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TNF Blockers for IBD: Drug and Anti-drug Antibody Levels: Laboratory Support of Management

TNF Blockers for IBD: Drug and Anti-drug Antibody Levels: Laboratory Support of Management

Clinical Focus

TNF Blockers for IBD: Drug and Anti-drug Antibody Levels

Laboratory Support of Management

  

Contents

Clinical Background

Table 1: Rates of Nonresponse to TNF Blockers for Treatment of IBD

Individuals Suitable for Testing

Test Availability and Selection

Table 2: Available Tests for TNF Blockers for IBD

Test Interpretation

Table 3: Interpretation of Results in Patients with TNF Blocker Treatment Failure

References

Clinical Background [return to contents]

Tumor necrosis factor (TNF) blockers, such as adalimumab (Humira®) and infliximab (Remicade®), are used to treat inflammatory bowel disease (IBD; Crohn disease, ulcerative colitis) and rheumatic diseases (eg, rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis).1,2 TNF blockers have had a major impact on the therapy of these conditions, but response rates vary by indication (Table 1) and other factors (eg, dose). Many patients do not initially respond (primary failure), while others respond initially but do not maintain the response (secondary failure).

Table 1. Rates of Nonresponse to TNF Blockers for Treatment of IBD

Indication

Adalimumaba,1

Infliximaba,2

Crohn disease

No clinical responseb
Week 26: 46%
Week 56: 57%

Not in remissionc
Week 30: 54%-61%a
Week 54: 66%-75%a

Pediatric Crohn disease

No clinical responsed
Week 26: 41%-52%a
Week 52: 58%-72%a

No clinical responsee
Week 30: 27%-53%a
Wee 54: 36%-67%a

Ulcerative colitis

Not in remissionf
Week 8: 83%
Week 52: 83%

No clinical responseg
Week 8: 31%-38%a
Week 54: 55%-56%a

Pediatric ulcerative colitis

Not indicated

Not in remission
Week 8: 60%f-67%a,h
Week 54: 80%h

a

Study design, dosage regimens, and patient population varied by drug and disease. Ranges are presented in this table if multiple doses or trial arms were presented in the package insert. See package insert for specific information.

b

Clinical response was defined as a decrease of CDAI ≥70.

c

Clinical remission was defined as Crohn disease activity index (CDAI) <150.

d

Clinical response was defined as a decrease of pediatric CDAI (PCDAI) of ≥15 points from baseline.

e

Clinical response was defined as a decrease of PCDAI of ≥15 points from baseline and total score ≤30.

f

Clinical remission was defined as a disease activity score ≤2 and no individual subscores >1.

g

Clinical response was defined as a decrease of the disease activity score by ≥30% and ≥3 points from baseline and a rectal bleeding subscore of ≤1 or a decrease of ≥1.

h

Clinical remission was defined as Pediatric Ulcerative Colitis Activity Index (PCUAI) of <10 points.

When treatment fails, a physician may need to consider other treatment options, such as adjusting dose or dosing intervals, switching to a different TNF blocker, or switching to a non-TNF blocker. Selecting a treatment option depends on the strategy being used by the physician. Strategies for addressing treatment failure include the following:

  • Empiric dose escalation: increasing the dose (eg, from 5 mg to 10 mg) as a first response to failure
  • Testing-based strategy: relying on characteristics related to treatment failure to guide therapy; characteristics include pharmacodynamic (PD, presence of drug but lack of effect) or pharmacokinetic (PK, lack or absence of drug due to metabolism) conditions

Comparisons of these approaches in infliximab-treated patients with Crohn disease indicate that the testing-based approach saves payers money (14% to 34%).3-5 The American Gastroenterology Association (AGA) suggests a testing-based strategy when control of active IBD is suboptimal.6

With a testing-based strategy, measuring adalimumab or infliximab drug levels can help differentiate PD from possible PK conditions associated with treatment failure. The presence of therapeutic drug levels can indicate PD conditions, whereas subtherapeutic drug levels can indicate PK issues, such as increased drug clearance or patient adherence issues. PK issues can be managed by higher dose, shortening the dosing interval, or addressing patient adherence.4,7 On the other hand, loss of response after induction (PD) is usually due to the formation of antibodies against the drug (anti-drug antibodies [ADAs]).7,8 Testing for ADAs can help determine if changing the treatment approach is appropriate.

ADAs can cause subtherapeutic drug levels. They form in about 25% of infliximab-treated and 14% of adalimumab-treated patients.9 In patients who have subtherapeutic drug levels and test positive for ADAs, switching to a different TNF blocker may be more effective than increasing dose.4,7 In patients who have subtherapeutic drug levels and test negative for ADAs, increasing dose or addressing adherence issues may be appropriate.

Evidence also suggests that optimizing the drug dose when initiating treatment can reduce failure rates. In a study of patients with IBD, escalating the dose of infliximab in Crohn disease patients with levels <3 μg/mL increased the rate of remission from 65% (pre-escalation) to 88%; the same trend was not observed among ulcerative colitis patients.10

Individuals Suitable for Testing [return to contents]

  • Individuals with IBD who have recently started treatment with adalimumab or infliximab (baseline testing) and those who experience failure with either drug

Test Availability and Selection [return to contents]

Quest Diagnostics offers tests for the TNF blockers adalimumab and infliximab for patients with IBD (Table 2). All tests use enzyme-linked immunosorbent assays (ELISA) to measure levels.

