The last decade has seen a revolution in the treatment of patients with inflammatory rheumatic diseases, including rheumatoid arthritis (RA), juvenile idiopathic arthritis, and ankylosing spondylitis. It started with the introduction of biopharmaceuticals that selectively inhibit the proinflammatory cytokine tumor necrosis factor α (TNFα). This group of drugs currently includes the monoclonal antibody constructs infliximab, adalimumab, and golimumab, the chimeric TNF receptor/IgG1 protein etanercept, and the monoclonal antibody Fab fragment certolizumab pegol. All these drugs lower disease activity and, in some patients, induce remission. Patients with many other chronic immunoinflammatory diseases (e.g., inflammatory bowel diseases and psoriasis) also respond to at least some of these TNF inhibitors. The effects have been so dramatic and the number of patients who benefit so high that this group of drugs now constitutes one of the heaviest medicinal expenditures in many countries.

Unfortunately, not all patients respond favorably to anti-TNF therapies. Some patients either do not respond at all or have insufficient responses (primary response failure), or they respond initially but have later relapses of disease despite an increased dosage and/or more frequent administration of the drugs (secondary response failure). The mechanisms underlying these response failures are not entirely clear, and the problem has received little attention until recently. However, since drug delivery resembles effective vaccination procedures (i.e., repeated and in most cases subcutaneous injections of nonself proteins), some patients may react with clinically overt side effects due to antibody- and/or cell-mediated reactions.

Immunogenicity is indeed a potential hazard of all protein drugs, and there is evidence that repeated injections of other biopharmaceuticals trigger antibody responses that can be associated with therapeutic failure and side effects. Examples are swine and human insulin for diabetes, growth hormone for growth hormone deficiency, factor VIII for hemophilia, type I interferons for multiple sclerosis, certain cancers, and chronic viral diseases, and erythropoietin for chronic kidney disease. In the last case, antierythropoietin antibodies have even been demonstrated to cause pure red cell aplasia, a life-threatening complication. Immunogenicity of anti-TNF antibody constructs given to RA patients is also well documented and associated with side effects and therapeutic failure (1–6). Phenomena assumed to be mediated by immune complexes (ICs) (e.g., serum sickness, bronchospasm, and Arthus reactions) have also been described in RA patients as well as in patients with Crohn's disease (6–8).

In this issue of Arthritis & Rheumatism, Korswagen et al report 3 cases of venous and arterial thromboembolic events associated with the occurrence of antiadalimumab antibodies (9). A retrospective search for similar side effects in a cohort of 272 consecutive adalimumab-treated RA patients revealed antiadalimumab antibodies in 28%. Eight patients developed thromboembolic events, the incidence rate of which was 3 times higher in those with demonstrable antiadalimumab antibodies. Although the number of patients with these side effects was small and a cause-and-effect relationship was not established, the article is important because thromboembolic events are potentially fatal. The findings of Korswagen et al add to other reports of serious arterial and venous thromboembolic events in patients receiving not only adalimumab but other anti-TNF agents as well (10, 11). It is therefore prudent to alert clinicians to a possible connection between human antidrug antibodies and IC-mediated side effects of all currently used anti-TNF biotherapies.

Some investigators hold the view that antibodies to TNF inhibitors are of limited importance because there are not always observable clinical consequences of antibody development. Several factors may have contributed to this, including the use of inaccurate and/or insufficiently sensitive tests in the clinical setting (see below). Also, as pointed out by Korswagen et al, the full impact of drug immunogenicity is not realized unless patients are routinely monitored for human antidrug antibodies or, at the very least, for every occurrence of side effects or treatment failure. If not, as is the usual approach today, clinicians will never know that human antidrug antibodies could be the underlying cause of therapeutic problems. It is also uncommon to monitor patients with disease in clinical remission, because they appear to benefit from continued medication. However, antibodies that interfere with therapeutic efficacy may develop before and during remissions, and if they are not detected, one may jump to the conclusion that the drug is effective despite its being neutralized by human antidrug antibodies. Monitoring patients for antibodies even when they are doing well with prolonged anti-TNF therapies may therefore help prevent unnecessary immunization, thus limiting the risk of side effects (6).

Concomitant use of immunosuppressive drugs such as methotrexate (MTX) has been shown to increase infliximab trough levels in the circulation, both in RA patients and in patients with Crohn's disease. It has been pointed out that the incidence of human antidrug antibodies may be reduced by cotreatment with MTX, which is usually attributed to the drug's immunosuppressive effect. This, however, is not necessarily correct, since the antiinflammatory effect of MTX may lower TNF production in inflamed tissues independently of antibody production. Assuming that MTX-treated and -untreated patients receive the same dosage of TNF inhibitor, a reduced “load” of TNF in those treated with MTX is likely to consume less anti-TNF antibody, and the resulting higher circulating drug levels might accelerate human antidrug antibody clearance. It is also important to note that the observed effect of MTX on human antidrug antibody levels may be transitory, since antibody development is a continuous process. Hence, the effects of concomitant therapies cannot be fully appreciated unless longitudinal studies are carried out.

