TDM across inflammatory bowel disease and inflammatory arthritis, with no associated harm.

About this guideline

This guideline contributes to the BMJ Rapid Recommendations series—a collaborative effort between MAGIC Evidence Ecosystem Foundation and TheBMJ—which is focused on providing clinicians with trustworthy recommendations for potentially practice changing evidence. Box 1 gives linked resources for this guideline, including a systematic review and meta-analysis evaluating proactive TDM of biologic drugs in immune-mediated inflammatory diseases.32 This systematic review synthesised findings from 10 randomised controlled trials, with a total of 2383 patients.32

Box 1

Linked resources in these BMJ Rapid Recommendations

  • Kawano-Dourado L, Kristianslund EK, Zeraatkar D, et al. Proactive therapeutic drug monitoring of biologic drugs in adult patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis: a clinical practice guideline. BMJ 2024;386:e079830.

  • Zeraatkar D, Pitre T, Kirsh S, et al. Proactive therapeutic drug monitoring of biologic drugs inpatients with inflammatory bowel disease, inflammatory arthritis, and psoriasis: systematic review and meta-analysis. BMJMED 2024;3:e000998.

  • MAGICapp. An expanded version of the guideline with multi-layered recommendations, evidence summaries, and decision aids for use on all electronic devices. https://app.magicapp.org/#/guideline/nBAezL.

RETURN TO TEXT

An international panel that included patients, healthcare professionals, and methodologists created these recommendations following globally accepted standards for trustworthy guidelines and using the GRADE approach.33 No panel member reported financial conflicts of interest. Intellectual and professional conflicts were minimised and managed. For more information on how this guideline was created please see MAGICapp (https://app.magicapp.org/#/guideline/nBAezL). Briefly, the recommendations synthesise the best available evidence on benefits and harms, the expertise and experience of the guideline panel (which also included patient representatives), and what we understood about the values and preferences of patients living with inflammatory bowel disease, inflammatory arthritis, or psoriasis.

The recommendations also take into account practical issues, geographical variation in practice, implementability, and patient burden. The recommendations do not explicitly take into account cost effectiveness or other healthcare system factors as we take an individual patient perspective.

The Recommendations

Recommendation 1: For adult patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis receiving treatment (maintenance) with intravenous infliximab we suggest proactive TDM rather than reactive TDM or no TDM

Go to MAGIC app to read more (https://app.magicapp.org/#/guideline/nBAezL)

Understanding the recommendation

When making a weak recommendation for the use of TDM in patients taking intravenous infliximab as maintenance treatment, we recognised the potentially important benefit of an absolute 14% rate increase (ranging from 8% to 22% increase) in sustained disease remission and/or disease control as compared with standard care (no TDM or reactive TDM) with no evidence of harm. We assumed that most patients would value proactive TDM if it increased sustained disease control and/or sustained remission by 5% without causing additional serious harm. As the lower bound of the 95% confidence interval is 8%, we considered it a significant benefit compared with standard care.

Nevertheless, the anticipated benefits and harms were informed by low to very low certainty evidence from four RCTs with a total of 872 patients identified in the systematic review.32 This uncertainty precluded us from making a strong recommendation for the use of TDM in these patients. The low certainty evidence rating stemmed from the risk of bias in the RCTs (owing to lack of blinding), indirectness in the body of evidence owing to grouping different diseases together (box 2) and limited follow-up of patients.

Box 2

Key points to check before reading the recommendations

Different diseases grouped together, separate recommendations for different drugs

Inflammatory bowel disease, inflammatory arthritis, and psoriasis were grouped together after careful guideline panel discussions. This decision was supported by a systematic review that did not suggest subgroup effects on the outcomes of interest.34 In such situations of uncertainty (subgroup effects may still exist as the evidence is limited in completely ruling it out), GRADE recommends grouping diseases (populations) under the same recommendation while assessing potential subgroup effects.34 On the other hand, recommendations for different drugs were segregated because of known differences between drugs that affect the effect of proactive TDM. For example, there may be increased immunogenicity with intravenous, chimeric drugs such as intravenous infliximab compared with subcutaneous fully human protein drugs such as adalimumab, which may influence the effectiveness of proactive TDM. For more detailed reasoning, see the methodology section in MAGICapp (https://app.magicapp.org/#/guideline/8158/section/174611).

