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

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

Clinical Focus

TNF Blockers for Rheumatic Diseases: Drug and Anti-drug Antibody Levels

Laboratory Support of Management

  

Contents

Clinical Background

Table 1: Rates of Nonresponse to TNF Blockers for Treatment of Rheumatic Diseases

Individuals Suitable for Testing

Test Availability and Selection

Table 2: Available Tests for TNF Blockers for Rheumatic Diseases

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 rheumatic diseases (eg, rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis) and inflammatory bowel disease (IBD; Crohn disease, ulcerative colitis).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 Rheumatic Diseases

Indication

Adalimumaba,b,1

Infliximaba,2

Ankylosing spondylitis (do not meet ASAS 20)c

Week 8: ~40%
Week 24: ~45%

Week 6: ~40%
Week 24: ~40%

Plaque psoriasis (do not meet PASI 75)d

Week 16: 22%-29%a

Week 10: 25%-30%a
Week 50: ~45%-70%a

Psoriatic arthritis (do not meet ACR 20 criteria)e

Week 12: 42%
Week 24: 43%

Week 14: 42%
6 months: 46%

Rheumatoid arthritis (do not meet ACR 20 criteria)e

Week 52: 27% (MTX-naïve)f
Week 104: 31% (MTX naïve)f

Week 30: 42%-50% (MTX-nonresponse)a,f
Week 54: 41%-58% (MTX-nonresponse)a,f
Week 54: 34%-38% (MTX-naïve)a

ACR indicates American College of Rheumatology; ASAS, Assessment in SpondyloArthritis International Society; MTX, methotrexate; PASI, Psoriasis Area and Severity Index.

a

Study design, dosage regimens, and patient population (eg, methotrexate-naïve vs no response to methotrexate) 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

Adalimumab, but not infliximab, is also indicated for treatment of juvenile idiopathic arthritis, hidradenitis suppurativa, and uveitis. See package insert1 for response rates.

c

ASAS 20 response is defined as ≥20% improvement for ASAS response criteria; for adalimumab, a 10-unit improvement on the Visual Analog Scale was also factored in.

d

PASI 75 response is defined as PASI score improvement of ≥75% from baseline.

e

ACR 20 response is defined as ≥20% improvement for ACR response criteria.

f

In combination with methotrexate.

When treatment fails, a physician may need to consider other treatment options, such as adjusting dose or dosing interval, 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

In one study, investigators used a decision-making model to compare these approaches in rheumatoid arthritis patients. In the model, each month of suboptimal treatment increased costs (mostly attributed to drug and visit costs) and the interval of follow-up visit varied from 3 to 6 months. The model showed that a testing-based strategy saved costs when it prevented nonoptimal treatment in as little as 2.5% to 5% (6- and 3-month follow-up, respectively) of patients.3

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.4,5 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]).4,6 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.7 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. In patients who have subtherapeutic drug levels and test negative for ADAs, increasing dose or addressing adherence issues may be appropriate.

Individuals Suitable for Testing [return to contents]

  • Individuals with a rheumatic disease who have experienced failure of adalimumab or infliximab treatment

Test Availability and Selection [return to contents]

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

Table 2. Available Tests for TNF Blockers for Rheumatic Diseases

Test Code

CPT Code(s)

Test Name

Clinical Use

36299

80299

Adalimumab Level for Rheumatic Diseases

Determine adalimumab levels

36295

83520

Adalimumab Anti-drug Antibody for Rheumatic Diseases

Determine presence of antibodies to adalimumab

36297

83520, 80299

Adalimumab Level and Anti-drug Antibody for Rheumatic Diseases

Determine adalimumab levels and presence of antibodies to adalimumab

36310

80299

Infliximab Level for Rheumatic Diseases

Determine infliximab levels

36302

83520

Infliximab Anti-drug Antibody for Rheumatic Diseases

Determine presence of antibodies to infliximab

36312

83520, 80299

Infliximab Level and Anti-drug Antibody for Rheumatic Diseases

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]

Studies suggest a target trough concentration of 5 to 12 µg/mL for adalimumab8 and 2 to 8 µg/mL or 2 to 10 µg/mL for infliximab.3,9 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

 

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. Laine J, Jokiranta TS, Eklund KK, et al. Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TNF-alpha blockers. Biologics. 2016;10:67-73.

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

  5. 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.

  6. 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.

  7. 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.

  8. Krieckaert CL, Nair SC, Nurmohamed MT, et al. Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects. Ann Rheum Dis. 2015;74:361-368.

  9. Mulleman D, Meric JC, Paintaud G, et al. Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis. Arthritis Res Ther. 2009;11:R178.
     

Content reviewed 12/2017

 

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