TNF-α antagonists and infections

In our pediatric patients who receive tumor necrosis factor-α (TNF-α) antagonists, fortunately we see few infectious complications.  In older patients, infections are much more important source of morbidity.  The main TNF-α inhibitors in clinical use include infliximab, etanercept, adalimumab, and certolizumab. Two large studies help quantify this risk:

  • Grijalva CG et al. JAMA 2011; 306: 2331-39.
  • Strangeld A et al. Ann Rheum Dis 2011; 70: 1914-20.

The first study assembled retrospective cohorts between 1998-2007 with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis/psoriatic arthritis or ankylosing spondylitis (group 3).  This study’s acronym is SABER: Safety Assessment of Biologic Therapy. This data was compiled from 4 large US automated databases.  In total, there were 10,484 RA, 2323 IBD, and 3215 group 3 patients.  1172 serious infections were identified, mostly (53%) pneumonia or skin/soft tissue infections.  Among IBD patients, hospitalization rates were 10.91 (per 100 person-years) for TNF-α antagonists and 9.6 for comparison group.  The rates of hospitalization were similar in RA (8.16 with TNF-α antagonists) and lower in the group 3 patients (5.41 with TNF-α antagonists).   In all groups, baseline glucocorticoid use was associated with a dose-dependent increase in infections.  Overall, there was not an increase risk of hospitalizations with TNF-α antagonists compared with nonbiologic treatments.

The second cited reference examined patients from Germany with RA, enrolled in the RABBIT registry.  Data was available for 5044 patients.  There were 392 serious infections in this cohort with fewer infections noted after 3 years.  Risks for infection included age (>60), chronic lung or renal disease, history of serious infections, and treatment with glucocorticoids.  Treatment with 7.5-14mg conferred at relative risk (RR) of 2.1; treatment with ≥15mg conferred a RR of 4.7.  The rates of serious infections has an exponential change when risk factors are added together.  In Figure 3, estimated risk of serious infections for patients receiving ≥15mg  glucocorticoids along with three additional risk factors was 45% per year; with two risk factors the risk was approximately 20% and with one additional risk factor approximately 10%.

While these studies confirm significant risks of infections with biologic agents, the absolute risk is low particularly when other risk factors are not present.  In pediatric populations, glucocorticoids are the most prominent risk factor.  In addition, the risk of serious infections may be reduced by effective therapy.  In the SONIC study, serious infectious complications were less frequent in patients on combination therapy (infliximab and azathioprine) than with either monotherapy.  This result was likely due to the decreased need for glucocorticoids.

Additional references/relevant previous blogs:

  • NEJM 2010; 362: 1383. Sonic study. Combination AZA/IFX with greater efficacy. 56.8% remission in combo Rx.
  • -IBD 2008; 14: 721.  Pneumocystis jiroveci (carinii) w infliximab -review of 84 cases.  Dig Dis Sci 2007; 52: 1481-84.  PCP most likely to occur on average 3 weeks after 2nd infusion (possibly due to concommitant drug use)
  • -Gastroenterology 2008; 134: 929.  n=100 consecutive IBD patients with opportunistic infections.  Any of drugs associated w ~2.9 OR in adutls (greatest in >50yrs).  OR 14.5 when multiple immune drugs. Steroids more associated with Candida. AZA/6MP more with viral: HSV, VZV (shingles), CMV.  IFX less commonly with infections -though increased histoplasma and atypical mycobacterium
  • -Gastroenterology 2009; 136: 1182.  Review of biologics.
  • -IBD 2007; 13: 769.  Review of safety of wide range of biologics
  • Clin Gastroenterol Hepatol. 2006; 5:621-30.  TREAT registry.  Steroids but not biologics associated with increased mortality risk.
  • Only one chance to make first impression

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