Angela Raval, PharmD; Gita Akhavan-Toyserkani, PharmD, MBA; Allen Brinker, MD, MS; Mark Avigan, MD, CM
In October 2001, the U.S. Food and Drug Administration (FDA) modified infliximab labeling to include a boxed warning about infliximab-associated tuberculosis that included instructions to screen for tuberculosis, treat latent tuberculosis before treatment, and monitor for tuberculosis during infliximab therapy.
This series reviewed 130 cases of infliximab-associated tuberculosis reported to the FDA after the labeling change and found that many cases occurred in patients who had a negative tuberculin skin test result but had risk factors for tuberculosis.
Clinicians need to be vigilant for tuberculosis in patients receiving infliximab even if pretreatment screening is negative, especially if risk factors for tuberculosis are present.
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Mark R Goldstein
Fountain Medical Court, Bonita Springs, FL
November 23, 2007
Infliximab, Statins, Tregs and Tuberculosis
Raval and colleagues (Nov 20 issue) reported spontaneous cases of tuberculosis associated with infliximab. We agree with their conclusion that clinicians should be vigilant in screening and monitoring for tuberculosis in patients receiving infliximab therapy. However, recent data suggest that there should be a heightened state of vigilance in those patients taking infliximab in combination with statins.
Statins have been shown to increase the concentration of CD4+CD25+ regulatory T cells (Tregs), in vivo, by inducing the transcription factor forkhead box P3 (FOXP3) . An increase in Tregs has been associated with immunologic hypo-responsiveness to many chronic infections . Tregs are increased in the blood and disease sites in patients with tuberculosis, and this may contribute to the suppression of Th1-type immune responses , potentially leading to the reactivation of latent tuberculosis. Furthermore, statin therapy has been reported to significantly increase the risk of tumor progression resulting in radical cystectomy during Calmette-Guerin treatment for bladder cancer . It is highly plausible that a statin induced increase in Tregs explains this observation during cancer immunotherapy.
Tumor necrosis factor alpha (TNF-alpha) inhibits Tregs activity, and it is not surprising that infliximab, an anti-TNF-alpha antibody, restores the suppressive function of Tregs . Therefore, the combination of infliximab and statins may be particularly potent in bolstering Tregs function.
It is also plausible that statins, by augmenting Tregs function, impair the host response to purified protein derivative (PPD), resulting in false-negative screening for tuberculosis. Perhaps, the authors have data on prevalent statin use in the large portion of subjects whom had a false-negative PPD before infliximab therapy. If statins do impair the response to PPD, the implications would be important, given the widespread use of statins.
In conclusion, the simultaneous use of a TNF-alpha antagonist and a statin may greatly increase the potential of latent tuberculosis reactivation. It is imperative that physicians be aware of this potential detrimental immunomodulatory effect, when using this combination.
Mark R. Goldstein, MD (USA)
Luca Mascitelli, MD (Italy)
Francesca Pezzetta, MD (Italy)
 Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG- CoA reductase inhibitors on naturally occuring CD4+CD25+ T cells. Atherosclerosis. Epub 2007 Sept 10.
 Belkaid Y, Rouse B. Natural regulatory T cells in infectious disease. Nat Immunol 2005; 6: 353-360.
 Guyot-Revol V, Innes JA, Hackforth S, Hinks T, Lalvani A. Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. Am J Respir Crit Care Med 2006; 173: 803-810.
 Hoffmann P, Roumeguere T, Schulman C, van Velthoven R. Use of statins and outcome of BCG treatment for bladder cancer. N Engl J Med 2006; 355: 2705-2707.
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Daniel G. Arkfeld
USC Keck School of Medicine
November 24, 2007
Yes, Potential TB in RA Patients Is Difficult For the Rheumatologist
It is with great interest that I read the article entitled " Brief Communication: Characteristics of Spontaneous Cases of Tuberculosis Associated with Infliximab" by Raval et al. In an era of new biological agents for the treatment of RA that target TNF, T cells, or B cells(and soon IL-6) it is imperative to understand the risks. This article reveals 130 reported cases of severe TB with an increased morbidity and mortality. However, due to inherent reporting biases with much misinformation one would expect to see the more severe cases reported to the FDA.
Additionally, many of the cases were anergic or had past BCG vaccination leading to a possible switch in the future to more accurate TB testing via interferon or DNA based assays. In rheumatology, we treat a positive skin test for 9 months with INH and rifampin starting the TNF agent either simultaneously or after 1-2 months of therapy. This is generated from opinions in the rheumatology community rather than evidence based. Noncompliance certainly can be a potential issue as well as the emerging drug resistant strains.
There is a need for better algorithms in treating a positive PPD in a patient being treated with an anti-TNF agent. Questions such as the length of treatment, appropriate followup, need for chest xrays, and testing based on specificity and sensitivity. Additionally it is argued that one TNF agent may be safer than another. Unfortunately, there are no head to head studies that could answer some of these questions. Hopefully future studies will address the above issues.
Jerome A Boscia
Centocor Research and Development, Inc.
The Context Statement of The Editors' Notes
In the article by Raval and colleagues, the Context statement of The Editors' Notes should read "In October 2001, Centocor Inc and the U. S. Food and Drug Administration (FDA) modified infliximab labeling to include a boxed warning about infliximab-associated tuberculosis that included instructions to screen for tuberculosis, treat latent tuberculosis before treatment, and monitor for tuberculosis during infliximab therapy."
I am Senior Vice President for Clinical Research and Development for Centocor Research and Development Inc. I have stock and stock options in Johnson & Johnson, the parent company of Centocor Research and Development Inc.
Raval A, Akhavan-Toyserkani G, Brinker A, Avigan M. Brief Communication: Characteristics of Spontaneous Cases of Tuberculosis Associated with Infliximab. Ann Intern Med. 2007;147:699-702. doi: 10.7326/0003-4819-147-10-200711200-00006
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Published: Ann Intern Med. 2007;147(10):699-702.
Infectious Disease, Mycobacterial Infections.
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