Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases.

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REVIEW ARTICLE Q1

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Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases MARIA A. V. WILLRICH, DAVID L. MURRAY, and MELLISA R. SNYDER ROCHESTER, MN

Tumor necrosis factor (TNF) production is amplified in several autoimmune disorders. In the 1990s, it became a validated therapeutic target used for the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease. Biologic drugs targeting TNF include engineered monoclonal antibodies and fusion proteins. Currently, there are 5 Food and Drug Administration–approved TNF inhibitors (infliximab, etanercept, adalimumab, certolizumab, and golimumab), representing close to $20 billion in sales. Clinical trials remain open to test their efficacy and safety compared with one another, as well as to assess for clinical outcomes in different conditions and patient populations. The industry is also eager to develop biotherapeutics that are similar but cheaper than the currently existing biologics or are safer with higher efficacy; these are the so-called ‘‘biosimilars.’’ Clinical utility of TNF inhibitors and indications of mono- or combined therapy with immunomodulators are reviewed here. Pharmacokinetics of the TNF inhibitors is affected by routes of administration, clearance mechanisms of immunoglobulins, and immunogenicity. Finally, strategies for management of treatment efficacy and increasing evidence for monitoring of serum concentration of TNF inhibitors are discussed, assessing for the presence of the antidrug antibodies and the different analytical methods available for laboratory testing. As clinical applications of the TNF inhibitors expand, and other classes join the revolution in the treatment of chronic inflammatory disorders, therapeutic drug monitoring of biologics will become increasingly important, with the potential to dramatically improve patient care and management. (Translational Research 2014;-:1–13) Abbreviations: --- ¼ ---

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INTRODUCTION History of therapeutic tumor necrosis factor inhibitors’ development. During the last 2 decades, the chime-

rization and humanization of monoclonal antibodies (mAbs) have led to an exciting new class of biologic

drugs. This class uses the central role that antibodies (aka immunoglobulins [Igs]) play in the adaptive immune system in recognizing and neutralizing antigens. As a class of drugs, the mAbs are engineered to recognize, inhibit, and/or remove human proteins involved in Q4

From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn.

1931-5244/$ - see front matter

Submitted for publication May 27, 2014; revision submitted September 9, 2014; accepted for publication September 10, 2014.

http://dx.doi.org/10.1016/j.trsl.2014.09.006

Ó 2014 Elsevier Inc. All rights reserved.

Reprint requests: Mellisa R. Snyder, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail: [email protected].

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disease processes. Tumor necrosis factor a (TNF-a) is one such example. TNF is a cytokine with both proinflammatory and immunoregulatory functions. The role for TNF in rheumatoid arthritis (RA) was identified in 1991.1 Soon after, clinical trials using a chimeric murine–human mAb directed against TNF showed significant clinical efficacy,2,3 validating TNF as a therapeutic target. Since this time, the anti-TNF biologics have revolutionized the treatment of diseases such as RA, ankylosing spondylitis (AS), inflammatory bowel disease (IBD), and psoriasis.4 mAb structure and nomenclature. The basic structure of therapeutic mAbs, such as the TNF inhibitors, is based on the general structure of Igs. Ig molecules are constructed of 4 polypeptide chains including 2 identical heavy chains and 2 identical light chains. Functionally, each antibody can be divided into 2 domains: the variable region (Fab) and the constant region (Fc).5 The Fab fragment contains the complementarity determining regions, which are specifically responsible for antigen binding. The Fc portion of the antibody determines the isotype of the Ig and is identified by the heavy chain (gamma, mu, alpha, delta, epsilon) and the light chain (kappa, lambda). The IgG isotypes in particular have effector functions attractive for therapeutics designed to clear harmful molecules, including complement activation and antibody-dependent cellular toxicity, which is mediated through interaction with specific Fc receptors (FcR). Clearance of IgGs occurs via proteolytic catabolism after receptor-mediated endocytosis in the reticuloendothelial system, resulting from interaction between the antibody and Fc gamma receptors I, II, or III. A second pathway functions to recycle IgGs, which requires binding to the Brambell receptor (FcRn). It is the balance between the proteolytic and FcRn pathways that determines IgG half-life.4 To successfully design a therapeutic mAb, the Ig must be able recognize the human antigen (a function not typically desired in a normal immune response) and still be able to interact with the human FcRn receptors. Therapeutic mAbs have a standardized nomenclature based on their structure. Murine antibodies are named omab (eg, capromab). They were the first in clinical studies; however, their high immunogenic potential, low affinity for FcRn receptors and short half-life compared with a human IgG were major drawbacks. Then, chimeric mAbs (minimum of 65% human) were developed, with murine variable regions and human Fc fractions; those are named ximab (eg, infliximab). Further improvements in therapeutic mAbs came with constructs containing murine hypervariable regions grafted into a human IgG structure, forming humanized mAbs (minimum of 95% human) with the designation

