TNFα Inhibitors Therapeutic Drug MonitoringCompiled by Prof E Vardas

NEWSLETTER

3 Quarter 2017rd

IntroductionTumour necrosis factor alpha (TNFα) is a pro-inflammatory cytokine involved in the pathogenesis of several chronic

inflammatory conditions. The introduction of monoclonal antibody derived �biologic� drugs targeting TNFα has

redefined the treatment of multiple chronic inflammatory diseases (see Figure 1) and has led to considerable

improvement in clinical outcomes for patients with these conditions.

TNFα inhibitors (TNFi)These biologic drugs are monoclonal antibodies of various designs (see Figure 2). Infliximab (Revellex ) was the first

TNFα inhibitor to be approved for the treatment of inflammatory bowel disorders. Infliximab is a chimeric monoclonal

IgG1 antibody composed of a murine variable region and a constant human region. Alternative tradenames for many of

these monoclonal antibody drugs exist because �biosimilars� produced by other manufacturers, after the patent of the

original drug has expired, have entered the market. Biosimilars contain a similar version of the active substance of an

original biological medicinal product and are very close to the reference product in terms of quality characteristics,

biological activity, safety, and efficacy based on comprehensive comparability studies done before registration of the

product as well as phase 4 effectiveness studies.

Rheumatoidarthitis

Juvenileidiopathicarthritis

Ankylosing Spondylitis

BeҫhetsDiseaseuveitis

Vasculiticdisease

In�ammatory BowelDiseases

- Crohn�s disease- Ulcerative colitis

PsoriaticarthritisPsoriasis

TNFα Inhibitors

Figure 1. Spectrum of chronic in�ammatory diseases in which TNFα inhibitors are used

Figure 2. Schematic representation of the structure of a few common TNFα inhibitors

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TNFi therapeutic drug monitoringThe management of patients receiving TNFα inhibitors has until recently been empirical, with dose adaptations based

on various complex clinical measures and derived scales that have been developed to quantitate patient symptoms,

and which may include both objective and subjective measures of improvement. Recent technological advances have

made therapeutic drug monitoring (TDM) of TNFα inhibitors possible. Consequently treatment with these very costly

biologicals can now be more personalised for the individual patient, and ultimately more cost-effective.

Multiple clinical studies have demonstrated a link between trough concentrations of in�iximab (IFX), the concentration

of the drug just before administration of the next dose, and clinical response in patients with in�ammatory bowel

disease (IBD). Low or undetectable concentrations correlated with poor response and adequate trough levels are

associated with a sustained response to IFX. In rheumatoid arthritis (RA), the use of a biologic disease-modifying anti-

rheumatic drug (DMARD) or the targeted kinase inhibitor tofacitinib is recommended for patients with moderate or high

disease activity despite monotherapy with a conventional (non-biologic) DMARD. The most commonly used biologics in

these patients are the TNFα inhibitors etanercept, adalimumab, and in�iximab. Newer TNFi (e.g. certolizumab pegol and

golimumab) are also used, but less frequently.

For any patient on TNFi biological therapy, treatment failure may occur and it can be either primary or secondary.

Primary failure occurs in approximately 30% of patients who are refractory to, and do not improve clinically while on

induction therapy with TNFα inhibitors. Secondary treatment failure, de�ned as decreased or lack of response in a

previously responsive patient, may also occur. Table 1 outlines the most common reasons for secondary treatment

failure on TNFi, which may occur in up to 50% of IBD/RA patients that responded initially.

The production of anti-drug antibodies (ADA), which neutralise and accelerate the clearance of the particular TNFα

inhibitor, results in reduced drug availability. ADA may occur transiently in some patients, which are of no clinical

consequence. High levels of ADA that in�uence treatment outcomes may also occur. The point prevalence of ADA is

approximately 60% in episodic treatment with TNFi and 6 � 25% in scheduled treatment. Most patients that develop

ADA do so within the �rst 12 months of treatment.

Table 1 also outlines the major adverse events that can occur in patients on biologicals. Especially important are

allergic reactions to the drug, increased risk for the development of active tuberculosis, major bacterial and viral

infections, as well as various malignancies.

