Correspondence

Tumor Necrosis Factor Inhibitors for Rheumatoid Arthritis

N Engl J Med 2006; 355:2046-2048November 9, 2006

Article

To the Editor:

In reviewing the pathophysiological process of rheumatoid arthritis, Scott and Kingsley (Aug. 17 issue)1 focus almost exclusively on dendritic cells and T cells. However, in mice, the maintenance of T-cell activation and tumor necrosis factor (TNF) production has been shown to be critically dependent on B cells.2 Indeed, B cells appear to be pivotal in the pathogenesis of rheumatoid arthritis: they can be 10,000 times as potent as dendritic cells in presenting antigen,3 they form germinal centers in synovium, and they produce injurious autoantibodies.

The appropriateness of this recent shift in focus from T cells to B cells was borne out by a randomized, controlled trial reported by Edwards et al.4 The investigators found that patients who had active rheumatoid arthritis despite methotrexate treatment had a substantial improvement in disease symptoms 24 and 48 weeks after the depletion of B cells with rituximab (a monoclonal antibody against CD20) given either alone or in combination with cyclophosphamide or methotrexate.4 Furthermore, a single course of rituximab can significantly improve symptoms in patients who have had an inadequate response to anti-TNF therapies,5 which suggests that B cells may be an important target in rheumatoid arthritis. B cells should feature prominently in any discussion of the pathophysiological process of rheumatoid arthritis.

Jonathan C. Roos, M.A.
Andrew J. Ostor, M.B., B.S.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom
jcpr2@cam.ac.uk

Dr. Ostor reports having received speaking fees and grants from Schering-Plough, Wyeth, Abbott, Bristol-Myers Squibb, and Roche.

5 References

1
Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 2006;355:704-712
Full Text | Web of Science | Medline

2
Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-4718
Web of Science | Medline

3
Lanzavecchia A. Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu Rev Immunol 1990;8:773-793
CrossRef | Web of Science | Medline

4
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
Full Text | Web of Science | Medline

5
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
CrossRef | Web of Science | Medline

To the Editor:

Scott and Kingsley have carefully reviewed the use of TNF inhibitors for the treatment of rheumatoid arthritis. Infliximab is a chimeric (human–murine) IgG1 antibody against TNF-α that is administered intravenously. The development of human antichimeric antibodies has led to infusion reactions and a reduced treatment response in patients treated with infliximab for rheumatoid arthritis1,2 or Crohn's disease.3 Evidence of the formation of infliximab–antiinfliximab complexes has been reported recently.4 Clinical strategies to reduce the frequency of the formation of human antichimeric antibodies include the induction of immunologic tolerance through the use of a regular injection regimen (every 8 weeks) and concomitant immunosuppressive therapy with methotrexate. However, temporary withdrawal of infliximab treatment is sometimes required because of severe infection, pregnancy, or the need for surgery. Withdrawal of treatment may induce the production of human antichimeric antibodies owing to the interruption of immunologic tolerance. Further clinical studies are needed to determine the appropriate interval for resumption of infliximab treatment.

Hiroshi Okamoto, M.D., Ph.D.
Tokyo Women's Medical University, Tokyo 1620054, Japan
hokamoto@ior.twmu.ac.jp

4 References

1
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;54:711-715
CrossRef | Web of Science | Medline

2
Wolbink GJ, Voskuyl AE, Lems WF, et al. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:704-707
CrossRef | Web of Science | Medline

3
Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348:601-608
Full Text | Web of Science | Medline

4
van der Laken CJ, Voskuyl AE, Roos JC, et al. Imaging and serum analysis of immune complex formation of radiolabeled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis (in press).

To the Editor:

Scott and Kingsley review major clinical studies that have shown beneficial effects of TNF inhibition in combination with methotrexate in rheumatoid arthritis. TNF has also been shown to play a key role in the pulmonary and systemic inflammation of chronic obstructive pulmonary disease (COPD).1,2 Furthermore, TNF seems to be involved in many systemic manifestations of COPD, such as cachexia.2 However, a multicenter, randomized, double-blind, placebo-controlled study revealed no effectiveness of infliximab for the treatment of patients with stage 2, 3, or 4 COPD, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification.3 In addition, van der Vaart et al.4 showed that infliximab did not affect local inflammation.

Recently, we analyzed the effects of infliximab on systemic features in a small group of patients with COPD who had cachexia. We observed no effects of infliximab on fat-free mass, muscle function, or exercise capacity. These data call into question the role of TNF blockade in the management of COPD.

Mieke A. Dentener, Ph.D.
Emiel F.M. Wouters, M.D., Ph.D.
University Hospital Maastricht, 6202 AZ Maastricht, the Netherlands
mieke.dentener@pul.unimaas.nl

4 References

1
Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530-534
Web of Science | Medline

2
Eid AA, Ionescu AA, Nixon LS, et al. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414-1418
Web of Science | Medline

3
Rennard SI. Results of the phase II, dose finding study evaluating safety and efficacy of infliximab in patients with moderate to severe chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:A541-A541
CrossRef

4
van der Vaart H, Koeter GH, Postma DS, Kauffman HE, ten Hacken NH. First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:465-469
CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Roos and Ostor that B cells have an important role in established rheumatoid arthritis. In reviewing TNF inhibition, we restricted our discussion to such factors as toll-like receptors and T cells, for which there is strong evidence of primary pathogenic roles in the disease. The evidence that B cells have central importance in modulating TNF inhibition and the onset of disease is more limited. This situation may change as the roles of B cells become better understood after the approval of rituximab for the treatment of rheumatoid arthritis.1

D.L. Scott, M.D.
G.H. Kingsley, M.B., Ch.B., Ph.D.
Kings College London School of Medicine, London SE5 9RS, United Kingdom

1 References