June 14, 2007

Question:
What biologic agent, if any, would you use in a patient with severely deforming, very active rheumatoid arthritis who is currently on leflunomide and prednisone? I have a male patient of this description who also has a history of bilateral partial nephrectomy for renal cell carcinoma 2 years ago. Renal function is normal, and there is no evidence of active malignancy at present. He did not respond to methotrexate. Thank you for your reply.

Answer:
The treatment of this patient presents two questions, one of which has been answered and one of which may not have been answered, although there is some data in the literature. The first question is whether a patient who is currently treated with leflunomide and prednisone and who has active disease can be treated with a biologic. Most of the data in the literature evaluated the efficacy of the anti–tumor necrosis factor (TNF) agents, anakinra, abatacept, or rituximab in combination with methotrexate (MTX). Significant efficacy was demonstrated with etanercept,^1,2 infliximab^3,3,4 adalimumab,^5,6 abatacept,^7,8 rituximab,^9-11 as well as with anakinra.¹² Efficacy was demonstrated with each of these agents with respect to clinical signs and symptoms as measured by ACR20/50/70 scores, patient function as measured by Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36) scores, and radiographic progression. Four trials have investigated the safety of several biologics in association with leflunomide. These trials have combined leflunomide with adalimumab,^13,14 abatacept¹⁵, and anakinra.¹⁶ One of the trials with adalimumab¹⁴ evaluated efficacy as a primary outcome and found positive results with the combination of leflunomide and adalimumab. The adalimumab and abatacept safety trials^13,15 also evaluated efficacy as measured by ACR20/50/70 and HAQ scores and found that both agents were efficacious with leflunomide, with no additional safety signals found. None of these trials, however, evaluated radiographic progression of leflunomide with any of the biologics. The trial with anakinra¹⁶ did not evaluate efficacy as an end point. No new safety signals with anakinra and leflunomide were found. There have been a number of abstracts presented of small, open-label studies of leflunomide in combination with etanercept or infliximab that have suggested efficacy as measured by clinical signs, symptoms, and patient function without new safety signals found. Taken together, these trials suggest that anti-TNF agents, anakinra, and abatacept can be used safely and with efficacy in terms of clinical and functional response in patients concomitantly treated with leflunomide. It is not clear that radiographic progression will be affected, however, as no studies have been performed to investigate this point. There are no reports of rituximab in combination with leflunomide. The second question is whether a patient with a tumor in remission can be treated with a biologic. None of the biologics have been shown to increase malignancies when utilized over time¹⁷ except for the development of lymphoma (which may be a manifestation of rheumatoid arthritis [RA] itself)¹⁸ and skin cancers, both melanoma and non-melanoma. There is some controversy, however, as to whether, early in treatment and with high-dose monoclonal antibodies to TNF (adalimumab and infliximab), there is an increase in malignancies.¹⁹ In this meta-analysis, more malignancies were found in patients treated with monoclonal antibodies than in placebo-treated controls. The conclusions of this publication have been questioned primarily because there was no adjustment for duration of therapy. This same increase has not yet been shown with etanercept, anakinra, abatacept, or rituximab. There is a recent report, however, from the British Society for Rheumatology Biologics Register (BSRBR), which evaluated 1,877 patients (58 with prior cancers) treated with disease-modifying anti-rheumatic drugs (DMARDs) and 9,999 patients (154 with prior cancers) treated with anti-TNF agents. The report suggests that patients treated with anti-TNF agents who have a history of cancer may be at increased risk for the development of another malignancy.²⁰ The authors found that in patients who had not had a previous malignancy, the incidence of cancer is the same or perhaps lower among patients treated with TNF inhibitors compared to those treated with DMARDs when adjusted for age, sex, disease severity, and smoking. In the group receiving DMARDs who did not have previous cancer, there were 14.1 cancers per 1,000 patient years; in the anti-TNF group with no prior cancer, there were 8.4 cancers per 1,000 patient years. In patients with prior cancer, there were 18.2 cancers per 1,000 patient years in the DMARD group vs 20.5 cancers per 1,000 patient years in the anti-TNF treated group. They concluded that a history of malignancy may predispose to the development of malignancy among RA patients treated with traditional DMARDs and TNF inhibitors, but there are caveats to the interpretation of this report: There were small numbers of cancers observed: 6 new cancers among patients with prior cancer who received TNF inhibitors; 2 of the 6 cancers were the same type of cancer. There may have been a bias involved, as clinicians tend to not use TNF antagonists to treat patients who have a history of cancer.

In summary, there is demonstrated efficacy of the concomitant use of leflunomide with all biologics other than rituximab with respect to clinical signs, symptoms, and patient function but not with respect to radiographic progression. In a patient with a prior malignancy, there may be an increased risk of another malignancy, whether the patient is treated with a DMARD or biologic. Thus, the decision as to whether to treat depends upon the activity and severity of the patient’s RA and whether the risk:benefit ratio favors treatment or not. With respect to a new malignancy, it may not make a difference whether the patient is treated with leflunomide monotherapy or in combination with a biologic.

Roy M. Fleischmann, MD

  Doctor to Doctor Home

References

1. Klareskog L, Van Der Heijde DM, de Jager JP. 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;363:675-681.
2. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340:253-259.
3. Lipsky PE, Van Der Heijde DM, St.Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343:1594-1602.
4. St.Clair EW, Van Der Heijde DM, Smolen JS. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis. Arthritis Rheum. 2004;50:3432-3443.
5. Weinblatt ME, Keystone EC, Furst DE. Adalimumab, a fully human anti-tumor necrosis factor a monclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate. Arthritis Rheum. 2003;48:35-45.
6. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26-37.
7. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:2263-2271.
8. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114-1123.
9. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54:1390-1400.
10. 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;350:2572-2581.
11. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54:2793-2806.
12. Cohen S, Hurd E, Cush J. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate. Arthritis Rheum. 2002;46:614-624.
13. Furst DE, Schiff MH, Fleischmann RM. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of the STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol. 2003;30:2563-2571.
14. Burmester GR, Mariette X, Montecucco C. Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: The Research in Active Rheumatoid Arthritis (ReACT) trial. Ann Rheum Dis. 2007;Epub Mar 20 2007:
15. Weinblatt M, Combe B, White A. Safety of abatacept in patients with active rheumatoid arthritis receiving background non-biologic and biologic DMARDs: 1-year results of the ASSURE trial. Ann Rheum Dis. 2005;64:60.
16. Fleischmann RM, Tesser J, Schiff MH, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:1006-1012.
17. Wolfe F, Michaud K. National Data Bank for Rheumatic Diseases. The association of new cases of cancer with biologic therapy. Presented at: ACR/ARHP Annual Scientific Meeting 2006. November 2006; Presentation 1321.
18. Baecklund E, Askling J, Rosenquist R. Rheumatoid arthritis and malignant lymphomas. Curr Opin Rheumatol. 2004;16:254-261.
19. Bongartz T, Sutton AJ, Sweeting MJ. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA. 2006;295:2275-2285.
20. Watson KD, Dixon WG, Hyrich KL. Influence fo anti-TNF therapy and previous malignancy on cancer incidence in patients with rheumatoid arthritis (RA): Results from the BSR biologic register. Presented at: Ann Rheum Dis. 2006; Presentation 512.