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Immunogenicity: implications for rheumatoid arthritis treatment.

In the past 15 years, the emergence and subsequent widespread use of biologic DMARDs has dramatically altered the expectations of both physicians and of patients, regarding outcomes in the treatment of rheumatoid arthritis. Increasingly, the target in a treat-to-target approach is DAS low disease activity or DAS remission. In terms of ACR disease activity scores, the bar has risen from an ACR20 to an ACR50 or ACR70.

In clinical trials ranging from 6 to 24 months, these goals can be achieved in 50% or more of patients. Unfortunately, clinical registries extending for longer periods of time have established that some patients who initially meet treatment goals, lose them over time. While there are multiple mechanisms by which a biologic agent may lose efficacy, far and away the most important is the emergence of antibodies against the biologic agent (AABs). The emergence of these antibodies affects both the efficacy and the safety of treatment with the biologic agent.

This article will review the published data regarding immunogenicity of biologic therapy and will discuss the impact of AABs on treatment outcomes. Suggestions will be made for rational switching between biologic DMARDs, taking into account whether or not loss of efficacy is AAB mediated.

What is Known

1. All biologic agents are immunogenic.

2. Antibody to drug influences the pharmacology of the drug, particularly peak and trough levels. The levels can be decreased either by direct binding of the antibody to the drug or by the formation of immune complexes with the drug, which accelerates clearance from the serum.

3. Standard dosing and dosing intervals are based upon serum levels that can be expected with the fixed dose and upon the biologic half-life of the agent. Antibodies to the drug will affect both the level and the drug clearances, hence the half-life.

4. Competitive binding assays for AABs are influenced by drug level.

5. Low serum concentrations of drug are associated with less favorable outcomes. (1)

6. Low trough levels are associated with loss of response, likely by favoring antibody formation. The interval between infusions should be sufficiently short to prevent low trough levels. (2)

7. Anti-nuclear antibodies and anti-DNA antibodies are associated with a loss of response to anti-TNF agents and may be predictors of an unfavorable clinical outcome based on the emergence of AABs. This association has been demonstrated in rheumatoid arthritis, psoriasis, and inflammatory bowel disease. (2-5)

What is Not Known

1. The true incidence of AABs is not known as there are no standardized assays for AAB. Drug levels are only commercially available for infliximab. The prevalence of AABs as reported by manufactures is far less than those reported in independent studies.

2. Non-neutralizing antibodies are difficult to measure. This is particularly true for etanercept where antibodies are typically directed against the hinge region of the fusion protein.

3. Assays for AABs are affected by serum concentrations of the drug and are thus dependent upon the time during the treatment interval when they are drawn. Studies suggesting that AABs are less common at higher doses of infliximab or adalimumab may not be accurate and may only reflect the limitations of the available assays for AABs.

4. The mechanism linking ANA and anti-DNA antibody production to loss of efficacy and the formation of AABs remains speculative.

Immunology of AABs

It is not at all surprising that administration of a complex protein structure at intervals ranging from once a week to once every 8 weeks would result in the emergence of antibodies directed against that protein structure. This is particular true when the immunogen is an intact antibody with both FAB and FC regions such as chimeric anti-TNF antibodies or human anti-TNF antibodies.

Antibodies may be directed against the antigen combining site, in which case they will serve as neutralizing antibodies. Human anti-human antibodies (HAHA) may be directed against either the framework region of the FAB fragment or against unique sequences in the antigen combining region, in which case they would be classified as anti-idiotypic. Such antibodies would also be classified as neutralizing antibodies because they block the ability of the antibody to bind its ligand (TNF).

Antibodies to chimeric antibodies (HACA) may be directed against a wide variety of epitopes in both the antigen combining site or framework epitopes in both the constant and variable regions of the immunoglobulin molecule. They may be either neutralizing or non-neutralizing.

Antibodies to fusion proteins, such as etanercept or abatacept, may be directed against the antigen binding site or against structural epitopes such as the hinge region of etanercept. While these antibodies are not neutralizing, they will have a biologic effect upon the half-life, clearance, and tissue dispersion of the molecule and may result in immune complex formation. The finding that the AAB is non-neutralizing does not mean that it does not have an impact upon treatment outcomes.

Factors that favor the formation of AABs include a long interval between doses, the intrinsic immunogenicity of the specific agent, and the trough level of drug (low trough levels encourage antibody formation). (6) The concurrent administration of non-biologic DMARD also has an impact on immunogenicity as will be discuss in detail later in this article.