Table 1. Common causes of treatment failure and complications of TNFα inhibitors

Causes of treatment failure

Complications

Severity of disease

Duration of disease

Smoking

High BMI

Pharmacokinetics � drug elimination

Drug binding

Anti-drug antibodies

Alternative non-TNFα mediated disease pathways

Concomitant treatment with immunosuppressants

Prior treatment failure with another TNFα inhibitor

Allergic reactions to drugs, e.g. urticaria, dif�culty swallowing or breathing, joint pain, fever or chills, swelling of the face or hands

Serious viral or bacterial infections, incl. tuberculosis, especially in people aged > 65 years

Skin reactions, incl. psoriasis (red scaly patches), rashes, skin lesions, ulcers and hives, swollen face and lips

Worsening of pre-existing cardiac condition

Increased cancer risk, e.g. lymphoma

Liver in�ammation

Multiple studies and cost effectiveness analyses provide guidance on the use of TNFi in patients with IBD. Locally

guidance is provided by the South African Gastroenterology Society (SAGES), which mostly uses the approach of the

TAXIT study in their guidelines. Similarly EULAR/SARAA recommendations exist for the use of TNFα inhibitors in

rheumatological conditions. Figure 3 outlines a symptomatic approach to IFX TDM for in�ammatory bowel diseases.

Lancet Laboratories is using an ELISA based system that detects levels of in�iximab and its biosimilars with a

reportable range of 0.5 � 48 �g/mL, and anti-drug antibodies (ADA) with a reportable range of 2.5 � 1 000 ng/mL. These

particular assays were chosen because of their superior performance compared to other TNFα inhibitor immunoassays

available in the market, in particular their ability to detect both in�iximab and its biosimilars, as well as increased

sensitivity to detect anti-drug antibodies.

Soon to be introduced is an adalimumab (ADM) assay with anti-ADM antibodies as well as more rapid TDM systems for

both in�iximab and adalimumab (Humira ) and its biosimilars.

References1. Aaltonen KJ, et al. Systematic review and meta-analysis of the ef�cacy and safety of existing TNF blocking

agents in the treatment of rheumatoid arthritis. PlosOne 2012; 7(1): e30275.

2. Bendtzen K. Anti-TNFα Biotherapies: perspectives for evidence-based personalized medicine. Immunotherapy

2012; 4(11): 1167 � 1179.

3. Freeman K, et al. Clinical effectiveness and cost-effectiveness of use of therapeutic monitoring of tumour

necrosis factor alpha (TNF-α) inhibitors [LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits,

TNF-α-Blocker ELISA kits and Promonitor® ELISA kits] versus standard care in patients with Crohn's disease:

systematic reviews and economic modelling. Health Technol Assess 2016; 20(83): 1 � 288.

4. Jørgensen KK, et al. Switching from originator in�iximab to biosimilar CT-P13 compared with maintained

treatment with originator in�iximab (NOR-SWITCH): a 52 week, randomised, non-inferiority trial. Lancet 2017;

389(10086): 2304 � 2316.

5. Khanna R, et al. Review article: A clinician's guide for therapeutic drug monitoring of in�iximab in in�ammatory

bowel disease. Aliment Pharmacol Ther 2013; 38(5): 447 � 459.

6. Schmitz EM, et al. Therapeutic drug monitoring of in�iximab: performance evaluation of three commercial

ELISA kits. Clin Chem Lab Med 2016; 54(7): 1211 � 1219.

7. Silva LC, et al. Anti-TNF-α agents in the treatment of immune-mediated in�ammatory diseases: mechanisms of

action and pitfalls. Immunotherapy 2010; 2(6): 817 � 833.

8. Ungar B, et al. The temporal evolution of antidrug antibodies in patients with in�ammatory bowel disease

treated with in�iximab. Gut 2014; 63(8): 1258 � 1264.

9. Van Stappen T, et al. An optimised anti-in�iximab bridging enzyme-linked immunosorbent assay for

harmonization of anti-in�iximab antibody titers in patients with in�ammatory bowel diseases. In�amm Bowel

Dis 2015; 21(9): 2172 � 2177.

10. Vande Casteele, N et al. Trough concentrations of in�iximab guide dosing for patients with in�ammatory bowel

disease. Gastroenterol 2015; 148(7): 1320 � 1329.

11. Watermeyer G, et al. Recommendations on the use of anti-TNFs in adults with in�ammatory bowel disease:

SAGES guidelines. South African Gastroeneterology Review, 2015; 13(3): 21 � 24.

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Figure 3. Symptom-guided approach to TNFα inhibitor and drug antibody monitoring

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