Who does this guideline apply to?

The recommendations apply to adult patients (aged 18 and older) with inflammatory bowel disease, inflammatory arthritis, or psoriasis. In this guideline, inflammatory arthritis refers to rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis.20

What is proactive TDM?

TDM is the practice of measuring serum drug levels and anti-drug antibodies, adjusting the drug dose to achieve target serum drug levels, usually within a predefined therapeutic range.17 The therapeutic range may be general, population specific, or specific to the individual patient.35 Also included in the concept is the change in biological drug for high levels of anti-drug antibodies.19 TDM can be proactive or reactive. In proactive TDM, the drug dosing is regularly adjusted based on drug serum levels that are measured at predefined intervals, irrespective of whether patients display symptoms or signs of clinical deterioration. In contrast, in reactive TDM, serum drug levels and anti-drug antibodies are only measured in response to disease worsening, non-response to treatment, or occurrence of an adverse event. Despite wide global variation in practice, reactive TDM is much more commonly used than proactive TDM and increasingly represents standard care.28293031

During what phases of treatment is proactive TDM applied?

Induction (start) of treatment—Biologic drugs are typically started when patients are in a state of active disease, and the aim of treatment during the first phase is to achieve disease control, preferably by reaching a state of remission.

Maintenance treatment—In this scenario, patients have achieved disease control and the aim is to avoid disease worsening.

Management approach to maintenance and induction treatment may vary by disease type. For example, for adalimumab in inflammatory arthritis, the same drug dose is given at the start of treatment and during maintenance, while for inflammatory bowel disease a higher dose is given at the start of treatment.

What is the difference between sustained disease control, sustained remission, and remission?

Different outcomes have been used in different clinical trials to measure the degree of disease control in maintenance treatment. Sustained disease control and sustained remission may sound similar, however, they reflect different measurements. Sustained disease control was defined as not having a significant increase in disease activity at any point during the study period. Sustained remission was defined as disease activity consistently below a predefined threshold throughout the study period. Sustained disease control and/or sustained remission were prioritised as critical outcomes and were combined into a single outcome for recommendations 1 and 2.

For the induction scenario (recommendation 3), remission was prioritised as a critical outcome. It refers to the proportion of patients in remission at the time the outcome was measured. For additional details on outcomes, see MAGICapp, “How this guideline was made” (https://app.magicapp.org/#/guideline/8158/section/174610).

Which patients would benefit most?

When considering implementing proactive TDM, clinicians should consider individual characteristics associated with worse prognosis, such as high baseline disease activity, high risk of non-adherence, previous loss of treatment effect, obesity, lack of immunosuppressive co-medication, and, for the particular case of patients with inflammatory bowel disease, persistently elevated faecal calprotectin.36

Access to serum drug level measurements and anti-drug antibody testing

To implement proactive TDM, access to drug level and anti-drug antibody measurements is needed. See the section “Implement and adapt the guideline” in MAGICapp for more details (https://app.magicapp.org/#/guideline/8158/section/174606).

RETURN TO TEXT

Finally, a key element leading to a weak (instead of a strong) recommendation was the concern about the influence of disease specific factors such as a lower risk of flare consequences in psoriasis and inflammatory arthritis, and a higher risk of flare consequences in inflammatory bowel disease (need of hospital admission, surgical intervention).