zumab (eg, eculizumab). Lastly, fully engineered human antibodies have been developed, with the naming structure umab (eg, adalimumab and golimumab), that have similar properties to a human IgG and significantly reduced immunogenicity. 5 TNF inhibitors. There are currently 5 Food and Drug Administration (FDA)-approved TNF inhibitors available in the United States (Fig 1). Infliximab, the first biologic in its class, was approved in August 1998 for the treatment of severe Crohn’s disease (CD). In 2002, it was also approved for treatment of refractory RA. Infliximab is a chimeric IgG1 mAb composed of a murine Fab region linked to a human IgG1 kappa constant region produced in cultured Chinese hamster ovary cells. Adalimumab is also produced in Chinese hamster ovary cells; however, it is composed of phagedisplay engineered human-derived variable regions. Golimumab, the newest TNF inhibitor to enter the market, is a human IgG1 kappa, produced in multiple glycoforms by a murine hybridoma cell line.6,7 In contrast to the full-length mAbs, certolizumab is a humanized IgG4 Fab fragment produced by cell culture in Escherichia coli and then chemically linked to polyethylene glycol. This modification of the Fab fragment decreases metabolic clearance rates and extends the half-life of the molecule. Lastly, the most unique of the approved TNF inhibitors is etanercept. Etanercept is a recombinant fusion protein between the TNF p75 receptor and the Fc fraction of a human IgG1. It is currently the most prescribed TNF inhibitor in the US; however, it is not approved for IBD. Since the early 1990s, numerous clinical trials have taken place to address the safety and efficacy of TNF inhibitors in multiple inflammatory conditions and to compare the use of one matched with the other. A total of 92 open clinical trials were identified by searching the term ‘‘TNF inhibitor’’ at http://www.clinicaltrials. gov as of May 13, 2014. The purpose of most of these trials is to evaluate the safety and efficacy of other biologics, such as rituximab (anti-CD20 mAb), vedolizumab (anti-a4b7 integrin mAb), tofacitinib (small molecule inhibitor of JAK 3 kinase), and clazakizumab (anti-IL6 mAb), in patients who are refractory or intolerant to TNF inhibitors. These trials are also addressing outcomes in TNF inhibitor ‘‘switchers,’’ or those patients who fail treatment with one biologic in the class and then move to another one. One new TNF inhibitor, named ozoralizumab, has recently completed phase II clinical trials in patients with RA; however, study results are not yet published. This humanized mAb fragment of approximately 38 KDa is a trivalent, bispecific single-domain antibody against TNF.8 Biosimilars. By 2015, several biologics will lose patent protection in Europe, including infliximab and

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Fig 1. TNF inhibitors currently available in the United States. Infliximab is a chimeric antibody with murine amino acid sequences in the Fab region. Adalimumab and golimumab have human amino acid sequences. Certolizumab pegol is a Fab humanized fragment chemically linked to polyethylene glycol. Etanercept is a fusion protein between the TNF receptor extracellular domain and the Fc portion of a human IgG1. It binds not only to TNF, but also to members of the lymphotoxin family, including the soluble LTa3 (figure reproduced with permission from data in Taylor, 20104). Ig, immunoglobulin; TNF, tumor necrosis factor.

etanercept, which has spurred the development of biosimilars.9 According to the World Health Organization, a biosimilar is a biotherapeutic product, which is similar to an already licensed reference product in terms of quality, safety, and efficacy. Similarity is defined as the absence of a relevant difference in the parameter of interest.10 In May 2014, the US FDA released a guideline statement describing the clinical pharmacology data needed to support a biosimilar application.11 Quality is a very important parameter for approval of any drug by the FDA. Although a biosimilar may have an identical amino acid sequence as the reference biologic, heterogeneity of mAbs may happen because of several types of modifications, such as incomplete disulfide bond formation, glycosylation, and oxidation, as well as noncovalent associations with other molecules, conformational diversity, and aggregation. Thousands of variations with the same sequence may coexist.12 Because proof of concept as well as in vitro analytical and in vivo animal studies to the original biotherapeutic are

