What causes inflammation in your body?

Have you or your loved ones been diagnosed with a chronic autoimmune disease such as Crohn’s disease, ulcerative colitis (UC), rheumatoid arthritis (RA), psoriasis, etc.? Then you may have heard your physician mention tumor necrosis factor alpha (TNF-α).1,2 This is a protein that causes inflammation, fever, and other events that eventually help your body fight against a potential threat. In your body, TNF acts like an army, instructing other immune cells (defense units) where to go and what to do.  Inflammation sometimes can be a good thing. It shows that your body’s immune system is fighting against a possible threat. For example, when you have a cold, you feel feverish and your sinuses swell or when you have a cut, the area turns warm and red. Although you may feel uncomfortable during these situations, it shows that your immune system is doing its job.

On the other hand, inflammation can also be harmful to your body. In the case of autoimmune diseases like RA or UC, the immune system is confused and begins attacking normal, healthy parts of your body like joints or intestine. In this situation, your body tends to have high levels of TNF-α due to a high inflammatory response. In RA, high concentrations of TNF-α cause joint swelling and redness resulting in joint inflammation. Inhibition of TNF-α resulting in a reduction in concentration has been crucial in alleviating symptoms in autoimmune diseases including inflammatory bowel disease 3, psoriasis3, cancer4, and Alzheimer’s disease5 among others.

Treatment for Inflammation: TNF-α inhibitors

It is important to have the right amount of TNF-α in your body. In a healthy person, the body naturally blocks any excess TNF-α in the system. However, this does not happen in people with certain autoimmune conditions. Therefore, there are increasing levels of TNF-α in the blood causing inflammation and other painful symptoms. These patients must take specific drugs to block excess TNF-α and alleviate these symptoms. This group of drugs is called TNF- α inhibitors. These drugs are classified as biologics and can block the inflammatory response thereby lowering inflammation in joints, intestine, and skin.6

Examples of TNF-α inhibitors include adalimumab and infliximab which work by lowering levels of TNF-α in the blood. Due to the high cost and intravenous administration of these drugs, these medications are not first line options in these conditions. Rather, they are typically given to patients with inadequate response to conventional medications (Figure 1).7 Typically, the last approach for these patients is surgery.

Figure 1. This pyramid depicts the general scheme of treatment for inflammatory conditions. After trying and failing preferred therapies (1st and 2nd line), these treatment-refractory patients can be given biologics such as infliximab or adalimumab. If unsuccessful, surgery is also an option.

Monitor TNF-α inhibitor Levels: Therapeutic Drug Monitoring Strategies

Once patients are administered with adalimumab or infliximab, it is crucial to monitor these drug levels. Physicians should monitor and adjust drug dosages individually so that the drug has maximum effectiveness and provides maximum improvement of symptoms for each patient.8 This is called Therapeutic Drug Monitoring (TDM). The optimal drug level depends on various factors such as patients’ age, sex, height, pre-existing conditions, and more.8 Therefore, the outcomes may differ significantly from patient-to-patient despite administering identical drug dosages.

TDM strategies enable individualized and targeted monitoring to optimize drug dosage and dosing interval. TDM has proven to be effective since clinicians can observe the differences in drug effects and how the levels correlate with the reduction of symptoms.9 It is crucial to continue monitoring until an optimal concentration range is achieved. Once the optimal concentration is achieved, any further increase of the dose of adalimumab or infliximab is no longer beneficial, and unwanted side effects may arise.

For precise monitoring of the drug level, it is crucial to initiate TDM at an early stage and continue after adjusting the drug dose to the optimal range.8 Continuous drug level monitoring accompanying treatment with TNF-α inhibitors is key to individualized, targeted, and cost-efficient patient care. The levels of TNF-α inhibitors in blood can be successfully achieved using MabTrack ELISAs available from EUROIMMUN.10

Why does treatment with TNF-α inhibitors fail?