Recommendation 2: For adult patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis receiving treatment (maintenance) with adalimumab or other biologic drugs we suggest not using proactive TDM

Go to MAGIC app to read more (https://app.magicapp.org/#/guideline/nBAezL)

Understanding the recommendation

In agreeing on a weak recommendation against the use of adalimumab, we were mostly concerned about the very low certainty evidence for use of proactive TDM during maintenance treatment: the only evidence available informing critical outcomes (sustained remission and/or sustained disease control) was a small trial with 78 children and adolescents, a group outside the scope of this guidance.37 A larger body of evidence (three studies, 633 patients) was available for the outcome remission (measured at the end of the follow-up period) but this estimate was imprecise, ranging from a reduction of 9% remission events to an increase of 30% in absolute terms. The very low certainty of the evidence combined with our decision to place a high value on avoiding patient burden of potential extra clinic visits for blood sampling (as adalimumab is most often self-administered subcutaneously at home), resulted in a weak recommendation against proactive TDM for adalimumab, while waiting for better trial evidence to become available (https://en.remedy-senter.no/project/ra-drum).

For other biologic drugs, no trial evidence was available for proactive TDM, leading to a weak recommendation against proactive TDM with other biologics.32 A strong recommendation against proactive TDM during maintenance treatment with adalimumab or other biologic drugs was deemed inappropriate given the uncertainty in the evidence added to the biological plausibility of a possible beneficial effect, especially for adalimumab. In this context, on a case-by-case basis, depending on values or preferences (ie, higher value placed on avoiding disease flares), some patients—such as those at highest risk of disease flares with major consequences—may prefer to receive the intervention.

A “weak recommendation against” may still offer room for the use of proactive TDM on an individual basis. In general, patients at the highest risk of disease flares will benefit most from proactive TDM (box 2).

Recommendation 3: For adult patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis starting treatment with intravenous infliximab, adalimumab, and other biologic drugs we suggest not using proactive TDM

Go to MAGIC app to read more (https://app.magicapp.org/#/guideline/nBAezL)

Understanding the recommendation

The weak recommendation against proactive TDM of intravenous infliximab at the start of treatment (induction scenario) is supported by the lack of benefit observed in one study with 398 patients.38 The effect of proactive TDM of intravenous infliximab could vary from a reduction of 8% remission events to an increase of 11% in absolute terms. Additionally, the certainty of the evidence was very low owing to the risk of bias, imprecision, and indirectness. We felt it inappropriate to extrapolate indirect evidence from maintenance to the induction (start of treatment) scenario given the differences in the induction scenario (when patients are experiencing a flare), and drug dosing may be greater than during maintenance treatment thus limiting the effect of dose adjustments and reducing the risk of generating anti-drug antibodies. This reduces the benefit of proactive TDM.19

The weak recommendation against proactive TDM for induction with adalimumab and other biologics was because of the lack of eligible evidence (RCTs). In the absence of evidence, we agreed that most well informed patients would prefer not to have the intervention. We also judged it inappropriate to extrapolate data on intravenous infliximab to adalimumab and to other biologics. Infliximab is expected to be more immunogenic than other biologics, which increases the risk of anti-drug antibodies and consequently the benefit from proactive TDM. Patient burden is also different between infliximab, which is given intravenously, and adalimumab, which is self-administered subcutaneously.

Uncertainties

Little robust research evidence is available on proactive TDM, apart from the maintenance treatment with intravenous infliximab. This led to weak recommendations against proactive TDM for drugs other than intravenous infliximab during maintenance treatment and for all drugs at the start of treatment (induction) scenario.

Limited research evidence also prevented the proper investigation of subgroup effects, especially related to different biologic drugs and different diseases. Although we did not find evidence that the effect of proactive TDM was different between disease groups or between studies with high and low risk of bias, not enough data were available that we could confidently exclude it. We anticipate the need for updates and revisions of these guidelines as new data emerge. If new evidence emerges that suggests different outcomes between disease groups, the guideline panel may need to reconsider whether separate recommendations are needed for individual diseases.

The length of follow-up (maximum of 68 weeks [44 to 68 weeks]) is another critical limitation of the available evidence. Like patients, healthcare providers and policy makers are interested in long term effects of the intervention, and the lack of direct evidence on outcomes measured after longer follow-up times adds uncertainty to decisions aiming at long term disease control and/or disease remission.

Data on patient values and preferences are lacking; no systematic review or survey was conducted on the topic. However, we agreed that most well informed patients would be willing to use an intervention for which there is evidence of benefit in critical outcomes without significant accompanying harms.