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needed to account for the molecules variation, most likely the biosimilars market will be in the domain of large pharmaceutical companies, as small biotech companies may not have the necessary resources. A financial analysis has estimated that by 2018 biosimilars will have close to 40% of market share for mAbs in Europe.13 A biosimilar to infliximab, CT-P13, with an identical amino acid sequence and produced in the same type of cell line, has been under development since 1999. Comparative studies for rheumatic diseases have been performed; however, because of regulatory and intellectual property issues, CT-P13 is not currently marketed in the United States, as infliximab’s patent will expire only in September 2018.13 Nonetheless, 2 pharmaceutical companies (Celltrion Biotechnology and Hospira) are filing an application with the FDA in a joint effort, for CT-P13 as the first biosimilar to infliximab (Remsima/ Inflectra). This biosimilar was approved in Europe in Q6 October 2013; FDA approval in the United States is expected in early 2015. Many other biosimilars are in the


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pipeline, according to the Generics and Biosimilars initiative website (http://www.gabionline.net), with some of the main targets being the TNF inhibitors infliximab, adalimumab, and etanercept. CLINICAL UTILITY General introduction. More than 2 million patients have received treatment with at least one of TNF inhibitors since they were approved in 1998 for systemic rheumatic disease and IBD. Over one million of these prescriptions have been for patients with RA.14,15 TNF inhibitors are approved for treatment of various inflammatory conditions within the main categories of systemic rheumatic disease and IBD (Table I). At our institution, for 2013, infliximab was the most frequently billed TNF inhibitor comprising 33% of all TNF biologics, followed closely by adalimumab at 29% and etanercept at 26%. The 2 newest medications, certolizumab and golimumab, were billed at only 10% and 2%, respectively (internal communication). The treatment approach for most chronic inflammatory diseases begins with an induction phase, the goal of which is to induce disease remission, followed by a maintenance phase, designed to maintain remission and prevent disease flares. FDA approval of the TNF inhibitors has addressed their role in both the induction and maintenance phases of treatment.

SYSTEMIC RHEUMATIC DISEASES

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Rheumatoid arthritis. RA is an inflammatory disease of unknown origin, which manifests as an ongoing peripheral polyarthritis. This disabling condition is thought to affect 0.3%–1.2% of the worldwide population.16 If left untreated the disease can lead to debilitating joint destruction through the erosion of cartilage and bone. Being incurable, the goal of treatment is to achieve the lowest possible level of arthritis disease activity, minimizing joint damage, and enhancing physical function. Pharmaceutical interventions are generally classified into 3 broad categories: nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs). The NSAIDS are for the control of inflammation and pain, whereas the corticosteroids and DMARDs are directed toward inhibiting the cellular immune response responsible for the inflammation. The goal of any treatment is to place the patient into strict complete remission. However, strict remissions by the preliminary criteria of the American College of Rheumatology (ACR)17 are rare and usually transient.18,19 Clinical outcomes can be improved using treatment strategies with predefined targets and tight control of disease activity.20,21 In light of these

findings, a 2010 international task force emphasized that the goal of treatment in RA should be remission.20 TNF inhibitors were the first of the biological DMARDs to be approved for the treatment of RA and, over the past decade, have become part of the routine treatment of patients with this disease. All 5 of the current TNF inhibitors are FDA approved for the treatment of RA. ACR treatment recommendations for this class of drugs are based on the duration of disease activity (greater or less than 6 months), disease activity (low, moderate, and high), and clinical features which correspond to prognosis. With the exception of early high disease activity with poor clinical prognosis, the use of TNF inhibitors is indicated only after patients have failed other therapies.22 In clinical trials, the combination of methotrexate and anti-TNF therapy is the most efficacious in showing reductions evidenced by radiographic damage.14 Juvenile RA. Juvenile RA is not a single disease, but is a term that encompasses all forms of arthritis, which have persisted for more than 6 weeks in patients younger than 16 years. It is classified in different subsets based on associated symptoms and number of joints involved. TNF inhibitors are used more commonly for the polyarthritic manifestations of disease, where they have proven efficacy.23-25 For systemic juvenile RA, TNF inhibitors have shown little efficacy.26 Etanercept is approved in patients aged 2 years or older as a monotherapy. Adalimumab is approved in pediatric patients aged 4 years and older, being used alone or with methotrexate. Ankylosing spondylitis. AS is a form of spondyloarthritis with great disease burden. It is a chronic inflammatory disease affecting the axial skeleton resulting in back pain and progressive stiffness of the spine. AS typically develops in young adults, between 20 and 30 years of age. It may also involve hips, shoulders, and peripheral joints. There is a strong correlation between the presence of the human leukocyte antigen B27 and incidence of AS. The prevalence of AS is estimated to vary between 0.1% and 1%.27 Multiple disease activity scores are available and have become common ways of managing the condition. Standard treatment options, including NSAIDs and opioids, are seldom effective during active AS. Infliximab was the first TNF inhibitor to show efficacy in AS clinical trials, improving signs, symptoms, function, and quality of life 2 weeks after the initiation of therapy.28 Adalimumab, golimumab, and etanercept have also shown similar efficacy.29-31 The combination of a TNF inhibitor with methotrexate does not seem to improve outcomes in AS.32,33 Adult plaque psoriasis and psoriatic arthritis. Plaque psoriasis (PsO) is a disease of young adults who present with symmetrically distributed demarcated


