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Drs. Rudwaleit and Song reply To the Editor: The interesting comments by Kast and Altschuler further illustrate the complexity of the mechanisms underlying immune mediated injuries that have been observed in patients treated with anti-TNF agents and can affect a variety of organs1. As discussed in our case series2 of 4 patients (3 patients described in detail in the manuscript and a fourth patient added in proof) with ankylosing spondylitis who developed new onset of Crohn's disease during etanercept therapy, we are currently far away from understanding the molecular pathways behind these unusual manifestations. Whether or not an increase of soluble TNF played a causative role in our cases cannot be decided, since soluble TNF was not measured in our case series. The serial measurement of CD4 and CD8 T cell production of the cytokines interferon-γ and TNF-α in one of our patients, however, did not provide conclusive information towards the underlying mechanism. We agree with Kast and Altschuler that an increase of soluble serum TNF during anti-TNF therapy that may precipitate immune mediated injuries later on is an interesting hypothesis. However, this hypothesis is unproven at this stage since to our knowledge no systematic investigations on this issue are available in patients with rheumatic diseases such as ankylosing spondylitis or rheumatoid arthritis. Large prospective registries of patients treated with anti-TNF agents, for example, would be needed to answer this research question. Given the available information, we would not advocate routine measurement of soluble TNF in patients treated with anti-TNF agents in daily practice for the following reasons: (1) Systematic studies demonstrating a temporal relationship between soluble TNF levels and the occurrence of immune mediated injuries are lacking in rheumatic diseases. (2) We have serious concerns about measuring soluble TNF-α serially (!) in too many patients too often (at what time intervals?) in order to detect one patient with an immune mediated injury (high number needed to test). This issue calls into question the cost effectiveness of such screening; although immune mediate injuries have been reported in a number of case reports by now, they still represent rather rare events among the 1 million patients treated with anti-TNF agents worldwide. The incidence of lupus-like syndromes and (cutaneous) vasculitis has been estimated to be 0.1-0.39% and 3.9%, respectively1,3,4, whereas there are no estimates on the incidence of interstitial lung disease and inflammatory bowel disease, which appear to be even more rare1,2,5. (3) Uncertainties about the consequences of detecting elevated soluble TNF-α. Should treatment with anti-TNF be stopped although the patient tolerates the drug very well and is doing fine regarding the rheumatic disease? For many patients, anti-TNF agents are very important drugs -- sometimes the only class of drugs -- to control the rheumatic disease. What would be a clinically relevant elevation of soluble TNF-α in serum? Two-fold above normal or 10-fold? Is there a need to have elevated soluble TNF on more than one occasion before taking steps? Measurement of soluble TNF-α in patients taking anti-TNF agents might be an interesting research question. Currently, the many unanswered questions preclude recommendations on routine measurement of soluble TNF in daily practice. MARTIN RUDWALEIT, MD; IN-HO SONG, MD, Department of Rheumatology, Charité Medical University, Hindenburgdamm 30, Berlin 12200, Germany. 2. Song IH, Appel H, Haibel H, et al. New onset of Crohn's disease during treatment of active ankylosing spondylitis with etanercept. J Rheumatol 2008;35:532-6. Epub 2008 Jan 15. [MEDLINE] 3. Schiff MH, Burmester GR, Kent JD, et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:889-94. [MEDLINE] 4. Shakoor N, Michalska M, Harris CA, Block JA. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002;359:579-80. 5. Braun J, Baraliakos X, Listing J, et al. Differences in the incidence of flares or new onset of inflammatory bowel diseases in patients with ankylosing spondylitis exposed to therapy with anti-tumor necrosis factor alpha agents. Arthritis Rheum 2007;57:639-47. [MEDLINE]
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