The costs of proactive TDM were not analysed or factored in these guidelines, nor were equity issues related to its implementation. These elements should be integrated into the decision to implement proactive TDM at the regional level.

Lack of a gold standard for the assay to measure drug levels and anti-drug antibodies is another source of uncertainty. The measurement of serum drug concentrations and, especially, anti-drug antibodies, comes with technological and practical challenges. This includes variation in measurements between different assays, especially for measurements of anti-drug antibodies. Because of the associated complexities, the World Health Organization advises that serum drug levels and anti-drug antibodies measurements may only be performed in experienced laboratories with the prerequisite expertise to provide informed interpretation of the data generated.39 More information on measurement methods can be found on MAGICapp (https://app.magicapp.org/#/guideline/8690/section/187577).

Implementation and adaptation of the guideline

To implement the weak recommendation in favour of proactive TDM for patients on maintenance treatment with intravenous infliximab, decision makers should consider a range of factors. We have identified some key implementation facilitators and barriers through published studies, semi-structured interviews with clinical experts, and panel discussions.2829303135 Before implementing the recommendations, we suggest you go to MAGICapp (https://app.magicapp.org/#/guideline/8690/rec/174043) to see what you need to:

  • Know (eg, access to validated assays, frequency)

  • Consider (eg, are the costs acceptable in your setting?)

  • Decide on (eg, the algorithm to use for dosing proactive TDM)

  • Do (eg, educate clinicians and inform patients).

Of note, little evidence is available on how often proactive TDM should be done to be beneficial. Both the Nor-drum trial and the Taxit trial took blood samples before every infusion for one year.2440 We recognise that the frequency of the proactive TDM would need to depend on local context and capacity. On MAGICapp (https://app.magicapp.org/#/guideline/8690/rec/174043), in the section on practical information on recommendation 1, a suggested algorithm for proactive TDM can be found.

One important point to consider in the implementation of proactive TDM relates to the assays for the measurement of serum drug levels and anti-drug antibodies. Different assays for the measurement of serum drug levels usually show a good correlation, and some guidance exists regarding therapeutic thresholds for serum drug levels.17 The same assay should be used when following individual patients over time to ensure comparability between measurements.171819 The measurement of anti-drug antibodies is often performed only when drug serum levels are low, aiming at investigating if anti-drug antibodies are the cause of low serum drug levels. Many different strategies are used for the measurement of anti-drug antibodies providing data that can be difficult to interpret.19 Particular consideration should be given to whether the assay only measures neutralising anti-drug antibodies (blocking the effect of the drug), or whether the assay also measures non-neutralising anti-drug antibodies, as well as whether the assay measures anti-drug antibodies in the presence or absence of drug.

This guideline takes an individual patient perspective, and national or local guidelines may modify recommendations, based on the same evidence on benefits and harms. Beyond perceived differences in patients’ values and preferences, several factors may influence decision making in terms of the healthcare system.41 For example, specific elements of the weak recommendation supporting proactive TDM for intravenous infliximab on maintenance treatment may not universally apply because of factors such as limited laboratory access, out-of-pocket costs, or the need to maintain laboratory capacity for groups with a higher burden of disease. Given the uncertainty in the existing evidence, we recommend exercising caution when making strong recommendations in local guidelines until more compelling evidence is available.

How patients were involved in the creation of this article

Our panel included two patients living with inflammatory bowel disease and inflammatory arthritis. Their perspectives helped the panel to consider better the values and preferences associated with decision making related to proactive TDM of biologic drugs.

Our patient partners have contributed in various ways, including but not limited to: collaborating in the identification of priority areas, drawing from their own experiences and those of the broader patient community; participating in guideline development meetings, where their perspectives were integral in crafting recommendations that resonate with the needs and preferences of patients; reviewing draft versions of the guideline, offering feedback from a patient's viewpoint to enhance clarity, accessibility, and relevance; and validating the final recommendations to ensure they are truly reflective of patient values, preferences, and experiences.