Screening for human antidrug antibodies in clinical trials, now a regulatory requirement in Europe, has also drawn attention to pharmacologic issues of anti-TNF therapies. Most prominent among these are the substantial inter- and even intraindividual variations in bioavailability and pharmacokinetics of anti-TNF antibodies (1, 2, 6). This, together with human antidrug antibody responses in some but not all patients, has reinforced the desire to treat individuals rather than diagnoses (i.e., optimizing therapies according to individual needs and antibody responses rather than using averaged regimens deducted from pivotal trials of large cohorts with substantial variations in age, comorbidities, and concurrent therapies).

Individualized or personalized medicine is commonly associated with products and services that use genomics and proteomics to provide therapy for individuals rather than groups of patients, including the use of laboratory tests to develop and use more effective therapies. The concept is not new. Even so, tailoring anti-TNF therapies to suit individual RA patients based on pharmacologic evidence has only been used sporadically. This is surprising, since there is no generally accepted standard for dealing with the approximately one-half of RA patients who obtain no lasting effect or show only modest improvement from anti-TNF therapies (12). Rheumatologists are currently left with only a few choices when TNF inhibitors fail, all based on clinical outcome. They can wait and see, intensify therapy, switch to another TNF inhibitor, or stop and choose a different treatment. This approach is not optimal, because patients risk irreversible joint destruction while physicians search for new effective drugs. A better approach would be to discover factors underlying treatment failure and side effects so that therapy can be optimized accordingly, and this can only be achieved by monitoring all patients for circulating levels of drugs and human antidrug antibodies (Figure 1).

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Figure 1. Proposed treatment algorithm in patients treated with anti–tumor necrosis factor (anti-TNF) antibody constructs. Beneficial effects of immunopharmacologic guidance are shown. Clinically relevant high and low cutoff levels of drug activity and cutoffs for the presence/absence of human antidrug antibodies must be established for each disease entity and for each method used for quantification.

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An example illustrates one of the benefits of early pharmacologic monitoring. Approximately one-third of RA patients starting current anti-TNF therapies experience primary therapeutic failure or at least insufficient responses (12). This often leads clinicians to intensify therapy by increasing the dosage and/or frequency of medication. Some patients react positively to this, but many do not, and after months of intensified therapy, both patient and clinician realize that a different approach is necessary. Had these nonresponders been monitored for circulating drug levels or, better yet, for levels of anti-TNF activity, one might have found a significant proportion with considerable anti-TNF capacity, as has been demonstrated in both RA and Crohn's disease (1, 13). These patients are not likely to benefit from intensified therapy and should be shifted to another treatment principle as early as possible. Hence, pharmacologic monitoring might have saved the patients months of futile and expensive therapy and allowed an earlier shift to effective treatment.

How should patients be monitored for anti- TNF activity and human antidrug antibodies? Unfortunately, standard laboratory techniques, usually various modifications of enzyme-linked immunosorbent assays (ELISAs), may not provide sufficiently useful data in the clinical setting. Most solid-phase methods are subject to matrix effects (e.g., epitope masking and neoepitope formation) when used to test serum or plasma samples, and blood components such as rheumatoid factors, antiallotypic antibodies (in previously immunized patients), and complement factors (C1qr2s2) may interfere with readouts and create data that jeopardize optimal decision making (6, 14). Some types of assays, the so-called bridging ELISAs, also fail to measure IgG4 antidrug antibodies, which are prominent after prolonged immunizations (6).

With the use of fluid-phase immunoassays, which better reflect the in vivo situation and appear to have fewer shortcomings than solid-phase assays (14, 15), my group and other groups of investigators have demonstrated vast variations in circulating infliximab and adalimumab trough levels (2–4, 16, 17). These investigations have also revealed that drug bioactivity disappears from the circulation as soon as antibodies develop (2). Not surprisingly, several investigations of RA patients and patients with Crohn's disease have shown that low blood levels of infliximab and adalimumab and the presence of human antidrug antibodies correlate with the requirement for dosage increase and with therapeutic failure; human antidrug antibodies also correlate with infusion reactions (1, 2, 4, 13, 17).

It is noteworthy that variations in bioavailability are likely to be augmented in cases in which TNF inhibitors are administered subcutaneously, since human antidrug antibodies may contribute to local IC formation, thus reducing the release of drug to the circulation (6). These effects would be expected whether or not the antibodies prevent the drugs from binding TNF. Hence, non-neutralizing human antidrug antibodies may reduce therapeutic efficacy indirectly by compromising bioavailability. In the circulation, such antibodies might also alter the pharmacokinetics, including tissue availability of TNF inhibitors, because formation of circulating ICs and subsequent removal by endothelial impact and filtering in the spleen are likely to be independent of the drug's ability to bind TNF. Side effects caused by drug–human antidrug antibody ICs would also be expected whether or not complex-bound drug binds TNF. Consequently, the tendency to attribute clinical importance only to the neutralizing effects of human antidrug antibodies is probably not warranted.

In this editorial, I have made the case that patients receiving therapies with anti-TNF antibody constructs, and indeed other protein drugs, should not be denied the benefits of individually tailored therapies guided by immunologic and pharmacologic evidence (i.e., safer and more effective therapies). It is also time for society to realize the advantages of such therapies: cost-effectiveness, fewer patients requiring hospitalization, and most likely, fewer patients with reduced working capacity.


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Dr. Bendtzen drafted the article, revised it critically for important intellectual content, and approved the final version to be published.


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