In some patients, TDM may reveal that they are not responding optimally to treatment. It is crucial to understand why the treatment is failing in these patients. In these patients, the medication should be discontinued due to serious adverse effects or loss of response.9 One of the reasons for insufficient clinical effectiveness may be the presence of specific antibodies against the drug itself (anti-drug antibodies (ADAs)).11 ADAs may either result in the drug not providing any effect, even in high doses or may reduce the efficacy of the drug via its premature clearance from the body.11 It is recommended to determine ADA levels only in case of drug levels dropping below a threshold of 0.5 μg/ml.12 A multi-national, non-interventional study showed that patients without ADAs showed better clinical outcomes, while those with ADA had lower serum drug concentrations leading to lower efficacy.13

Diagnostic Test Systems

MabTrack ELISAs (Sanquin Reagents; exclusively distributed by EUROIMMUN) enable the monitoring of adalimumab, infliximab, and their respective ADA levels.12 This “sandwich-type” ELISA can be fully automated, is easy to perform, and can detect free ADA levels. This ELISA technique provides specific, semi-quantitative results using plasma or serum samples.12 The MabTrack ELISA is useful during TDM for monitoring therapeutic levels of adalimumab and infliximab.

Key Takeaways

In patients taking TNF-α inhibitors, there is a need for continuous monitoring of therapeutic levels of TNF-α inhibitors to promote individualized treatment while affirming that patients receive the most accurate and cost-effective regimen available. With the MabTrack ELISA, clinicians can make effective adjustments based on semi-quantitative results and can facilitate simplified decision-making with their patients for improved long-term response.

Healthy individuals can naturally reduce TNF levels through regular physical exercise. Exercise can help get rid of fat, where TNF resides.6 Additionally, consuming a diet that consists of green leafy vegetables, fatty fish, fruits, and nuts can help fight inflammation. It helps to avoid foods with high fatty content such as margarine, lard, fried foods, red meat, white bread, soda, and sugary drinks.

References

  1. Probert L. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience. 2015;302:2-22.
  2. Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech. 2000;50(3):184-195.
  3. Brynskov J, Foegh P, Pedersen G, et al. Tumour necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut. 2002;51(1):37-43.
  4. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF Receptor Superfamilies: Integrating Mammalian Biology. Cell. 2001;104(4):487-501.
  5. Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry. 2010;68(10):930-941.
  6. DerSarkissian C. How Does TNF Cause Inflammation? https://www.webmd.com/rheumatoid-arthritis/how-does-tnf-cause-inflammation. Published 2020. Accessed March 22, 2021, 2021.
  7. Judith Stewart B. How many biosimilars have been approved in the United States? https://www.drugs.com/medical-answers/many-biosimilars-approved-united-states-3463281/. Published 2021. Accessed March 4, 2021, 2021.
  8. William J. Marshall ML, Andrew Day, Ruth Ayling. Therapeutic Drug Monitoring. In: Clinical Biochemistry : Metabolic and Clinical Aspects. Elsevier; 2014:767-787.
  9. Papamichael K, Juncadella A, Wong D, et al. Proactive Therapeutic Drug Monitoring of Adalimumab Is Associated With Better Long-term Outcomes Compared With Standard of Care in Patients With Inflammatory Bowel Disease. J Crohns Colitis. 2019;13(8):976-981.
  10. EUROIMMUN. TNF-α inhibitors. https://www.euroimmun.com/products/antigen-detection/id/therap-drug-monitoring-of-biologics/tnf-a-inhibitors/. Accessed March 22, 2021, 2021.
  11. Pratt KP. Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity. Antibodies (Basel). 2018;7(2).
  12. Sanquin. MabTrack. https://www.sanquin.org/products-and-services/bioanalysis-of-biologics/elisa-kits/brandname-mabtrack. Published 2018. Accessed March 5, 2021.
  13. Moots RJ, Xavier RM, Mok CC, et al. The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study. PLoS One. 2017;12(4):e0175207.

Related Links

  • EUROIMMUN Mab Track ELISAs [Click Here]
  • Monitoring therapeutic drug dosage in rheumatic diseases, chronic inflammatory bowel diseases and psoriasis [Click Here]
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