Footnotes

  • This BMJ Rapid Recommendations article is one of a series that provides clinicians with trustworthy recommendations for potentially practice changing evidence. BMJ Rapid Recommendations represent a collaborative effort between the MAGIC group (www.magicproject.org) and The BMJ. A summary is offered here, and the full version including decision aids is on the MAGICapp (www.magicapp.org), for all devices in multilayered formats. Those reading and using these recommendations should consider individual patient circumstances and their values and preferences and may want to use consultation decision aids in MAGICapp to facilitate shared decision making with patients. We encourage adaptation of recommendations to allow contextualisation of recommendations and to reduce duplication of work. Those considering use or adaptation of content may go to MAGICapp to link or extract its content or contact The BMJ for permission to reuse content in this article. The series adviser is Rafael Perera-Salazar.

  • Patient partners: Arne Schatten, Camilla Stabell.

  • Clinical experts: Eirik Klami Kristianslund (rheumatologist), Tine Jess (gastroenterologist), Catherine Smith (dermatologist), Johanna Gehin (clinical biochemist), Andrew Owen (pharmacologist), Meghna Jani (rheumatologist), Glen Hazlewood (rheumatologist), Paul Moayyedi (gastroenterologist), Govind Makharia (gastroenterologist), Iazsmin Bauer-Ventura (rheumatologist), Peter Tugwell (rheumatologist), Ana Veronica Wolff Cecchi (rheumatologist), Andrea Shimabuco (rheumatologist), Leonin Katsidzira (gastroenterologist), David Weinberg (gastroenterologist).

  • Methodologists: Leticia Kawano-Dourado, Per Olav Vandvik, Gordon Guyatt, Thomas Agoritsas, Dena Zeraatkar, Siri Seterelv.

  • Funding: Centre for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY) is funded as a Centre for Clinical Treatment Research by the Research Council of Norway (project 328657). Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT) is a Center of Excellence funded by the Danish National Research Foundation (DNRF148). MAGIC has provided methodological contributions and support throughout the guideline process. The project has received funding from the European Union’s Horizon Europe research and innovation programme under grant agreement number 101095052.

  • Competing interests: All authors have completed the BMJ Rapid Recommendations interest of disclosure form. MAGIC and The BMJ judged that no panel member or co-chair had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions. MAGIC and TheBMJ assessed declared interests from other coauthors of this publication and found no relevant conflicts of interests.

  • Provenance and peer review: This publication was commissioned by The BMJ in partnership with the MAGIC Evidence Ecosystem Foundation, in the context of the BMJ Rapid Recommendations. Pre-publication internal and external peer review was managed by MAGIC, and internal review was managed by The BMJ. Post-publication review through rapid responses is facilitated on bmj.com and through MAGICapp.

