Prevalence of Antibodies Against JC Virus in Patients With Refractory Crohn's Disease and Effects of Natalizumab Therapy

Abstract

Background & aims: Natalizumab, a humanized antibody against the α4 integrin subunit, effectively induces and maintains remission in patients with Crohn's disease (CD) refractory to conventional treatments. Progressive multifocal leukoencephalopathy is a rare but fatal brain infection caused by John Cunningham (JC) virus and has been associated with natalizumab use. We assessed the prevalence of and risk factors for antibodies to JC virus in serum of patients with refractory CD who were candidates for, or already were receiving, natalizumab. We also assessed the effects of natalizumab treatment of these patients.

Methods: In a retrospective study, we analyzed clinical charts from 191 patients with CD (74 males; mean age, 38.7 y; mean duration of disease, 14.9 y) tested for serum JC virus antibody from December 2012 through May 2014 at 2 medical centers in the United States. We calculated JC virus antibody prevalence and compared the characteristics of patients who tested negative vs those who tested positive, to identify risk factors. We also assessed the rate of subsequent natalizumab use, surgery, and seroconversion during natalizumab therapy.

Results: A total of 129 of the patients (67.5%) tested positive for serum JC virus antibody. Multivariate analysis showed that past use of thiopurine was a risk factor for testing positive for JC virus antibody (odds ratio, 7.8; 95% confidence interval, 2.0-30.4; P = .003). Twenty-two of the patients who tested negative for JC virus antibody (35.5%) and 16 of the 129 patients who tested positive (12.4%) had been treated with natalizumab. Cox regression analysis determined that natalizumab use was the only factor associated with avoiding subsequent surgery (hazard ratio, 0.23; 95% confidence interval, 0.06-0.98). Seroconversion (from testing negative to positive for JC virus antibody) occurred in 1 of the 22 patients (4.5%) who initially tested negative during natalizumab therapy.

Conclusions: The prevalence of CD patients exposed to JC virus is comparable with that of the general population. In this retrospective study, prior thiopurine use was associated with an increased risk for testing positive for JC virus antibody. Natalizumab use reduced the risk of subsequent surgery.

Keywords: Biologic; IBD; Inflammatory Bowel Disease; PML; Thiopurine.

Figure 1

(a) Cox proportional hazards regression analysis was performed to identify risk factors for surgery in the present population. Fistulizing disease, history of Crohn’s surgery, natalizumab use after JCV testing, and perianal disease were included in the Cox regression analysis as they demonstrated relevance with increasing/reducing the risk of surgery based on a p value of <0.10 on a log-rank test (Kaplan-Meier analysis). Natalizumab use after JCV testing was associated with significantly reducing the risk of surgery (Hazard ratio 0.23, 95%CI 0.06–0.98, p = 0.048). (b) Probability of avoiding surgery in the study population according to the use of natalizumab or not after JC virus testing adjusted with fistulizing disease, history of Crohn’s surgery, and perianal disease as the covariates. Time to surgery after JCV testing was analyzed using Kaplan-Meier estimator. Patients without follow-up at a certain time point or those who discontinued due to adverse effects were regarded as censored and shown as ticks on the graph.

Figure 2

Survival analysis based on the JCV Antibody serology and the subsequent use of natalizumab. Patients were categorized into 4 groups (JCV (−) NTZ (−), JCV (−) NTZ (+), JCV (+) NTZ (−), JCV (+) NTZ (+)). The probability of avoiding surgery was significantly different among groups as assessed by log-rank test (p = 0.029). Log-rank trend test demonstrated a trend in outcome across the four groups (p = 0.039). Analysis was done as in Figure 1b.