Potential Risks of AntiTNFa Therapy

Infliximab is a chimeric (human-murine) IgGlK monoclonal antibody with an approximate molecular weight of 149100 daltons, in the pharmacological class of selective immunosuppressive agents. It is composed of human-constant and murine-vari-able regions and binds specifically to human TNF-a with an association constant of 10-10 M (Fig. 1). Infliximab has a well-documented safety profile throughout clinical development and in post-marketing safety surveillance for the approved indications of Crohn's disease and RA [62-65].

However, the potential impact of immunosuppressive, anti-TNF-a treatment on the development of infections, autoimmunity, underlying cancer, and any new malignancy must be monitored closely in any proposed study. The biological basis of concern pertaining to immunosuppression warrants heightened vigilance and consideration of the benefit-to-risk ratio when prescribing anti-TNF therapies.

Because of the adaptive, protective purpose of inflammation, pharmacological inhibition of this proinflammatory cytokine could have adverse effects in the host, unrelated to the target disease of the anti-TNF-a therapy. The risk of reactivation of latent tuberculosis is addressed in the prescribing information for infliximab [66]. Pre-emptive systemic antifungal therapy is recommended for patients receiving infliximab for treatment of graft-versus-host disease [67]. Smith and Skelton

Fig. 1. Infliximab is a chimeric monoclonal antibody, which binds to tumour necrosis factor-alpha. Infliximab has been shown to bind to all three forms of TNF-a: transmembrane, soluble and receptor-bound

Inhibition Tnf

Fig. 1. Infliximab is a chimeric monoclonal antibody, which binds to tumour necrosis factor-alpha. Infliximab has been shown to bind to all three forms of TNF-a: transmembrane, soluble and receptor-bound reported cases of squamous cell carcinoma (SCC) that became evident and grew rapidly during an initial period of etanercept therapy for RA [68]. The tumours may have been present, but occult and controlled, prior to disruption of immunological control. Etanercept could disable innate anti-tumour surveillance by blockade of both lympho-toxin a, and the direct cytotoxic effects of TNF-a and/or by inhibition of the TH1 cytokine pattern and impairment of cytotoxic T cells. All cases of SCC were in chronically UV-damaged, actinic skin predisposed to tumorigenesis by long-term, low-level production of TNF-a. No new SCCs developed in patients who continued treatment for more than 1 year, suggesting prolonged anti-TNF-a therapy could be preventive of cutaneous malignancies.

Pharmacovigilance data on etanercept, inflix-imab and adalimumab were reviewed by the FDA in 2003, with a focus on lymphoproliferative disease in patients treated with these anti-TNF-a agents, relative to the rate expected in populations with immune-mediated diseases [69]. The potential role of TNF-a-blocking therapy in the long-term development of malignancies is not known. A prospective study of 18 572 RA patients treated with anti-TNF-a therapy plus methotrexate reported an increased standard incidence ratio (SIR) compared to patients not receiving methotrexate or biologics, but confidence intervals overlapped for all treatments [70]. Patients with highly active disease and/or chronic exposure to immunosuppressant therapies may have several-fold higher risk for development of lymphoma, thus caution should be exercised when considering use of anti-TNF-a agents in patients with a history of malignancy or who develop malignancy during treatment.

The FDA reported on the risks of histoplasmo-sis [71], lymphoma [72], and/or listeriosis [73]. The Mayo clinic reviewed the safety of infliximab in 500 Crohn's patients treated with infliximab

[74]. The biological basis of concern warrants heightened vigilance and consideration of the benefit-to-risk ratio when prescribing anti-TNF therapies.

The role of TNF-a in cisplatin-mediated renal injury was demonstrated in a mouse model. Treatment of animals with TNF-a synthesis inhibitors or anti-TNF-a antibodies prevented kidney damage in the model [75].

TNF-a appears to play a complex role in side-effects of radiotherapy as well and anti-TNF-a treatments may be useful in their management [76, 77]. TNF-a is also a known activator of osteoclasts [78] and mediator of neuropathic pain [79]. An intriguing pair of clinical cases in which etan-ercept was used to treat refractory metastatic bone pain suggest that anti-TNF-a agents may be useful to control cancer pain [80]. The potential value of anti-TNF-a agents in these debilitating conditions presents broad opportunities to improve cancer care.

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