In the name of God

Formation of anti-drug antibodies and infliximab A PubMed search, Dr P Alavinejad 2016

Patient is a 30y old man known case of Crohn’s disease with colonic involvement since 14 years ago He has been on treatment with Remicade since 1 years ago and complain of watery diarrhea during an abroad His past medical regimen included 6MP 100mg/d and Pentasa 2gr daily but due to chronic interstitial nephritis, his drugs changed to Remicade

Currently he complain of stool frequency more than 10 times/day what is your next step? CBC ESR & CRP Stool exam for CD toxin Stool exam for fecal Calprotectin Colonoscopy Anti Infliximab Ab (ADA) Normal >30 Negative Highly positive (↑↑↑) Endoscopic remission with histologic activity

What is your next step?

Optimization of anti-TNF therapy in patients with Inflammatory Bowel Disease. use of anti-TNF therapy is complicated by loss of response. In order to maintain remission, adequate serum levels are required. Hence, therapeutic drug monitoring (TDM) is important in order to optimize serum drug levels, especially in patients with loss of response to these agents. Optimization of anti-TNF therapy by applying TDM enables clinicians to regain response to TNF blockers in a significant proportion of patients. It is important to use anti-TNF agents in their most optimal way. Optimization of anti-TNF therapy in patients with Inflammatory Bowel Disease. Expert review of clinical pharmacology. 2016 Mar 3(just- accepted). Expert Rev Clin Pharmacol. 2016 Jan 28:1-11.

The Pharmacokinetics of Biologics: A Primer. Dig Dis The Pharmacokinetics of Biologics: A Primer. Dig Dis. 2015 Sep 14;33 Suppl 1:61-69 Monoclonal antibodies (MAbs) exhibit complex pharmacokinetics (PK) and pharmacodynamics (PD, response) against tumor necrosis factor (TNF). Many factors impact anti-TNF MAb PK, altering MAb clearance and therefore the half- life: albumin, weight (particularly, obesity), disease (severity, stage and co-morbidities) and concomitant administration of immunosuppressants (e.g. mtx). These factors can alter MAb exposure, impacting on the likelihood of clinical response. Formation of anti-drug antibodies (ADAs) is another potential factor that can affect MAb PK.

The Pharmacokinetics of Biologics: A Primer. Dig Dis The Pharmacokinetics of Biologics: A Primer. Dig Dis. 2015 Sep 14;33 Suppl 1:61-69 Factors impacting the likelihood of developing ADA are classified as patient-related (concomitant immunosuppressants, prior ADA against other anti-TNF MAb) or product- related (structure, manufacturing process, aggregate formation, route of administration and dosing regimen). Repeated episodic exposure can induce ADAs, shortening the effective treatment interval. Avoiding intervals where anti-TNF MAbs are non-measurable is important for efficacy and may delay onset of ADAs. Thus, patients whose factors predispose them to having faster clearance (or short half-life) such as severe disease, low albumin or high body weight may need shorter dose intervals to reduce the likelihood of intermittent exposure.

The Pharmacokinetics of Biologics: A Primer. Dig Dis The Pharmacokinetics of Biologics: A Primer. Dig Dis. 2015 Sep 14;33 Suppl 1:61-69 ADAs can have no effect or can impact efficacy through MAb binding, thus inhibiting its function or potentially causing hypersensitivity reactions (PD). ADA can also increase MAb clearance (PK) and have been linked to lower serum drug concentrations

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 Aug;29(4):241-58. doi: 10.1007/s40259-015-0134-5. Of the patients using infliximab, 25.3 % developed ADAs compared with 14.1 % using adalimumab, 6.9 % for certolizumab, 3.8 % for golimumab, and 1.2 % for etanercept. ADAs reduced the odds of clinical response by 67 % overall The use of concomitant immunosuppressives (mtx, 6-mp, azathioprine, and others) reduced the odds of ADA formation in all patients by 74 %.

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 Aug;29(4):241-58. doi: 10.1007/s40259-015-0134-5. CONCLUSION: ADAs developed in 13 % of patients. All five TNF inhibitors were associated with ADAs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADAs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADA formation.

Immunogenicity of biologic agents in rheumatoid arthritis patients: lessons for clinical practice. Rheumatology (Oxford). 2016 Feb;55(2):210-20. doi: 10.1093/rheumatology/kev277. Epub 2015 Aug 12. the development of ADAs is associated with a poorer clinical response and with an increased risk of adverse effects. The detection of these antibodies and/or the dosage of the biologic agent itself could have consequences for the bedside practice of clinicians and should be well understood.

Influence of Immunogenicity on the Efficacy of Long-Term Treatment with TNF α Blockers in Rheumatoid Arthritis and Spondyloarthritis Patients. Biomed Res Int. 2015;2015:604872. doi: 10.1155/2015/604872. Epub 2015 Apr 27. Patient with anti-ADA Ab and 57.1% patients with anti-INF Ab were considered nonresponders to treatment. 5.3% of patients with high serum anti-INF Ab levels developed infusion related reactions.