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Table I. Characteristics of the FDA-approved TNF inhibitors Infliximab

Adalimumab

Origin

Chimeric, murine Fab

Biologic type Molecular weight (kDa) Mode of production

IgG1 kappa 150 Culture in CHO cells

Fully human, recombinant human Fab IgG1 kappa 150 Fab produced by phage display, cell culture in CHO cells Subcutaneous every other week 10–20 2002

Route of administration

Intravenous every 6–8 weeks Half-life of molecule (days) 8–10 Year of first FDA approval 1998 Conditions where treatment is FDA approved Rheumatoid arthritis X Psoriatic arthritis X Ankylosing spondylitis X Adult plaque psoriasis X Juvenile rheumatoid arthritis Adult Crohn’s disease X Pediatric Crohn’s disease X Adult ulcerative colitis X Pediatric ulcerative colitis X

Golimumab

Certolizumab

Etanercept

Fully human

Humanized Fab

TNF receptor fusion protein

IgG1 kappa 150 Produced in transgenic mice

Fab of IgG4 91 Expressed in Escherichia coli and conjugated to polyethylene glycol Subcutaneous every other week 14 2008

Fc of IgG1 150 DNA recombinant technology in CHO cells

X

X X X X X

Subcutaneous once a month 14 2009

X X X X X X

X X X

X

X

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Subcutaneous once or twice a week 4 1998

X

Abbreviations: CHO, Chinese hamster ovary; FDA, Food and Drug Administration; TNF, tumor necrosis factor.

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erythematous plaques, involving the scalp, elbows, knees, and back. There is increasing evidence supporting the recognition of psoriasis as a multisystem chronic inflammatory disorder, with multiple associated comorbidities, including extracutaneous disorders such as psoriatic arthritis (PsA). PsA generally manifests as an inflammatory arthritis associated with psoriasis, which can significantly affect a patient’s quality of life. Pain and stiffness in affected joints are common symptoms, with significant joint deformity.34 NSAIDs, physical therapy, and DMARDs were the only treatment options for these conditions before TNF inhibitors became available. For PsO, topical therapies and ultraviolet light are recommended first. Systemic treatment options include DMARDs and infliximab, adalimumab, and etanercept as TNF inhibitors. For moderate to severely active PsA, infliximab, adalimumab, golimumab, and etanercept are considered first line of treatment,35-37 as they have shown marked improvements in these conditions. Inflammatory bowel disease. IBD consists of 2 unique diseases—ulcerative colitis (UC) and CD. Both UC and CD are chronic diseases resulting from inflammation within the gastrointestinal tract.38,39 The inflammation appears to be initiated by an uncontrolled immune response, presumably against flora present within the gut. It is estimated that nearly one million people in the United States are affected with IBD. UC and CD can be distinguished from one another based on clinical symptoms, affected sites within the gastrointestinal tract, and patterns of inflammation. UC tends to be restricted to the colon and is characterized by continuous inflammation of the mucosa. In contrast, CD may involve any area of the gastrointestinal tract, with inflammation that tends to be patchy and transmural, sometimes with evidence of granulomas. Standard therapy differs significantly between CD and UC, and is also affected by the site and extent of inflammation and disease severity. In general, first-line treatment for IBD centers on immunosuppressive therapy, such as corticosteroids, azathioprine, or methotrexate. Antibiotics have also proven to be effective for some patients.40,41 Infliximab and adalimumab are both approved for the treatment of moderate to severe CD and UC in adult patients who have demonstrated inadequate responses to standard therapies, such as antibiotics, corticosteroids, and aminosalicylates. Both are approved for induction and maintenance phases of treatment. In contrast, certolizumab is only approved for moderate to severe CD as a second-line therapy in adults, whereas golimumab is approved only for moderate to severe UC in adult patients who have failed previous therapies or who are steroid dependent. For treatment of pediatric IBD, infliximab is the only TNF inhibitor that

