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Brief Communication: Characteristics of Spontaneous Cases of Tuberculosis Associated with Infliximab FREE

Angela Raval, PharmD; Gita Akhavan-Toyserkani, PharmD, MBA; Allen Brinker, MD, MS; and Mark Avigan, MD, CM
[+] Article and Author Information

From the U. S. Food and Drug Administration, Silver Spring, Maryland.


Disclaimer: The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the U.S. Food and Drug Administration or the U.S. government.

Acknowledgment: The authors thank Dr. Gerald Dal Pan, Office of Surveillance and Epidemiology, for his thoughtful review and critique of the manuscript.

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement: The protocol is provided in the text of the article and was not prospectively designed for this specific case series. An overview of the history and treatment of adverse drug event reports (MedWatch reports) at the FDA's Center for Drug Evaluation and Research is included in the paper by Brinker and Beitz (7). No statistical models or code were used. Because of the presence of personal and confidential information, the MedWatch cases included in this case series are not available to the general public. Aggregated and truncated MedWatch reports by calendar year with redaction of personal identifiers are available for purchase as electronic data sets from the National Technical Information Service (http://www.ntis.gov).

Requests for Single Reprints: Gita Akhavan-Toyserkani, PharmD, MBA, Office of Surveillance and Epidemiology, Division of Drug Risk Evaluation, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 3469, Silver Spring, MD 20993.

Current Author Addresses: Dr. Raval: 7272 Wisconsin Avenue, Bethesda, MD 20814.

Drs. Akhavan-Toyserkani, Brinker, and Avigan: Office of Surveillance and Epidemiology, Division of Drug Risk Evaluation, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Silver Spring, MD 20993.

Author Contributions: Conception and design: A. Raval, G. Akhavan-Toyserkani, M. Avigan.

Analysis and interpretation of the data: A. Raval, G. Akhavan-Toyserkani, A. Brinker, M. Avigan.

Drafting of the article: A. Raval, G. Akhavan-Toyserkani, A. Brinker, M. Avigan.

Critical revision of the article for important intellectual content: A. Raval, G. Akhavan-Toyserkani, A. Brinker, M. Avigan.


Ann Intern Med. 2007;147(10):699-702. doi:10.7326/0003-4819-147-10-200711200-00006
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Editors' Notes
Context

  • 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.

Contribution

  • 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.

Implication

  • 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.

—The Editors

Infliximab (Remicade, Centocor, Malvern, Pennsylvania) is a chimeric monoclonal antibody to tumor necrosis factor-α (TNF-α) that is approved by the U.S. Food and Drug Administration (FDA) for treating Crohn disease, rheumatoid arthritis, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, psoriasis, and pediatric Crohn disease (1). Tumor necrosis factor-α has a central role in both the host immune response to Mycobacterium tuberculosis infection and the immunopathology of tuberculosis (2). In addition, TNF-α production is required for the formation of granulomas, which help to sequester mycobacteria and prevent their dissemination (3). Therefore, it was not surprising that the FDA received adverse event reports of tuberculosis in association with infliximab treatment after the initial marketing of infliximab in the United States in September 1998. These reports were summarized in an article published in October 2001 (4). Coincidentally, a boxed warning was added to the infliximab package insert in October 2001, advising physicians to screen patients for tuberculosis before treatment with infliximab therapy, pretreat those with latent disease, and monitor patients for signs and symptoms of tuberculosis during treatment with infliximab. It should be noted that approved labeling for the 2 other commercially available TNF-α antagonists in the United States, etanercept (Enbrel, Immunex Corporation, Thousand Oaks, California) and adalimumab (Humira, Abbott Laboratories, North Chicago, Illinois), also include warnings about tuberculosis.

We examined spontaneous adverse event reports of tuberculosis associated with infliximab that were submitted to the FDA from 1 November 2001 through 30 May 2006, after the boxed warning was added to the drug labeling, to assess the continuing safety concern of infliximab-associated tuberculosis. We analyzed the reports to determine whether the tuberculosis cases were due to failure of prescribers to test for latent tuberculosis, as mandated in the prescribing information, or (if prescribers are performing tuberculosis screening) due to false-negative purified protein derivative results. We also examined whether patients with latent tuberculosis were being treated before starting infliximab therapy and, if so, whether those patients subsequently developed tuberculosis. In addition, we analyzed patient risk factors associated with the development of tuberculosis during treatment with infliximab.

Health care professionals, consumers, drug manufacturers, and others submit reports of adverse events associated with FDA-licensed drug products through interaction with drug manufacturer representatives or directly via the FDA's MedWatch program (5). Because reporting is voluntary for everyone except manufacturers, the proportion of all incident adverse events attributable to a drug product that are actually reported to the FDA is unknown (56). Adverse drug event reports (also known as MedWatch reports) submitted to the FDA are maintained and retrieved through the FDA's Adverse Event Reporting System (AERS) database (7). We used the Medical Dictionary for Drug Regulatory Affairs grouping term tuberculous infection to retrieve adverse event reports of tuberculosis from this database. We included reports of cases of active tuberculosis among patients receiving infliximab in the United States with received dates ranging from 1 November 2001 through 30 May 2006.

