Tumor necrosis factor inhibitors (TNFis) have revolutionized the treatment of rheumatoid arthritis (RA) and spondyloarthritis (SpA), and are now commonly used to manage both diseases. While TNFis have been shown to result in clinical remission in subsets of patients, they require close monitoring due to the potential of serious adverse events such as the development of infection or tumors.

In addition, it has previously been found that approximately 20% to 30% of patients with RA or SpA are not responsive to TNFis, suggesting that a primary resistance may develop via TNFi-induced immune response.1 In a paper published in January 2018 in Autoimmunity Reviews, a group of researchers explored similarities and differences between various currently available TNFis for the treatment of RA and SpA.2

They concluded that, despite variation in molecular structure, morphology, pharmacokinetic characteristics, and in vitro and in vivo activity, all of the TNFis “ultimately neutralise TNF-α, and the fact that they have been formally approved for the treatment of a very similar range of diseases indicates that this is more important than any structural differences,” the investigators stated.

While there is comparable clinical efficacy across TNFis, it has not yet been elucidated whether drug retention and safety are similar; findings on these issues have been mixed, indicating that “other significant contributory factors are the heterogeneity of the studies, clinical biases, differences between European National Health Systems, and differences in physician education, culture, and ethics.”


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For additional clinical perspective, Rheumatology Advisor interviewed Iris Navarro-Millan, MD, a rheumatologist at Hospital for Special Surgery and assistant professor of medicine at Weill Cornell Medical College and New York-Presbyterian Hospital in New York City.

Rheumatology Advisor: What are some of the key similarities and differences of anti-TNF drugs in RA and in SpA?

Dr Navarro-Milan: There is definitely more data available on patients with RA than patients with SpA. In general, the survival of the anti-TNF molecule is longer in patients with SpA than in patients with RA.3 We should interpret that cautiously because this could be a result of having less data regarding this question in patients with SpA due to the lower prevalence of SpA compared with RA.

If we look at the efficacy of switching anti-TNFs in patients with RA, we can conclude that patients who do not respond to a first anti-TNF may also not respond to a second anti-TNF. In the case of patients not responding to primary treatment, changing to non-TNF biologics rather than a second anti-TNF should be considered.

Among the similarities, it is important to highlight that in patients with both RA and SpA, infliximab has the lower drug survival. Systematic reviews suggest that this anti-TNF has been associated with a higher risk for infections, which can definitely play a role in its survival, not only from the standpoint of efficacy standpoint but also with regard to the side effects.4

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Rheumatology Advisor: What are the overall takeaways on this topic for our clinical audience?

Dr Navarro-Milan: It is important to take into consideration the reasons a patient needs to switch anti-TNFs. In patients whose reasons are related to side effects of the first anti-TNF drug, considering a second anti-TNF could be a reasonable approach. However, if the patient has not responded to an anti-TNF because of a lack of efficacy, given the broader treatment options available now, we have compelling data and treatment guidelines that support changing the mechanism of action of a biologic instead of using another that is in the same drug class.

[EDITOR’S NOTE: According to results of a prospective study published in 2007, when an initial TNFi was discontinued due to inefficacy, switching to rituximab (RTX) led to more substantial improvement in disease activity.5 When the first TNFi was discontinued because of drug intolerance, switching to RTX or a different TNFi showed similar effectiveness. 

Similar results were found in a 2013 observational study in patients with RA who switched to either RTX or another TNFi after not responding to the initial TNFi, and a 2016 open-label, randomized trial demonstrated less improvement in disease activity in patients who switched to another TNFi vs a non-TNFi biological drug.6,7

In patients with SpA, there are currently fewer controlled studies evaluating switching from a TNFi to a different biologic agent. However, this “decision may be guided by the effect of the biological agent on the severity of psoriasis, the concomitant presence of uveitis, inflammatory bowel disease, enthesitis and/or dactylitis,” the investigators in a recent review article reported.8

These patients should be constantly reassessed in order to adjust treatment regularly (every 3 months according to the current treat-to-target guidelines). By doing this we can increase the probability of achieving remission, which is strongly associated with good long-term clinical and radiographic outcomes.  

Rheumatology Advisor: What should be the focus of future research in this area?

Dr Navarro-Milan: The treat-to-target paradigm establishes remission as the ultimate target. However, most clinical trials and cohort studies of anti-TNF users mainly establish an American College of Rheumatology 20% (ACR20) improvement criteria response rate. In order to better determine the actual benefit of switching between anti-TNFs, or from anti-TNFs, it would be more relevant to establish a different target such as remission or low disease activity instead of ACR20.

This touches on another problem: the limited data available in disease activity measurement collected systematically in actual patient cohorts. Another area to expand upon would be the value of switching to a non-TNF biologic, with the adequate response being remission or low disease activity rather than ACR20.

References

  1. Atzeni Fl, Benucci M, Sallì S, Bongiovanni S, Boccassini L, Sarzi-Puttini P. Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev. 2013;12(5):575-579.
  2. Rubbert-Roth A, Atzeni F, Masala IF, Caporali R, Montecucco C, Sarzi-Puttini P. TNF inhibitors in rheumatoid arthritis and spondyloarthritis: Are they the same? Autoimmun Rev. 2018;17(1):24-28.
  3. Scirè CA, Caporali R, Sarzi-Puttini P, et al. Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database. Clin Exp Rheumatol. 2013;31(6):857-863.
  4. Singh JA, Cameron C, Noorbaloochi S, et al. The risk of serious infection with biologics in treating patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015; 6736(14):61704-61709.
  5. Finckh A, Ciurea A, Brulhart L, et al. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis. patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum. 2007; 56(5):1417-1423.
  6. Emery P, Gottenberg JE, Rubbert-Roth A, et al. Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global observational comparative effectiveness study. Ann Rheum Dis. 2013;74(6):979-984.
  7. Gottenberg JE, Brocq O, Perdriger A, et al. Non-TNF targeted biologic vs a second anti-TNF drug to treat rheumatoid arthritis in patients with insufficient response to a first anti-TNF drug: a randomized clinical trial. JAMA. 2016;316(11): 1172-1180.
  8. Atzeni F, Sarzi-Puttini P, Gorla R, Marchesoni A, Caporali R. Switching rheumatoid arthritis treatments: an update. Autoimmun Rev. 2011;10(7):397-403.