Considerations When Switching Patients to Biologic Therapy

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.

References

References 1. Smolen JS, Aletaha D, Bijlsma JW, et al; T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631-637.

2. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400-1411.

3. Klareskog L, van der Heijde D, de Jager JP, et al; TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) Study Investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363(9410):675-681.

4. St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432-3443.

5. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009;4:CD007848. 6. Taylor PC. Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases. Curr Opin Pharmacol. 2010;10(3):308-315.

7. Villeneuve E, Haraoui B. To switch or to change class-the biologic dilemma in rheumatoid arthritis. Nat Rev Rheumatol. 2010;6(5):301-305.

8. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum. 2006;54(12):3782-3789.

9. Haraoui B, Cameron L, Ouellet M, White B. Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response. J Rheumatol. 2006;33(1):31-36.

10. Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006; 54(3):711-715.

11. 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;68(11):1739-1745. 12. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. Ann Rheum Dis. 2010;69(5):817-821.

13. Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460-1468.

14. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009;4:CD007848.

15. Pavelka K, Závada J, Mann H, Chroust K, Burešová L, Vencovský J. Comparison of survival rates of TNF-α antagonists in rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis and psoriatic arthritis in Czech national registry ATTRA. Ann Rheum Dis. 2010;6(suppl 3):525.

16. Hetland ML, Christensen IJ, Tarp U, et al; All Departments of Rheumatology in Denmark. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum. 2010;62(1):22-32. 121 17. Du Pan SM, Dehler S, Ciurea A, Ziswiler HR, Gabay C, Finckh A; Swiss Clinical Quality Management Physicians. Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis. Arthritis Rheum. 2009;61(5):560-568.

18. Du Pan SM, Kristensen LE, Saxne T, Geborek P. The LUNDEX, a new index of drug efficacy in clinical practice: results of a five-year observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in southern Sweden. Arthritis Rheum. 2006;54(2):600-606.

19. Marchesoni A, Zaccara E, Gorla R, et al. TNF-alpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions of standard clinical practice. Ann NY Acad Sci. 2009;1173:837-846.

20. Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis. 2004;39(8):1254-1255. 21. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 2004;50(2): 372-379.

22. Gómez-Reino JJ, Carmona L, Angel Descalzo M; Biobadaser Group. Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. Arthritis Rheum. 2007;57(5):756-761.

23. Tubach F, Salmon D, Ravaud P, et al; Research Axed on Tolerance of Biotherapies Group. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009;60(7):1884-1894.

24. Dixon WG, Hyrich KL, Watson KD, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69(3):522-528.

25. Dixon W, Hyrich K, Watson K, Lunt M, Symmons D. The influence of anti-TNF therapy upon the incidence and severity of serious lower respiratory tract infections in patients with rheumatoid arthritis: results from the BSR biologics register (BSBR). Rheumatology. 2008;47(suppl 2):ii47.

26. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301(7):737-744.

27. Salmon-Ceron D, Tubach F, Lortholary O, et al; RATIO group. Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. Ann Rheum Dis. 2011;70(4):616-623.

28. Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology. 2010; 49(7):1215-1228.

29. Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11(suppl 1):S1. 30. Lloyd S, Bujkiewicz S, Wailoo AJ, Sutton AJ, Scott D. The effectiveness of anti-TNF-alpha therapies when used sequentially in rheumatoid arthritis patients: a systematic review and meta-analysis. Rheumatology. 2010;49(12):2313-2321.

31. Rémy A, Avouac J, Gossec L, Combe B. Clinical relevance of switching to a second tumour necrosis factor-alpha inhibitor after discontinuation of a first tumour necrosis factor-alpha inhibitor in rheumatoid arthritis: a systematic literature review and meta-analysis. Clin Exp Rheumatol. 2011;29(1):96-103.

32. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572-2581.

33. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349(20):1907-1915.

34. Maini RN, Taylor PC, Szechinski J, et al; CHARISMA Study Group. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006;54(9): 2817-2829.

35. National Institute for Health and Clinical Excellence. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. www.nice.org.uk/nicemedia/live/13108/50413/50413.pdf. Accessed March 21, 2014.

36. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516-1523.