After reviewing each of the 278 reports of infliximab-associated tuberculosis reported to the FDA within the specified time interval, we included 130 reports within the case series and excluded 148. The most frequent reasons for exclusion included duplicate reports, reports of latent disease, foreign (non-U.S.) reports, hearsay reports, reports from a clinical trial or registry, nontuberculous mycobacterial infection, and reports from patients more than 1 year after cessation of infliximab therapy.

By year, the case series contains 9 reports from 2001, 35 from 2002, 30 from 2003, 24 from 2004, 21 from 2005, and 11 from 2006. Table 1 shows the demographic and clinical characteristics of the patients. Four reports of tuberculosis were in patients treated for psoriasis (1 patient was concurrently being treated for rheumatoid arthritis). The median time to onset from initiation of infliximab therapy to diagnosis of tuberculosis was 10 months, with a range of 1 to 72 months. Twenty-two cases reported tuberculosis onset within 3 months, and 40 cases reported time to tuberculosis onset as greater than 1 year. Approximately one third (37%) of cases reported tuberculosis restricted to the lungs; 31 (23%) cases reported patients with disseminated tuberculosis; and 28 reported extrapulmonary tuberculosis. Extrapulmonary tuberculosis included peritoneal disease (n = 7), lymph node disease (n = 4), bone or joint disease (n = 4), enteric disease (n = 4), meningeal disease (n = 4), hepatic disease (n = 2), pericardial disease (n = 2), and pelvic disease (n = 1). Sixty-seven patients were hospitalized, and 19 died.

Table Jump PlaceholderTable 1.  Characteristics of Patients with Infliximab-Associated Tuberculosis

The 19 patients who died were nearly equally distributed in sex and ranged from 26 to 78 years of age, with a median age of 61 years. The most commonly reported indication was for the treatment of rheumatoid arthritis (68%). Infection was identified most frequently as the cause of death (n = 10), including 6 cases in which tuberculosis was the specified cause of death. Most (89%) of the fatal cases reported concomitant risk factors for tuberculosis. Fourteen patients were reported to have received 1 or more immunosuppressive medications concomitantly. Risk factors other than immunosuppressant use were present in 9 cases. These factors included having been born, living, or traveling in an area with an increased tuberculosis rate; exposure to a person with tuberculosis; gastrointestinal resection; and occupational exposure.

Most patients seemed to have at least 1 risk factor for tuberculosis other than infliximab use, including 52 patients with at least 1 risk factor other than immunosuppressant use. The most commonly reported risk factor other than immunosuppressant use (68%) was a history of latent or active tuberculosis (n = 33 [25%]). Seventeen (55%) of these 33 cases reported previous treatment for tuberculosis. Twenty-five (20%) cases described patients who were born or had spent extensive time in an area where tuberculosis is endemic.

The revised infliximab label recommends that patients receive a tuberculin skin test before starting infliximab therapy. We conducted an analysis of the skin test results from the subset of 67 cases who started infliximab therapy after the addition of the boxed warning in October 2001 (Table 2). By report, 47 (70%) patients received a tuberculin skin test before initiation of therapy. Of these patients, 34 had a negative initial result (insufficient data were provided on the actual induration size). Two of the 6 patients who did not receive a tuberculin skin test before starting infliximab therapy listed the reason as “prior bacille Calmette–Guérin vaccination.” Of these 67 cases, 12 had a history of latent or active tuberculosis. As described in the case reports, 8 of these 12 individuals were treated for tuberculosis before starting infliximab therapy.

Table Jump PlaceholderTable 2.  Summary of Tuberculin Skin Testing and Tuberculosis History in a Subset of Patients

Eleven patients had received a bacille Calmette–Guérin vaccine. Of these, 6 received a tuberculin skin test before starting infliximab therapy; 2 had negative results and 4 had positive results. Two patients did not receive a tuberculin skin test because of their previous bacille Calmette–Guérin vaccination. Whether the remaining 3 patients were tested before starting infliximab therapy is unknown.

We also analyzed the subset of 67 patients for the results of prescreening chest radiography performed before infliximab therapy. Twenty-three patients had had radiography done before starting infliximab therapy. Of those patients, 22 had a normal chest radiograph and 1 result was unknown. Fourteen of the patients with a normal chest radiograph developed pulmonary tuberculosis, 5 developed extrapulmonary tuberculosis, and 3 developed disseminated tuberculosis.

The infliximab label carries a prominent warning about the risk for tuberculosis. Nineteen (15%) of the 130 cases of infliximab-associated tuberculosis that we studied were associated with a fatal outcome. It is important to note that almost half (45%) of the cases of infliximab-associated tuberculosis reported to the FDA since the revision of the product labeling in 2001 presented with disseminated (23%) or extrapulmonary (22%) disease. Clinicians caring for patients who are receiving infliximab therapy should be aware of the clinical manifestations of disseminated or extrapulmonary tuberculosis. In addition, these data suggest that most of the reported patients who were treated with infliximab after the labeling change received a tuberculin skin test before starting infliximab therapy. Patients who had had a negative result developed active tuberculosis after starting therapy, as have patients treated for latent tuberculosis or tuberculosis—suggesting that sterilization of the M. tuberculosis bacterium may not have been achieved in some cases.