References

  1. ↵
    1. GBD 2017 Inflammatory Bowel Disease Collaborators
    . The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol2020;5:17-30. doi:10.1016/S2468-1253(19)30333-4 pmid:31648971
    OpenUrlCrossRefPubMed
  2. ↵
    1. GBD 2021 Rheumatoid Arthritis Collaborators
    . Global, regional, and national burden of rheumatoid arthritis, 1990-2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol2023;5:e594-610. doi:10.1016/S2665-9913(23)00211-4 pmid:37795020
    OpenUrlCrossRefPubMed
  3. ↵
    1. Griffiths CEM,
    2. Armstrong AW,
    3. Gudjonsson JE,
    4. Barker JNWN
    . Psoriasis. Lancet2021;397:1301-15. doi:10.1016/S0140-6736(20)32549-6 pmid:33812489
    OpenUrlCrossRefPubMed
  4. ↵
    1. Gossec L,
    2. Baraliakos X,
    3. Kerschbaumer A,
    4. et al
    . EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update. Ann Rheum Dis2020;79:700-12. doi:10.1136/annrheumdis-2020-217159 pmid:32434812
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Smolen JS,
    2. Aletaha D,
    3. McInnes IB
    . Rheumatoid arthritis. Lancet2016;388:2023-38. doi:10.1016/S0140-6736(16)30173-8 pmid:27156434
    OpenUrlCrossRefPubMed
  6. ↵
    1. Smolen JS,
    2. Landewé RBM,
    3. Bergstra SA,
    4. et al
    . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis2023;82:3-18. doi:10.1136/ard-2022-223356 pmid:36357155
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Ramiro S,
    2. Nikiphorou E,
    3. Sepriano A,
    4. et al
    . ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis2023;82:19-34. doi:10.1136/ard-2022-223296 pmid:36270658
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Sieper J,
    2. Poddubnyy D
    . Axial spondyloarthritis. Lancet2017;390:73-84. doi:10.1016/S0140-6736(16)31591-4 pmid:28110981
    OpenUrlCrossRefPubMed
  9. ↵
    1. Le Berre C,
    2. Honap S,
    3. Peyrin-Biroulet L
    . Ulcerative colitis. Lancet2023;402:571-84. doi:10.1016/S0140-6736(23)00966-2 pmid:37573077
    OpenUrlCrossRefPubMed
  10. ↵
    1. Torres J,
    2. Bonovas S,
    3. Doherty G,
    4. et al
    . ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis2020;14:4-22. doi:10.1093/ecco-jcc/jjz180 pmid:31711158
    OpenUrlCrossRefPubMed
  11. ↵
    1. MacKenna B,
    2. Kennedy NA,
    3. Mehrkar A,
    4. et al
    . Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune-modifying therapies: a nationwide cohort study in the OpenSAFELY platform. Lancet Rheumatol2022;4:e490-506. doi:10.1016/S2665-9913(22)00098-4 pmid:35698725
    OpenUrlCrossRefPubMed
  12. ↵
    1. Guerriero F,
    2. Orlando V,
    3. Monetti VM,
    4. Russo V,
    5. Menditto E
    . Biological therapy utilization, switching, and cost among patients with psoriasis: retrospective analysis of administrative databases in Southern Italy. Clinicoecon Outcomes Res2017;9:741-8. doi:10.2147/CEOR.S147558 pmid:29238210
    OpenUrlCrossRefPubMed
  13. ↵
    1. Alulis S,
    2. Vadstrup K,
    3. Olsen J,
    4. et al
    . The cost burden of Crohn’s disease and ulcerative colitis depending on biologic treatment status - a Danish register-based study. BMC Health Serv Res2021;21:836. doi:10.1186/s12913-021-06816-3 pmid:34407821
    OpenUrlCrossRefPubMed
  14. ↵
    1. Bergstra SA,
    2. Branco JC,
    3. Vega-Morales D,
    4. et al
    . Inequity in access to bDMARD care and how it influences disease outcomes across countries worldwide: results from the METEOR-registry. Ann Rheum Dis2018;77:1413-20. doi:10.1136/annrheumdis-2018-213289 pmid:29980576
    OpenUrlCrossRefPubMed
  15. ↵
    1. Barreiro-de Acosta M,
    2. Molero A,
    3. Artime E,
    4. et al
    . Epidemiological, clinical, patient-reported and economic burden of inflammatory bowel disease (ulcerative colitis and Crohn’s disease) in Spain: a systematic review. Adv Ther2023;40:1975-2014. doi:10.1007/s12325-023-02473-6 pmid:36928496
