TNF Receptor Blockade and Sepsis
Abstract & commentary
Synopsis: TNF blockade may be associated with an increased risk of infection.
Source: Baghai M, et al. Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept. Mayo Clin Proc. 2001;76:653-656.
Baghai and colleagues at the mayo clinic in Rochester report a case of fatal pneumococcal sepsis in a patient receiving etanercept, a TNF-receptor antagonist.
This 37-year-old woman with seropositive rheumatoid arthritis presented with necrotizing fasciitis of the left leg and septic arthritis of the left ankle and prosthetic left hip and knee due to Streptococcus pneumoniae. Despite antibiotic therapy with levofloxacin, metronidazole, and vancomycin, as well as surgical intervention, the patient died.
The patient had been receiving corticosteroid therapy almost continuously since age 16, as well as aggressive treatment with disease-modifying agents. Despite this, her disease progressively worsened. At the time of her presentation with fever and swelling of her left leg, she was receiving prednisone 5 mg daily and etanercept 25 mg weekly.
Comment by Stan Deresinski, MD, FACP
Etanercept (Enbrel®) is one of 2 tumor necrosis factor-alpha (TNFa) antagonists currently available for therapeutic use in the United States. TNF activity is initiated by binding to 2 distinct receptors (p55 and p75), and present on almost all cell types designated by their individual molecular weights.1 The higher molecular mass receptor (p75) appears to largely interact with membrane-bound TNF, while p55 predominantly interacts with the soluble form of TNF. Most of the biologic effects of this cytokine are mediated through this receptor. In an apparent negative feedback system involved in modulating the inflammatory response, cells that are activated shed TNF receptors, which may then bind soluble TNF, preventing its interaction with target cells.
Etanercept appears to act much like the shed TNF receptors. It is a dimeric fusion protein in which the extracellular ligand-binding portion of the p75 TNF receptor is linked to human IgG1.2 As a soluble form of the p75 TNF receptor, etanercept specifically binds to TNF and prevents the interaction of both TNFa and TNFb with TNF receptors.
The other TNF antagonist available for clinical use in the United States, infliximab (Remicadeâ), is a chimeric human/murine monoclonal antibody that binds to human TNFa, neutralizing both the soluble and transmembrane form of this cytokine, and thereby blocking the interaction of TNF with its receptor.
Infliximab and etanercept are each approved for use in the United States for treatment of both rheumatoid arthritis and Crohn’s disease. Infliximab is also approved for the treatment of polyarticular juvenile rheumatoid arthritis. These highly effective therapies were developed as a consequence of the recognition of the role played by TNF in the pathophysiology of these and other inflammatory diseases. TNF is, however, also a critical component of the innate immune response to infection. More specifically relevant to the case report by Baghai et al, some experimental evidence suggests a protective role of TNF in pneumococcal infection. Thus, endogenous intrapulmonary production of TNFa serves a protective role in a murine model of pneumonia, preventing bacteremia after intracheal instillation of S pneumoniae.3 In addition, administration of anti-TNFa antibody leads to increased bacteremia and death in this model.4
Serious infection may accompany diseases such as rheumatoid arthritis in the absence of therapy with TNF antagonists, especially in patients receiving potentially immunosuppressive disease-modifying agents, although the incidence of such infections appears to be a matter of dispute. Kroot and colleagues reported that the death rate of 622 patients with rheumatoid arthritis during the first 10 years of their disease did not differ from that of the general population, and only 1 patient died with sepsis.5 On the other hand, a smaller case-control study with 17-year follow-up of patients found that infection was one of the 2 major causes of death.6
Therapeutic TNF blockade in patients with sepsis and septic shock has also been associated with an increased risk of death, possibly as the consequence of uncontrolled infection. In a large multicenter, randomized, clinical trial, a single infusion of etanercept provided no benefit in the treatment of septic shock and the highest dose administered, 1.5 mg/kg, was associated with increased mortality.7 Increased mortality was seen more frequently in patients with Gram-positive infection; no such trend was noted in patients with Gram-negative or polymicrobial infection. Another trial demonstrated a nonsignificant trend toward increased mortality in patients receiving the highest dose of an anti-TNFa monoclonal antibody.8
In randomized trials, the incidence of serious infection in etanercept recipients with rheumatoid arthritis was not significantly greater than that observed in placebo recipients (1.3% of placebo recipients and 0.9% of etanercept recipients). In examining all 745 etanercept recipients in open-label and randomized trials, 22 (3.0%) developed serious infection. In the first 5 months after its approval, 30 of approximately 25,000 drug recipients were reported to have developed serious infection.
In clinical trials of infliximab in the treatment of Crohn’s disease, infection occurred in 21% of patients receiving infliximab and 11% of placebo recipients.9 However, only 3% of infliximab recipients and 2% placebo recipients developed "serious" infections. As a consequence, the manufacturers, in cooperation with the US FDA, issued a "Dear Health Professional Letter" stating the following: "Patients who develop a new infection while undergoing treatment with ENBREL should be monitored closely. Treatment with ENBREL should be discontinued in patients with serious infections or sepsis. Treatment with ENBREL should not be initiated in patients with active infections including chronic or localized infections. Physicians should exercise caution when considering the use of ENBREL in patients with a history of recurring infections or with underlying conditions, which may predispose patients to infections such as advanced or poorly controlled diabetes."2
Similarly, the European Agency for the Evaluation of Medicinal Products issued a statement concerning the safety of infliximab on Dec. 20, 2000, as a result of the reporting of 28 cases of tuberculosis among an estimated 100,000 recipients of the product.10 Infliximab had already been contraindicated in patients with serious infections. To this warning was added one that infliximab administration should be discontinued if tuberculosis is suspected and that patient should be evaluated for both active and latent tuberculosis prior to the institution of therapy. This advice is, of course, complicated by the fact that many chronically ill patients, especially those receiving immunosuppressive therapies, are anergic, rendering PPD skin testing of questionable value.
Thus, there is a strong suspicion that therapeutic TNF blockade may increase the risk of serious infection, including tuberculosis. It is interesting to consider the possibility that this risk may be increased in individuals with certain TNF polymorphisms, such as those that may be associated with increased risk of adverse outcome in sepsis.11 Whether true or not, the use of TNF blockade will increase in the years ahead as new target diseases (eg, congestive heart failure) are identified.12 v
References
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2. http://www.fda.gov/medwatch/safety/1999/enbrel. Accessed June 14, 2001.
3. Takashima K, et al. Role of tumor necrosis factor alpha in pathogenesis of pneumococcal pneumonia in mice. Infect Immun. 1997;65:257-260.
4. van der Poll T, et al. Passive immunization against tumor necrosis factor-alpha impairs host defense during pneumococcal pneumonia in mice. Am J Respir Crit Care Med. 1997;155:603-608.
5. Kroot EJ, et al. No increased mortality in patients with rheumatoid arthritis: Up to 10 years of follow-up from disease onset. Ann Rheum Dis. 2000;59:954-958.
6. Riise T, et al. Total mortality is increased in rheumatoid arthritis. A 17-year prospective study. Clin Rheumatol. 2001;20:123-127.
7. Fisher CJ Jr, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996;334:1697-1702.
8. Abraham E, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome: A randomized, controlled, double-blind, multicenter clinical trial. JAMA. 1995;273:934-941.
9. Remicade® manufacturing prescribing information. Centocor, Inc. August 1998.
10. http://www.eudra.org/emea.html. Accessed June 14, 2001.
11. Majetschak M, et al. Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg. 1999;230:207-214.
12. Bozkurt B, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation. 2001;103:1044-1047.
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