These data also suggest that patients with demographic risk factors, such as having been born, living, or traveling in a country with higher background tuberculosis rates than those of the United States, may be at an increased risk for active tuberculosis while receiving infliximab therapy. We found reports of patients with previous bacille Calmette–Guérin vaccination who developed active tuberculosis after initiation of infliximab therapy, both with and without screening for latent tuberculosis before infliximab therapy.

Clinicians should be aware of the risk for tuberculosis and the need to appropriately screen patients for tuberculosis risk factors before starting infliximab therapy, as outlined in the current drug labeling. In this highly immunosuppressed patient population, false-negative tuberculin skin test results can occur. Maximizing the sensitivity of the tuberculin skin test by using a cutoff induration size of 5 mm and taking a thorough patient history with regard to tuberculosis risk factors before and during infliximab therapy are warranted (8). Physicians should also monitor such patients for signs and symptoms of extrapulmonary tuberculosis. Because patients may develop active tuberculosis even when their prescreening tuberculin skin test result is negative, physicians need to evaluate for tuberculosis risk factors before and during therapy. Communication of these risks to physicians and patients is important to help mitigate the risk for active tuberculosis in patients treated with infliximab.

Remicade [product label]. Malvern, PA: Centocor; 2006. Accessed athttp://www.remicade.com/pdf/HCP_PPI.pdfon 25 January 2007.
 
Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R. et al.  Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003; 3:148-55. PubMed
CrossRef
 
Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P.  The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989; 56:731-40. PubMed
 
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD. et al.  Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001; 345:1098-104. PubMed
 
Kessler DA.  Introducing MEDWatch. A new approach to reporting medication and device adverse effects and product problems. JAMA. 1993; 269:2765-8. PubMed
 
Goldman SA.  Limitations and strengths of spontaneous reports data. Clin Ther. 1998; 20:Suppl CC40-4. PubMed
 
Brinker A, Beitz J.  Use of a spontaneous adverse drug events database for identification of unanticipated drug benefits. Clin Pharmacol Ther. 2002; 71:99-102. PubMed
 
Small PM, Fujiwara PI.  Management of tuberculosis in the United States. N Engl J Med. 2001; 345:189-200. PubMed
 

Figures

Tables

Table Jump PlaceholderTable 1.  Characteristics of Patients with Infliximab-Associated Tuberculosis
Table Jump PlaceholderTable 2.  Summary of Tuberculin Skin Testing and Tuberculosis History in a Subset of Patients

References

Remicade [product label]. Malvern, PA: Centocor; 2006. Accessed athttp://www.remicade.com/pdf/HCP_PPI.pdfon 25 January 2007.
 
Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R. et al.  Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003; 3:148-55. PubMed
CrossRef
 
Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P.  The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989; 56:731-40. PubMed
 
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD. et al.  Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001; 345:1098-104. PubMed
 
Kessler DA.  Introducing MEDWatch. A new approach to reporting medication and device adverse effects and product problems. JAMA. 1993; 269:2765-8. PubMed
 
Goldman SA.  Limitations and strengths of spontaneous reports data. Clin Ther. 1998; 20:Suppl CC40-4. PubMed
 
Brinker A, Beitz J.  Use of a spontaneous adverse drug events database for identification of unanticipated drug benefits. Clin Pharmacol Ther. 2002; 71:99-102. PubMed
 
Small PM, Fujiwara PI.  Management of tuberculosis in the United States. N Engl J Med. 2001; 345:189-200. PubMed
 

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

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Yes, Potential TB in RA Patients Is Difficult For the Rheumatologist
Posted on November 24, 2007
Daniel G. Arkfeld
USC Keck School of Medicine
Conflict of Interest: None Declared

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.

Infliximab, Statins, Tregs and Tuberculosis
Posted on November 23, 2007
Mark R Goldstein
Fountain Medical Court, Bonita Springs, FL
Conflict of Interest: None Declared

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) [1]. An increase in Tregs has been associated with immunologic hypo-responsiveness to many chronic infections [2]. 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 [3], 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 [4]. 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 [5]. 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)

[1] 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.

[2] Belkaid Y, Rouse B. Natural regulatory T cells in infectious disease. Nat Immunol 2005; 6: 353-360.

[3] 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.

[4] 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.

[5] Valencia X, Stephens G, Goldbach-Mansky R, et al. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 2006; 108: 253-261.

Conflict of Interest:

None declared

The Context Statement of The Editors' Notes
Posted on November 24, 2007
Jerome A Boscia
Centocor Research and Development, Inc.
Conflict of Interest: None Declared

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."

Conflict of Interest:

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.

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