    OpenUrlCrossRefPubMed
  16. ↵
    1. Perrone V,
    2. Losi S,
    3. Filippi E,
    4. et al
    . Analysis of the pharmacoutilization of biological drugs in psoriatic arthritis patients: a real-world retrospective study among an Italian population. Rheumatol Ther2022;9:875-90. doi:10.1007/s40744-022-00440-1 pmid:35316515
    OpenUrlCrossRefPubMed
  17. ↵
    1. Krieckaert CL,
    2. van Tubergen A,
    3. Gehin JE,
    4. et al
    . EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases. Ann Rheum Dis2023;82:65-73. doi:10.1136/annrheumdis-2022-222155 pmid:35551063
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Krieckaert C,
    2. Hernández-Breijo B,
    3. Gehin JE,
    4. et al
    . Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: a systematic literature review informing EULAR points to consider. RMD Open2022;8:002216. doi:10.1136/rmdopen-2022-002216 pmid:35980738
    OpenUrlCrossRefPubMed
  19. ↵
    1. Gehin JE,
    2. Goll GL,
    3. Brun MK,
    4. Jani M,
    5. Bolstad N,
    6. Syversen SW
    . Assessing immunogenicity of biologic drugs in inflammatory joint diseases: progress towards personalized medicine. BioDrugs2022;36:731-48. doi:10.1007/s40259-022-00559-1 pmid:36315391
    OpenUrlCrossRefPubMed
  20. ↵
    National Institute for Health and Care Excellence. Therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis. Diagnostics guidance [DG36] 2019. https://www.nice.org.uk/guidance/dg36.
  21. ↵
    1. Jani M,
    2. Isaacs JD,
    3. Morgan AW,
    4. et al.,
    5. BRAGGSS
    . High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort. Ann Rheum Dis2017;76:208-13. doi:10.1136/annrheumdis-2015-208849 pmid:27245864
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Papamichael K,
    2. Afif W,
    3. Drobne D,
    4. et al.,
    5. International Consortium for Therapeutic Drug Monitoring
    . Therapeutic drug monitoring of biologics in inflammatory bowel disease: unmet needs and future perspectives. Lancet Gastroenterol Hepatol2022;7:171-85. doi:10.1016/S2468-1253(21)00223-5 pmid:35026171
    OpenUrlCrossRefPubMed
  23. ↵
    1. Wallace ZS,
    2. Sparks JA
    . Therapeutic drug monitoring for immune-mediated inflammatory diseases. JAMA2021;326:2370-2. doi:10.1001/jama.2021.21315 pmid:34932096
    OpenUrlCrossRefPubMed
  24. ↵
    1. Syversen SW,
    2. Jørgensen KK,
    3. Goll GL,
    4. et al
    . Effect of therapeutic drug monitoring vs standard therapy during maintenance infliximab therapy on disease control in patients with immune-mediated inflammatory diseases: a randomized clinical trial. JAMA2021;326:2375-84. doi:10.1001/jama.2021.21316 pmid:34932077
    OpenUrlCrossRefPubMed
  25. ↵
    1. Feuerstein JD,
    2. Nguyen GC,
    3. Kupfer SS,
    4. Falck-Ytter Y,
    5. Singh S,
    6. American Gastroenterological Association Institute Clinical Guidelines Committee
    . American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology2017;153:827-34. doi:10.1053/j.gastro.2017.07.032 pmid:28780013
    OpenUrlCrossRefPubMed
  26. ↵
    1. Cheifetz AS,
    2. Abreu MT,
    3. Afif W,
    4. et al
    . A comprehensive literature review and expert consensus statement on therapeutic drug monitoring of biologics in inflammatory bowel disease. Am J Gastroenterol2021;116:2014-25. doi:10.14309/ajg.0000000000001396 pmid:34388143
    OpenUrlCrossRefPubMed
  27. ↵
    1. Fraenkel L,
    2. Bathon JM,
    3. England BR,
    4. et al
    . 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol2021;73:1108-23. doi:10.1002/art.41752 pmid:34101376
    OpenUrlCrossRefPubMed
  28. ↵
    1. Bjørlykke KH,
    2. Jahnsen J,
    3. Brynskov J,
    4. et al
    . Therapeutic drug monitoring in inflammatory bowel disease: implementation, utilization, and barriers in clinical practice in Scandinavia. Scand J Gastroenterol2023;58:25-33. doi:10.1080/00365521.2022.2108684 pmid:35996928