is approved by the FDA, specifically for children aged .6 years.42 Potential adverse effects. Adverse effects associated with TNF inhibitor therapy have been identified both through clinical trials and postmarket surveillance programs, such as the FDA Adverse Event Reporting System. Some adverse effects are relatively mild and can be managed such that discontinuation of the TNF blocking treatment is not necessary. However, other adverse effects are more serious requiring patients to change to another class of agents for treatment of their inflammatory disease (Fig 2). Infusion reactions, both acute and delayed, have been documented, particularly with infliximab. Acute reactions usually occur within 4 hours of infusion. Although sometimes associated with production of IgE antibodies, most acute reactions are actually anaphylactoid, or nonallergic, in nature. Treatment of acute reactions generally involves stopping the infusion, at least temporarily, and administration of diphenhydramine. Delayed infusion reactions, in contrast, appear to be a type III hypersensitivity reaction, mediated by production of immune complexes. Symptoms of a delayed reaction include rash, arthralgias, myalgias, and fatigue. Delayed infusion reactions seem to be related to the immunogenicity of the TNF inhibitor and the presence of antidrug antibodies. Because of this, strategies to reduce the immune response against the biologic, such as administration of methotrexate or azathioprine, can be helpful in preventing delayed infusion reactions.43,44 Because TNF plays an important proinflammatory role in the immune response, it should not be surprising that blockage of this pathway leads to increases in rates of infection. A variety of infections have been evaluated in the context of TNF inhibitor therapy, including mycobacterial, bacterial, fungal, and viral. Treatment with TNF inhibitors is associated with an increased incidence of mycobacterial tuberculosis (TB) infections, mostly attributed to reactivation of latent infection. Data from the FDA Adverse Event Reporting System have estimated that the incidences of TB infections were 54 and 28 per 100,000 patient years on infliximab and etanercept, respectively, which is 4- to 10-fold higher than in the general population. Bacterial infections also appear to be an issue.45 A study in hospitalized patients with RA has demonstrated that treatment with a TNF inhibitor resulted in an odds ratio of 4.2 for development of a bacterial infection within 6 months of initiation of Q8 treatment.45,46 Similar to TB, it appears that the risk of bacterial infection is greater with infliximab compared with etanercept. TNF inhibitors also appear to be a risk factor for fungal infection, likely because of impairments in granuloma formation. In 2008, the FDA released a statement warning of the risk of


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Fig 2. Main adverse effects of the use of TNF inhibitors. DMARDs, disease-modifying antirheumatic drugs; TNF, tumor necrosis factor.


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invasive fungal infections for patients receiving a TNF inhibitor. Lastly, the risk of viral infections for patients on TNF therapy is more of a question. There have been conflicting reports in the literature, which may be because of different effects associated with various viruses. On the basis of all available data, it is recommended that TNF inhibitor therapy be avoided in patients with any active infection, including bacterial and viral.47-55 In addition, all patients should be screened for TB, hepatitis B, hepatitis C, and possibly also HIV infections, and appropriately treated before initiating TNF inhibitor therapy. One of the original properties characterized for TNF was its ability to lyse tumor cells. This raises the question of whether blocking this pathway could lead to an increased risk of malignancy. The first evidence of this potential association was an increased risk of lymphomas, primarily non-Hodgkins, in patients on infliximab or etanercept therapy. Over the years, numerous studies have addressed this issue, with mixed results.50 As a result, whether TNF inhibitor therapy results in a general increased risk of malignancy, whether it is specific for certain biologics or disease states, or whether it is restricted to patients with an underlying predisposition to cancer is unclear. However, in 2004, a statement was added to the infliximab label, warning of the lymphomas risk. Hopefully, continue surveillance and prospective studies will help us to address this potentially significant adverse effect. Reports of neurologic disorders have also been associated with TNF inhibitors. In a case of aseptic meningitis in a 53-year-old man receiving infliximab for RA, the abnormalities in the cerebrospinal fluid had cleared on repeat examination a month later, which suggested a transient drug reaction rather than a chronic inflammatory neurologic disorder.56 Infliximab has also been associated with a worsening of multiple sclerosis in 2 patients,57 and at least 4 cases of demyelination with etanercept, which all had resolved by 6 weeks, have been reported to the US FDA. Therefore, TNF inhibitors should not be given to people with a history of demyelinating disease, and they should be withdrawn if such a disorder develops. Pharmacokinetics. Although the TNF inhibitors and therapeutic mAbs have been available for more than 2 decades, knowledge of the factors that affect pharmacokinetics is still poorly elucidated. A greater understanding of how mAb therapeutics are metabolized is of critical importance, as studies have shown, in a variety of disease states, that circulating concentrations of the drug are linked to clinical efficacy. There are certain patient-specific characteristics that impact the pharmacokinetics of the therapeutic TNF mAbs. Particularly relevant to chronic autoimmune