Impact of AABs on Therapeutic Outcomes (7-9)

A recent article published in JAMA offered a systemic literature review of published studies regarding the immunogenicity of biologic therapies in immune mediated inflammatory diseases (IMIDs). (7) Sixty references were selected for review, including 59 studies of anti-TNF monoclonal antibodies, one of etanercept, two of rituximab, and two of abatacept. They looked at studies involving patients with rheumatoid arthritis, juvenile inflammatory arthritis (JIA), inflammatory bowel disease, spondyloarthritis, and psoriasis. The primary endpoint of the analysis was the association of AABs with treatment outcomes. The secondary endpoint concerned the association of AABs with safety.

Impact on Efficacy

Five studies regarding the use of infliximab or adalimumab analyzed EULAR responses from 12 to 192 weeks. Significantly better responses were seen in patients who did not develop AABs. Five studies looked at the association of AABs with ACR response in infliximab, adalimumab, golimumab, abatacept, and rituximab. Of these, one study of adalimumab showed a lower ACR 20 response in patients who had measurable AABs.

Loss of response was reported in four studies with antiTNF monoclonal antibodies. Patients who were seropositive for AAB had numerically higher rates of loss of response.

Looking at IBD, there was one study with infliximab and one study with certolizumab pegol where no seropositive patient achieved remission.

In a separate review from Hong Kong, the investigators looked at 58 consecutive patients with rheumatoid arthritis treated with anti-TNF agents. (8) Antibodies against infliximab, adalimumab, and etanercept were demonstrated in 51%, 21%, and 0%, respectively. Patients who had antibodies to infliximab and adalimumab had lower levels of the drug and a higher withdrawal rate due to lack of efficacy (64.7% and 71.8% versus 10.3% and 10.3% at months 12 and 24 months).

Impact on Safety

Two studies reported an increased risk of infusion reactions in patients with AABs. Seventeen studies reported on an increased risk of hypersensitivity reactions in patients who had AABs.

Overall Impact of Continuation of Initial Drug Therapy

In rheumatoid arthritis, discontinuation of a biologic agent for any cause was more common in patients who were seropositive for AABs.

Impact of Concomitant Treatment with Nonbiologic DMARDs on AAB Formation (10-13)

Thirty studies suggested that patients receiving treatment with monoclonal anti-TNF agents plus DMARD were less likely to form AABs than patients receiving anti-TNF monotherapy. The bulk of these studies related to monoclonal anti-TNF therapies with limited data available on etanercept and agents with alternative MOA. In rheumatoid arthritis, methotrexate was the most effective companion agent, while in Crohn's disease, azathioprine and 6-mercaptopurine seemed to be effective in preventing AABs. Oral corticosteroids did not prevent AAB formation.

In a Scandinavian registry of patients on anti-TNF therapy, there were 847 patients with RA, 172 with PsA, and 249 patients with AS. Overall drug retention rates were 65.4%, 77.3%, and 77.5%, respectively. Drug retention correlated with methotrexate use in patients with RA and PsA but not patients with AS. (14)

In addition to its effect on AAB formation, the concurrent use of methotrexate with monoclonal anti-TNF agents has a direct effect on the serum concentration and half-life of the agent. For example, the concurrent use of methotrexate with adalimumab results in a 38% increase in the serum concentration of the adalimumab. (15) This effect has also been demonstrated with infliximab. It has not been shown for etanercept or certolizumab.

Implications of Immunogenicity of Biologic DMARDs on the Treatment of Rheumatoid Arthritis (16)

1. Patients should be closely monitored for loss of efficacy after they have achieved target treatment goals.

2. The initial treatment plan should focus on achieving short-term clinical targets with eye towards maximizing the chance of long-term efficacy of the treatment by taking steps to reduce the likelihood of AAB formation.

3. Loss of efficacy should lead to consideration of the role of AABs.

4. In a patient who is losing response to a first anti-TNF agent optimize dose, consider optimizing the drug dose and when possible the interval between doses. For infliximab, consider reducing dosing interval. For adalimumab, consider switching to weekly therapy. Optimize dose of companion DMARD.

5. Patients who respond well to treatment with a first anti-TNF agent but then lose efficacy are likely to respond well to a second anti-TNF agent, as the efficacy of TNF inhibition has already been validated for that patient. (17)

6. In choosing a second anti-TNF agent in the presence of AABs to the first anti-TNF agent:

a. When possible use a less immunogenic agent. (Etanercept or certolizumab are likely to be less immunogenic than chimeric or humanized intact antibody.)

b. Optimize dose of companion DMARD or if first drug was given as monotherapy, give the second drug in combination with DMARD.

c. Optimize dosing intervals to avoid low trough levels. (Use Q2week dosing rather than Q4week dosing for golimumab or certolizumab.)

7. For patients who lose efficacy of multiple biologic agents, consider switching to combination DMARD therapy to avoid the issue of AABs. In these patients, the new JAK kinase inhibitor tofacitinib may be considered.

8. Serial measurements of ANA and anti-DNA positivity may identify patients at risk for AABs and allow for interventions to preserve response to therapy.