    OpenUrlCrossRefPubMed
  29. ↵
    1. Grossberg LB,
    2. Papamichael K,
    3. Feuerstein JD,
    4. Siegel CA,
    5. Ullman TA,
    6. Cheifetz AS
    . A survey study of gastroenterologists’ attitudes and barriers toward therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease. Inflamm Bowel Dis2017;24:191-7. doi:10.1093/ibd/izx023 pmid:29272486
    OpenUrlCrossRefPubMed
  30. ↵
    1. Nigam GB,
    2. Nayeemuddin S,
    3. Kontopantelis E,
    4. Hayee B,
    5. Limdi JK
    . UK National Survey of Gastroenterologists’ attitudes and barriers toward therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease. Frontline Gastroenterol2020;12:22-9. doi:10.1136/flgastro-2019-101372 pmid:33493247
    OpenUrlCrossRefPubMed
  31. ↵
    1. Patel RN,
    2. Nigam GB,
    3. Jatale RG,
    4. et al
    . An Indian national survey of therapeutic drug monitoring with anti-tumor necrosis (TNF) medications in inflammatory bowel disease. Indian J Gastroenterol2020;39:176-85. doi:10.1007/s12664-020-01047-6 pmid:32483692
    OpenUrlCrossRefPubMed
  32. ↵
    Zeraatkar D, Jassal T, Ling M, et al. Therapeutic drug monitoring for immune mediated inflammatory diseases: a systematic review and meta-analysis. In process to BMJ Medicine, 2024.
  33. ↵
    1. Laine C,
    2. Taichman DB,
    3. Mulrow C
    . Trustworthy clinical guidelines. Ann Intern Med2011;154:774-5. doi:10.7326/0003-4819-154-11-201106070-00011 pmid:21646561
    OpenUrlCrossRefPubMedWeb of Science
  34. ↵
    1. Guyatt G,
    2. Zhao Y,
    3. Mayer M,
    4. et al
    . GRADE guidance 36: updates to GRADE’s approach to addressing inconsistency. J Clin Epidemiol2023;158:70-83. doi:10.1016/j.jclinepi.2023.03.003 pmid:36898507
    OpenUrlCrossRefPubMed
  35. ↵
    1. Alsoud D,
    2. Moes DJAR,
    3. Wang Z,
    4. et al
    . Best practice for therapeutic drug monitoring of infliximab: Position statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit2024;46:291-308. doi:10.1097/FTD.0000000000001204 pmid:38648666
    OpenUrlCrossRefPubMed
  36. ↵
    1. Heida A,
    2. Park KT,
    3. van Rheenen PF
    . Clinical utility of fecal calprotectin monitoring in asymptomatic patients with inflammatory bowel disease: a systematic review and practical guide. Inflamm Bowel Dis2017;23:894-902. doi:10.1097/MIB.0000000000001082 pmid:28511198
    OpenUrlCrossRefPubMed
  37. ↵
    1. Assa A,
    2. Matar M,
    3. Turner D,
    4. et al
    . Proactive monitoring of adalimumab trough concentration associated with increased clinical remission in children with Crohn’s disease compared with reactive monitoring. Gastroenterology2019;157:985-996.e2. doi:10.1053/j.gastro.2019.06.003 pmid:31194979
    OpenUrlCrossRefPubMed
  38. ↵
    1. Syversen SW,
    2. Goll GL,
    3. Jørgensen KK,
    4. et al
    . Effect of therapeutic drug monitoring vs standard therapy during infliximab induction on disease remission in patients with chronic immune-mediated inflammatory diseases: a randomized clinical trial. JAMA2021;325:1744-54. doi:10.1001/jama.2021.4172 pmid:33944876
    OpenUrlCrossRefPubMed
  39. ↵
    World Health Organization. WHO Expert Committee on Biological Standardization. Seventy-seventh report. 77th report: https://www.who.int/publications/i/item/97892400781162023.
  40. ↵
    1. Vande Casteele N,
    2. Ferrante M,
    3. Van Assche G,
    4. et al
    . Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology2015;148:1320-9.e3. doi:10.1053/j.gastro.2015.02.031 pmid:25724455
    OpenUrlCrossRefPubMed
  41. ↵
    1. Alonso-Coello P,
    2. Oxman AD,
    3. Moberg J,
    4. et al.,
    5. GRADE Working Group
    . GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ2016;353:i2089. doi:10.1136/bmj.i2089 pmid:27365494
    OpenUrlFREE Full Text
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