Table 2. Available Tests for TNF Blockers for IBD

Test Code

CPT Code(s)

Test Name

Clinical Use

36298

80299

Adalimumab Level for IBD

Determine adalimumab levels

36294

83520

Adalimumab Anti-drug Antibody for IBD

Determine presence of antibodies to adalimumab

36296

83520, 80299

Adalimumab Level and Anti-drug Antibody for IBD

Determine adalimumab levels and presence of antibodies to adalimumab

36303

80299

Infliximab Level for IBD

Determine infliximab levels

36301

83520

Infliximab Anti-drug Antibody for IBD

Determine presence of antibodies to infliximab

36311

83520, 80299

Infliximab Level and Anti-drug Antibody for IBD

Determine infliximab levels and presence of antibodies to infliximab

Testing for drug levels will indicate bioavailability, whereas testing for ADAs can help differentiate causes of insufficient bioavailability.

  • Measuring only drug levels may be appropriate if a sequential approach is preferred to concurrent testing. It may also be appropriate for therapeutic drug monitoring (TDM), though TDM is not routine for TNF blocker treatment because thresholds and testing intervals have not been established.
  • Measuring only ADAs may be appropriate if insufficient bioavailability has already been established.
  • Measuring both drug and ADA levels at the same time may expedite identification of the bioavailability of the drug and the cause of treatment failure.

Test Interpretation [return to contents]

The AGA recommends an optimal adalimumab trough concentration of ≥7.5 µg/mL in patients with active IBD.6 Data from separate clinical studies suggest an optimal adalimumab trough concentration >4.5 µg/mL or 8 to 12 µg/mL.11,12 The AGA recommends an optimal infliximab trough concentration of ≥5 µg/mL in patients with active IBD.6 Data from separate clinical studies suggest an optimal infliximab trough concentration of >3.8 μg/mL or 6 to 10 µg/mL.11,12

Subtherapeutic drug levels may be caused by a patient not yet achieving a steady state trough level early in therapy; they may also be caused by inadequate dosing, a dosing interval that is too long, or accelerated drug clearance. Accelerated drug clearance may be explained by ADAs or rheumatoid factor (RF) in the patient's serum or by other diseases that indirectly lead to immunoglobulin loss (eg, kidney disease, protein-losing gastroenteropathy).

Adalimumab or infliximab ADA levels ≥10 AU indicate detectable serum levels, which can lead to accelerated drug clearance, reduced trough levels, and a compromised clinical response. Levels <10 AU are considered "not detected" and suggest treatment failure is not caused by ADAs. Some ELISA-based tests for adalimumab or infliximab ADAs are susceptible to false-negative results caused by cross-reactivity with RF. However, Quest Diagnostics uses ELISAs that measure both free and bound ADAs, so serum RF will not cause false-negative results.

Table 3 contains result interpretation and management strategies when both drug and ADA levels are tested.

Table 3. Interpretation of Results in Patients with TNF Blocker Treatment Failure4,7

 

ADA Not Detected (absent)

ADA Detected (present)

Drug Levels Subtherapeutic

Suggests insufficient bioavailability caused by nonimmune PK or patient adherence issues

Consider increasing therapeutic dose or addressing potential adherence issues

Suggests insufficient bioavailability caused by immunogenicity

Consider switching to different TNF blocker

Drug Levels Therapeutic

Suggests PD issue caused by TNF-independent disease

Consider switching to a non-TNF treatment  

Rare situation that may be caused by a false-positive result or nonfunctional ADAs

Consider retest or testing for neutralizing antibody by cell-based assay

ADA indicates anti-drug antibody; PD, pharmacodynamic; PK, pharmacokinetic; TNF, tumor necrosis factor.

References [return to contents]

  1. Humira [package insert]. North Chicago, IL: AbbVie Inc; 2016.

  2. Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc; 2015.

  3. Steenholdt C, Brynskov J, Thomsen OO, et al. Implications of infliximab treatment failure and influence of personalized treatment on patient-reported health-related quality of life and productivity outcomes in Crohn's disease. J Crohns Colitis. 2015;9:1032-1042.

  4. Steenholdt C, Brynskov J, Thomsen OO, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63:919-927.

  5. Velayos FS, Kahn JG, Sandborn WJ, et al. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol. 2013;11:654-666.

  6. Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease. Gastroenterology. 2017;153:827-834.

  7. Lazar-Molnar E, Delgado JC. Immunogenicity assessment of tumor necrosis factor antagonists in the clinical laboratory. Clin Chem. 2016;62:1186-1198.

  8. Steenholdt C, Bendtzen K, Brynskov J, et al. Optimizing treatment with TNF inhibitors in inflammatory bowel disease by monitoring drug levels and antidrug antibodies. Inflamm Bowel Dis. 2016;22:1999-2015.

  9. Thomas SS, Borazan N, Barroso N, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. a systematic review and meta-analysis. BioDrugs. 2015;29:241-258.

  10. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148:1320-1329.e1323.

  11. Ungar B, Levy I, Yavne Y, et al. Optimizing Anti-TNF-alpha Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2016;14:550-557.e552.

  12. Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13:522-530.e522.
     

Content reviewed 12/2017

 

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* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.