diseases is that systemic inflammation affects mAb clearance. Increased C-reactive protein (CRP), increased TNF-a, and hypoalbuminemia are all associated with decreased concentrations of TNF inhibitors. In addition, hypergammaglobulinemia also may result in accelerated clearance of the mAb, which is likely attributable to saturation of the FcRn recycling system by endogenous Igs. It also appears, at least for infliximab, that body mass and male gender are risk factors for decreased circulating concentrations.58 One exogenous parameter that affects pharmacokinetics is the route of administration. Infliximab is administered intravenously, whereas all other TNF inhibitors are self-administered with subcutaneous injections. Large volumes of drug may be delivered intravenously, compared with the relatively small volumes that can be administered subcutaneously. In addition, the differences between peak and trough concentrations of the drug are much larger when given by intravenous (IV) infusion, in comparison with the more consistent concentrations observed with subcutaneous delivery. This is likely because of the fact that IV administration has a more rapid distribution, which is contrasted by the slower absorption after subcutaneous injections. Also, with IV administration, mAbs are more readily bioavailable with less interindividual variability and reduced immunogenicity.58 With subcutaneous injections, absorption likely occurs through lymphatic drainage, where antigen processing increases the immunogenic properties of the mAb.58 All mAb therapeutics, including the TNF inhibitors, are ‘‘foreign’’ proteins, with the potential to be recognized by the adaptive immune system. The presence of the therapeutic mAb may activate a humoral immune response, resulting in the production of antidrug antibodies. This property is referred to as immunogenicity. The presence of antidrug antibodies has a substantial effect on the pharmacokinetics of the TNF inhibitors. Most studies have demonstrated that the presence of antidrug antibodies is associated with significantly lower concentrations of circulating therapeutic mAb. This likely results from rapid phagocytic clearance of immune complexes that form between the antidrug antibody and the therapeutic mAb. This subsequently leads to decreased concentration of the TNF inhibitor in circulation. The immunogenic potential of the TNF inhibitor is closely linked to the degree of humanization of the mAb. Incidence of antibodies against the human/ murine chimeric infliximab has been shown to be as Q10 high as 12%–70% of patients receiving the drug.59 However, it has also been shown that adalimumab, which is more fully humanized, is also immunogenic.60,61 Etanercept has what appears to be the lowest immunogenic potential, being composed only of the


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TNF receptor extracellular domain and human Ig sequences. In fact, the incidence of anti-etanercept antibodies appears to be relatively low, in comparison with infliximab and adalimumab. The humanized anti-TNF inhibitors certolizumab and golimumab likely share similar immunogenic properties to adalimumab. However, studies assessing for the incidence of anticertolizumab and anti-golimumab antibodies are lacking in the public literature. The link between antidrug antibodies, decreased drug concentration, and clinical efficacy is clear. As such, strategies aimed at reducing the incidence antidrug antibodies can lead to improved outcomes for patients receiving a TNF inhibitor. Two approaches demonstrated to reduce the immunogenicity of the TNF mAbs are coadministration of an immunomodulator and scheduled maintenance dosing. Combination therapy of infliximab or adalimumab and an immunosuppressive agent has been demonstrated to decrease the incidence of antidrug antibodies in comparison with the TNF inhibitor alone. There does not appear to be significant differences between methotrexate and azathioprine, which are the most commonly used immunosuppressive agents for combination therapy.14,62 Some studies have further shown that the decreased incidence of antidrug antibodies in combination therapy is associated with increased concentrations of the TNF inhibitor and improved clinical outcomes.59,63,64 However, there is some concern that this approach may lead to overimmunosuppression and an increased risk of infection and malignancy. This may especially be a concern for patients on long-term maintenance therapy. In addition to combination therapy, scheduled treatment as opposed to episodic treatment appears to offer some advantages related to the formation of antidrug antibodies. Scheduled treatment is defined as a standardized approach to maintenance therapy, rather than episodic treatment driven by disease flares or worsening clinical symptoms. Particularly with infliximab, decreased incidence of antidrug antibodies and improved clinical outcomes have been seen in patients on scheduled rather than episodic maintenance therapy.32 It appears that a combination of the 2 strategies, scheduled therapy of anti-TNF, and a concomitant immunosuppressant, may alleviate some of the immunogenicity of these biological agents. Management and monitoring of TNF inhibitors. For RA, monitoring of disease activity is achieved using disease activity scores. The most commonly used is a Simplified Disease Activity Index, comprising evaluation of tender and swollen joint counts, patient and physician global assessments, and CRP concentrations. The index is used by the ACR and European League Against Rheumatism for the definition of remission.65 Patients are