9. The occurrence of infusion reactions or persistent injection site reactions should encourage consideration of the role of AABs.

Disclosure Statement

The author has no financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

References

(1.) Ebert EC, Das KM, Mehta V, Rezac C. Non-response to infliximab may be due to innate neutralizing anti-tumour necrosis factor-alpha antibodies. Clin Exp Immunol. 2008 Dec; 154(3): 325-31. doi: 10.1111/j.1365-2249.2008.03773.x. Epub 2008 Sep 23.

(2.) Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009 Nov; 68(11): 173945. doi: 10.1136/ard.2008.092833. Epub 2008 Nov 19.

(3.) Pink AE, Fonia A, Allen MH, et al. Antinuclear antibodies associate with a loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study. Br J Dermol. 2010 Apr; 162(4): 780-5. doi: 10.1111/j.13652133.2009.09563.x. Epub 2009 Oct 26.

(4.) Yukawa N, Fujii T, Kondo-Ishikawa S, et al. Correlation of antinuclear antibody and anti-double stranded DNA antibody with clinical response to infliximab in patients with rheumatoid arthritis: a retrospective clinical study. Arthritis Res Ther. 2011; 13(6): R213. doi: 10.1186/ar3546. Epub 2011 Dec 22.

(5.) Danes S, Fiorino G, Reinsch W. Review article: causative factors and the clinical management of patients with Crohn's disease who lose response to anti-TNF-a therapy. Aliment Pharmacol Ther. 2011 Jul; 34(1): 1-10. doi: 10.1111/j.13652036.2011.04679.x. Epub 2011 May 3.

(6.) Anderson PJ. Tumor necrosis factor inhibitors: clinical im plications of their different immunogenicity profiles. Semin Arthritis Rheum. 2005 Apr; 34(5 Suppl1): 19-22.

(7.) Maneiro JR, Salgado E, Gomex-Reino JJ. Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune mediated inflammatory conditions: systemic review and meta-analysis. JAMA Intern Med. 2013 Jun 24: 113. doi: 10.1001/jamainternmed.2013.7430. [Epub ahead of print]

(8.) Mok CC, van der Kleij D, Wolbink GJ. Drug levels, anti-drug antibodies and clinical efficacy of the anti-TNFa biologics in rheumatic diseases. Clin Rheumatol. 2013 Jul 26. [Epub ahead of print]

(9.) Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune mediated inflammatory diseases: a systemic review of the literature with a meta-analysis. Ann Rheum Dis. 2012 Dec 6. [Epub ahead of print]

(10.) Krieckaert Cl, Numohamet MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012 Nov; 71(11): 1914-5. doi: 10.1136/annrheumdis-2012-201544. Epub 2012 May 14.

(11.) Krieckaert CL, Bartelds GM, Lems WF, Wolbink GJ. The effect of immonomodulators on the immunogenicity of TNF-blocking monoclonal antibodies: a review. Arthritis Res Ther. 2010; 12(5): 217. doi: 10.1186/ar3147. Epub 2010 Oct 20.

(12.) Jani M, Barton A, Warren RB, et al. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford). 2013 Aug 14. [Epub ahead of print]

(13.) Plasencia C, Pascula-Salcedo D, Nuno L, et al. Influence of immunogenicity on the effect of long-term treatment of spondyloarthritis with infliximab. Ann Rheum Dis. 2012 Dec; 71(12): 1955-60. doi: 10.1136/annrheumdis-2011-200828. Epub 2012 May 6.

(14.) Heiberg MS, Koldingsnes W, Mikkelsen K, et al. The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis; results from a longitudinal, observational, multicenter study. Arthritis Rheum. 2008 Feb 15; 59(2): 234-40. doi: 10.1002/art.23333.

(15.) Humira (adalimumab) package insert.Abbott Park, Illinois: Abbott Laboratories. Available at www.humira.com. Accessed September 12, 2013.

(16.) Garces S, Antunes M, Benito-Garcia E, et al. A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitior therapies. Ann Rheum Dis. 2013 May 11. [Epub ahead of print]

(17.) Jamnitski A, Bartelds GM, Nurmohamed MT, et al. The presence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2011 Feb; 70(2): 284-8. doi: 10.1136/ard.2010.135111. Epub 2010 Nov 10.

Gary Solomon, M.D., is the Associate Director of Rheumatolgy, NYU Langone Center for Musculoskeletal Care, New York, New York.

Correspondence: Gary Solomon, M.D., NYU Langone Center for Musculoskeletal Care, 333 East 38th Street, 4th Floor, New York, New York 10016; gary.solomon@nyumc.org.
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Author:Solomon, Gary
Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Report
Geographic Code:1USA
Date:Jul 1, 2013
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