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Quantifying Risk of PML with Natalizumab

May 25, 2012 7:15 am

Given the limited number of treatment options for inflammatory bowel disease, when Natalizumab became available, there was a great deal of enthusiasm.  This quickly diminished as reports of progressive multifocal leukoencephalopathy (PML) emerged.  So far, I have not prescribed this agent.

Due to its efficacy for multiple sclerosis and IBD, there has been continued interest in understanding the risk for PML (NEJM 2012; 366: 1870-80, editorial pg 1938-39).

Key findings:

• 212 cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000)
• Three main risk factors: positive JC-virus antibody, previous use of immunosuppressants, and receiving natalizumab more than 2 years

Patients who were negative for anti-JC virus antibodies had an incidence of 0.09 cases or less per 1000 patients.  Among patients who test positive for anti-JC virus antibodies, the risk remained <1 per 1000 patients if no use of immunosuppressants and 2 per 1000 if prior use of immunosuppressants during the first two years of therapy.  The risks were five-fold higher after 2 years in both groups.

While the risks are becoming more clear, the benefits of natalizumab are fairly well-established for multiple sclerosis.  Natalizumab decreased the annualized rate of relapse among patients with relapsing–remitting multiple sclerosis by 68%.

Additional references:

• -NEJM 2009; 361: 1067, 1075, 1081.  Asymptomatic detection of JC virus common in urine noted in patients Rx’d with natalizumab (19% baseline to 63% on Rx); actual leukoencephalopathy ~1/1000 patients.
• -Gastroenterol 2007; 132: 1672.  ENCORE trial.
• -JPGN 2007; 44: 185. n=31 children/adolescents.  55% response, 29% remission; dosed at 3mg/kg.
• -IBD 2007; 13: 2.  n=79.  Trial of combination natalizumab & infliximab.
• -NEJM 2006; 354: 899, 911, 924.  Natalizumab slows progression of MS.  Risk of PML due to JC virus 1:1000 in 18 months of Rx.
• -NEJM 2005; 353: 1912/1965.  Natalizumab not significantly effective for Crohn’s in this study
• -NEJM 2005; 353: 362, 369, 375, 414.  3 cases of PML associated with Natalizumab
• -JPGN 2004; 39: S49 [abstract 0107].  Natalizumab in 38 adolescents was effective (Hyams et al).
• -Gastroenterol 2004; 126: 1574-81. review.  Natalizumab benefitted subjects with elevated CRP. (dosing 300mg every 4 weeks.)
• -NEJM 2003; 24-32 & 68.  Natalizumab improved response rates in pts c Crohn’s dz (similar to infliximab).  Drug blocks alpha4 integrins which are required for lymphocytes to enter the intestine.
• -Gastroenterol 2001; 121: 268-74. Infusion of 3mg/kg decreases CDAI in Crohn’s dz.

Posted by gutsandgrowth

Categories: inflammatory bowel disease, Pediatric Gastroenterology Intestinal Disorder, Uncategorized

Tags: Crohn's disease, multiple sclerosis, natalizumab, PML, progressive multifocal leukoencephalopathy

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   By Running out of options | gutsandgrowth on January 3, 2013 at 7:03 am

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