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Drs. Baraliakos and Braun reply To the Editor: We thank our Japanese colleagues for their comments on our study1. Toki, et al describe an allergic infusion reaction in a patient with rheumatoid arthritis (RA) after discontinuation and retreatment with infliximab, and comment on our published experience in patients with ankylosing spondylitis (AS) who had been treated with infliximab for some years before it was discontinued and later readministered. The incidence of allergic and other immunologic reactions in response to infliximab therapy has long been studied. This includes antibody formation (antibodies to infliximab, ATI), low infliximab trough levels, infusion reactions, and loss of response. However, the relationship between laboratory measurements and clinical symptoms has not been impressive2. From early data it became clear that the dosage of infliximab has an effect on antibody formation2. Later, it was found that the hit-and-run strategy that was often used initially in patients with Crohn's disease was also associated with increased antibody formation and other problems; this was partly attenuated by immunosuppressants3. The patients in our study had been treated with infliximab without interruption for 3 years4. Thus, this was a highly selected group of responders to therapy. This likely contributed to the low frequency of allergic reactions, since patients who had developed infusion reactions had dropped out earlier. Further, as mentioned by Toki, et al, the role of ATI with respect to development of infusion reactions is not clear. In our study we found ATI in only one patient (without clinical relevance); this may be explained in part by well known technical problems, such as high levels of infliximab in the serum. Correlation of ATI and clinical symptoms such as infusion reactions and loss of response has been reported in patients who were episodically treated with infliximab for active Crohn's disease3. The patients in our study had not been treated episodically. However, using a different technique for antibody detection, recent data from The Netherlands have suggested a stronger correlation of ATI and clinical symptoms5. Finally, infliximab in RA is mainly used and approved in combination with methotrexate (MTX) because of superior efficacy6; this is different in AS, where MTX has no proven clinical efficacy on back symptoms7. In the case reported by Toki, et al the first infusions of the patients were performed in combination with MTX, and it is unclear how long this was continued and which dosage was used. Whether the relatively low dosages of MTX used in Japan8 have the same potency to suppress antibody formation is also unclear. XENOFON BARALIAKOS, MD; JOACHIM BRAUN, MD, Rheumazentrum Ruhrgebiet, Herne; Ruhr University, Bochum, Germany. 2. 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;348:601-8. [MEDLINE] 3. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol 2004;2:542-53. [MEDLINE] 4. Braun J, Baraliakos X, Brandt J, et al. Persistent clinical response to the anti-TNF antibody infliximab in patients with ankylosing spondylitis over 3 years. Rheumatology Oxford 2005;44:670-6. [MEDLINE] 5. de Vries MK, Wolbink GJ, Stapel SO, et al. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis 2007;66:1252-4. [MEDLINE] 6. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATRACT Study Group. Lancet 1999;4:1932-9. [MEDLINE] 7. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187-93. [MEDLINE] 8. Ideguchi H, Ohno S, Ishigatsubo Y. Risk factors associated with the cumulative survival of low-dose methotrexate in 273 Japanese patients with rheumatoid arthritis. J Clin Rheumatol 2007;13:73-8. [MEDLINE]
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