New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis. Autoimmun Rev. 2015 Sep;14(9):812-29. doi: 10.1016/j.autrev.2015.05.001. Epub 2015 May 15. A total of 57 original research articles were included in the analysis (infliximab n=34; adalimumab n=18; etanercept n=5). The timing of occurrence and the persistence of anti-drug antibodies appeared to be influenced by administration schedules and concomitant immunosuppressive therapy. Monitoring of circulating drug levels and anti-drug antibodies appears to be an emerging and cost-effective strategy for the management of the individual patient.

Managing unwanted immunogenicity of biologicals. Autoimmun Rev Managing unwanted immunogenicity of biologicals. Autoimmun Rev. 2015 Jul;14(7):569-74. doi: 10.1016/j.autrev.2015.02.007. Epub 2015 Mar 2. the assessment of unwanted immunogenicity can be improved by using prediction tools, optimizing the performance of immunogenicity assays and learning from the clinical impact of other biologicals that have already been administered to patients. A multidisciplinary approach is warranted

Pharmacokinetics of anti-TNF monoclonal antibodies in inflammatory bowel disease: Adding value to current practice. J Clin Pharmacol. 2015 Mar;55 Suppl 3:S39-50. doi: 10.1002/jcph.374. Although a large proportion of patients (70-90%) initially respond to the treatment, remission rates after induction are still low (20-50%) and patients are at risk to lose response to the drug over time. This inter-individual variability in response is likely to be influenced by the observed inter-individual variability in pharmacokinetics.

A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn's disease. Aliment Pharmacol Ther. 2014 May;39(10):1126-35. doi: 10.1111/apt.12733. Epub 2014 Apr 1. The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration ( P = 0.083), but was associated with the mean change in CRP concentration. Trough infliximab concentrations below 2.8-4.6 μg/mL best predicted a ≥ 70 point increase in the CDAI between infusions, and those below 2.7-2.8 μg/mL best predicted CRP >5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P < 0.001 for both comparisons).

A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn's disease. Aliment Pharmacol Ther. 2014 May;39(10):1126-35. doi: 10.1111/apt.12733. Epub 2014 Apr 1. This prospective study confirms the relationship between trough infliximab concentrations, inflammation and antibodies-to-infliximab. Infliximab trough concentrations below 3 μg/mL may increase the likelihood of symptoms and inflammation.

Anti-drug antibodies in psoriasis: a critical evaluation of clinical significance and impact on treatment response. Expert Rev Clin Immunol. 2013 Oct;9(10):949-58. doi: 10.1586/1744666X.2013.836060. ADA have been reported in patients treated with etanercept, infliximab, adalimumab or ustekinumab at rates of 0-18.3%, 5.4-43.6%, 8.8-44.8% and 3.8-5.4%, respectively. Antibodies against etanercept have no apparent effects on clinical response, whereas antibodies against infliximab or adalimumab have been associated with diminished clinical response. some evidence suggests that concomitant immunomodulators such as methotrexate may suppress ADA development in psoriasis. ADA specific to one biologic do not appear to carry cross-linking potential with other biologic agents.

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther. 2013 Sep;38(5):447-59. doi: 10.1111/apt.12407. Epub 2013 Jul 14. Treatment algorithms for IBD have evolved from episodic monotherapy used in refractory cases to long-term combination therapy initiated early in the disease course. nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost- effective. Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX.

Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol. 2013 Mar;9(3):164-72. doi: 10.1038/nrrheum.2013.4. Epub 2013 Feb 12. In the case of adalimumab and infliximab, immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response Low ADA levels might not influence the efficacy of anti-TNF therapy, whereas high ADA levels impair treatment efficacy by considerably reducing unbound drug levels.

The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013 Dec;72(12):1947-55. doi: 10.1136/annrheumdis-2012-202220. Epub 2012 Dec 6. Of 865 patients, ADA against infliximab or adalimumab reduced drug response rate by 68% (RR=0.68), an effect attenuated by concomitant methotrexate Of 936 patients, concomitant MTX or azathioprine/mercaptopurine reduced ADA frequency by 47% (RR=0.53) CONCLUSIONS: ADA reduces drug response, an effect that can be attenuated by concomitant immunosuppression

Assessing response and loss of response to biological therapies in IBD Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011 Apr;106(4):685-98. doi: 10.1038/ajg.2011.103. Epub 2011 Mar 22. Favorable clinical outcome appears to be the consequence of sustained therapeutic drug levels, and the current literature supports a practice of dose adjustments. When immunogenicity develops to a single biological agent, response can be regained by introduction of an alternative biological agent of the same or different class. Efficacy is reduced with second-line agents either within or across classes compared with naive patients. In the absence of direct measurement of drug levels and anti-drug antibodies, clinical judgment is necessary to assess the mechanisms of loss of response, and more empiric decision making may be necessary to determine the choice of second-line biological agents.

Algorithm Based on Therapeutic Anti-TNF Agent Concentrations Sub-therapeutic IFX concentration increase infliximab dose or frequency If no response, change to different anti-TNF agent or change mechanism of action endoscopy/CTE with active disease change to Rx with different mechanism of action (non anti-TNF agent) * Therapeutic IFX concentration endoscopy/CTE with inactive disease investigate for alternate etiology of symptoms Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.

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