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usually evaluated at least every 3 months to monitor response to therapy using the same measures, and adjustments to therapy are made to maintain control of disease activity if targeted treatment goals (remission or low disease activity) are not achieved. Response criteria are defined for both moderate and major changes in disease activity and are applied to patients in clinical trials. A common response criterion is defined by the ACR, in which the variables outline a 20% improvement (ACR20). Given the relatively high cost of TNF inhibitor treatment, several health systems have set up monitoring programs to track usage and outcomes. The Swedish biologics register ‘‘Anti-Rheumatic Therapy in Sweden,’’ a nationwide database on patients prescribed biologic therapies for the treatment of rheumatic diseases, has been active since biologics were first available in clinical practice in 1999. The cohort in this registry is quite large covering 87% of the RA patients.66 Within this cohort, the TNF inhibitors represent the vast majority of prescribed biologics. Analysis of this cohort showed half of patients starting infliximab, adalimumab, or etanercept during the period 2005–2012 discontinued treatment for various reasons. The most common reason for discontinuing treatment was nonresponse. Of these patients, one-third switched within 2 months to a second TNF inhibitor (infliximab, etanercept, or adalimumab). Around 35% of patients achieved low disease activity or remission at 6 months. Best results were observed among patients who switched from infliximab to etanercept because of (secondary) inefficacy. Etanercept as a second TNF inhibitor was associated with longer drug survival compared with infliximab.67 A similar national drug registry, BIOBADASER 2.0, is composed of pa- Q11 tients with rheumatic diseases treated with any biological agent in 14 large public university hospitals in Spain.68 Patients entering the registry are followed prospectively and evaluated at the time when an adverse event or a change in the biological occurs. A total of 2907 RA patients were included in the study. This group found similar results to the Anti-Rheumatic Therapy in Sweden cohort. Patients receiving their first TNF inhibitor were discontinued in the first year at a rate of 17%, 19%, and 21% in 2000–2003, 2004–2006, and 2007– 2009, respectively (no statistical differences between the drugs, P 5 0.074). In the early years, the main reason for discontinuation of a TNF inhibitor was adverse reactions, whereas in recent years the most common reason for discontinuation was inefficacy. Given the relatively high rate of loss of efficacy, some studies have been undertaken to measure the drug concentrations in patients treated with TNF antagonists. Jamnitski et al69 measured drug levels in 292 RA patients on etanercept and demonstrated that lower drug


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levels were associated with nonresponse. A similar study was performed by Daien et al,70 which had recommended that etanercept concentrations measured 3 months post-treatment could explain the absence of response. However, there are currently no recommendations for following drug concentrations in RA patients as part of routine clinical care. Loss of response is also associated with the development of antidrug antibodies. However, only a limited number of studies have been done on etanercept and infliximab in patients with RA. In other rheumatic diseases, such as AS, PsA, and PsO, no guidance on whether monitoring TNF inhibitors is associated with improved outcomes is available. In IBD, multiple systems have been validated for assessment of disease activity. Most of these systems are specifically designed for either CD or UC. For CD, the Clinical Disease Activity Index is the most commonly used, and includes clinical variables (number of liquid stools per day, abdominal pain, and number of complications), patient characteristics (body weight), and laboratory criteria (hematocrit). This scoring system can be used to assess for response, induction of remission, and maintenance of remission based on the absolute score or a change in score compared with baseline value. There are also several tools for evaluation of endoscopic response to treatment. These systems are based on assessment of various types of lesions evident on endoscopy. Similarly, various systems have been developed for use in UC. Many of these systems combine clinical evaluation, laboratory testing, and endoscopic findings into a single score. For IBD, there is accumulating evidence that the circulating concentrations of the TNF inhibitor and the presence of antidrug antibodies are associated with clinical outcomes. Low trough concentrations of infliximab, for instance, are associated with a shorter duration of response and less mucosal healing, and are inversely correlated with clinical and endoscopic remission in CD.62,71 The same holds true for certolizumab, where higher concentrations of the drug were associated with endoscopic response and remission in a clinical trial with 89 adult patients with moderate to severe CD, whereas lower certolizumab concentrations were associated with increased CRP and greater body weight.72 Because of the association with clinical responses, assessment of TNF inhibitor concentrations and antidrug antibodies is increasingly being advocated for use in routine clinical practice in patients with IBD.38,73-75 According to a recent study, the primary indications for testing of infliximab concentrations in the context of IBD were loss of response, partial response on initiation of therapy, and autoimmune or

