Published: May 2008
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Tumour Necrosis Factor Inhibitors - Recognise and Treat Infection Promptly

Prescriber Update 29(1): 5-6
May 2008

Ruth Savage, Senior Medical Assessor, New Zealand Pharmacovigilance Centre, Dunedin

Serious infections, such as pneumonia, sepsis and tuberculosis (TB), have been reported in patients using the TNFα inhibitors: adalimumab, etanercept, or infliximab.  The infections can be severe and progress rapidly, leading to fatalities in some instances.  Reactivation of TB or hepatitis B can also occur.  Prescribers should consider infection in patients taking TNFα inhibitors who present with unexplained illness.  Dental abscesses have been the likely initial source of infection in two NZ case reports.  Early recognition with prompt treatment of any infection in patients taking TNFα inhibitors is essential to prevent the development of life-threatening or fatal sepsis.

TNFα inhibitors are potent immunosuppressants used for severe inflammatory diseases

Three tumour necrosis factor alpha inhibitors (TNFα inhibitors) are approved for use in New Zealand: adalimumab, etanercept, and infliximab.  These medicines are potent immunosuppressants, and are indicated for severe forms of rheumatoid arthritis (RA) and other conditions such as psoriatic arthritis, ankylosing spondylitis, and psoriasis.1-3

 Serious infections including pneumonia, sepsis, tuberculosis (TB), reactivation of tuberculosis and other opportunistic infections, some of which have been fatal, have been reported with TNFα inhibitors.1-3  Reactivation of hepatitis B in chronic carriers can also occur.4  Patients taking TNFα inhibitors have severe inflammatory disease and are already at increased risk of infection with co-morbidities and other immunosuppressant agents contributing.5

Studies support an increased risk of infections

One longitudinal non-randomised study comparing patients with RA taking TNFα inhibitors (7664) with those taking disease modifying anti-rheumatic drugs (DMARDs) without TNFα inhibitors (1354) found no significant increase in the incidence of serious infection overall, but a significantly greater incidence of skin and soft tissue infections (11.9 v 3.0/1000 patient-years).6  However, when the analysis was confined to the first 90 days after commencing a TNFα inhibitor, the risk of serious infection increased four-fold compared with users of DMARDs alone (72.2 v 24.4/1000 patient-years).7  Tuberculosis occurred in patients (ten) exposed to TNFα inhibitors but not those exposed only to DMARDs. In more cases than expected, the TB was extrapulmonary.6  In a study of serious infections associated with TNFα inhibitors, the majority were pneumonias, followed by cellulitis and soft tissue infections, and renal/urinary tract infections.5

Severity and rapid progression of infection requires expedient action

The rapid progression and severity of infections occurring in patients taking TNFα inhibitors also needs to be considered. CARM reports for adalimumab and infliximab indicate that infection developing in patients taking these agents can rapidly become disseminated and profound, leading to life-threatening or fatal sepsis.  It is, therefore, important to treat any infection occurring in patients taking TNFα inhibitors at an early stage, even if it appears minor.  Dental abscesses appear to have been the initial source of infection in two of the cases reported to CARM.  It is also important to include infection, including opportunistic infection, in the differential diagnosis of patients presenting with unexplained illness; for example, an elderly patient presenting with confusion who had encephalitis due to toxoplasmosis.  TNFα inhibitor treatment should be discontinued if serious infection occurs.1-3

Monitor patients during and after treatment with TNFα inhibitors

Product information for the TNFα inhibitors available in New Zealand clearly outlines the steps for infection screening and management prior to initiating treatment, which is by a specialist.1-3  During treatment, it is important to respond promptly to presentations suggestive of infection and to monitor patients at risk of TB or hepatitis B reactivation.  This also applies after treatment has been discontinued as the immunosuppressant effect of TNFα inhibitors may persist for several months.1-3

Competing interests (author): none declared.

  1. Abbott Laboratories (NZ) Ltd. Humira (adalimumab) data sheet. 22 January 2008.
  2. Schering-Plough. Remicade (infliximab) data sheet. 5 October 2007.
  3. Wyeth Consumer Healthcare Pty Limited. Enbrel (etanercept) data sheet. 12 March 2008.
  4. Medsafe. Hepatitis B reactivation associated with the anti-TNF agents, Enbrel (etanercept), Humira (adalimumab) and Remicade (infliximab) - letter sent to specialists. 8 November 2006.
  5. Curtis JR, Patkar N, Xie A, et al. Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis & Rheumatism 2007;56:1125-1133.
  6. Dixon WG, Watson K, Lunt M, et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy. Results from the British Society for Rheumatology Biologics Register. Arthritis & Rheumatism 2006;54:2368-2376.
  7. Dixon WG, Symmons DPM, Lunt M, et al. Serious infection following anti-tumour necrosis factor therapy in patients with rheumatoid arthritis. Lessons from interpreting data from observational studies. Arthitis & Rheumatism 2007;56(9): 2896-2904.