In recent years, introduction of biologic agents for treatment of patients with rheumatoid arthritis (RA) has changed the landscape of RA management.
In recent years, introduction of biologic agents for treatment of patients with rheumatoid arthritis (RA) has changed the landscape of RA management. Tumor necrosis factor (TNF) antagonists such as adalimumab, etanercept, and infliximab have demonstrated efficacy in treatment of RA, but patients frequently switch therapy because of inadequate response, loss of response, or development of intolerable adverse events.1-5
The major biologic classes used in treatment of RA possess different mechanisms of action. Even within the TNF antagonist class, available agents differ with respect to their structure, bioavailability, pharmacokinetics, stability, and binding specificities; these characteristics explain differences in therapeutic response and toxicities.6,7 Immunogenicity has also been demonstrated to affect the therapeutic efficacy and toxicity of these agents. Several clinical studies have shown that the presence of antibodies directed against adalimumab and infliximab has been associated with lack or loss of clinical response in RA.8-13
Several recent meta-analyses examined potential differences between available agents. Specifically, anakinra was associated with a significantly lower likelihood of treatment success compared with etanercept and adalimumab. In addition, fewer toxicity-related withdrawals were evident among patients treated with etanercept compared with those treated with anakinra, infliximab, or adalimumab.14 Evidence from several national observational registries has also demonstrated differences among anti-TNF biologics. The Czech National Registry (ATTRA) showed higher survival rates among patients with RA who were treated with adalimumab or etanercept compared with infliximab during 4 years of treatment15; similar results were demonstrated in the nationwide Danish DANBIO Registry.16 Other studies have shown lower retention and adherence rates for infliximab-treated patients.17,18 Finally, the Italian Lombardy Rheumatology Network registry reported a significantly greater likelihood of survival in patients treated with etanercept compared with those treated with adalimumab or infliximab after 3 years.19
Differences in incidence and type of adverse events also play a role in choice of biologic agent for treatment of RA. A potentially higher incidence of granulomatous infection (eg, tuberculosis [TB]) was reported in several studies for patients treated with infliximab compared with etanercept.20-24 Recent registry data suggest that the risk for TB is significantly higher in patients treated with either infliximab or adalimumab compared with those treated with etanercept.23,24 Other studies have also reported a lower risk of other infection types with etanercept compared with infliximab and adalimumab; these include lower respiratory tract infections, herpes zoster, and nontuberculosis opportunistic infections.25-28 Physicians should consider these potential effects when choosing treatment for patients who may be at particular risk for infection.
Patients with RA who have inadequate response or unacceptable toxicities to a biologic therapy may benefit from switching to a different biologic agent. In fact, guideline recommendations support the use of sequential biologic therapies in these situations. In some cases, cost may be a factor in switching to an alternative biologic agent in patients who are responding to treatment, although the ultimate consequences of this practice are not well understood.29
Despite a potential decrease in efficacy with sequential therapies, the evidence on clinical switching among TNF antagonists is generally favorable. A review and meta-analysis examined findings from 20 observational studies and 2705 lack of/loss of efficacy or toxicity benefited from switching to another agent in that same class.30 Authors of a 2011 review and meta-analysis of patients with RA (N = 4441) who switched to a second TNF antagonist after discontinuation of the first agent in the same class reported that this strategy is a clinically acceptable practice.31
Switching to biologic agents with mechanisms of action not related to TNF inhibition is an alternate approach for patients who do not achieve an optimal outcome with TNF antagonist therapy. Three such agents include rituximab, abatacept, and tocilizumab. Rituximab is a CD20 monoclonal antibody that interferes with B-cell inflammatory pathways.32 Abatacept, a fusion protein, blocks the second costimulatory signal required for activation of T cells.33 Tocilizumab is an antihuman monoclonal antibody against the IL-6 receptor.34
Available evidence indicates that, in patients with an inadequate response or toxicity to a TNF antagonist, rituximab may be a successful alternative.35
Tocilizumab was also shown to be effective compared with placebo in patients who had a suboptimal response to at least one TNF antagonist. There was no difference according to the specific TNF-antagonist therapy previously received or the number of prior failed treatments.36
Importantly, the potential for adverse events should be carefully considered when choosing therapy with a biologic agent for RA.
“Biologics have their downsides, which can include infections and increased risk of malignancies and lymphoma. There are also administration reactions and skin reactions and there can be autoantibodies formed to these drugs,” said Gary M. Owens, MD, independent health care management consultant and leader in the evaluation and management of biotechnology drugs.
“There are also some relative contraindications to these drugs that include hepatitis B infection, multiple sclerosis with optic neurosis, active serious infections or chronic/recurrent infections, current neoplasia, history of TB or positive PPD, and, because TNF-α does play a role in congestive heart failure, people with advanced congestive heart failure should be approached carefully,” Owens explained.
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