hypersensitivity reactions.76 Specifically in the context of loss of response or lack of initial response, assessment of drug concentration and antidrug antibodies has the potential to directly impact patient management. For example, patients with decreased concentrations of the TNF inhibitor but no detectable antidrug antibodies may benefit from dose escalation. In contrast, this approach is less likely to be effective in patients with decreased concentrations of drug in the presence of antidrug antibodies. For these individuals, a switch to another TNF inhibitor may be indicated. In some cases, patients will be found to have an apparently adequate concentration of the TNF inhibitor. This may occur in the presence or absence of antidrug antibodies. Regardless, loss of response in the context of adequate concentrations of drug may suggest that the patient is not responding to TNF inhibition and that perhaps another class of biologics may be beneficial.38,62,72,74,75,77,78 However, this raises the question of what is the optimal therapeutic dose for the various TNF inhibitors. Some studies have addressed this for infliximab and adalimumab, although there is some variation in the data.61,62,76,79-82 In contrast, there are no data in the literature on therapeutic targets for etanercept, certolizumab, and golimumab. Analytical perspectives. Given the frequency of loss of response to biologics and the presence of antidrug antibodies, methods to measure drug concentrations in patients on TNF inhibitors are useful in patient management.62 As a class of drugs, the therapeutic mAbs present a unique challenge for serum quantitation in comparison with traditional small molecule drugs. For the small molecule drugs, isolation of the analyte from background proteins can be accomplished by precipitation, extraction, or size exclusion chromatography. The mAbs are not only part of the protein background; they are also structurally very similar to the native high abundance Igs. First-generation assays developed for measurement of serum TNF inhibitors and antidrug antibodies were based on radioimmunoassays83 and solid-phase, double-antigen, and enzyme-linked immunosorbent assay.84 An analyte specific method using cell lines that have a TNF sensitive reporter gene has demonstrated to quantitate the activity of TNF in patients treated with TNF inhibitors.85 A liquid-phase mobility shift assay for measurement of TNF inhibitors and antidrug antibodies in the presence of drug has been described for infliximab and adalimumab.61,86 The mobility shift assay is based on the shift in retention time of the antigen-antibody immunocomplex vs free antigen on size-exclusion chromatography. A proteomics-based assay for the quantitation of TNF inhibitors using tryptic peptides and mass spectrometry has also been


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described87 and may overcome some of the limitations of immunoassays, with the potential of being more costeffective. CONCLUSIONS

TNF inhibitors are an important class of biologics for the treatment of chronic inflammatory conditions such as RA and IBD. Monitoring for the concentration of the TNF inhibitor and the presence of antidrug antibodies in patients is associated with improved outcomes; however, clinical assays are expensive and not yet widely available, so most presented studies are retrospective. As more affordable and better methods become available to quantitate TNF inhibitors in serum of patients undergoing therapy, it will allow for the execution of robust prospective studies to better understand pharmacokinetics, immunogenicity, and therapeutic thresholds to optimize therapy. As the applications of the TNF inhibitors expand, and other classes of biologics join the revolution in the treatment of chronic inflammatory disorders, complete elucidation of mechanism of action of biologics and therapeutic monitoring with laboratory tests will become increasingly important, saving costs and at the same time guiding providers’ decisions instead of empirically adjusting doses or switching therapies. Moreover, it has the potential to ease the burden of uncontrolled disease and dramatically improve patient care and therapy success rates. ACKNOWLEDGMENTS

Conflicts of Interest: All authors declare no conflict of interest concerning any financial or personal relationship with organizations that could potentially be perceived as influential on the described research. All authors have read and agreed on the journal’s authorship agreement and policy on disclosure of potential conflicts of interest. REFERENCES

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Tumor necrosis factor inhibitors for inflammatory bowel disease.

Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases.

Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk.

Tumor necrosis factor-alpha.

Tumor necrosis factor and external beam radiation: preliminary clinical observations.

Clinical Outcomes and Biologic Costs of Switching Between Tumor Necrosis Factor Inhibitors in US Veterans with Rheumatoid Arthritis.

Effects of glucocorticoids and tumor necrosis factor-alpha inhibitors on both clinical and molecular parameters in patients with Takayasu arteritis.

Clinical significance of tumor necrosis factor-α inhibitors in the treatment of sciatica: a systematic review and meta-analysis.

Tumor necrosis factor and hypermetabolism.

Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: A single center report of 8 cases.

Unmet clinical need in autoimmune liver diseases.

Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes.

The use of tumor necrosis factor inhibitors in pregnancy: what is the evidence?

Determinants associated with work participation in patients with established rheumatoid arthritis taking tumor necrosis factor inhibitors.

B-Cell Activating Factor Belonging to the Tumor Necrosis Factor Family and Interferon-γ-Inducible Protein-10 in Autoimmune Hepatitis.

Drug survival rates of tumor necrosis factor inhibitors in patients with rheumatoid arthritis and ankylosing spondylitis.

Persistence and dose escalation of tumor necrosis factor inhibitors in US veterans with rheumatoid arthritis.