Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity

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Abstract

Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.

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Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up.

Geertje M Bartelds, Charlotte L M Krieckaert, Michael T. Nurmohamed … (2011)

Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up. To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3-year) follow-up of patients with rheumatoid arthritis (RA). Prospective cohort study February 2004-September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic. Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies. After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies--51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, -4.5; 95% CI, -6.0 to -2.9; P < .001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, -7.1; 95% CI, -8.4 to -5.8; P < .001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n = 29 [38%]; hazard ratio [HR], 3.0; 95% CI, 1.6-5.5; P < .001) compared with antiadalimumab antibody-negative ones (n = 28 [14%]). Ninety-five of 196 patients (48%) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (< 3.2; HR, 3.6; 95% CI, 1.8-7.2; P < .001) compared with antiadalimumab antibody-negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody-negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 < 2.6; HR, 7.1; 95% CI, 2.1-23.4; P < .001) compared with antiadalimumab antibody-negative ones. Among outpatients with RA in whom adalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission.

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Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective.

Xavier Mariette, E Morand, Christian Marcelli … (2013)

The introduction of biologics, especially tumour necrosis factor (TNF) inhibitors, has revolutionized the management of chronic inflammatory diseases. However, at least one third of patients with these diseases, receiving TNF inhibitors either do not respond to treatment, or lose initial responsiveness. For a significant proportion, improvement of clinical response is achieved after switching to another anti-TNF drug, suggesting a basis for failure unrelated to the therapeutic target itself. A likely explanation for this is immunogenicity, as all biologics are potentially immunogenic, and the resulting anti-drug antibodies (ADAb) can theoretically decrease the efficacy of biologics and/or induce adverse events. Indeed, in these chronic inflammatory diseases, many studies have now established correlations between ADAb formation, low serum drug levels, and the failure or loss of response to anti-TNF antibodies. This article will review key findings related to ADAb, and propose a model wherein monitoring of drug levels and ADAb may be a predictive tool leading to a better choice of biologics. Such an approach could improve chronic inflammatory disease management toward a personalized and more cost-effective approach.

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The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial.

Arthur Kavanaugh, R. Clair, Thomas Schaible … (2002)

To investigate the relationship between serum concentrations of infliximab, a monoclonal anti-tumor necrosis factor alpha antibody, and clinical improvement from infliximab therapy for rheumatoid arthritis (RA). Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the clinical efficacy and safety of infliximab therapy. Serum levels of infliximab were measured by enzyme-linked immunosorbent assay. Dose-response trends were analyzed using generalized logistic regression techniques. Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial. At week 54, 26% of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (P < 0.001). Increased magnitude of American College of Rheumatology (ACR) response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR 20% response criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (P < 0.001), as was less progression of radiographic joint damage (P = 0.004), providing support for a dose-response relationship. Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg. These results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Lab Med

Journal ID (iso-abbrev): Ann Lab Med

Journal ID (publisher-id): ALM

Title: Annals of Laboratory Medicine

Publisher: The Korean Society for Laboratory Medicine

ISSN (Print): 2234-3806

ISSN (Electronic): 2234-3814

Publication date (Print): March 2020

Publication date (Electronic): 23 October 2019

Volume: 40

Issue: 2

Pages: 101-113

Affiliations

[1 ]Rheumatology Unit, S.Giovanni di Dio Hospital, Florence, Italy.

[2 ]Immunology and Allergology Laboratory Unit, S.Giovanni di Dio Hospital, Florence, Italy.

[3 ]Department of Medicine, University Hospital San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy.

[4 ]Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.

[5 ]SDN SPA-Synlab Laboratory, Pagani, Salerno, Italy.

[6 ]Division of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.

[7 ]Rheumatology Unit, University of Messina, Messina, Italy.

[8 ]Italian Society of Rheumatology, Milan, Italy.

[9 ]World Association of Societies of Pathology and Laboratory Medicine, Milan, Italy.

[10 ]Department of Experimental Medicine Sapienza University of Rome, Rome, Italy.

Author notes

Corresponding author: Roberto Verna, M.D., Ph.D. Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy. Tel: +393711547775, Fax: +0082313898817, roberto.verna@ 123456fondazione.uniroma1.it

Author information

Maurizio Benucci https://orcid.org/0000-0001-8180-6660

Valentina Grossi https://orcid.org/0000-0001-6327-0874

Mariangela Manfredi https://orcid.org/0000-0001-9242-2793

Arianna Damiani https://orcid.org/0000-0003-2817-4822

Maria Infantino https://orcid.org/0000-0002-6200-4467

Paolo Moscato https://orcid.org/0000-0002-8980-5141

Luigi Cinquanta https://orcid.org/0000-0002-2287-3027

Elisa Gremese https://orcid.org/0000-0002-2248-1058

Barbara Tolusso https://orcid.org/0000-0002-9108-6609

Luca Petricca https://orcid.org/0000-0003-3544-3162

Anna Laura Fedele https://orcid.org/0000-0001-9148-1548

Stefano Alivernini https://orcid.org/0000-0002-7383-4212

Fabiola Atzeni https://orcid.org/0000-0002-9328-3075

Giovanni Minisola https://orcid.org/0000-0003-4702-7094

Roberto Verna https://orcid.org/0000-0002-1869-3912

Article

DOI: 10.3343/alm.2020.40.2.101

PMC ID: 6822010

PubMed ID: 31650726

SO-VID: 3ac45ea1-28cc-4e56-bcb2-1e290ab29aeb

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 04 March 2019

Date revision received : 09 June 2019

Date accepted : 15 October 2019

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Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity

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Most cited references 72

Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up.

Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective.

The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial.

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